Abstract
Cardiovascular disease is the leading cause of death around the world, in which myocardial infarction (MI) is a precipitating event. However, current therapies do not adequately address the multiple dysregulated systems following MI. Consequently, recent studies have developed novel biologic delivery systems to more effectively address these maladies. This review utilizes a scientometric summary of the recent literature to identify trends among biologic delivery systems designed to treat MI. Emphasis is placed on sustained or targeted release of biologics (e.g. growth factors, nucleic acids, stem cells, chemokines) from common delivery systems (e.g. microparticles, nanocarriers, injectable hydrogels, implantable patches). We also evaluate biologic delivery system trends in the entire regenerative medicine field to identify emerging approaches that may translate to the treatment of MI. Future developments include immune system targeting through soluble factor or chemokine delivery, and the development of advanced delivery systems that facilitate the synergistic delivery of biologics.
Keywords: Biologics, Drug Delivery, Controlled Release, Myocardial Infarction, Scientometric Review, Growth Factors, Chemokines, Nucleic Acids, Stem Cells, Extracellular Vesicle
Graphical Abstract
1. Introduction
Cardiovascular disease, characterized by the narrowing and blockage of coronary vasculature including acute or chronic disorders such as stroke, atherosclerosis, and myocardial infarction (heart attack), remains the leading cause of death around the world. The etiology of cardiovascular disease is multifaceted, but acute or chronic ischemia, presenting as myocardial infarction (MI), is a precipitating event. MI leads to rapid progression of cardiovascular disease due to early tissue injury and later pathologic tissue remodeling [1]. The mortality rate associated with MI has steadily declined in the past 20 years, but 9.5 million deaths annually can be attributed directly to MI as of 2016 data [2]. Further, patients surviving their first MI have a 20% likelihood of being re-hospitalized due to refractory MI or a related cardiac event [2]. With nearly 153.5 million people living with ischemic heart disease, worldwide [2], there is a great need to provide better solutions to a disease that significantly taxes health care systems, debilitates affected individuals, and results in significant loss of life.
MI induces significant damage to the heart that instigates continuing damage and adverse tissue remodeling due to dysregulated cellular processes. MI occurs when coronary blood flow is blocked or reduced creating a local hypoxic environment causing cardiomyocytes (CMs) to necrose (ischemic injury). The time delay between ischemic injury and re-establishment of blood flow (reperfusion) directly control infarct size; specifically increased reperfusion delay will create larger infarcts [3, 4]. Larger infarcts translate to significantly reduced cardiac function and drastically increase the likelihood of developing heart failure. Table 1 details first-line treatments and procedures commonly used for MI to reperfuse tissue. However, reperfusion can paradoxically exacerbate damage to the heart, referred to as reperfusion injury (RI). RI can account for nearly half of the final infarct size [4]. Reperfusion injury can be caused by several factors including inflammation, Ca2+ overload, mitochondrial dysfunction, oxidative stress, and restoration of neutral pH [4]. Small animal studies have identified potential methods or new therapeutics to reduce or prevent RI, but little success has been demonstrated in the clinic as succinctly reviewed [4]. A common issue is that MI causes multiple cellular processes to become dysfunctional while causing significant damage to tissue structure that cannot be adequately repaired by the body. Thus, the infarct size, which predicts post-MI outcome, is not well controlled or mitigated.
Table 1:
First-line treatments and procedures for myocardial infarction
The size of the infarcted area also controls pathologic tissue remodeling due to tissue dysfunction and disruption to homeostatic cardiovascular signaling. Myofibroblasts, cells that secrete collagen and other extracellular matrix (ECM) proteins necessary for scar formation, initially become activated following ischemic injury due to local inflammatory cytokines and increased ventricular wall stress [8]. Larger infarcts create increased wall stress both in the infarcted area and in the surrounding myocardium leading to significantly increased cardiac fibrosis [9]. In normal tissues, myofibroblasts undergo apoptosis following re-establishment of the ECM and resolution of the repair phase [10]; however, the newly formed scar does not adequately resolve the increased wall stress resulting in prolonged myofibroblast activation and collagen deposition. This dysregulated signaling initiates pathologic tissue remodeling that is characterized by diminished tissue contractility due to excessive collagen deposition and stiffening in healthy myocardium surrounding the infarct [11]. Consequently, the heart’s capacity to circulate blood becomes severely diminished, and the sympathetic nervous system and renin-angiotensin-aldosterone system become chronically activated. These systems cause the heart to work harder, exacerbating the mechanical forces experienced in the infarct and creating a positive feedback loop until the organ totally fails [12, 13]. Figure 1 pictorially summarizes the pathogenesis of MI damage to the myocardium and subsequent fibrotic remodeling.
Figure 1 – Pathophysiology of myocardial infarction and cardiac remodeling.
(1) Localized hypoxia in the left ventricle due to disrupted blood flow causes cardiomyocytes (CM) necrosis (grey, top) and apoptosis (brown, bottom). (2) Upon reperfusion, inflammatory cells migrate to the tissue and become activated and differentiate into inflammatory cells by necrotic cell debris, damage associated molecular patterns, and inflammatory cytokines. This exacerbates CM necrosis and apoptosis. (3) Local inflammatory cells release soluble factors that also activate quiescent myofibroblasts to differentiate and release pro-fibrotic factors. (4) As a consequence, the infarcted myocardium replaces necrotic or damaged tissue (grey) with a fibrous scar (light blue) consisting of cross-linked collagen (blue lines). As remodeling progresses, more collagen is deposited and cross-linked, stiffening not only the infarct but also surrounding, healthy cardiac tissue referred to as the infarct border zone. (5) This occurs because the initial scar is not mechanically strong enough to overcome deforming forces during ventricle contraction (a) causing myofibroblasts to become or continue to be activated and secrete more fibrotic factors (b). This continues until the infarcted and surrounding tissue stiffens resulting in reduced contractility of the ventricle (c). Under these conditions, the renin-angiotensin-aldosterone system (RAAS) becomes activated and signals to the heart to increase contractile force and vasoconstriction in an attempt to increase blood flow and blood pressure (d). The increased contractile force is now able to displace the infarcted wall, maintaining this fibrotic cycle. Graphics were created with BioRender.com
Clinical intervention with chemotherapeutics fail to address the dysregulated cellular processes that occur following MI. The listed therapeutics and interventions that are first-line treatments for treating MI focus exclusively on re-establishing blood flow to the infarcted heart and do not address reperfusion injury or pathologic remodeling. Because reperfusion injury is largely a result of the inflammatory response following MI, some studies have trialed immunosuppressant chemotherapeutics as a potential treatment. Specifically, non-specific anti-inflammatory drugs (e.g. steroids, NSAIDs) that suppress both inflammatory and reparative functions of the immune system have previously been trialed, but they are not recommended for use following MI [14] due to the detriment to repair, numerous side effects, and in some cases an increased risk for re-infarction or death [15]. Similarly, treatment with alternative immunosuppressants (e.g. corticosteroids, methotrexate, and cyclosporine A) did not lead to benefits in patients [16]. In contrast, chemotherapeutic treatments for cardiac remodeling and fibrosis following MI have shown some success. Specifically, renin angiotensin aldosterone system (RAAS) inhibitors can reduce cardiac fibrosis due to hypertension or hypertrophy [17, 18]. However, cardiac remodeling and fibrosis caused by hypertension or hypertrophy presents more gradually compared to MI, which causes faster loss of viable tissue and subsequent replacement with collagen and other fibrous proteins. Consequently, RAAS inhibitor efficacy has been shown to be diminished in patients exhibiting heart failure [19], which is common in MI patients [20].
The inability of these chemotherapeutics to make significant impacts on MI and subsequent tissue remodeling is a result of using broad, non-specific therapies to control complex cellular processes. These immunosuppressive therapies indiscriminately inhibit both inflammatory and reparative functions of the immune system, of which the latter is critical for shaping proper repair and beneficial remodeling of the wound [21]. In the case of antifibrotic therapies, the activation and proliferation of myofibroblasts following MI is multifaceted and current therapies may address one activating signal but do not address the other signals requiring a multifaceted approach or targeting downstream signaling cascades common to each activating impulse. More specific chemotherapeutics have been developed that can target specific intracellular signaling molecules (e.g. JAK/STAT inhibitors), however, side effects will accordingly increase as chemotherapeutics circulate systemically and affect all tissues and cell types. Thus, there is a significant unmet need in MI therapy to develop more specific therapies that are better equipped to directly modulate cellular processes and signaling.
Novel, biomimetic therapies that administer biologics to address the underlying failure of cellular processes following MI are an emerging area of research that have the potential to significantly improve upon existing therapeutics. In similar diseases that display significant dysregulation and deviation from homeostasis, researchers have demonstrated biomimetic delivery strategies to be a potential remedy [22, 23]. Biomimetic delivery was originally intended to enhance targeting, efficacy, and bioavailability of small molecule therapeutics through the employ of systems that mimic the physiochemical presentation of paracrine and endocrine factors. As the ability to manufacture recombinant protein therapeutics improved, this field grew to include the delivery of cell factors or recombinant proteins (cytokines, chemokines, growth factors, therapeutic DNA/RNA), often called biologics, that directly interact with extracellular (cell receptors, soluble factors) or intracellular (DNA, RNA, transcription factors) signaling moieties to illicit a localized and highly specific effect [23]. The increased fidelity of biologics relative to traditional chemotherapeutics affords the ability to more effectively treat dysregulated cellular processes by amplifying or abrogating only the aberrant portion of a given process or cascade. Additionally, biologics applied in immunotherapies, for example, have been shown to be able to utilize the body’s own cells or systems to amplify repair and tolerance while minimizing inflammatory damage [24]. In the context of treating MI, the primary therapeutic targets that biologics have been used and shown great improvement are angiogenesis, cardiac remodeling, cardioprotection, and modulating the inflammatory response. Each of these targets will be discussed in greater detail in section 2.3. Herein, we discuss research advances that utilize the delivery of biological products to directly address the dysregulated cell signaling and pathology following MI.
In support of this review, we employed a novel approach to quantify and display research trends within the field of MI research. Myocardial infarction is a well-studied field constituting over 10,000 new publications each year since 2013. Similarly, the development of biologic delivery systems reports greater than 3,000 new publications each year since 2015. Understanding the work others have done in these fields can provide researchers with novel delivery approaches for biologics or identify new applications of delivery systems. To that end, we performed a series of literature searches to assess trends within the field of MI research. This approach can identify paradigms, elucidate emerging areas of research with quantitative or qualitative data, and exemplify potential approaches that may be underutilized in the field. One such benefit that this approach offers is greater representation for niche approaches that may otherwise be quashed by the majority. This data is displayed throughout this review using tools that have been developed in other fields as applied to allow readers to visualize trends in the field, specifically Chord diagrams and Sankey diagrams. Readers who are unfamiliar with interpreting these types of diagrams are directed to Supplementary Figure 1, in which we show a sample data set and provide a guide for interpreting the data shown. In addition, there is a methods section appended to the end of this review detailing the literature searching method and the creation of Chord and Sankey diagrams. In this way, we are presenting to the reader a new kind of review that may help to reduce review bias and improve dissemination of relevant information in a more easily digestible manner.
2. Background
2.1. Biologics
Biological products, or more commonly referred to as biologics, are a class of therapeutics derived from living organisms that are often large, complex biomolecules such as polypeptides [25]. One of the most well-known biologics that have a proven record of FDA approval and been utilized to treat several diseases are monoclonal antibodies (MAB), such as checkpoint inhibitors. The application of checkpoint inhibitors targeting PD-1 and CTLA-4 [26] have revolutionized cancer treatments, and MAB targeting cytokines or their receptors (IL-6, IL-1, IFN, etc.) have greatly improved outcome in inflammatory diseases such as rheumatoid arthritis [27]. While researchers have developed controlled release systems for MAB targeting other tissues, little has been done to develop systems for the heart [28]. One reason for this is that intravenous application of free antibodies can easily access the heart, and most antibody applications for treating infarction are focused on early pathology [29-32]. In addition, MAB, unlike rapidly inactivated growth factors or cytokines, can remain effective for days because they have comparatively extended half-lives. [33]. Therefore, MABs will not be discussed within the context of this review, which aims to highlight controlled release delivery systems for biologics applied to treat MI. The therapeutic and diagnostic potential of MAB in cardiac diseases has been extensively evaluated and readers are referred to several reviews on this topic [29-32, 34]. In this review, we focused upon the following categories of biologics that have been explored the most for cardiac applications: Growth factors, chemokines, nucleic acids, and stem cells.
“Growth factors” (GFs) is a broad term describing polypeptides involved in tissue growth, development, differentiation, and proliferation that act through receptor binding [35]. These molecules are large polypeptides with relatively short half-lives [36] and are typically found bound to tissue ECM [37-39]. Table 2 details common growth factors and their intended use in the treatment of MI. The most common application is to initiate angiogenesis (see Figure 2A) to revascularize the infarct, which requires sustained spatiotemporal control of one or more factors [40].
Table 2:
Therapeutic uses of biologics in myocardial infarction
| Biologic type | Name | Uses | Reference |
|---|---|---|---|
| Growth factors | VEGF | Initiate angiogenesis, enhance tissue remodeling | [52-60] [61] [62-65] |
| PDGF | Stabilize neovasculature, anti-apoptotic | [64-66] | |
| BFGF/FGF-2 | Initiate angiogenesis, enhance tissue remodeling | [67-70] | |
| ANG | Initiate angiogenesis, enhance tissue remodeling | [71, 72] | |
| IGF | Initiate angiogenesis, enhance tissue remodeling, anti-apoptotic | [73] | |
| HGF | Initiate angiogenesis, enhance tissue remodeling, anti-apoptotic | [74-76] | |
| Chemokines | CCL2 | Upregulated following MI to attract macrophages | [77] |
| CXCL12/SDF-1α | Attract MSCs | [60, 68, 75, 78] | |
| CCL7 | B-Cell secreted factor to mobilize monocytes from the bone marrow | [79] | |
| CXCL10 | Angiostatic and antifibrotic molecule critical to controlling initial inflammatory response | [80] | |
| Nucleic acids | pDNA | Insert new genes | [53, 57, 72, 81-95] |
| mRNA | Amplify protein transcription and/or gene expression | [62, 73, 81, 96-99] | |
| miRNA | [100-104] | ||
| siRNA | Inhibit gene expression and/or protein transcription | [105-107] | |
| sliRNA | [108] | ||
| Stem cells | BMMSCs/MSCs | Replace lost CM tissue with viable, proliferative cells. Provide secreted factors that reduce cell death, modulate the immune system, and promote angiogenesis | [52, 60, 62,71,83, 86, 93] |
| AD-MSCs | [109] | ||
| CSCs | [61] |
Figure 2 – Biologics employed to treat myocardial infarction.
(A) Growth factors are employed to induce angiogenesis along a concentration gradient. (B) Similarly, chemokines attract various cell types from one organ in the body (Spleen, bone marrow) to traffic in a concentration dependent manner to a depot of chemokine being continuously released from a delivery system. (C) Various nucleic acids can be delivered to manipulate transcription and expression of mRNA or proteins. (D) Pluripotent stem cells can improve the infarct through replication to replace lost tissue and reduce collagen deposition or by releasing paracrine factors that can induce angiogenesis, prevent/reduce CM apoptosis, or modulate the immune response. Graphics were created with BioRender.com, Fig 2.1D was also created with Blender 3D modelling & rendering package [357].
Chemokines are a type of small, polypeptide molecule (~8-14 kDa) that cause cytoskeletal rearrangement upon binding to their target receptor, such that the cell body moves toward the source of the secreted factor [41, 42] (see Figure 2B). Chemokines can also act on endothelial cells to upregulate adhesion ligands locally, thus increasing cell trafficking to a target tissue [43]. While most often implicated in leukocyte and lymphocyte migration and tissue trafficking, chemokines also play roles in a variety of cellular process such as proliferation [44][133], differentiation [44, 45], activation [44, 45], angiogenesis [46], tumor metastasis [47], and ECM remodeling [48, 49]. Table 2 lists chemokines that can significantly affect infarct spreading and repair following MI.
Unlike GFs and chemokines, Nucleic acids (NAs) require cell internalization where they act to control expression and activation of different pathways [50] (see Figure 2C). Common NAs employed in MI are detailed in Table 2. NAs target a precise and compatible nucleotide sequence facilitating improved target specificity relative to other biologics. However, to be functional NAs must be transported across the cell membrane, which can present a significant hurdle to overcome [51]. Despite this challenge, researchers have reported a plethora of applications employing NAs to treat MI ranging in complexity from gene transfection or DNA editing to enhancing or abrogating signaling pathways native to the target cell. For example, one study delivered shRNA to target mRNA for transient receptor potential vanilloid type 1 (TRPV1), which plays a critical role in detecting myocardial ischemia, resulting in reduced infarction size [108].
Distinctly separate from GFs, chemokines, and NAs, Stem cells are pluripotent cells that have generated significant interest for regenerative medicine and tissue repair due to their ability to enhance the healing process [110]. CMs lose the ability to proliferate because the centrosome, a key organelle required for cell division, is dismantled upon cell maturation [111]. Thus, stem cells present a key possibility to facilitate reversal of an infarct rather than conventional approaches to minimize damage or stabilize the infarct. Table 2 details common cell types employed in MI. Each of these cell types has been indicated to differentiate into contractile cells that can respond to electrical stimulation [110]. Not only can these cells contribute to repair by potentially differentiating/proliferating to replace lost or damaged tissue at the injury site, but they can also secrete factors that are anti-inflammatory, pro-angiogenic, and anti-apoptotic [112] (see Figure 2D).
Recently, controversy has emerged surrounding the use of stem cells in treatment of cardiac disease spurred on by a series of failed clinical trials [113]. A succinct review discussing various factors that may influence the success or failure of clinical trials with progenitor cells lays out many of the reasons for failure but does note that overall progenitor cell delivery during PCI can impart some benefit [114]. As a result, several publications reporting the regenerative capacity of stem cells in cardiac applications have been retracted [115], and some clinical trials with stem cells have been paused [116]. In addition, a recent study directly compared a sustained release system for the delivery of progenitor cell derived EVs to the delivery of progenitor cells, alone, and found either approach provided similar benefit [117]. This study supports a growing idea that the principal benefit of progenitor cell delivery is their ability to continuously deliver EVs that impart a therapeutic effect. Therefore, the publications regarding the beneficial effects of stem cells reviewed herein should be scrutinized.
2.2. Therapeutic targets
Following MI, there are various dysregulated cellular processes that can be targeted by biologic molecules to reduce damage, direct healing, and mitigate pathogenic remodeling. While different pathways exist, the goal is the same: improve heart function by maintaining tissue contractility and minimizing the amount of functional tissue lost. Specifically, reducing the size of the infarct [4], enhancing vascularization of the myocardium [118], and limiting fibrotic scarring [119] are key approaches demonstrated to have beneficial effects on heart function.
One method of improving infarct vascularization is through targeting angiogenesis, which is an encompassing term describing the complex cellular processes that control the induction of new blood vessels [120, 121]. Understanding of angiogenesis has been greatly advanced through cancer research investigating tumorigenesis and identifying key GFs necessary to vascularize tissue [122]. To induce angiogenesis, tissues must become activated by environmental cues (e.g. hypoxia) [40] and pro-angiogenic factors such as GFs, peptides, genes, and chemokines can then be delivered to initiate vessel sprouting and formation. During infarction, the myocardium experiences hypoxia causing up-regulation of hypoxia inducible factors (HIFs) [122]. HIFs include genes encoding pro-angiogenic factors, such as VEGF, and their receptors flt-1 [40, 123]. Angiogenesis then occurs along a concentration gradient of pro-angiogenic signals, such as growth factors, from healthy vasculature surrounding the infarct [124]. Because the damage sustained during an infarction destroys endothelial cells or causes massive cellular dysfunction, vascularization of the infarct cannot occur spontaneously and angiogenic signals must be supplemented locally to revascularize the tissue. Successful induction of angiogenesis following MI can increase oxygen supply to reduce hypoxia-induced CM apoptosis, facilitate progenitor cell migration and engraftment, and help guide beneficial remodeling that stabilizes the infarct. In an experimental model of MI in rats, for instance, VEGF was administered via an injectable hydrogel to induce angiogenesis as measured by increased arteriole density [58]. The authors of this study reported significantly reduced infarct size, CM apoptosis, collagen deposition, and ventricular dilation relative to controls. Similarly, lymphangiogenesis, the process of creating lymphatic vessels, has also been shown to be beneficial following MI reducing oedema and inflammation [125, 126]. Lymphangiogenesis was induced by delivering microparticles loaded with VEGF-C, an isotype of VEGF selective for VEGFR3 that is principally expressed by lymphatic endothelial cells, following MI in rats [126]. This resulted in significantly improved lymphatic vasculature relative to MI control, even matching SHAM groups by some metrics. Most significantly, the authors demonstrated induction of lymphangiogenesis prevented cardiac fibrosis in tissue surrounding the infarct and reduced macrophage density [126]. An indirect effect of angiogenesis is modulating tissue and ECM remodeling, which translates to a reduction in collagen deposition and fibrosis.
Targeting cardiac remodeling aims to stabilize dysregulated cellular signals and modulate the mechanical stress within the infarct translating to improved tissue contractility and function. Without intervention, the repair process will become dysregulated following initial scar establishment causing increased collagen deposition and stiffening in the infarct and surrounding myocardium. This leads to loss of contractility and ultimately manifests as total heart failure [119, 127]. There are several approaches to reduce pathologic remodeling, such as direct targeting of proteinases that degrade the ECM – specifically matrix metallopeptidases (MMP) [107, 128], reduction (or prevention) of activated myofibroblast collagen deposition [84, 94], transplantation of progenitor cells to replace lost CMs [61, 109], or injection/application of a bulking agent [107, 129, 130]. Locally delivering an MMP inhibitor, TIMP-3, from a hydrogel, for example, was shown to significantly reduce cardiac remodeling and infarction size [131]. Successful remodeling therapies are measured by reduced collagen deposition and improved tissue contractility as shown by an amalgam of echocardiogram – left ventricle (LV) dilation, ejection fraction (EF), fractional shortening (FS), cardiac output (CO), stroke volume (SV) – or pressure volume loop measures [132, 133]. One such example involved adenoviral supplementation of Id2, which is a transcriptional repressor implicated in fibrotic disease for other organs, following MI induction in rats [94]. This study demonstrated Id2 overexpression reduced left ventricular end-diastolic/systolic diameter (LVEDD/LVESD) and collagen I & III deposition through reduced TGF-β1 & IL-11 secretion and inhibition of smad3 and HIF-1α signaling pathways [94]. Further, both remodeling and angiogenesis can be influenced by the immune response, requiring immune regulation and control to proceed uninhibited [134].
Immunomodulatory therapies tailored to MI aim to direct and control the immune system, both locally and systemically, to reduce damage and improve the wound healing process. Numerous infarct infiltrating immune cells are known to significantly shape the repair and remodeling process following injury by clearing cellular debris, activating fibroblasts, and modulating collagen deposition & cross-linking [21]. Preexisting chronic inflammatory signaling can exacerbate immune-mediated damage after MI [135], and uncontrolled inflammation following infarction can damage healthy tissue, a phenomenon referred to as infarct spreading [4, 135]. Therefore, therapeutic intervention targeting the immune system, or immunomodulation, aims to employ the complex signaling pathways that control trafficking, activation, polarization, and regulation of immune effector cells (e.g. Helper T cells, monocytes, macrophages, dendritic cells, etc.). This approach has been extensively utilized in cancer treatment and research [136] and it has shown promise in tissue repair and remodeling [137, 138]. For example, delivery of IL-10, an immunoregulatory cytokine, via osmotic minipump in a mouse model of MI polarized infiltrating monocytes to an M2 reparative phenotype translating to improved left ventricular dilation and improved cardiac EF, each by nearly 1.5x [139]. Another study demonstrated delivery of a C-X-C motif chemokine receptor 4 (CXCR4) antagonist enhanced mobilization of splenic Tregs reducing inflammatory cytokine and gene expression resulting in decreased left ventricular dilation relative to controls [140]. Despite these recent successes in mice, immunomodulatory clinical trials treating MI through targeting inflammatory mediators and cell infiltration have not shown significant improvements, indicating a need to better understand immunomodulatory targets [16]. In addition to directing or potentially enhancing tissue repair through control of the immune response, healthy CM death during reperfusion injury can also be reduced – imparting cardioprotective effects.
Cardioprotective therapies aim to minimize loss of healthy myocardium due to hypoxia or reperfusion injury through therapeutic or surgical interventions at various timepoints following MI onset. Preventing myocardium loss has been the primary focus of conventional therapies that aim to rapidly reperfuse tissue or reduce reperfusion injury through ischemic post-conditioning. Both approaches have contributed significantly to lower acute mortality following MI and have become the standard of care for MI patients [141, 142]. Beyond therapies to reduce the magnitude of the infarct in the acute phase of MI, this treatment group also includes efforts to reverse damage [83], prevent sustained apoptotic signaling [53], and precondition tissue to be more resilient to hypoxic stress [143]. Directly targeting apoptotic signaling by delivering soluble factors that induce pro-survival signaling through phosphorylation of Akt [144] and Erk [145] signaling pathways or administering nucleic acids to modulate their genetic expression are commonly employed cardioprotective approaches [53, 73, 76, 81, 92]. HGF is one such factor that can activate PI3K and ERK1/2 signaling pathways to reduce CM apoptosis following hypoxia significantly. Sustained delivery of HGF from an injectable, shear-thinning hydrogel significantly attenuated CM loss following induced MI in rats [146].
All of these biologic compounds suffer from poor therapeutic efficacy when administered as a bolus injection. Biologics have relatively short half-lives due to naturally abundant proteolytic enzymes throughout the body [147], rendering a single bolus injection ineffective. Further, the beneficial effects of administered biologics can often take several hours to days to occur [148] translating to little therapeutic potential without repeated doses. The problems associated with the delivery of bolus doses of biologics have been well established and discussed in an expert panel summary, published 20 years ago, discussing several clinical trials attempting to induce coronary angiogenesis [149]. Briefly, biologics not only require sustained dosing, but also need to be localized to induce an effect. Consequently, the authors identified the need to develop delivery systems that could practically administer biologics, locally, suggesting heparin alginate sustained release systems as one possible solution [149]. In the years following, researchers have developed numerous systems that address one or more of these issues translating to dramatically improved efficacy in small animal models relative to single or multiple bolus injections.
2.3. Biologic delivery systems
Drug delivery systems (DDS) were originally devised to enhance the bioavailability of drugs and reduce dosage frequency, but in the years since their conception they have been repurposed to facilitate new therapeutic modalities. The first DDSs served to enhance bioavailability of poorly absorbed drugs, improve patient compliance, and minimize side effects of existing therapeutics [150]. This technology was ultimately developed into the foundation of modern medicine as reviewed [151-153]. In short, the first delivery systems were rather large and cumbersome, eventually being replaced by more advanced systems in the micro or nanoscale. In recent years, these systems have been repurposed to facilitate new medical interventions with biologics delivered in place of small molecule drugs facilitating biomimetic therapies [22]. Several authors have discussed biomimetic delivery in a variety of settings and readers are referred to their reviews [22, 154-157]. In the context of the biologic classes detailed in section 2.1, key design considerations must be made when selecting or creating a biologic delivery system as detailed in Table 3. Several classes of delivery systems have been designed to overcome these challenges and applied in cardiac applications including nanocarriers, microparticles, injectable hydrogels, and implantable patches.
Table 3:
Delivery system design considerations for common biologics
| Biologic Type | Key Challenges | Strategies to Overcome |
|---|---|---|
| Growth factors & chemokines | Protein degradation | - Minimize contact with solvents - Minimize exposure to physical forces - Avoid high temperatures |
| Nucleic acids | Intracellular delivery | - Utilize systems that facilitate cell membrane diffusion - Employ receptor-mediated uptake strategies - Utilize vehicles that can escape endosomes |
| Stem cells | Maintenance of cell viability | - Use materials with scaffolding properties - Amplify DDS water permeability - Maximize DDS surface area - Introduce interconnected pores and channels |
Nanocarriers are nanoscale systems of both polymeric and biologic origin that can facilitate tissue targeting and retention of biologic cargo through a variety of mechanisms. Nanocarriers’ common features include characteristic length ranging in the hundreds of nanometers or less [158] and the ability to shield encapsulated biologics from enzymatic degradation [159]. Examples of common nanocarrier delivery systems include polymeric nanoparticles, dendrimers, liposomes, extracellular vesicles (EVs), modified peptides or polypeptides to include targeting moieties, and viral carriers (see Figure 3A). Fabrication methods and biologic loading are widely different and dependent upon the physical and chemical properties of the encapsulating system. All nanocarriers share a common advantage: their small size facilitates intracellular uptake [51], which is required to effectively deliver nucleic acids.
Figure 3 – Delivery devices for cardiac delivery of biologics.
(A) Inorganic nanocarriers – quantum dots, gold nanoparticles, mesoporous silica nanoparticles, polymeric micelle (left to right) – and organic nanocarriers – viral, dendrimer, liposome, lipid micelle (left to right) – with representative images of systemic distribution of a nanocarrier loaded with GFP 3 hours after administration (top) and 6 hours after administration (bottom) following MI induction. (B) Representative histology images of microparticle retention in MI denoted by white arrows (top) and characteristic SEM images (bottom). (C) Methods of hydrogel formation and responsive gelation (top), sequestration of biologics (pink sphere) can occur within the matrix, on the hydrogel backbone, or within matrix connections (bottom-left). Upon degradation or through passive diffusion, biologics are released (bottom-right). Representative histology showing hydrogel applied to an infarct to increase ventricle wall thickness, enhanced zoom is representative of the boxed region and arrows indicate hydrogel (black) and myocardium staining positive for α-smc (blue). (D) Implantable cardiac patches applied over the infarcted region of the heart include dense polymeric structures (top) or porous meshes (bottom). Representative H&E stained histology of an implanted delivery system in an infarcted heart shows the ability to increase the wall thickness (top thickness compared to mid-left thickness). Graphics were created with BioRender.com and Blender 3D modelling & rendering package [357]. Fig. 2.2A reprinted from [70]. Copyright (2018) Nature. Fig. 2.2B reprinted from [56] & [59]. Copyright (2016) with permission from Elsevier and (2015) American Physiological Society, respectively. Fig. 2.2C reprinted from [358]. Copyright (2009) with permission from Elsevier. Fig. 2.2D reprinted from [56] & [61]. Copyright (2015) with and (2016), respectively, with permission from Elsevier.
As a consequence of their size, most nanocarriers are easily washed out from target tissues and accumulate in blood filtration organs (liver, spleen, kidney) 24 hours following administration and are cleared from the body by phagocytes or as excrement [160, 161]. One method to overcome this issue is to take advantage of tissues displaying an enhanced permeability and retention (EPR) effect. The EPR effect can be leveraged by nanocarriers with sizes less than 380-780 nm to aid targeting and prevent washout [159, 162, 163]. This phenomenon has attracted controversy, however, due to failed clinical trials with nanocarriers using the EPR effect to treat tumors, which have been largely attributed to differences in tumor establishment in animal models [164, 165]. Immediately following MI, however, the tissue does display enhanced permeability due to the acute inflammatory response creating leaky vasculature [163, 166]. Further, the infarcted myocardium also displays increased retention, due to dysfunctional lymphatic drainage [125]. Thus, an EPR effect is established and utilizing appropriately sized nanocarriers may facilitate relatively non-invasive delivery to the infarcted heart. Additionally, researchers have developed a variety of approaches to evade phagocytic clearance, including PEGylation [167], surface expression of “stealth” peptides [168], and employing cell membranes [169]. Surface modification of nanocarriers can also enhance tissue targeting and retention based on factor expression unique to the tissue [54, 70, 95, 170].
Microparticles can be designed to facilitate improved control and duration of release, yet can be prone to issues during fabrication due to potential interactions of the biologics with the polymeric matrix and also organic solvents. Similarly, polymeric microparticles, or sometimes called polymeric microspheres, can also protect encapsulated biologics from proteolytic enzymes [171, 172], but this delivery system is larger than nanocarriers with diameters ranging from a few micrometers to one thousand micrometers [173]. One common method to produce microspheres is a solvent evaporation technique, in which encapsulating polymer is dissolved in an organic solvent and emulsified with an aqueous phase containing the biologic [173]. This method can be suboptimal due to losses during washing steps and solvent evaporation as well as polydisperse size distributions, yet it is still commonly employed due to its relative simplicity [173-176]. Other fabrication methods include spray-drying [177] and microfluidics [178], which impart greater control over the final particle size distributions. While particle size can be variable, most microparticles are fabricated to have sufficiently large diameters to evade phagocytic immune clearance from tissues to prolong retention of the delivery system and further extend release duration. Specifically, spherical particles with diameters greater than 5 μm (non-opsonized) [179] or 15 μm (opsonized) [180] can effectively evade phagocytic uptake. Phagocytosis of non-spherical particles is highly dependent on shape and readers are referred to a comprehensive study investigating the phagocytosis of microparticles of various shapes and sizes to learn more [180]. Larger particle diameter, however, limits tissue accessibility/targeting from systemic circulation, requiring localized injection to the target tissue [162].
Microparticles’ distinct advantage relative to other delivery systems is their predictable, tunable, and sustained release of therapeutic payload for an extended duration (weeks to months) based on the erosion rate of the encapsulating polymer [171]. While some nanocarriers can facilitate sustained release up to 3 weeks, the majority display significant burst release and have exhausted their payload after only a few days [181]. Like nanoparticles, microparticles’ surfaces can be functionalized to evade phagocytic clearance via PEGylation [182]. Common polymers employed to create microparticles, representative morphology, and their appearance in vivo is presented in Figure 3B. Despite their versatility and beneficial characteristics, several challenges can limit their application to deliver biologics. Electrostatic interactions with the encapsulating polymer and the encapsulated biologic can drastically impact release kinetics either resulting in burst release (Repulsive interactions) or drastically lagged release (Attractive interactions) [183]. Encapsulation of biologics into microparticles can cause significant losses of biologic, in which extended contact with organic solvents and exposure to shear forces can cause proteins to denature or aggregate [174, 176, 184]. In addition, the encapsulation efficiency of biologics into microparticles can be relatively low because the encapsulating polymer typically occupies an organic phase while the biologic resides in an aqueous phase resulting in reduced available volume.
Injectable hydrogels, referred to as hydrogels henceforth, are networks of polymeric (Bio or synthetic) chains that cross-link to provide controllable and tunable release, like microparticles and nanocarriers, and confer additional functions uniquely suited to treat myocardial infarction. Unlike microparticles or nanocarriers, hydrogels can simultaneously deliver biologics while providing mechanical support to the infarct by acting as a bulking agent [107]. Bulking stabilize the infarct by increasing the myocardial wall thickness. Wall thickness and mechanical stress are inversely related [185], so increasing the myocardial wall thickness reduces stress placed on the tissue translating to reduced fibroblast proliferation and ECM production [130]. Clinical trials based only on this benefit have been reported for decellularized ECM hydrogels and alginate hydrogels indicating both safety and efficacy for MI patients [186, 187]. In addition to alginate or decellularized ECM, hydrogels can be fabricated from a variety of materials that can be physically or chemically cross-linked to form three-dimensional (3D) networks [188]. Common materials include biocompatible synthetic polymers (e.g. PEG, PNIPAAm, hyaluronic acid, PLLA, PDLLA, PLGA), bio-derived materials (e.g. chitosan, alginate, fibrin, gelatin, polysaccharides), or a combination of the two [189]. A key characteristic of hydrogels is their hydrophilicity, in which a significant portion of their total weight is composed of water [188]. This allows these materials to maintain mechanical properties (upon cross-linking) while allowing penetration to interstitial fluid [190]. In addition, hydrogels can be designed to be injectable through the process of shear thinning, utilization of environmentally (thermal, pH, ion) responsive cross-linking, or sequential delivery of a cross-linking agent to facilitate in situ gelation [191]. These attributes make hydrogels attractive polymeric delivery systems for targeting the infarcted heart with a variety of biologics including nucleic acids, growth factors, and stem cells. Hydrogels can encapsulate these biologics through incorporation into the polymer network within a polymer chain, passive (diffusive) loading between hydrogel cross-links, encapsulation between hydrogel cross-links, and electrostatic binding to polymer chains or cross-linkers [188]. Through selection of cross-linking groups or polymer modifications, hydrogels can be designed to respond to physical or chemical stimuli including pH [192], temperature [58, 128], electric fields [193], ultrasound [194], shear forces [75, 107, 146, 195], enzymes [107], and others [188]. Figure 3C summarizes the multiple attributes of hydrogels for myocardial application. While this delivery system can be highly functional, control over the loading capacity and release kinetics can be relatively poor due to the formation of interconnected pores [196]. Consequently, release from hydrogels typically presents as a large burst followed by sustained release for a variable time determined by the interaction strength between the loaded biologic and the polymeric matrix.
In stark contrast to the other delivery systems introduced, implantable cardiac patches, referred to as implants or implantable systems henceforth, are the most invasive to apply but have the greatest ability to assimilate macro-scale features of the heart such as curvature. Implantable materials encompass a wide variety of systems that require surgical application to the infarcted heart. Such materials include polymeric meshes [61, 197], hydrogel or cellularized sheets [56, 69, 97], and other 3D scaffolding materials [198, 199] (see Figure 3D). These systems provide mechanical support, without direct injection into the site of the infarction, and they can significantly improve cell transplantation efficacy by providing 3D structural orientation required for tissue growth and function [61]. In addition, implantable delivery systems can facilitate local release of biologics through encapsulation within their polymeric structure, which can be tuned much like microparticles to achieve targeted release profiles and durations [61, 91]. A distinct disadvantage of implantable materials is the requirement for invasive surgery to administer, whereas the other delivery approaches can be systemically administered or delivered through significantly less invasive intramyocardial injection. There is some overlap in terminology and intended use between hydrogels and implant; specifically injecting a hydrogel or suturing/adhering a patch to the infarct can sometimes both be referred to as an “implant” and both approaches can help stabilize the infarcted ventricle by increasing effective wall thickness. However, in the scope of this review they are discussed as separate entities, in which implants do not include injectable hydrogels and this group is focused on delivery systems that require more complex administration (e.g. suturing, adhesive) than direct injection into the ventricle.
3. Biologic delivery trends in myocardial infarction research
In this section we present trends in MI research related to biologic delivery and discuss why these trends exist. The trends are displayed using Chord diagrams and Sankey diagrams. Readers unfamiliar with these types of diagrams are directed to Supplementary Figure 1 for a brief example and tutorial in interpreting the data shown. Further, readers are reminded that diagram generation and the data used is detailed in the methods section found at the end of this article.
3.1. Application of delivery systems
Localizing biologic delivery systems to the heart is non-trivial due to various complexities including tissue accessibility, the potential to cause tissue trauma, and off-target effects of systemically administered delivery systems. Effective delivery of biologics requires local and sustained signaling, which is often accomplished through localization of delivery systems in target tissues. Administering biologic delivery systems to the heart, however, presents unique challenges in comparison to other solid organs. The rib cage limits surgical access to the heart requiring invasive surgery to perform more complicated procedures such as coronary artery bypass grafting, implantation of devices such as pacemakers or LVADs, and cardiomyoplasty [200]. Further, the thoracic cavity must be maintained below atmospheric pressure (negative pressure) to facilitate lung function [201]. During surgery, this cavity is exposed to atmospheric pressure requiring patients to be ventilated, increasing surgical complexity and patient risk [202]. Together, delivery systems that require surgical implantation are disadvantageous and primarily reserved for patients with no alternative treatment approach. However, surgical advances in laparoscopic surgery have translated to a marked reduction in invasiveness during standard cardiac surgical procedures [203, 204] and may facilitate less invasive DDS implantation for compatible systems.
Direct injection into the myocardium is a less invasive option to localize therapies, but the successful placement of a delivery system is not trivial. Unlike other solid organs, the heart’s mobility presents a potential risk of needle trauma or induction of an arrhythmia while injecting material via a catheter or guided needle [40]. Direct injection can also increase the chances of left ventricular free-wall rupture (LVFWR), a potential complication following MI caused by excessive thinning of the myocardium. MI research spans numerous animal models, each with varying myocardial thickness. For these models, the healthy heart myocardium ranges from 7-9mm thick in humans [205], 11.4 ± 1.0mm thick in pigs [206], 8.0 ± 1.3mm in canines [207], 2.5-2.8 mm thick in Rats [208], and 0.9-1.2mm thick in mice [209]. Larger animal models that have thicker myocardium, therefore, have decreased risk of LVFWR following direct injection. In addition, larger animals can also facilitate intrapericardial delivery as an alternative to myocardial injection due to their larger pericardial sacs. Intrapericardial delivery provides an avenue to localize therapy to the heart in minimally invasive ways [210]. Small rodent models, however, have markedly increased risk of LVFWR [211] and the surgical technique for inducing MI destroys the pericardial sac [212]. Despite these challenges, direct injection remains a common approach employed for MI research, across all animal models, because it provides a simplistic method to administer a biologic delivery system to the infarcted tissue. Systemic delivery of DDS is an alternative and highly sought-after approach; however, nanocarriers are the only delivery system that can accomplish this due to size constraints.
3.2. Delivery system trends
3.2.1. Nanocarriers
Nanocarriers are one of the most prevalent biologic delivery systems employed in MI research to facilitate the delivery of all major biologic classes. Nanocarriers have nearly uniform application in each of the therapeutic targets explored, in which they represent a majority both among the delivery systems and for each therapeutic target (see Figure 4A). A brief list of common nanocarrier materials or viral carriers that have been reported in MI research recently is listed in Table 4, a more detailed version of this table can be found in the supplementary information. As expected from their unique ability to enhance intracellular delivery relative to other delivery systems, nearly half of all nanocarriers identified from the coincidence search are employed to deliver nucleic acids (see Figure 4B). For the other biologics explored, chemokines and growth factors have been reported to be delivered from various nano encapsulated formulations such as heparin coacervates [64] or micelles [65]. The relationship between nanocarriers and stem cells is unique to this class of delivery system. However, it represents delivery to stem cells rather than the delivery of stem cells. Delivering biologics to engineer stem cells that are capable of enhancing their engraftment and regenerative capacity through transducing pro-angiogenic [62, 83, 86], cardioprotective [83], and immunomodulatory [93] genes or factors is an emerging approach in regenerative medicine. Manipulating these cells in such a way before engraftment converts the cells into a delivery vehicle for these beneficial factors [213]. Nanocarriers’ size can facilitate systemic application rather than direct application, which the other delivery systems explored require. Because direct application is significantly more invasive, this may provide one reason why nanocarriers are the favored delivery system. However, Figure 5 shows that systemic administration is not a primary approach for nanocarriers. One explanation for this trend is that the systemic delivery of nanocarriers requires increased DDS complexity to facilitate targeting and retention of the infarct to avoid rapid clearance from the heart [160, 161]. Thus, without modifications made to enhance targeting or retention, administering a bolus dose of the nanocarrier locally provides the greatest opportunity for localized delivery and cellular uptake. In addition, combinatory delivery systems that contain a nanocarrier (liposome, micelle, adenovirus, heparin coacervate) suspended within themselves would present as localized delivery of the nanocarrier. One such example involves the suspension of micelles within an injectable hydrogel facilitating the prolonged release of encapsulated PDGF [65].
Figure 4 – Biologic delivery trends in myocardial infarction research.
Chord diagrams displaying the relationship between therapeutic targets and delivery systems (A), delivery systems and biologics (B), and therapeutic targets and biologics (C) were constructed according the literary search detailed in the methods section. Connecting ribbons display the strength of the correlation (thickness) and percentages listed along the grid for specific classes of targets, delivery systems, or biologics correspond to their contribution to their respective classifier as it relates to the other. For example, Figure 4C shows 35% of all biologics utilized among the therapeutic targets in MI that were considered are Growth Factors, of which the majority (nearly half) are employed to induce angiogenesis. Represents data for references [52-76, 78, 81-109, 195, 237, 238] obtained on Elsevier’s Scopus search engine for dates 1/1/2015 – 5/14/2020 inclusive. Chord diagrams were generated in RStudio version 3.6.1 using the circlize package [356].
Table 4:
Nanocarrier delivery systems employed in myocardial infarction research
| Material/ Viral Carrier |
Mean Diameter (nm) |
Reference |
|---|---|---|
| AAV | N/A | [62, 81, 88, 89, 91, 95, 96, 223] |
| Adenovirus | N/A | [57, 82, 84, 86, 87, 93, 94, 224, 225] |
| Lentivirus | N/A | [97, 99, 102, 108, 226] |
| DA-PEI | 140 - 250 | [53] |
| EVs | 30-100 | [100] |
| 104 | [103] | |
| 87.6 | [104] | |
| Gold | -- | [227] |
| Heparin coacervate | 540.8 | [64] |
| Mesoporous silica | 476 - 514 | [83] |
| Modified RNA | -- | [98, 105] |
| mPEG-PLA-TPGS | 100 - 200 | [228] |
| PAM-ABP dendrimer | 103.8 - 128 | [90] |
| PEG-CMCS | -- | [143] |
| PEG-PLA | 105 - 121.4 | [170] |
| PEG-PSHU-PEG micelle | 216.5 | [65] |
| PEGylated-lipid | 130 | [229] |
| PEI | N/A | [230] |
| Plasmid MC | N/A | [92] |
| PLGA | 100 | [231] |
| -- | [232] | |
| -- | [233] | |
| Poly-ethylenimine | -- | [73] |
| 80 | [106] | |
| Polyketal | 934.2 | [101] |
| PPA | 50 | [234] |
| Silicon | 220 - 320 | [235] |
| Thiolated chitosan | 182 | [236] |
| UTMD | 2500 | [85] |
Figure 5 – Drug delivery system types and attributes.
Delivery systems shown in Figure 2 (Nanocarriers, Hydrogels, Implants, and Microparticles) are further described using a Sankey Diagram created via sankeymatic.com beta software [359]. Data shown is the number of publications identified by the searching method – for brevity, only the delivery systems have the publication number shown – the individual data and reference number can be found in the supplementary data for this publication (Table 1 & 2). The distribution of delivery systems directly corresponds to Figure 2 data obtained from the coincidence search while subsequent classification was performed manually, in absence of appropriate keywords. Only nanocarriers were quantified as being locally or systemically administered because the other DDS lack the ability to be systemically administered. In some cases, applications could not be adequately described and so they were omitted (e.g. one non-viral application was in vitro only and so was not locally or systemically administered to treat MI). Data was obtained on Elsevier’s Scopus search engine for dates 1/1/2015 – 5/14/2020, inclusive. Represents data for references [52-76, 78, 81-109, 128, 143, 170, 195, 223-238, 250, 251] obtained on Elsevier’s Scopus search engine for dates 1/1/2015 – 5/14/2020, inclusive.
Both viral and non-viral delivery systems have been developed and employed to deliver nucleic acids in MI research and other fields. Key decision criterion for selecting one system over the other include target gene size, allowable immunogenicity, and targeting fidelity. Viral vectors can facilitate high efficacy gene transfection [214] and different viral carriers can be selected based on allowable immunogenicity, intended gene expression duration, and the size of the gene to deliver [215]. For example, lentivirus can assimilate into the host cell genome and confer sustained gene expression, which is particularly helpful for addressing chronic disease. Lentiviral delivery of miRNA-29b, a microRNA that silences a pro-fibrotic gene, in a rat model of MI demonstrated significantly increased miRNA-29b expression at 28 days following disease induction [102]. As a result, rats treated with lentivirus encoding miRNA-29b exhibited significantly improved EF and reduced deposited collagen relative to controls [102]. In MI research, adenoviruses, adeno-associated viruses (AAV), and lentiviruses are all commonly utilized (see Figure 5). Yet retroviruses are not used at all - likely because retroviruses require cell division to transfect cells and adult CMs (one of the most abundant cell types in the myocardium) do not divide [215]. However, viral carriers can also activate an immune response in the infected tissue and indiscriminately infect all tissues [215]. These drawbacks are significant challenges as they often prohibit scale up to larger animal models or clinical translation. This is especially true if a subject has pre-existing immunity [92, 216]. Non-viral nanocarrier alternatives, consisting of nanoparticles, EVs, micelles, liposomes, and others, have significantly reduced immunogenicity in comparison. However, these systems have reduced transfection efficacy relative to viral carriers due in large part to difficulties facilitating endosomal escape or transport into the nucleus [217, 218]. Despite this efficiency reduction, they can deliver larger strands of genetic information relative to viral carriers [217, 218] and can be more easily modified to target cells expressing specific ligands or receptors [219]. For instance, conjugation of an IL-13 peptide to a nanocarrier facilitated receptor specific targeting of carcinogenic glial cells, which overexpress IL-13Rα2 [220]. EVs, in particular, have been shown to provide additional benefit in the treatment of MI and cardiac fibrosis [221, 222]. This nanocarrier has also been combined with a shear thinning hydrogel to facilitate extended (21+ days) release of the exosomes in the treatment of MI [117]. This study reported improved EF, CO, and SV with reduced ventricular dilation relative to controls [117].
The most significant challenge related to nanocarrier use remains target tissue and cell fidelity. Due to their size, nanocarriers typically accumulate in blood filtration organs. Thus, there is a need to either ensure control their accumulation, which may be impractical, or control their activity. Section 4.1 details some recent successes in this regard, but in brief the utilization of targeting ligands or addition of moieties that render nanocarriers inert unless activated show significant promise in overcoming these challenges. If overcome, nanocarriers are positioned to transform the treatment of MI in the clinic as other methods of delivering biologics require more invasive application, which often does not occur for days to weeks following MI.
3.2.2. Microparticles
In contrast to nanocarriers, microparticles are among the least employed delivery systems in MI research due to several challenges that limit their effectiveness when applied to the infarcted heart. Microparticles can be made from synthetic polymers (PLGA, PLLA, PEG) or biopolymers (alginate, collagen, dextran). A brief list of common microparticle materials that have been reported in MI research recently is listed in Table 5, a more detailed version of this table can be found in the supplementary information. Synthetic biodegradable polymeric microparticles have been used extensively and continue to be a common design choice for new formulations. Biopolymeric microparticles are a novel approach that has been gaining increasing interest for their ability to better encapsulate biologics or interface with the host [239]. Collagen-based microspheres, for example, were developed recently to encapsulate and deliver MSCs in a murine model of MI [240]. The microspheres were reported to enhance cell attachment and engraftment translating to improved EF, SV, and CO 28 days after treatment [240]. Readers are encouraged to familiarize themselves with other examples of biopolymeric microparticles [241]. In MI research, biopolymeric microparticles are used about as frequently as biodegradable, synthetic microparticles (see Figure 5) and may continue to gain relevance as more studies demonstrate their efficacy. Figure 4A shows that microparticles are a less favored delivery system in MI research, in which they have been employed in some studies to induce angiogenesis or address fibrotic remodeling. Microparticles’ ability to deliver larger quantities of biologics over a more extended period, relative to other DDS, provides some benefit to these therapeutic targets that require biologic delivery to be maintained for several weeks. In like manner, the biologics delivered are primarily growth factors with some chemokines (see Figure 4B), neither of which are dominantly delivered by microparticles.
Table 5:
Microparticle delivery systems employed in myocardial infarction research
The low prevalence of microparticles in MI research may be a result of several disadvantages microparticles exhibit in cardiac applications. Microparticles’ larger size prevents systemic administration requiring the direct injection of suspended particles into the infarct. The allowable needle diameter imposes limits on the particle size. In the case of small rodent models, microparticle diameter is restricted to ~5 μm to maintain injectability through a 28 to 30-gauge needle [242]. Consequently, microparticle application in small rodent MI research is susceptible to phagocytosis from infiltrating macrophages [179, 243]. A study trialed PEGylation of microparticles injected into the myocardium as a way to counter macrophage phagocytosis but found no improvement in efficacy compared to non-PEGylated microparticles. This was primarily attributed to the inflammatory response following MI [67]. Furthermore, microparticles are susceptible to physical clearance as the heart beats both from the contractile shear forces and increased coronary blood flow causing microparticle washout [244]. Specifically, only 5% of microparticles were shown to be retained from a single injection and multiple injections negligibly increased retention to 8% [244]. Consequently, unlike implants and hydrogels, microparticles alone do not possess the ability to act as a bulking agent to help stabilize the heart and deliver biologics [107, 130, 185]. The issue of retention can potentially be addressed in a similar manner to nanocarriers suspended within a hydrogel or implantable delivery system. Outside of the field of MI research, several studies have documented this approach to successfully enhance microparticle retention at the injection site by suspending microparticles within a hydrogel [245-247].
Microparticle fabrication methods are also poorly compatible with most biologics. Several fabrication methods for polymeric sustained release systems can cause polypeptide proteins to unfold or aggregate rendering them unusable [173-176]. For instance, oil/water emulsions are commonly employed to encapsulate biologics (water phase) within polymers solvated in organic solvents (oil phase), but these oil/water interfaces can cause protein unfolding or aggregation due to solvent interaction with thiol or disulfide bonds [184, 248]. There is evidence that the use of stabilizing compounds such as albumin, sugars (e.g. mannitol, sucrose, trehalose, etc.), or cyclodextrins (HPCD) can competitively reduce interface degradation of proteins and minimize aggregation [248]. However, these carriers often require relatively large concentrations to function reducing maximal loading capacity [248]. By comparison, many hydrogels and nanocarriers have been developed to be more biocompatible or biomimetic, respectively, conferring fabrication methods and opportunities that decrease the risk of damage to biologics [239, 249].
3.2.3. Hydrogels
The application of hydrogels in MI therapies presents multiple opportunities for therapeutic intervention not only from the encapsulated biologics but also the delivery system itself. This class of delivery system is the second largest biologic delivery system employed in MI research (see Figure 4A). This delivery system offers multiple benefits that can directly address the pathophysiology associated with post-MI remodeling. A brief list of common hydrogel materials that have been reported in MI research recently is listed in Table 6, a more detailed version of this table can be found in the supplementary information. While originally utilized to act as a functional bulking agent [107, 130, 185], hydrogels have shown significant potential in recent years as an injectable, 3D cell scaffold that can significantly improve cell engraftment and retention [252, 253]. As a result, hydrogels are principally employed to deliver stem cells [60, 75, 109] and growth factors [58, 63-65, 69, 71, 76] (see Figure 4B) as a regenerative therapy. To a lesser extent, this system is used to deliver nucleic acids such as siRNA to inhibit the production of ECM destructive enzymes [107] (see Figure 4B). There are several types of hydrogels employed in MI research including thermoresponsive [58, 65, 109, 128], in situ-forming [63, 64, 71, 250], enzyme responsive [107], and shear thinning [75, 107]. Thermoresponsive and in-situ forming hydrogels are most frequently employed likely due to their production and loading simplicity compared to more functionalized, responsive hydrogels or shear-thinning hydrogels (see Figure 5). For example, Rocker and colleagues employed a thermally responsive hydrogel to encapsulate and deliver VEGF, IL-10, and PDGF-loaded micelles [65]. The subcutaneous application of this system in a mouse model facilitated significantly increased endothelial (CD31+) and pericyte counts (α-SMA+) relative to controls (see Figure 6) [65]. However, shear thinning hydrogels, which are covalently cross-linked, are gaining increased interest due to their superior potential for translation via minimally invasive catheter injection systems while retaining superior mechanical properties relative to in-situ forming hydrogels, which are physically cross-linked [129]. A study conducted at Stanford University reported the development of a shear thinning hydrogel, for instance, that had a measured strength of 195 Pa and could be injected both in small and large animal models of MI to significant effect [75].
Table 6:
Hydrogel delivery systems employed in myocardial infarction research
| Material | Function | Reference |
|---|---|---|
| Alginate | Injectable | [60] |
| Dex-PCL-HEMA/ PNIPAAm | Thermoresponsive | [58] |
| ECM-derived | -- | [76] |
| Fibrin gel | -- | [64] |
| Gelatin | Implantable | [69] |
| Hyaluronic Acid | Shear-thinning | [75] |
| Responsive & Shear-thinning | [107] | |
| Naphthalene | -- | [109] |
| PEG-Fibrinogen | Injectable | [63] |
| PNIPAAM/HEMA/AOLA | Thermo-responsive | [128] |
| SAP | Self-assembly | [71, 236, 250] |
| Sulfonated PNIPAM | Thermo-responsive | [65] |
Figure 6 – Synergistic delivery enhances angiogenesis.
IHC staining of pericytes (α-SMA+, red) and endothelial cells (CD31+, green) 21 days following injection of saline, sulfonated reverse thermal gel (SRTG), SRTG + VEGF, SRTG + VEGF + PDGF, SRTG + VEGF + PDGF-loaded micelles, or SRTG + VEGF + IL-10 + PDGF-loaded micelles. Scale bar = 100 μm. Reprinted from [65]. Copyright (2020) American Chemical Society.
The use of hydrogels to deliver biologics still presents several challenges. The first and most significant challenge is that hydrogels have the majority of their volume occupied by water. This results in relatively low volume to encapsulate biologics, which is a critical consideration given that the heart is not a large tissue. Further, hydrogel hydrophilicity often results in burst release kinetics of encapsulated biologics. Several researchers have overcome this burst release through the modification of the biologics to bind the hydrogel backbone [107] or by first encapsulating biologics in a separate delivery system that can better control release rate [64]. However, both approaches significantly increase delivery system complexity. As methods to predict the release of combined delivery systems are developed and more simplistic and robust methods for biologic modification are created, this system may become more widely used.
3.2.4. Implants
Like hydrogels, implants can provide multiple benefits in treating MI, yet this delivery system sees limited use as better alternatives have been created. Implants can take on a variety of forms, such as polymeric patches [56, 91], biomolecular sheets [97], and fibrous meshes [61]. These systems can confer structural support to the infarct externally while acting as a depot to deliver various biologics. Implants are predominantly utilized to facilitate cell engraftment in regenerative therapies (see Figure 4B) due to their ability to confer highly engineered 3D geometries necessary for cell function and survival [61]. A brief list of common implant materials that have been reported in MI research recently is listed in Table 7, a more detailed version of this table can be found in the supplementary information. An emerging approach is to utilize electrospinning technologies to produce polymer meshes that can facilitate improved cell attachment and migration relative to cell sheets due to their increased surface area and microporous structure [61]. In one example, a poly(L-lactic acid) (PLLA) mesh that encapsulated VEGF within its fibers was shown to significantly enhance both CSC and human umbilical vein endothelial cell (HUVEC) migration and engraftment into the structure forming a tissue structure expressing canonical CM markers, in vitro (see Figure 7). This patch was implanted, following CSC seeding, in a rat model of MI increasing infarct ventricular wall thickness, EF, and FS while reducing fibrosis relative to controls [61]. Beyond stem cell delivery, implants also supply other biologics that aim to enhance cell survival and engraftment in the infarct such as anti-apoptotic signaling [97], IL-10 [93], or VEGF [61, 62] (see Figure 4B). Despite these benefits, the most common form of implantation, however, is the simple injection of cells [62, 83, 86, 93] without an implantable scaffolding or delivery system (see Figure 5). In these studies, cells are typically genetically altered prior to injection to express or deliver factors that can enhance engraftment [62, 83, 86] or provide additional benefit to the local infarct environment [83, 86, 93]. A plausible reason for why these studies chose not to employ a polymeric delivery system to implant these cells may be that MSCs have some inherent tropism to the infarct via SDF-1/CXCR4 chemoattraction [254, 255]. However, MSC migration to target tissues has relatively low efficacy [256]. There may also be a desire to reduce study complexity at an allowable cost of significantly reduced cell engraftment and retention.
Table 7:
Implant delivery systems employed in myocardial infarction research
Figure 7 – In vitro seeding of CSCs expressing cardiomyocyte markers.
Microphotographs of PLLA mesh [24] populated with CSCs after 7 days. The cells formed a tissue-like structure and expressed canonical CM markers – cTnI, Mhc, and α-SA. Scale bar = 50 μm. Reprinted from [61]. Copyright (2015) with permission from Elsevier.
Nevertheless, the application of implants is rarely employed in MI research (see Figure 4A). One reason for this trend is that most implants are attached to the myocardium through multiple sutures [56, 61, 69], significantly increasing surgical complexity and risk of damage to the heart. Consequently, injectable hydrogels, which are comparatively easier to deliver, have overtaken implants as a primary means of localizing both cells and other biologics to the infarcted heart (see Figure 4.1B). Furthermore, injectable hydrogels are gaining the ability to match implants’ highly structured 3D geometry. For example, a hydrogel was recently developed to contain a capillary microstructure with pro-angiogenic factors encapsulated throughout the structure [257]. This system facilitated sustained release up to 90 days, in vitro. Application of this technology in a rat model of MI was shown to significantly reduce infarct size 28 days after administration [257].
The key advantages that implantable materials confer are that current technologic advances, such as 3D printing and electrospinning, enable this system to have enhanced control over their 3D structure and straightforward application. Highly engineered 3D structures are necessary for effective cell engraftment, cell migration, and access to interstitial fluid to provide nutrients and remove waste from engrafted cells. While surgical application may be more invasive, it is more familiar to clinicians, and it can be performed with any hard or soft implant facilitating a reduction in study complexity. Where most implantable materials fail, however, is the encapsulation efficiency and release of biologics. Many implantable materials exhibit low encapsulation efficiency relying on either the available surface area to deliver biologics (e.g. stem cells) or randomly distributed pockets of biologic distributed in the implantable material. Thus, implants are best suited to the delivery of biologics that do not require significant quantities be delivered or that would have their effects amplified in a system that provides high structural control such as stem cell engraftment or neovascularization.
3.3. Biologic trends
3.3.1. Growth factors
Growth factors are a common biologic delivered in MI research principally to revascularize the infarct while providing additional benefits. These polypeptide molecules are the second most common biologic delivered to treat MI (see Figure 4C) and every major DDS type has been employed to facilitate delivery to the infarct (see Figure 4B). GFs are principally used to induce angiogenesis and remodel the infarct and only a handful of applications aim to leverage or quantify their cardioprotective or immunomodulatory capacity (see Figure 4C). Angiogenic GFs include VEGF, PDGF, HGF, FGF-2 (bFGF), and ANG-1, of which VEGF is dominant (see Figure 8). GF delivery can be classified as either monotherapy, in which only a single GF is administered, and multitherapy, in which either dual GFs are delivered, or a GF and another biologic type are delivered together. Because functional induction of angiogenesis requires spatiotemporal control of multiple GFs [40] and revascularizing the infarct can enhance the efficacy of other biologic delivery (chemokines, stem cells) [60-62, 68, 75], one might infer that the majority of GF delivery applications would be multitherapy. However, monotherapy of GFs is actually shown to hold a slight majority (see Figure 8). One explanation may be that researchers often choose the simplest therapeutic application to demonstrate the potential of novel delivery systems, which encompasses significant research focus in MI biologic delivery. In addition, delivery of multiple angiogenic GFs has been shown to be difficult due to the potential for antagonistic effects requiring precise spatiotemporal control of both factors to impart optimal effects [258-260]. Specifically, early stage angiogenic signals that target endothelial cells, such as VEGF, are inhibited by late stage angiogenic signals that target pericytes, such as PDGF [261]. This effect is more greatly pronounced by Ang1 and Ang2 antagonism, in which the late stage, maturation signal Ang1 completely arrests Ang2 mediated early-stage angiogenesis [261]. This may also explain why VEGF presents as the dominant GF employed in MI research due to its widely studied and significant role in angiogenesis initiation resulting in the greatest potential to induce angiogenesis with the delivery of a single factor [262].
Figure 8 – Biologic types and attributes.
Biologics shown in Figure 2 (Growth Factors, Nucleic Acids, Chemokines, and Stem Cells) are further described using a Sankey Diagram created via sankeymatic.com beta software [359]. Data shown is the number of publications identified by the searching method – for brevity, only the Biologics have the publication number shown – the individual data and reference number can be found in the supplementary data for this publication (Supplementary Table 1 & 2). The distribution of biologics directly corresponds to Figure 2 data obtained from the coincidence search while subsequent classification was performed manually, in absence of appropriate keywords. Because of multi-faceted therapy strategies (e.g. delivery of multiple growth factors or nucleic acids), which caused an increase in the number of examples where specific types of biologics were administered causing the diagram to appear unbalanced (e.g. Growth Factors, Nucleic Acids). Represents data for references [52-76, 78, 81-109, 128, 143, 170, 195, 223-238, 250, 251] obtained on Elsevier’s Scopus search engine for dates 1/1/2015 – 5/14/2020 inclusive
Studies that do accomplish multifactor delivery of GFs, typically employ multiple delivery systems, such as hydrogels (short-term signaling) and embedded nanocarriers (long-term signaling) to accomplish temporal control of multiple factors [64, 65]. FGF-2, PDGF, and ANG-1 also have primary angiogenic effects serving as alternate initiators of the process or to stabilize newly formed vessels in combination with VEGF [40, 63, 65]. Continuing, HGF administration has been shown to reduce CM apoptosis and reduce fibrotic signaling [262] in addition to imparting an angiogenic effect [263]. Non-canonical GFs have been shown to provide some benefit as well. Neuron-derived Neurotrophic Factor (NDNF), for example, is an activator of the Akt endothelial nitric oxide synthase (eNOS) signaling pathway [264]. Adenoviral delivery of NDNF in a mouse model of MI resulted in a negligible reduction to infarct size, but only a nominal reduction in LV dilation and FS [82].
3.3.2. Chemokines
Chemokines have significant potential in MI but their application has been limited to primarily attracting progenitor cells. Chemoattraction of progenitor cells has been shown to provide several benefits that can reduce damage and enhance healing following MI [265]. Their chemoattraction occurs through two primary signaling axes: stromal derived factor 1α (SDF-1α) and its target receptor CXCR4 or stem cell factor (SCF) and its target ligand CD117 (c-KIT) [254, 265-267] – both of which are the primary chemokines delivered to treat MI (see Figure 8). This approach is limited by the poor vascularization of the infarct, which reduces the ability of these cells to access and survive [266]. Some studies attempt to address this issue through multitherapy approaches (see Figure 8) that deliver SDF-1α or SCF alongside pro-angiogenic factors to increase vessel permeability in the infarct microenvironment and vascularize the tissue [60, 68, 75]. Due to the complexities of multifactor delivery and the reduced efficacy of chemoattraction of progenitor cells compared to the alternative approach of implantation, chemokines are the least employed biologic (see Figure 4C). However, there are some instances, in which other chemokines are delivered or inhibited to target different aspects of MI pathophysiology. Specifically, immunomodulatory intervention can be targeted explicitly through selective bolstering or abrogation of chemoattractive pathways. A recent conceptual approach demonstrated the use of macrophage targeting acetalated dextran-based nanoparticles to facilitate drug delivery to the heart [268]. Experimental studies showed that these nanoparticles associated with macrophages rather than becoming internalized, in vitro, indicating that this system has the potential to take advantage of the inherent tropism of macrophages to the infarct following MI. However, small animal models and clinical trials that have aimed to suppress or block the chemoattraction of effector immune cells (neutrophils, monocytes, etc.) to the infarct have demonstrated poor or mixed results as reviewed [269]. Deliberate chemoattraction of immune cells that have immunosuppressive capabilities has not yet been established in MI research, but this approach has shown potential in a number of other disease models [24, 270, 271] and would likely be beneficial if applied to treat MI.
Chemokine delivery presents additional challenges that local targeting of the infarct does not have. Endogenous chemokine gradients do not exceed a few hundred micrometers due to binding to glycosaminoglycans located in the ECM [272]. This implies that delivery of chemokines may be limited to tissue resident cells, nearby lymphatic tissue, or systemically circulating cells. Thus, for more distant tissues (bone marrow, spleen) chemokine delivery may require significantly larger quantities to be delivered and sustained release kinetics to facilitate migration. Utilization of a chemokine delivery system that initially displays a large burst dose or that is combined with a brief systemic administration of the chemokine may address the issue. Large quantities administered upfront either locally or systemically have a better chance of accessing the target tissue to mobilize target cells into the systemic vasculature where they will eventually transit to the heart. Further, for applications aiming to attract immune cells, a chemokine may need to be delivered in combination with a factor able to induce lymphangiogenesis to enhance lymphatic permeability in the tissue [125, 126].
3.3.3. Nucleic acids
Nucleic Acids are a widely applied biologic in MI research yet there are some applications in which they are underutilized. Nucleic acids are the largest class of biologics applied in MI research (see Figure 4C), in which they have demonstrated significant utility in addressing pathologic remodeling or bolstering angiogenesis. These molecules are typically administered as a monotherapy, without any other biologics delivered, in which applications are evenly split between pDNA and various forms of RNA (mRNA, siRNA/shRNA, miRNA) (see Figure 8). There are several reasons for these trends including continued focus to identify genetic targets for therapy [273], the growing scientific interest of nanomedicine [274], and their breadth in addressing multiple pathologies/therapeutic targets relative to other biologics [50]. In addition, nucleic acids are primarily used positively (supplementation, enhancement, replacement) in MI research with a minority of studies exploring negative signaling (Silencing, blocking) (see Figure 8). One explanation may be that most studies aim to amplify the healing process rather than block damage, which has a smaller window of opportunity and can be more challenging to achieve due to the multifaceted nature of hypoxia and reperfusion induced cell injury.
Because nucleic acids must transport across the cell membrane to enact their effect, nanocarriers are the primary delivery vehicle employed due to their ability to facilitate intracellular transport [51] (see Figure 4B). Of note, there are a few instances of nucleic acid delivery using responsive hydrogels. One recent report detailed how siMMP2, a siRNA targeting MMP-2, was delivered following enzymatic cleavage of the injected hydrogel by MMP-2 [107]. While delivery of this hydrogel system demonstrated reduced fibrotic remodeling in a rat model of MI relative to PBS control as measured by increased LV wall thickness, EF, CO, and SV, only EF was shown to be improved relative to siRNA control gel treatment group [107]. This is likely due to the poor intracellular delivery of free siRNA and the confounding benefit that hydrogels confer as bulking agents [107, 130, 185]. Continuing, nucleic acids are employed in every major therapeutic target except immunomodulation, which is significantly underutilized relative to the other targets (see Figure 4C). The few applications that do target immunomodulation with nucleic acids are focused on suppressing the receptor for advanced glycation end products (RAGE) signaling cascades [95, 106] to reduce inflammatory injury. Like chemokines, the potential for immunomodulatory therapies using nucleic acids is significantly larger than the current utilization. There have been several nucleic acids identified that can polarize infiltrating immune cells to a more reparative state [104, 275] and these same approaches may confer benefit following MI.
3.3.4. Stem cells
Despite their controversy, stem cells continue to be delivered in MI research but typically in conjunction with other biologics. Stem cells constitute a significant portion of biologics delivered in MI research, following closely behind growth factors (see Figure 4B & C). The most common type of pluripotent stem cell delivered in MI research is BMMSC (see Figure 8). This trend is of note because AD-MSCs are more easily harvested with improved yield relative to BMMSCs [276, 277], indicating this cell type also has a greater potential to be scaled to meet clinical needs and is therefore more suitable for evaluation. In addition, multiple studies have indicated AD-MSCs are better suited for cardiac repair [278, 279] citing an enhanced rate of proliferation and expression of beneficial paracrine factors. In a direct in vitro comparison between human AD-MSC and BMMSC, results indicated AD-MSC express increased HIF-1 and angiogenic response when co-cultured with a rat aorta [278]. In vivo comparison was less promising showing no improvement in infarct area for either cell type and only marginal improvements in cardiac functional measures (LV dilation) [278]. Considering these cells were administered as a free injection, which is a significantly low efficacy approach to deliver stem cells, further study with more advanced scaffolding systems (e.g. injectable hydrogel, implantable cardiac patch) is merited. When completed, these studies may indicate that AD-MSCs should become the new standard in MI research.
Continuing, multitherapy is the primary mode of application (see Figure 8), in which in vitro transfection beneficial plasmids [83, 86, 93] or encapsulation & release of beneficial factors [62, 71, 109] is performed in tandem. A multitherapy approach is performed to enhance engraftment and function of the implanted stem cells. Adenoviral mediated overexpression of the immunoregulatory cytokine, IL-10, in BMMSCs before implantation, for example, significantly reduced infarct size, in a rat model of MI, relative to vehicle control, MSC, or adenovirus encoding IL-10, alone, indicating a synergistic effect [93]. Another instance delivered AD-MSC with an injectable hydrogel that releases nitric oxide (NO) in response to β-galactosidase resulting in improved cell retention and survival following a mouse model of MI [109]. The NO release significantly improved angiogenesis and facilitated improved performance (AD-MSC engraftment & survival, FS, EF) relative to AD-MSC implantation in an injectable hydrogel alone [109].
4. Advances in biologic delivery
4.1. Novel methods to target the infarct
There is a need to improve the way biologic therapies become localized to the infarct to facilitate earlier clinical intervention. Localizing therapy requires more invasive procedures (PCI/Catheter injection/open heart surgery) however there is often a time delay from patients suffering an MI to receiving surgical intervention. In some cases, patients may wait over four weeks post-MI to receive some cardiac surgical procedures (bypass surgery/PCI) due to demand and surgeon availability [280]. Such a delay prevents early intervention targeting reperfusion injury or CM apoptosis. If biologic therapies could be systemically administered and have the ability to traffic to the heart and be retained, then these earlier therapeutic targets would become more accessible. The following constitute recent advances in systemic delivery & targeting to or enhanced retention within the infarcted myocardium of biologic therapies.
4.1.1. Polypeptide modifications to enhance infarct targeting and retention
Several factors that are upregulated following infarction can be targeted to facilitate biologic trafficking to the infarct following systemic administration. The modification of polypeptide molecules to include additional functionality or binding ligands is an emerging field [281-283], though not trivial. A simplified diagram demonstrating this concept is displayed in Figure 10. Modifying proteins to become their own delivery system is attractive as it can improve delivery efficacy. This approach also circumvents encapsulation of biologic within a delivery system increasing the available volume and avoiding losses during fabrication [248]. However, the resultant self-delivering protein must still escape degradation from proteolytic enzymes to accomplish sustained delivery of the therapeutic protein. Both attributes are advantageous for targeting the infarcted myocardium. In one example, VEGF was modified (IMT-VEGF) to include a cardiac troponin I (cTnI) targeting peptide (STSMLKA) with linkers that connect through the carboxy terminal on VEGF [54]. cTnI is a contractile regulatory protein released into the extracellular space upon myocardial damage [284]. Intravenous injection of IMT-VEGF conuugated to a fluorophore in a rat model of MI showed significant enhancement of VEGF within the myocardium compared to controls [54] [see Figure 9]. Several other reports have identified alternative infarct targeting peptides that could be used in a similar fashion [285, 286]. Lacking from this study, however, is an evaluation of proteolytic degradation of IMT-VEGF compared to naïve VEGF and its ability to bind to ECM, which is the canonical method of GF retention [37-39]. The IMT-VEGF study did quantify retention of this molecule in the heart out to a few hours [54], but a timepoint comparing the concentration out to a few days, when cTnI expression decreases [284], would have been beneficial.
Figure 10 – Novel approaches to target delivery to the infarct.
(1.) Synthetic modifications of polypeptide molecules to include a peptide binding domain specific to proteins upregulated in the infarct. (2.) Electrostatic coating (top) or synthetic modification of polypeptide molecules to include a binding domain specific for ECM proteins upregulated following MI. (3.) Steric hindrance of viral spike proteins prevents cell transduction. (4.) Enzymatic cleavage of the peptide inhibiting spike protein binding facilitates localized cell transduction. Graphics were created with BioRender.com
Figure 9 – IMT-VEGF infarct targeting.
Dylight 488 fluorophore (left), complexed to VEGF (middle), or complexed to IMT-VEGF (right) was injected intravenously following MI induction and a reperfusion duration of 10 minutes. One hour following injection, the heart was washed with PBS, removed, and sectioned. Reprinted from [54]. Copyright (2015) with permission from Elsevier.
ECM proteins present in large quantities in the myocardium, such as collagen, elastin, and proteoglycans [287], provide additional enhanced targeting and retention opportunities. In one report, tannic acid (TA), which can bind to several of these biomacromolecules while exhibiting minimal binding to glycocalyx present in systemic vasculature, was leveraged to enhance the binding affinity of proteins and peptides to the myocardium [70]. In a process dubbed “TANNylation”, biomolecules were incubated with TA to obtain nanoscale particles, in which the particle size is controlled by the ratio of TA to biomolecule and the incubation duration (see Figure 11). A number of biomolecules, including GFP, bFGF, and AAV, were TANNylated and administered following MI induction in rats [70]. This approach demonstrated drastically increased blood concentration, accumulation in the myocardium, and reduced liver accumulation compared to un-TANNylated biomolecules. Further, the delivery of TANNylated bFGF through tail vein injection showed significantly reduced infarction size and improved SV, CO, and LV pressure relative to treatment control and intramyocardial injection of a bFGF loaded hydrogel 28 days after MI induction [70]. It is interesting that the TANNylated bFGF outperformed the hydrogel delivering bFGF considering that the hydrogel is also able to provide mechanical support to the infarct. This may be a consequence of a relatively short burst release profile from the hydrogel compared to significantly longer presence of TANNylated bFGF in the infarct. Notably, utilization of tannic acid to enhance cardiac targeting and retention was recently reported for nanoparticles targeting myofibroblasts [288]. Thus, this simple approach has significant potential to improve the efficacy of both free biologic delivery and nanocarrier mediated biologic delivery following MI.
Figure 11 – TANNylation of GFP.
(1.) Mixing green fluorescent protein (GFP) with tannic acid (TA) results in the formation of aggregated nanoparticles that (2.) have the ability to bind to the ECM without binding to glycocalyx located in systemic vasculature. Reprinted from [70]. Copyright (2018) Nature.
Targeting biomolecules that increase following infarction, such as fibrin [240], was recently demonstrated to be a similarly viable approach to improve infarct targeting. The authors of this study complexed CREKA, a peptide that binds to clots through fibrin interactions, to PEG-PLA NP containing thymosin beta 4 (Tβ4). Tβ4 is a therapeutic peptide that confers a myriad of benefits following MI [170]. Systemic administration of these fibrin targeting NP loaded with a fluorophore indicated improved cardiac retention though there was similar clearance and accumulation in the liver and spleen [170]. The administration of these NP in a mouse model of MI significantly improved EF, FS, and LV wall thickness while reducing the total infarct size four weeks after administration relative to NP without CREKA targeting, Tβ4 alone, or PBS controls [170].
In summary, the chemical modification or coating of biologics with molecules that can afford greater targeting and retention in the infarct can afford significant benefit. Passive or non-destructive methods of accomplishing this, such as the use of intermolecular interactions, is the simplest approach and should be considered first prior to exploring more permanent modifications that may cause changes in receptor binding. Regardless, utilization of these methods can either omit the need for a delivery system or significantly improve the effectiveness of an existing system.
4.1.2. Enzymatic gated targeting
Increased enzymatic activity specific to the infarct microenvironment can also be used to facilitate localized delivery. MMP expression is significantly upregulated in the infarct microenvironment following MI and throughout the repair process [289]. Many reports have described capitalizing on this approach to enable localized, responsive delivery [107, 128, 195]. A novel approach is to take advantage of MMP expression to facilitate improved targeting of systemic therapies. One such example involved the development of a novel method to make adeno-associated virus serotype 2 (AAV2) functional only in the presence of MMPs [290] [see Figure 10]. The virus’ cell-binding domain was modified to include MMP-cleavable sequences acting as “locks” that upon cleavage would allow the virus to bind and transfect cells locally [290]. Following successful in vitro testing with AAV2, a significantly less immunogenic and easier to produce version of the virus, AAV9, was similarly modified and administered to a mouse model of MI [95]. This was the first demonstration of this approach in-vivo and delivery of MMP-AAV9 encoding infrared fluorescent protein (iRFP) indicated significantly reduced expression of iRFP in the liver, kidneys, and lungs relative to AAV9 control while the brain, spleen, and muscles did not show statistically significant improvements [95]. The study did not trial MMP-AAV9 encoding any beneficial factor to address MI pathology and so further research is merited to verify the ability to treat MI pathophysiology. However, the successful translation of this approach to multiple viral serotypes demonstrates the potential to develop highly tailored viral carriers for specific targeting of tissues. Continuing, a similar study reported the creation of a NP system that reacts with MMP to increase tissue retention. The technology described in these experiments is a novel type of micelle constructed from polymer amphiphiles on a polynorbornene backbone expressing MMP degradable peptide sequences. Upon MMP cleavage of the peptide sequences, the micelle disassembles into a cross-linked scaffold significantly enhancing tissue retention and facilitating the diffusion-controlled release of encapsulated biologics [234].
In comparison to using molecular interactions or ligands to target specific tissues, this approach may be less specific. MMP enzymes upregulated in the infarcted myocardium are present in other tissues undergoing remodeling or following exercise [291-293], increasing the potential for off-target delivery. MMP activity is also transient in the infarct limiting the window that enzyme gated targeting could be employed. More appropriate enzymes to use may be those upregulated during later stages of the disease such as lysyl oxidases [294], that are responsible for collagen cross-linking, may be more suitable for repeated or subsequent dosing.
4.2. Encapsulation using electrostatic interactions
Utilizing biologics’ electrostatic interactions with polymeric delivery systems is an emerging approach used to modulate release [295, 296] and can facilitate solvent-free encapsulation [297, 298]. Technologies that utilize electrostatic encapsulation, such as LbL [52, 297], can even facilitate encapsulation of multiple factors [299], which is necessary to address multiple pathologies associated with MI. Also, utilizing electrostatic interactions to encapsulate biologics follows the endogenous storage of GFs.
4.2.1. ECM-mimetic encapsulation
Materials that mimic ECM properties can enhance biologic loading and provide a tool to control release. GFs do not exist as free entities in the tissues but are rather electrostatically bound to heparan-sulfate found in ECM [300-302]. This relationship creates a naturally occurring delivery depot that can respond to ECM damage or degradation during tissue damage, inflammation, or ECM remodeling [68]. Injection of heparinized hydrogels or coacervates can mimic these natural depots translating to significantly improved encapsulation efficiency and control release of GFs [64, 68]. Coacervates are phase partitions created by electrostatic charge interactions between soluble molecules; upon interaction, the solubility decreases, creating phase partitions encapsulating solvated or bound biologics [303]. One report of protein encapsulation using coacervates detailed the use of polypeptides with opposite charge – poly(L-lysine) and poly(D/L-glutamic acid) – to encapsulate bovine serum albumin (BSA). The study reported that encapsulation efficiency could be directly controlled by the ratio of polypeptide to protein reporting nearly 100% encapsulation for 0.05 (BSA:polypeptide) [249]. Coacervates can also be designed specifically for GF delivery by exploiting their natural propensity to bind to heparin, which is a more commonly used analogue of heparan-sulfate. This is done by complexing heparin to a polycation linking molecule [303]. The binding affinity of the biologic to heparin or the polycation linker can modulate release to occur through diffusion, be erosion controlled, or require enzymatic degradation (e.g. heparinase, esterase) [303]. One such example employed a heparin-based coacervate to encapsulate and release PDGF in tandem with VEGF (see Figure 12A) [64]. The PDGF coacervate loading efficiency was reported to be 97%, in which 100 ng of PDGF were added during fabrication [64]. This study’s authors also previously reported similar results with VEGF & HGF [304]. Their later study with SDF-1α & FGF-2 [68] encapsulation within a heparinized coacervate significantly extended release duration due to increased heparin binding affinity.
Figure 12 – Encapsulation and release of VEGF and PDGF from a coacervate & hydrogel system.
(A) Conceptual diagram detailing how PDGF and VEGF were encapsulated in the delivery system. (B) Cumulative release of VEGF and PDGF, in which the loading efficiency was 87% and 97%, respectively, for 100 ng attempted encapsulation. Reprinted from [64]. Copyright (2015) with permission from Elsevier.
Continuing, while VEGF and PDGF would typically have an antagonistic effect on angiogenesis induction, VEGF was encapsulated within a fibrin hydrogel to facilitate quick (5-7 days) release, while PDGF was encapsulated into the coacervate to enable longer release (>20 days). In this way, they could allow for temporal dissociation of the two factors (see Figure 12B) [64]. This ratio of VEGF:PDGF release was sufficient to mitigate antagonistic as determined by aortic sprouting experiments ex vivo [64]. This combinatory approach resulted in significantly reduced infarction size, improved ventricular wall thickness, and improved arteriogenesis relative to vehicle control or free GFs [64]. However, this study lacked experimental groups employing VEGF fibrin gel alone or PDGF coacervate in unloaded fibrin gel which would be needed to verify that there was indeed synergistic effects.
In addition to heparinized coacervates, ECM-derived hydrogels, which express large quantities of sulfated glycosaminoglycans, can facilitate improved encapsulation and retention of growth factors. For example, a decellularized ECM hydrogel was employed to enhance HGF encapsulation and release resulting in significantly reduced burst release as compared to a collagen hydrogel [76]. Release from the ECM-derived hydrogel was also more resistant to the addition of collagenase, which is beneficial following MI as remodeling enzymes like collagenase or MMP are upregulated and can accelerate biologic release rate. This system was then applied in a rat model of MI, resulting in improved EF and capillary/arteriole density relative to controls, but reduced efficacy toward reduction of fibrosis relative to vehicle or factor control [76]. Another study employed a thermoresponsive hydrogel that contained negatively sulfonated groups to facilitate encapsulation of positively charged proteins, IL-10 and VEGF [65]. Both VEGF and IL-10 have a strong binding affinity for heparin [300-302] and as a result interact strongly with the sulfonated groups in the hydrogel modulating release and loading. This hydrogel was combined with micelles encapsulating PDGF. This created a delivery system that provides a burst release of VEGF and IL-10, followed by sustained release, and in tandem sustained release of PDGF [65]. Together, this approach significantly improved angiogenesis, as measured by increased CD31+ and α-SMA+ cells and reduced infiltrating CD68+ macrophages at day 21 relative to controls [65].
ECM-mimetic encapsulation strategies are one of the most rationally designed approaches to enhance encapsulation of biomolecules and will likely become an emerging standard. These systems are inherently biocompatible or biodegradable without eliciting an immune response or other adverse reactions. In regard to growth factors and other cytokines that readily bind to the ECM, it makes perfect sense to develop sustained release systems that capitalize on these interactions. Methods to modify the interaction strength are straightforward and do not require alteration of the encapsulated biologic providing more approachable and robust strategies to enhance loading into delivery systems. The current drawback, however, is that loading occurs passively through surface binding, which is an equilibrium adsorption process. Increasing the loading density requires either stronger interactions between the delivery system and biologic or higher concentrations of the biologic in the bulk fluid. The former will prevent desorption from the delivery system causing significantly diminished or lagged release while the latter increases waste.
4.2.2. Manipulation of peptide charge interactions
Multidomain peptides (MDPs), another system that can facilitate electrostatic encapsulation, express multiple features – hydrophilic, hydrophobic, charged, etc. – that work in concert to assemble a matrix based on the interactions of these forces. For example, hydrogen bonding between domains with opposite charge – the balance of attractive and repulsive forces determines the structure’s strength. MDPs can form hydrogels through hydrophilic domain entanglement and they can become shear thinning (facilitating injection) through non-covalent interactions. These structures can electrostatically load and control the release rate of GFs or charged nanocarriers such as liposomes. Thus, MDPs provide an opportunity to create highly engineered and functionalized delivery systems. One such example reported developing an MDP to degrade in response to MMP and incorporated a fibronectin moiety to enhance infiltration and adhesion of migrating cells while anchoring liposomes containing angiogenic GFs [195]. This MPD could create a depot of biologic, localized to the infarct that could dynamically respond to ECM degrading enzymes. Another MDP system built from a sequence, K(SL)3RG(SL)3KGRGDS, was developed to enhance angiogenesis through the delivery of PLGF-1 [195]. The authors trialed free encapsulation of PLGF-1 within the MDP or the loading of liposomes containing PLGF-1, of which the latter displayed superior performance as measured by increased vessel density and cellular infiltration [195]. This study was employed subcutaneously but the approach and findings could certainly be translated to enhance angiogenesis following MI.
Polypeptides can also be modified to facilitate electrostatic loading to specific substrates. In one example, researchers modified secretoneurin (SN), an angiogenic GF, to contain a thiol residue to facilitate incorporation directly into thiolated chitosan nanoparticles [236]. Modification of SN enabled the GF loaded chitosan NP to resist enzymatic degradation due to disulfide bond formation guarding oxidative reduction [236, 305]. One study took this idea a step further and demonstrated electrostatic, self-assembling polymeric nanocarriers loaded with both pDNA encoding hypoxia inducible VEGF for angiogenesis and SHP-1 siRNA to reduce apoptosis [53]. They electrostatically complexed both siRNA (negatively charged) and pDNA in a two-step process to a cationic, amphiphilic polymer (DA-PEI) (see Figure 13). This combinatorial approach significantly reduced CM apoptosis and infarction size in a rat model of MI relative to controls; demonstrating the synergistic effects of targeting multiple pathways through effective dual delivery [53].
Figure 13 – Electrostatic loading of both siRNA and pDNA using an amphiphilic cationic polymer.
Reprinted from [53]. Copyright (2016) with permission from Elsevier.
Electrostatic loading approaches face similar challenges associated with ECM-mimetic systems such as balancing binding affinity and encapsulation efficiency. The key benefit that these systems provide is a greater degree of flexibility and fidelity in their applications. These systems can facilitate responsive delivery to multiple stimuli including enzyme activity, pH changes, and reactive oxygen species. As a result, it may be possible to design a system that displays binding affinity changes from in vitro loading of biologics to in vivo release. For instance, loading biologics under salt-free conditions into MDP with peptide linkers may be susceptible to osmolyte-induced folding upon application in the body facilitating release. Others have discussed and identified methods of predicting osmolyte-induced folding of proteins and peptides, and interested readers are referred to these publications [306, 307].
4.3. Improvements to uptake and transfection efficiency of nucleic acids
Utilizing receptor/ligands signaling to trigger endocytosis may improve cell or tissue specific uptake of nanocarriers [308, 309]; however, endosomal escape is non-trivial and presents an additional barrier to overcome [310]. Nucleic acids that successfully enter the cytoplasm are typically met with intracellular defenses (e.g. proteosomes, triggered apoptosis) activated in response to foreign RNA or DNA transfection [311]. These defense responses degrade any delivered nucleic acid preventing sustained, altered genetic expression. Thus, improvements to NA delivery that subverts the intracellular immune response, enhances cellular uptake, and facilitates tissue or cell targeting are necessary. The following subtopics highlight advances in nanocarrier technology that address these issues associated with nucleic acid delivery.
4.3.1. Extracellular vesicle mediated enhancement of cellular uptake and transfection
There are a variety of polymeric nanoparticles that have been shown to improve cellular specificity and uptake relative to free Nucleic Acids; however, they lack tissue localization [51]. EVs, naturally derived vesicles secreted by cells, are an alternative nanocarrier that can improve cellular targeting through enhanced uptake [312]. This improved localizing is derived from EVs displaying natural targeting ligands or receptors from their originating cells [103, 313]. MSC-derived EVs are a popular choice for treating MI due to their natural cardioprotective and angiogenic effects in the infarcted heart [314-316]. For instance, one study aimed to utilize MSC derived EV targeting to deliver miRNA-181a [104], a microRNA (Non-coding RNA that regulates transcription) that has been indicated to provide immunoregulatory effects such as DC and Treg polarization through TGF-β signaling pathways [317]. The EVs were generated from cells transfected with lentivirus encoding miRNA-181a in vitro and customized EVs injected following MI resulting in reduced infarct size and improved heart function (see Figure 14) [104]. The beneficial effects resulted from local induction of Tregs, which created a more immunosuppressive environment characterized by increased FoxP3+CD25+ cells expressing IL-10 and decreased local inflammatory cytokines such as IL-6 and TNF-α [104].
Figure 14 – EV delivery of miRNA-181a improves heart function by increasing Foxp3+ Treg cells.
Reprinted from [104]. Copyright (2019) with permission from Elsevier.
Despite their therapeutic potential, EVs remain difficult to fabricate consistently and at large scale. These limitations hamper their translatability to the clinic [318]. However, one group of authors recognized that peripheral blood-derived EVs are relatively abundant and can be harvested from stocks of donated blood potentially addressing the challenge of supply if demonstrated to be efficacious delivery vehicles [103]. These researchers demonstrated that peripheral blood-derived EVs are effective delivery vehicles of miRNA but commented that they lacked specificity requiring local administration [103]. This challenge can be overcome, however, through selective overexpression of targeting ligands that can confer infarct or CM specificity. For example, the application of a lentiviral vector in vitro to cause BMMSCs to overexpress CXCR4 [97]. This enhanced EV uptake by CMs and reduced apoptosis by a factor of 5 relative to normal EVs containing siRNA [97]. Also, lentiviral overexpression of the cTnI ligand on MSC derived EVs loaded with hsa-miR-590-3p greatly improved infarct targeting and transfection [319].
While these studies indicate EVs have significant potential to transform the way that nucleic acids are delivered to the heart, there are still significant hurdles to overcome prior to entry to the clinic. Recent discussion by members of the International Society for Extracellular Vesicles and the Society for Clinical Research and Translation of Extracellular Vesicles identified key areas that require additional development prior to clinical translation [320]. In short, serum free culture conditions, producing cell type, purity, isolation, and production systems are all aspects in need of further development. Characterization and purity assessments are particularly difficult as most methods available today are prohibitively costly, may impair function, or are destructive [321].
4.3.2. Peptide modifications to enhance uptake and nuclear localization
For some small nucleic acids, such as siRNA/shRNA/mRNA, chemical modification can be achieved without altering their effect providing beneficial effects including increased resistance to degradation and improved cell or tissue targeting [318]. Inclusion of hydrophobic groups, such as aromatic rings [105] or cholesterol [56], can improve nucleic acids solubility and facilitate carrier-free diffusion across the cell membrane. In one example, RAGE siRNA was modified to include aromatic rings that encouraged increased trans-membrane delivery through non-endocytic pathways [105] . This increased intracellular delivery and translated to an 85% reduction in RAGE associated inflammatory signaling following intramyocardial injection [105]. Another report devised an injectable and MMP responsive delivery system for cholesterol-modified siRNA to knockdown MMP2 [107]. The inclusion of cholesterol not only facilitated trans-membrane diffusion. It also facilitated siRNA loading into the hydrogel via cholesterol binding to β-cyclodextrin (CD) that was covalently conjugated to hyaluronic acid macromers on the hydrogel backbone (see Figure 15) [107]. This system’s application significantly reduced MMP2 expression translating to increased infarct wall thickness, EF, CO, and SV relative to untreated control [107].
Figure 15 – Modification of siRNA to include a cholesterol molecule can facilitate increased transduction and encapsulation.
An MMP-degradable, hydrazide-modified HA macromer (HA-MMP-HYD) and a cyclodextrin and aldehyde-modified HA macromer (CD-ALD-HA) were combined to form an MMP-2 responsive hydrogel. The CD group provided a binding site for cholesterol, facilitating loading of cholesterol-modified siRNA. The inclusion of this cholesterol group can facilitate improved cell transduction of the nucleic acid. Reprinted from [107]. Copyright (2018) with permission from Elsevier.
In addition to a need to bypass the cell membrane, nucleic acids also require improved nuclear localization and transport, which can be achieved through synthetic modification. While there have been several improvements devised to improve cell targeting and uptake of nanocarriers’ contents to the cytoplasm and their transcription, DNA fragment transport from the cytoplasm to the nucleus efficiency [322]. Free diffusion through nuclear pores can occur for smaller nucleic acids (<40kDa), but larger molecules require nuclear localization signal (NLS) active transporters that are energy intensive [323, 324]. Ultrasound-targeted microbubble destruction (UTMD) of the lipid and subsequent nuclear penetration continues to be a major issue affecting gene transfection bilayer membrane, a novel approach to permeabilize the membrane and enhance nucleic acid transport, releases energy into the cell [85] that could be used to power the NLS active transporters [325]. UTMD functions by utilizing ultrasound to collapse microbubbles, creating localized cavitation areas that form pores in the lipid bilayer of cells facilitating diffusive transport of large molecules, such as polypeptides and pDNA [326]. By conjugating NLS peptides to pDNA for angiopoietin 1, nuclear trafficking and uptake were significantly improved resulting in increased microvessel formation in canine hearts following MI [85].
The critical consideration when altering a peptide is where to make the modification on the peptide backbone and the best way to retain function. These decisions can be non-trivial, and requires analysis of each peptide for advantageous side chains that can be sites for chemical modification but that do not eliminate biological activity. In addition, in order to minimize loss of function, reaction temperature, pH, and solvent interactions, among others, must by stringently controlled during these reactions. Others have recently assembled detailed toolboxes to help researchers select compatible chemistries or identify target sites for modification that readers interested in learning more are referred [281, 327]. Most of these methods, however, result in changes to multiple sites in the peptide increasing the likelihood that peptide function may be lost. Thus, developing new technologies that can provide improved specificity will empower this approach to become more feasible and accessible to researchers. Tools such as CRISPR-Cas9 have been reported to improve the specificity to some degree [328, 329], though this is an active area of research. Regardless, modifying a peptide introduces increased risk and researchers must ultimately decide if the intended modification and its associated risk are more attractive than utilizing highly engineered nanocarriers to facilitate cell uptake and nuclear localization.
4.3.3. Immune evasion
Combating immunogenicity and clearance of delivered nucleic acids through chemical modification or alternative production methods can significantly prolong expression. Delivery of mRNA typically results in fleeting effects due to intracellular defenses evolved to combat viral infection and transcription [330]. Specifically, activation of toll-like receptors 7 or 8 (TLR-7/8) can shutdown cell transcription and induce apoptosis of mRNA targeted cells [311]. Chemical modification can enable immune evasion in addition to facilitate cell membrane diffusion or tissue targeting. Chemically modified RNA, in which nucleotides are changed to synthetic analogues, has emerged in recent years to circumvent these intracellular defenses prolonging the expression of delivered RNA [330]. Delivery of chemically modified RNA results in pulse-like kinetics over 5-7 days in vitro and up to 10 days in vivo [331]. In one study, a modified RNA fragment encoding insulin growth factor 1 (IGF1), an anti-apoptotic growth factor that activates Akt and Erk signaling pathways, was delivered to treat MI [73]. Expression of modRNA-IGF1 and secreted IGF1 was shown to be sustained for 48 hours in vitro [73]. This system’s application in a mouse model of MI significantly reduced caspase-9 while increasing phosphorylated Akt relative to a modified RNA for GFP control [73]. Another study delivered modified RNA to transiently induce CM proliferation in a mouse model following MI to significantly reducing scar size and improving capillary density [98].
Delivery of pDNA poses similar immunogenic challenges as well as common issues associated with production. Bacterial-derived pDNA can cause transcriptional gene silencing, introduce antibiotic-resistant genes, and potentially alter gene expression, and may trigger a pro-inflammatory immune response if pDNA is recognized as foreign, non-self material [92]. Plasmid minicircles (MCs) are an alternative to bacterial derived pDNA that do not contain bacterial components, reducing the potential for immune activation, and MC have significantly reduced potential for transcription errors [332]. Further, MCs have been shown to dramatically enhance and prolong expression relative to standard plasmids [333]. Lui and colleagues [92] applied MC technology to deliver a pro-survival gene, PIM1, which is cardioprotective through involvement in several signaling pathways blocking apoptotic signaling and promoting cell proliferation [334]. Carrier-free MC administration in vitro indicated a 29% transfection efficiency and in vivo delivery of carrier-free MC for PIM1 improved EF as measured by day seven echo but negligible improvements were shown for FS [92].
Creation of chemically modified RNA and pDNA is difficult, however, due to stability issues. Stability concerns and strategies to overcome or avoid them have previously been reviewed [332, 335]. Key takeaways from these discussions are that larger RNA and pDNA structures are more prone to stability issues due to increased potential for direct or inverted repeats or insertion sequences. Additionally, choice of delivery system is an important consideration as it may increase immunogenicity potential or shift the immune system toward a non-desirable response.
4.4. Synergistic biologic delivery
The delivery of multiple biologics can confer additional beneficial effects following MI facilitating several therapeutic targets to be addressed. The approaches that have been reported in the literature will be discussed in this section with a key emphasis placed on the synergistic improvement of progenitor cell engraftment efficacy.
4.4.1. Biopolymeric coating of cells to enhance infarct retention and biologic delivery
Cellular therapies can be enhanced through the application of a biopolymeric coating, which confers several benefits, including improved retention and co-delivery of relevant biologics. Several chemotactic signals (chemokines and ligands) are upregulated within the infarcted heart, including SDF-1α, which signals through the CXCR4 axis [265]. Of interest, MSCs have been shown to readily migrate along SDF-1α concentration gradients to the infarcted heart [60, 68, 75, 78]. One reported approach obtained MSCs and coated the cell surfaces with VEGF through Layer-by-Layer (LbL) self-assembly, a technique in which thin films are deposited using electrostatic charge interactions [336]. VEGF was loaded between deposited layers of gelatin and alginate and the effects of the coating process were characterized in vitro (see Figure 16) [52]. LBL coating of the MSCs reduces the rate that the cells can rearrange their cytoskeleton but does not entirely impair spreading or chemotaxis. The release of VEGF from the coating was quantified indicating a release duration of 9 days, in vitro. The coated MSCs were then injected into the tail vein and successfully trafficked to the infarcted heart resulting in significantly perfused myocardium, vascular density, and engraftment of MSCs within the heart compared to controls [52]. This approach demonstrates the ability to utilize chemotactic cells to direct the delivery of biologics to the infarct. In a parallel study, BMMSCs were coated with a polymerized layer of gelatin and injected directly into the heart following the induction of MI in mice. The coated cells were shown to have significantly improved retention in the infarct due to gelatin’s affinity for ECM proteins and the coating did not alter cell viability or function [337]. While the authors did not load any biologics within this gelatin layer or deliver these cells systemically, this study does indicate that other coatings can be employed to confer additional benefits beyond biologic delivery. Different cell types can also be encapsulated or coated with a biopolymer to enhance tissue retention without impairing function. Specifically, a subset of pro-angiogenic macrophages were encapsulated within alginate and applied in a model of hind-limb ischemia. This treatment enhanced retention and pro-longed angiogenic signaling [338]. While this study did not directly address MI pathology, the induction of angiogenesis to treat tissue ischemia is of interest. Together, adoptive transfer of cell types that display tropism to the infarct or that provide beneficial signaling can be modified with biopolymeric coatings to enhance function, retention, or facilitate the co-delivery of other biologics.
Figure 16. Characterization of LBL-coated MSC function.
(A) Representative SEM images of MSCs (top) and coated MSCs (bottom) for day 1, 3, and 7 of culture. (B). Quantification of cell spreading indicates that LBL MSCs have lagged spreading rate relative to non-coated. (C). LBL coated MSC recruitment in a scratch assay is also lagged relative to non-coated in a scratch test assay. Reprinted from [52]. Copyright (2017) with permission from Elsevier.
While this approach is novel, it can be counterintuitive and, in comparison to other technologies, may not add value. Applying a polymeric or biologic coating to the cell membrane is the exact opposite of current efforts in nanomedicine that aim to apply cell membranes to nanoparticles [339], which are intended to reduce immunogenicity. Thus, this approach has potential to increase the immunogenicity of delivered cells. Further, this field of research is lacking a direct comparison between competing methods to convert cells into biologic delivery systems, such as genetic editing or plasmid insertion. While the latter has its own safety concerns and uncertainty related to the stability and long-term effects of delivering genetically altered cells, it does have the potential for significantly longer therapeutic effects as it is not limited by biologic loading capacity.
4.4.2. Engineering the infarct microenvironment to improve engraftment efficacy
Coupling stem cell delivery with angiogenic, anti-apoptotic, or anti-inflammatory signaling can significantly improve engraftment translating to improved cardiac function following MI. Several challenges must be overcome when transplanting cells, including loss prevention due to migration, poor/ineffective attachment, and induced apoptosis due to local hypoxia or inflammatory signaling [340]. The infarcted heart is inhospitable to transplant stem cells due to significant inflammatory and reactive oxygen signaling from the acute response to hypoxia [341], damaged and actively remodeling ECM [342], and the mechanical force of the contracting heart [343]. Implantable systems can be designed to deliver growth factors and other biologics that direct the local environment to become more hospitable to transplanted cells enhancing engraftment and guiding the repair process [60, 71, 109]. For example, a PLLA mesh with VEGF encapsulated within the polymer strands created a highly porous delivery system that improved cell loading onto its surface[61]. The high porosity of an implanted delivery system is beneficial because effective cell migration is necessary for microvessel and capillary formation during angiogenesis. Another approach co-delivered VEGF and SDF to enhance systemically injected stem cell engraftment in a model of hind-limb ischemia [60]. Concurrent angiogenesis with chemoattraction of stem cells can avoid cell engraftment into hypoxic environments. Alternatively, providing anti-apoptotic signaling can prevent the apoptosis of grafted and surrounding cells. This will effectively buy more time for healing to begin. In one instance, a pro-survival peptide, QHREDGS, was co-delivered with MSCs in a self-assembling peptide [71]. This system demonstrated a 50% reduction in apoptotic cells in vitro and significantly improved EF and FS after MI. Both collagen deposition and infarction size was reduced by ~50% relative to controls [71].
Without question, the use of more advanced engineering approaches to deliver multiple biologics concurrently to address multiple disease targets will confer the greatest benefit. However, this approach is still limited by current controlled release technology, which can be limited in terms of delivering multiple factors each with independently controlled release kinetics. Emerging technology that employs microfluidic assembly of composites, [344] however, may provide the potential to build sustained releasing systems with distinct release profiles for multiple biologics.
5. Challenges and future directions
5.1. Challenges in biologic delivery to the heart
Significant advancements have been made to the way biologic delivery systems are designed and employed for use in cardiac delivery following myocardial infarction, but there are still several challenges. Section 2.3 previously discussed specific challenges and considerations for individual delivery systems in this application. Table 8 summarizes these key challenges and suggests some approaches to overcome them. More broadly, all biologic delivery systems for the treatment of MI share other limitations that have not yet been met.
Table 8:
Biologic delivery system challenges
| Challenges | Affected delivery system | Strategies to overcome |
|---|---|---|
| DDS retention | Microparticles | - Immobilize in injectable or implantable secondary delivery system - Utilize surface coated ligands to bind to ECM |
| Nanocarriers | - Utilize targeting ligands - Employ inhibitory ligands that are cleavable only in the infarct - Utilize surface coated ligands to bind to ECM |
|
| Implantation | Hydrogels | - Employ rapidly gelling formulations - Utilize shear-thinning or thermoresponsive hydrogels |
| Implants | - Minimize sutures - Employ bioadherent films |
|
| Burst release | Hydrogels | - Utilize secondary release system to control release - Provide binding sites on the hydrogel backbone for biologics - Incorporate biologics into the hydrogel crosslinks |
| Nanocarriers | - Select materials with high binding affinity to the biologic - Environmentally gated degradation conditions |
The first, and most stringent, limitation is that the heart has a low tissue volume. Because the heart is composed principally of connective tissue, muscle, and vasculature [345] there is little interstitial space (~15% by mass) for a delivery system to occupy. Biologic delivery systems for cardiac applications should, therefore, be designed to have high vehicle loading. Most delivery systems currently designed for biologic delivery, however, either have relatively low loading due to high void space or, for hydrogels, have a significant portion of available volume occupied by water. For local delivery targets, high loading may not be as critical of a design feature because several biologics such as cytokines and growth factors can elicit a response with very low quantities, typically in the range of picograms. For other applications that do require larger quantities of biologics to create sustained concentration gradients such as chemoattraction of distant cells, this may present more of an issue.
Continuing, several systems employed to act as local delivery depots that also act as fillers or bulking agents to stabilize the infarct are not adequately biomimetic. Systems such as injectable hydrogels or implantable patches significantly minimize LV remodeling and dilation, but they lack the ability to contract similar to the surrounding tissue. Depending on the size of the infarct, this may advance hypertrophy or heart failure because the remaining healthy tissue is attempting to contract but encounters resistance from the injected gel or implanted patch. If new materials could be designed that could contract or have some elastic properties, then LV function could be further improved. Similarly, the degradation of implantable or injectable filler materials needs to be considered. As these materials degrade it would be advantageous to have the size of the infarct minimized. While this will reduce the total LV volume, it would prevent ventricular dilation following clearance of the delivery system, and as a result, may prevent patients from developing heart failure by preventing ventricular dilation.
5.2. Emerging biologic delivery trends
Thus far, this review has focused primarily on biologic delivery trends and advances relative to MI. In this section, however, we explore the field of biologic delivery, in its entirety, to identify emerging trends that have not yet been translated to MI research. We applied our searching methodology with the MI constraint relaxed for two 5-year periods: 2015 – 2019 and 2010 – 2014. We assigned the data gathered for 2010 – 2014 as our baseline for research in this field and compared it to 2015 – 2019 data. Figure 17 displays the output of this work as the percent change during 2015 – 2019 relative to baseline. As expected, all therapeutic targets and delivery systems show increases, yet immunomodulation and hydrogels display the most significant growth relative to the other targets and delivery systems, respectively (see Figure 17A). The underlying reason for the increase in the trend of hydrogel use in regenerative medicine is likely multifaceted. In recent years, several authors have reviewed significant advances in hydrogel technology that afford greater control of physical properties, degradation and release of therapeutics, and formation technologies that can afford enhanced encapsulation of biotherapeutics and/or improved 3D geometry [346, 347]. These advances have positioned hydrogels to become the more dynamic, biocompatible, and robust delivery system in comparison to polymeric implantable materials. Consequently, there has been a concurrent reduction in implant use coupled with the rise of hydrogels for biologic delivery (see Figure 17B), which indicates that more research groups are adopting hydrogels in place of implants across all applications. Hydrogels as a softer material, also can confer mechanical benefits compared to harder materials, such as polymeric implants [348]. Studies employing hydrogels to treat MI will continue to increase as this technology matures and offers improved control over biologic loading & release and mechanical properties. The increase in immunomodulation may be principally associated with researchers aiming to control the immune response to hydrogels or implants (see Figure 17A). Yet, some work is being done to identify the immunomodulatory effects of growth factors and stem cells (see Figure 17C).
Figure 17 – 5-year changes in biologic delivery research:
Chord diagrams displaying the individual changes (ribbons) and their net impact (outer grid) for research conducted in 2015-2019 as compared to the previous 5 year period, 2010-2014. Chords represent the relationship between therapeutic targets and delivery systems (A), delivery systems and biologics (B), and therapeutic target and biologics (C). Individual changes are quantified in the table, in which the cell color, green denotes a gain and red denotes a loss, matches the ribbon color in A-C. (D). Delivery system use has shown a prominent increase in hydrogel usage, more therapies/studies have targeted/explored immunomodulation, and nominal reductions in studies employing nucleic acids has translated to increases in chemokine, growth factor, and stem cell delivery. Data was obtained on Elsevier’s Scopus search engine for dates 1/1/2015 – 5/14/2020, inclusive. Chord diagrams were generated in RStudio version 3.6.1 using the circlize package [356].
Interestingly, immunomodulation displays the largest increase in this field, yet it continues to have a diminished presence in MI research (see Figure 4C). One reason for this may be that there is a paradigm surrounding MI research that the immune response is of interest for only a short duration (0-7 days). After this time other factors, such as infarct size and myofibroblast activation, have a greater influence over the repair and remodeling process. However, it is well known that immune cells continue to shape the remodeling and repair of damaged tissue long after the acute inflammation has been resolved. It is also clear that immune cells have the potential to enhance local regeneration [21, 138, 349]. Therefore, the expansion of immunoengineering research to the infarcted heart will likely be an area of increasing interest. Similarly, our analysis found that chemokines were under-represented in MI research (see Figure 4B), yet the broader field indicates a growing interest (see Figure 17B). It is unclear why chemokines do not show a similar increase to immunomodulation because one growing approach to modulate the immune response is to deliver chemokines that attract regulatory cells to a target tissue [350, 351]. This approach has shown to be beneficial in several disease models including limb transplantation [24], periodontitis [270, 351], and dry-eye disease [271], among others. A potential explanation is that researchers have attributed a duality to the application of chemokines. Under this duality chemokines are a means of inducing repair by the attraction of reparative, pluripotent cell types [60, 68, 75] or instead, chemokines are viewed as a means of addressing diseases characterized by immune dysfunction [271]. However, chemokines are significantly more nuanced as the premier factors used in the body to respond to a variety of stimuli that would be relevant to treating MI, such as angiogenesis [46], immune cell trafficking and function [45], endothelial cell migration [44], and potentially anti-fibrotic signaling [352]. Future research identifying and delivering new chemokines to enhance and direct MI repair and remodeling is merited.
5.3. Synergistic and enhanced delivery systems
Myocardial infarction induces failures of multiple cellular processes that are best controlled by multifunctional delivery systems. Effective treatments should aim to address these issues simultaneously, requiring new methods to deliver multiple factors. A common strategy is to couple angiogenic signaling with chemoattraction of progenitor cells [52, 60, 68, 75] or block CM apoptosis [53, 81]. Researchers employ various methods to accomplish multifactorial delivery, such as tuning the binding strength of encapsulated biologics to a hydrogel backbone [63, 75]. However, combining delivery systems imparts the best effects and most control over release. Specifically, combining hydrogels with nanocarriers to accomplish release at two different time scales is one of the most popular approaches [64, 65, 68]. Not only can these multi-faceted systems facilitate improved control over multifactor release kinetics, but they can also synergistically function to abrogate delivery system disadvantages. Take coacervate nanocarrier embedding into hydrogels, for example [68]. The hydrogel imparts mechanical stability as a bulking agent [107, 130, 185] while preventing the coacervate nanocarrier from washing out in the absence of a targeting or retention ligand. Following similar logic, hydrogel microparticles were created using microfluidics and combined with an injectable hydrogel to enhance retention in the infarct [344]. An alternative approach to improve microparticles was demonstrated recently, in which VEGF-loaded alginate-microspheres were compressed to form an implantable patch secured by a chitosan sheet (see Figure 18) [56]. This approach addressed the potential for washout and allowed microparticles, as a delivery system, to also confer mechanical support akin to hydrogels. Another advance of interest was made at the University of Pittsburgh, in which AAV was encapsulated within an implantable patch composed of electrospun core-sheath fibers [91]. AAV release from these fibers was shown for eight weeks, significantly increasing total transfection in the implanted tissue measured at 12 weeks [91]. Release kinetics and burst were controlled by tuning the polymer properties analogous to the encapsulation of proteins. This approach significantly prevented off-target tissue transfection in the kidneys, liver, lungs, and skeletal muscle.
Figure 18 – Compressed microsphere cardiac patch.
(Top) Conceptual diagram showing the application of a compressed microsphere patch secured by a chitosan sheet. (Bottom) Representative image of a microsphere patch implanted onto a rat heart at day 0 (left) and MRI at day 56 (right). Arrows denote the edges of the patch. Reprinted from [56]. Copyright (2016) with permission from Elsevier.
Delivery systems have also been enhanced to provide additional functions such as responsive delivery. Through the course of this review, several responsive systems have been discussed. These systems can change their chemical structure in response to local stimuli, facilitating the release of encapsulated biologics in targeted tissues. However, a novel approach is to utilize responsive delivery systems to enhance retention or alter physical properties of a delivery system. For example, a novel nanocarrier was designed to unravel into a 3D polymer matrix exhibiting a similar structure to a hydrogel following interaction with MMP [234]. Additional modifications to this delivery system may facilitate this technology to gain the ability to swell in vivo and act as a bulking agent in addition to enhancing retention. Further, if this system can be modified to preferentially “stick” to disassembled carriers, retention may become an autocatalytic process, potentially allowing more extensive networks to form. If both properties can be realized, then a system to locally deliver a hydrogel from systemic, and markedly less invasive, administration could be realized. A technology fitting this description could drastically change the potential of biologic drug delivery to the infarcted heart and potentially facilitate access to patients in the earlier stages of pathology when these therapies can have maximum effect. It will be very exciting to watch as this concept and technology develops.
Another technology that is being evaluated for MI treatment is microneedle arrays (MNAs). While originally developed to enhance transdermal drug delivery and vaccinations [269, 353], MNAs have recently been employed to treat MI [198, 354]. In a study published from North Carolina State University CSCs were attached to an MNA that forms a hydrogel following insertion [198]. This technique facilitated paracrine factors to be released from the CSC reservoir to the infarct and eventual assimilation of the MNA into the myocardium as CSCs migrated and proliferated (see Figure 19). Because paracrine factors were able to diffuse through the MNA, a possible extension of this technology may be to replace the CSCs with microparticles or nanocarriers to enhance their retention and deliver their encapsulated biologic. A recent publication in Science Advances [354] suggested the feasibility of this approach using MNAs coated with an AAV encoding for VEGF (AAV-VEGF) in a Rat model of MI. Delivery of AAV-VEGF displayed a large VEGF burst followed by sustained release of the angiogenic factor over the course of a day as measured by in vitro AAV titer. The prolonged retention and release rate of AAV-VEGF facilitated improved transfection relative to intramyocardial injection controls and displayed significantly improved functional endpoints (EF & FS improvement; ventricular dilation & infarct size reduction) as measured by echocardiogram 28 days following treatment [354]. This example exemplifies this delivery system as an emerging and viable approach for extending release and retention of biologics to the heart. In addition to the paracrine release of biologics coated on or within microneedle tips, an MNA could be designed with a depot connected to the needles. The reservoir would be positioned on the epicardium and release would occur through the needles into the infarcted myocardium. In addition, the reservoir could be designed to be refillable through minimally invasive injection into the delivery system or connection to a subcutaneous portal facilitating longer term therapies with biologics. While not combined with a microneedle array, an epicardial implantable path was recently reported that was designed to be refillable via a subcutaneous portal and it facilitated the repeated injection of progenitor cells [355].
Figure 19 – CSC-loaded microneedle array patch.
An example microneedle array (MNA) swells to form a hydrogel facilitating paracrine factor release to the infarcted tissue and CSC migration. The MNA also acts as a scaffold for the implanted cells. Reprinted from [198]. Copyright (2018) AAAS.
6. Conclusions
Significant strides have been made toward improving the delivery of numerous biologic molecules including polypeptides, nucleic acids, and pluripotent cells. Research being conducted to alleviate the deleterious effects of MI through biologic delivery has considerable range. Still clear trends are present within the ongoing investigations and the novel approaches that may be developed. Of note, existing research appears to be skewed toward canonical MI therapeutic targets such as the induction of angiogenesis, the suppression of fibrotic remodeling, and, to a lesser extent, on-going attempts to employ cellular engineering to regenerate the heart. This research trend may create paradigms within the community and bias new investigators resulting in lagged translation of novel approaches or technologies reported in similar fields. Specifically, publishing trends in the broader field of biologic delivery have displayed a burgeoning area of immunomodulation or immune engineering, yet this treatment modality remains a minority in MI research. Studies seeking to recapitulate the reported benefits of immune approaches for similar disease models likely will begin to gain more traction within the MI research space. In addition, novel approaches to synergistically deliver multiple biologics or to develop advanced delivery systems that exhibit multiple attributes (e.g. cellular scaffold, mechanical support, responsive delivery) are emerging. These systems are necessary to adequately address the numerous treatment modalities required to treat MI in a way that maximizes biologic efficacy, enhances infarct targeting, and provides mechanical support. One may expect to see such novel encapsulation and delivery approaches reported at an increasing rate over the next ten years within this field.
7. Methods
Elsevier’s Scopus search engine was utilized to generate association matrices (Biologics & Target; Biologics & Delivery System; Delivery System & Target) between types of biologics, commonly employed drug delivery systems, and MI therapeutic target.
Keywords:
The search was built by identifying example articles’ keywords that were representative of the delivery system, therapeutic target, biologic employed (Association Indices); or MI, Biologics in general, and Drug delivery systems in general (Search Space). Keywords include, but are not limited to, engineering controlled terms, engineering uncontrolled terms, engineering main heading, EMTREE drug terms, EMTREE medical terms, and MeSH terms. Supplementary Table 3 displays the identified keywords for each association index term. Identified keywords were added to a word bank that was used to generate a word cloud to identify keyword frequency. Commonly occurring words were combined using the AND Boolean operator to develop the searching criteria employed for the Association Indices or Search Space. In the event no commonly occurring words were identified or there were synonyms for a commonly occurring keyword, terms were combined with the OR Boolean operator.
Building the Search:
The search space was defined by applying MI, biologics (general), and drug delivery systems (general) keywords (Key). The search space was then refined through restriction to articles (Doc type “ar”), restriction to publication in the last 5 years (2015 – present), and omission of any articles containing “review” in the title, abstract, or keyword text (Title-Abs-Key). This searching method identified 425 articles (as of 5/14/2020); within these articles, coincidence searches were performed to build the association matrices. The coincidence searches were performed by applying identified keywords for a combination of Association Indices (Key) – e.g. Angiogenesis (Therapeutic Target) and Chemokine (Type of Biologic).
Data Collection and Interpretation:
The number of documents appearing for a given coincidence search was logged into an association matrix. Because the searches did not omit the keywords for the other association indices, coincidence searches are not mutually exclusive. This was necessary because there is inherent overlap within the Association Indices – e.g. angiogenesis can impact remodeling, growth factors can also have chemotactic properties, etc. – and exclusion of terms would prevent the accounting of multifactorial approaches. The goal of this searching approach was not to identify a definitive grouping of articles within the search space but rather identify trends in the ways that researchers are thinking about delivery of biologics to treat MI. For subsequent classification of identified publications, manual categorization was performed in absence of appropriate keywords that could facilitate another level of searching depth. The data collected and their classification is displayed in Supplementary Table 1 & 2.
Generation of Diagrams:
Chord diagrams were developed using R version 3.6.1 and utilizing the “circlize” package created by “Gu, Z. (2014) circlize implements and enhances circular visualization in R. Bioinformatics” [356]. The circlize package creates the chord diagrams from a dataframe matrix input in R. In this graphical illustration, the ribbons display relationships between categories, in which the ribbon thickness indicates relationship strength as measured by frequency or proportion. Sankey diagrams were created using an online interface (sankeymatic.com) that employs D3.js, a JavaScript tool that can facilitate improved visualization of data. Like the chord diagrams, the thickness of ribbons displays quantitative data with the added benefit of multiple layers of data and comparisons.
Supplementary Material
Highlights.
Biologic delivery trends in myocardial infarction research
Scientometric search of literature in the past 5 years by keyword
Combinatorial systems and synergistic delivery identified as emergent approaches
Cardiac research lags regenerative medicine’s recent inclusion of immunomodulation
8. Acknowledgments
Special thanks to Dr. Jason A. Burdick, Robert D. Bent Professor of Bioengineering at the University of Pennsylvania, for helpful review and comments. M. Borrelli is supported by the National Institutes of Health [grant number 5T32HL076124-13]. Dr. Turnquist is supported by the National Institutes of Health [grant numbers R01AR073527, R01HL22489, and R56AI139327].
Abbreviations
- DDS
Drug Delivery System
- EV
Extracellular Vesicle
- MI
Myocardial Infarction
- LV
Left Ventricle
- EF
Ejection Fraction
- FS
Fractional Shortening
- CO
Cardiac Output
- CM
Cardiomyocyte
- RI
Reperfusion Injury
- IABP
Intra-Aortic Balloon Pump
- LVAD
Left Ventricular Assist Device
- ECMO
Extracorporeal Membrane Oxygenation
- CXCR
C-X-C motif receptor
- CCL
C-C motif ligand
- MIF
Macrophage inhibitory factor
- IHC
Immunohisto-chemical
- VEGF
Vascular Endothelial Growth Factor
- PDGF
Platelet Derived Growth Factor
- BFGF/FGF-2
Basic Fibroblast Growth Factor
- ANG
Angiopoietin
- IGF
Insulin-like Growth Factor
- HGF
Hepatocyte Growth Factor
- SDF-1α
Stromal Derived Factor-1α
- pDNA
plasmid DNA
- mRNA
messenger RNA
- miRNA
micro RNA
- siRNA
small interfering RNA
- shRNA
short hairpin RNA
- BMMSCs/MSCs
bone marrow-derived mesenchymal stem cells
- AD-MSCs
adipose-derived mesenchymal stem cells
- CSCs
cardiac stem cells
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
9. References
- [1].Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE, Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment, JACC Cardiovasc Imaging, 4 (2011) 98–108. [DOI] [PubMed] [Google Scholar]
- [2].Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O'Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani E, American Heart Association Council on, C. Prevention Statistics, S. Stroke Statistics, Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association, Circulation, 139 (2019) e56–e528. [DOI] [PubMed] [Google Scholar]
- [3].Hasche ET, Fernandes C, Freedman SB, Jeremy RW, Relation Between Ischemia Time, Infarct Size, and Left Ventricular Function in Humans, Circulation, 92 (1995) 710–719. [DOI] [PubMed] [Google Scholar]
- [4].Yellon DM, Hausenloy DJ, Myocardial reperfusion injury, N N Engl J Med, 357 (2007) 1121–1135. [DOI] [PubMed] [Google Scholar]
- [5].Hirsh J, Guyatt G, Albers GW, Harrington R, Schunemann HJ, Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition), Chest, 133 (2008) 110S–112S. [DOI] [PubMed] [Google Scholar]
- [6].Chatterjee K, Parmley WW, Vasodilator therapy for acute myocardial infarction and chronic congestive heart failure, Journal of the American College of Cardiology, 1 (1983) 133–153. [DOI] [PubMed] [Google Scholar]
- [7].Van De Werf F, Baim DS, Reperfusion for ST-segment elevation myocardial infarction: an overview of current treatment options, Circulation, 105 (2002) 2813–2816. [DOI] [PubMed] [Google Scholar]
- [8].Turner NA, Porter KE, Function and fate of myofibroblasts after myocardial infarction, Fibrogenesis Tissue Repair, 6 (2013) 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Olivetti G, Capasso JM, Meggs LG, Sonnenblick EH, Anversa P, Cellular basis of chronic ventricular remodeling after myocardial infarction in rats, Circ Res, 68 (1991) 856–869. [DOI] [PubMed] [Google Scholar]
- [10].Desmouliere A, Redard M, Darby I, Gabbiani G, Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar, Am J Pathol, 146 (1995) 56–66. [PMC free article] [PubMed] [Google Scholar]
- [11].Burchfield JS, Xie M, Hill JA, Pathological ventricular remodeling: mechanisms: part 1 of 2, Circulation, 128 (2013) 388–400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Brunton LL, A positive feedback loop contributes to the deleterious effects of angiotensin, Proc Natl Acad Sci U S A, 102 (2005) 14483–14484. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Zhang DY, Anderson AS, The sympathetic nervous system and heart failure, Cardiol Clin, 32 (2014) 33–45, vii. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14].O'Gara PT, Kushner FG, Ascheim DD, Casey DE Jr., Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso JE, Tracy CM, Woo YJ, Zhao DX, Force CAT, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, Circulation, 127 (2013) 529–555. [DOI] [PubMed] [Google Scholar]
- [15].Gislason GH, Jacobsen S, Rasmussen JN, Rasmussen S, Buch P, Friberg J, Schramm TK, Abildstrom SZ, Kober L, Madsen M, Torp-Pedersen C, Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction, Circulation, 113 (2006) 2906–2913. [DOI] [PubMed] [Google Scholar]
- [16].Panahi M, Papanikolaou A, Torabi A, Zhang JG, Khan H, Vazir A, Hasham MG, Cleland JGF, Rosenthal NA, Harding SE, Sattler S, Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition, Cardiovasc Res, 114 (2018) 1445–1461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17].Shimada YJ, Passeri JJ, Baggish AL, O'Callaghan C, Lowry PA, Yannekis G, Abbara S, Ghoshhajra BB, Rothman RD, Ho CY, Januzzi JL, Seidman CE, Fifer MA, Effects of losartan on left ventricular hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy, JACC Heart Fail, 1 (2013) 480–487. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Lopez B, Querejeta R, Varo N, Gonzalez A, Larman M, Martinez Ubago JL, Diez J, Usefulness of serum carboxy-terminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihypertensive treatment in hypertensive patients, Circulation, 104 (2001) 286–291. [DOI] [PubMed] [Google Scholar]
- [19].Querejeta R, Lopez B, Gonzalez A, Sanchez E, Larman M, Martinez Ubago JL, Diez J, Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis, Circulation, 110 (2004) 1263–1268. [DOI] [PubMed] [Google Scholar]
- [20].Cahill TJ, Kharbanda RK, Heart failure after myocardial infarction in the era of primary percutaneous coronary intervention: Mechanisms, incidence and identification of patients at risk, World J Cardiol, 9 (2017) 407–415. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Park JE, Barbul A, Understanding the role of immune regulation in wound healing, The American Journal of Surgery, 187 (2004) S11–S16. [DOI] [PubMed] [Google Scholar]
- [22].Venkatesh S, Byrne ME, Peppas NA, Hilt JZ, Applications of biomimetic systems in drug delivery, Expert Opin Drug Deliv, 2 (2005) 1085–1096. [DOI] [PubMed] [Google Scholar]
- [23].Yoo JW, Irvine DJ, Discher DE, Mitragotri S, Bio-inspired, bioengineered and biomimetic drug delivery carriers, Nat Rev Drug Discov, 10 (2011) 521–535. [DOI] [PubMed] [Google Scholar]
- [24].Fisher JD, Zhang W, Balmert SC, Aral AM, Acharya AP, Kulahci Y, Li J, Turnquist HR, Thomson AW, Solari MG, Gorantla VS, Little SR, In situ recruitment of regulatory T cells promotes donor-specific tolerance in vascularized composite allotransplantation, Science Advances, 6 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [25].C.f.B.E.a.R. (CBER), What Are "Biologics" Questions and Answers, U.S. Food & Drug Administration, Center for Biologics Evaluation and Research (CBER). [Google Scholar]
- [26].Curran MA, Montalvo W, Yagita H, Allison JP, PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors, Proc Natl Acad Sci U S A, 107 (2010) 4275–4280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [27].Tanaka T, Hishitani Y, Ogata A, Monoclonal antibodies in rheumatoid arthritis: comparative effectiveness of tocilizumab with tumor necrosis factor inhibitors, Biologics, 8 (2014) 141–153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28].Schweizer D, Serno T, Goepferich A, Controlled release of therapeutic antibody formats, Eur J Pharm Biopharm, 88 (2014) 291–309. [DOI] [PubMed] [Google Scholar]
- [29].McKenzie ME, Gurbel PA, The potential of monoclonal antibodies to reduce reperfusion injury in myocardial infarction, BioDrugs, 15 (2001) 395–404. [DOI] [PubMed] [Google Scholar]
- [30].Buckley LF, Abbate A, Interleukin-1 blockade in cardiovascular diseases: a clinical update, Eur Heart J, 39 (2018) 2063–2069. [DOI] [PubMed] [Google Scholar]
- [31].Carroll MB, Tocilizumab in the treatment of myocardial infarction, Mod Rheumatol, 28 (2018) 733–735. [DOI] [PubMed] [Google Scholar]
- [32].White CM, Therapeutic Potential and Critical Analysis of the PCSK9 Monoclonal Antibodies Evolocumab and Alirocumab, Ann Pharmacother, 49 (2015) 1327–1335. [DOI] [PubMed] [Google Scholar]
- [33].Lencer WI, Blumberg RS, A passionate kiss, then run: exocytosis and recycling of IgG by FcRn, Trends Cell Biol, 15 (2005) 5–9. [DOI] [PubMed] [Google Scholar]
- [34].Khaw B, Antibodies as delivery systems for diagnostic functions, Advanced Drug Delivery Reviews, 37 (1999) 63–80. [DOI] [PubMed] [Google Scholar]
- [35].Lee K, Silva EA, Mooney DJ, Growth factor delivery-based tissue engineering: general approaches and a review of recent developments, J R Soc Interface, 8 (2011) 153–170. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [36].Eppler SM, Combs DL, Henry TD, Lopez JJ, Ellis SG, Yi JH, Annex BH, McCluskey ER, Zioncheck TF, A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans, Clin Pharmacol Ther, 72 (2002) 20–32. [DOI] [PubMed] [Google Scholar]
- [37].Taipale J, Keski-Oja J, Growth factors in the extracellular matrix, FASEB J, 11 (1997) 51–59. [DOI] [PubMed] [Google Scholar]
- [38].Macri L, Silverstein D, Clark RA, Growth factor binding to the pericellular matrix and its importance in tissue engineering, Adv Drug Deliv Rev, 59 (2007) 1366–1381. [DOI] [PubMed] [Google Scholar]
- [39].Uebersax L, Merkle HP, Meinel L, Biopolymer-based growth factor delivery for tissue repair: from natural concepts to engineered systems, Tissue Eng Part B Rev, 15 (2009) 263–289. [DOI] [PubMed] [Google Scholar]
- [40].Epstein SE, Kornowski R, Fuchs S, Dvorak HF, Angiogenesis therapy: amidst the hype, the neglected potential for serious side effects, Circulation, 104 (2001) 115–119. [DOI] [PubMed] [Google Scholar]
- [41].Serrador JM, Nieto M, Sánchez-Madrid F, Cytoskeletal rearrangement during migration and activation of T lymphocytes, Trends in Cell Biology, 9 (1999) 228–233. [DOI] [PubMed] [Google Scholar]
- [42].Zlotnik A, Yoshie O, Chemokines: a new classification system and their role in immunity, Immunity, 12 (2000) 121–127. [DOI] [PubMed] [Google Scholar]
- [43].Montresor A, Toffali L, Constantin G, Laudanna C, Chemokines and the signaling modules regulating integrin affinity, Front Immunol, 3 (2012) 127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [44].Speyer CL, Ward PA, Role of endothelial chemokines and their receptors during inflammation, J Invest Surg, 24 (2011) 18–27. [DOI] [PubMed] [Google Scholar]
- [45].Luther SA, Cyster JG, Chemokines as regulators of T cell differentiation, Nat Immunol, 2 (2001) 102–107. [DOI] [PubMed] [Google Scholar]
- [46].Dimberg A, Chemokines in angiogenesis, Curr Top Microbiol Immunol, 341 (2010) 59–80. [DOI] [PubMed] [Google Scholar]
- [47].Ben-Baruch A, The multifaceted roles of chemokines in malignancy, Cancer Metastasis Rev, 25 (2006) 357–371. [DOI] [PubMed] [Google Scholar]
- [48].Johnson ZI, Mahoney C, Heo J, Frankel E, Julian DR, Yates CC, The Role of Chemokines in Fibrotic Dermal Remodeling and Wound Healing, Fibrosis in Disease 2019, pp. 3–24. [Google Scholar]
- [49].Hocking AM, The Role of Chemokines in Mesenchymal Stem Cell Homing to Wounds, Adv Wound Care (New Rochelle), 4 (2015) 623630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [50].Sridharan K, Gogtay NJ, Therapeutic nucleic acids: current clinical status, Br J Clin Pharmacol, 82 (2016) 659–672. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [51].Stewart MP, Lorenz A, Dahlman J, Sahay G, Challenges in carrier-mediated intracellular delivery: moving beyond endosomal barriers, Wiley Interdiscip Rev Nanomed Nanobiotechnol, 8 (2016) 465–478. [DOI] [PubMed] [Google Scholar]
- [52].Liu G, Li L, Huo D, Li Y, Wu Y, Zeng L, Cheng P, Xing M, Zeng W, Zhu C, A VEGF delivery system targeting MI improves angiogenesis and cardiac function based on the tropism of MSCs and layer-by-layer self-assembly, Biomaterials, 127 (2017) 117–131. [DOI] [PubMed] [Google Scholar]
- [53].Kim D, Ku SH, Kim H, Jeong JH, Lee M, Kwon IC, Choi D, Kim SH, Simultaneous regulation of apoptotic gene silencing and angiogenic gene expression for myocardial infarction therapy: Single-carrier delivery of SHP-1 siRNA and VEGF-expressing pDNA, J Control Release, 243 (2016) 182–194. [DOI] [PubMed] [Google Scholar]
- [54].Yang Y, Shi C, Hou X, Zhao Y, Chen B, Tan B, Deng Z, Li Q, Liu J, Xiao Z, Miao Q, Dai J, Modified VEGF targets the ischemic myocardium and promotes functional recovery after myocardial infarction, J Control Release, 213 (2015) 27–35. [DOI] [PubMed] [Google Scholar]
- [55].Oduk Y, Zhu W, Kannappan R, Zhao M, Borovjagin AV, Oparil S, Zhang JJ, VEGF nanoparticles repair the heart after myocardial infarction, Am J Physiol Heart Circ Physiol, 314 (2018) H278–H284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [56].Rodness J, Mihic A, Miyagi Y, Wu J, Weisel RD, Li RK, VEGF-loaded microsphere patch for local protein delivery to the ischemic heart, Acta Biomater, 45 (2016) 169–181. [DOI] [PubMed] [Google Scholar]
- [57].Wang C, Zhang B, Lin Y, Dong Y, Effects of Adenovirus-mediated VEGF165 Gene Therapy on Myocardial Infarction, Ann Clin Lab Sci, 48 (2018) 208–215. [PubMed] [Google Scholar]
- [58].Zhu H, Jiang X, Li X, Hu M, Wan W, Wen Y, He Y, Zheng X, Intramyocardial delivery of VEGF165 via a novel biodegradable hydrogel induces angiogenesis and improves cardiac function after rat myocardial infarction, Heart Vessels, 31 (2016) 963–975. [DOI] [PubMed] [Google Scholar]
- [59].Uitterdijk A, Springeling T, van Kranenburg M, van Duin RW, Krabbendam-Peters I, Gorsse-Bakker C, Sneep S, van Haeren R, Verrijk R, van Geuns RJ, van der Giessen WJ, Markkula T, Duncker DJ, van Beusekom HM, VEGF165A microsphere therapy for myocardial infarction suppresses acute cytokine release and increases microvascular density but does not improve cardiac function, Am J Physiol Heart Circ Physiol, 309 (2015) H396–406. [DOI] [PubMed] [Google Scholar]
- [60].Anderson EM, Kwee BJ, Lewin SA, Raimondo T, Mehta M, Mooney DJ, Local delivery of VEGF and SDF enhances endothelial progenitor cell recruitment and resultant recovery from ischemia, Tissue Eng Part A, 21 (2015) 1217–1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [61].Chung HJ, Kim JT, Kim HJ, Kyung HW, Katila P, Lee JH, Yang TH, Yang YI, Lee SJ, Epicardial delivery of VEGF and cardiac stem cells guided by 3-dimensional PLLA mat enhancing cardiac regeneration and angiogenesis in acute myocardial infarction, J Control Release, 205 (2015) 218–230. [DOI] [PubMed] [Google Scholar]
- [62].Zak MM, Gkontra P, Clemente C, Squadrito ML, Ferrarini A, Mota RA, Oliver E, Rocha S, Aguero J, Vazquez J, De Palma M, Ibanez B, Arroyo AG, Sequential Bone-Marrow Cell Delivery of VEGFA/S1P Improves Vascularization and Limits Adverse Cardiac Remodeling After Myocardial Infarction in Mice, Hum Gene Ther, 30 (2019) 893–905. [DOI] [PubMed] [Google Scholar]
- [63].Rufaihah AJ, Johari NA, Vaibavi SR, Plotkin M, Di Thien DT, Kofidis T, Seliktar D, Dual delivery of VEGF and ANG-1 in ischemic hearts using an injectable hydrogel, Acta Biomater, 48 (2017) 58–67. [DOI] [PubMed] [Google Scholar]
- [64].Awada HK, Johnson NR, Wang Y, Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction, J Control Release, 207 (2015) 7–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [65].Rocker AJ, Lee DJ, Shandas R, Park D, Injectable Polymeric Delivery System for Spatiotemporal and Sequential Release of Therapeutic Proteins To Promote Therapeutic Angiogenesis and Reduce Inflammation, ACS Biomaterials Science & Engineering, 6 (2020) 1217–1227. [DOI] [PubMed] [Google Scholar]
- [66].Tuuminen R, Dashkevich A, Keranen MA, Raissadati A, Krebs R, Jokinen JJ, Arnaudova R, Rouvinen E, Yla-Herttuala S, Nykanen AI, Lemstrom KB, Platelet-derived Growth Factor-B Protects Rat Cardiac Allografts From Ischemia-reperfusion Injury, Transplantation, 100 (2016) 303–313. [DOI] [PubMed] [Google Scholar]
- [67].Pascual-Gil S, Simon-Yarza T, Garbayo E, Prosper F, Blanco-Prieto MJ, Cytokine-loaded PLGA and PEG-PLGA microparticles showed similar heart regeneration in a rat myocardial infarction model, Int J Pharm, 523 (2017) 531–533. [DOI] [PubMed] [Google Scholar]
- [68].Awada HK, Long DW, Wang Z, Hwang MP, Kim K, Wang Y, A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction, Biomaterials, 125 (2017) 65–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [69].Kumagai M, Minakata K, Masumoto H, Yamamoto M, Yonezawa A, Ikeda T, Uehara K, Yamazaki K, Ikeda T, Matsubara K, Yokode M, Shimizu A, Tabata Y, Sakata R, Minatoya K, A therapeutic angiogenesis of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel sheets in a canine chronic myocardial infarction model, Heart Vessels, 33 (2018) 1251–1257. [DOI] [PubMed] [Google Scholar]
- [70].Shin M, Lee HA, Lee M, Shin Y, Song JJ, Kang SW, Nam DH, Jeon EJ, Cho M, Do M, Park S, Lee MS, Jang JH, Cho SW, Kim KS, Lee H, Targeting protein and peptide therapeutics to the heart via tannic acid modification, Nat Biomed Eng, 2 (2018) 304–317. [DOI] [PubMed] [Google Scholar]
- [71].Cai H, Wu FY, Wang QL, Xu P, Mou FF, Shao SJ, Luo ZR, Zhu J, Xuan SS, Lu R, Guo HD, Self-assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction, FASEB J, 33 (2019) 8306–8320. [DOI] [PubMed] [Google Scholar]
- [72].Deng Q, Hu B, Cao S, Song HN, Chen JL, Zhou Q, Improving the efficacy of therapeutic angiogenesis by UTMD-mediated Ang-1 gene delivery to the infarcted myocardium, Int J Mol Med, 36 (2015) 335–344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [73].Huang CL, Leblond AL, Turner EC, Kumar AH, Martin K, Whelan D, O'Sullivan DM, Caplice NM, Synthetic chemically modified mrna-based delivery of cytoprotective factor promotes early cardiomyocyte survival post-acute myocardial infarction, Mol Pharm, 12 (2015) 991–996. [DOI] [PubMed] [Google Scholar]
- [74].Suarez SL, Munoz A, Mitchell A, Braden RL, Luo C, Cochran JR, Almutairi A, Christman KL, Degradable acetalated dextran microparticles for tunable release of an engineered hepatocyte growth factor fragment, ACS Biomater Sci Eng, 2 (2016) 197–204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [75].Steele AN, Paulsen MJ, Wang H, Stapleton LM, Lucian HJ, Eskandari A, Hironaka CE, Farry JM, Baker SW, Thakore AD, Jaatinen KJ, Tada Y, Hollander MJ, Williams KM, Seymour AJ, Totherow KP, Yu AC, Cochran JR, Appel EA, Woo YJ, Multi-phase catheter-injectable hydrogel enables dual-stage protein-engineered cytokine release to mitigate adverse left ventricular remodeling following myocardial infarction in a small animal model and a large animal model, Cytokine, 127 (2020) 154974. [DOI] [PubMed] [Google Scholar]
- [76].Sonnenberg SB, Rane AA, Liu CJ, Rao N, Agmon G, Suarez S, Wang R, Munoz A, Bajaj V, Zhang S, Braden R, Schup-Magoffin PJ, Kwan OL, DeMaria AN, Cochran JR, Christman KL, Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction, Biomaterials, 45 (2015) 56–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [77].Tarzami ST, Cheng R, Miao W, Kitsis RN, Berman JW, Chemokine expression in myocardial ischemia: MIP-2 dependent MCP-1 expression protects cardiomyocytes from cell death, J Mol Cell Cardiol, 34 (2002) 209–221. [DOI] [PubMed] [Google Scholar]
- [78].Zamani M, Prabhakaran MP, Thian ES, Ramakrishna S, Controlled delivery of stromal derived factor-1alpha from poly lactic-co-glycolic acid core-shell particles to recruit mesenchymal stem cells for cardiac regeneration, J Colloid Interface Sci, 451 (2015) 144–152. [DOI] [PubMed] [Google Scholar]
- [79].Kim ND, Luster AD, To B or not to B--that is the question for myocardial infarction, Nat Med, 19 (2013) 1208–1210. [DOI] [PubMed] [Google Scholar]
- [80].van den Borne P, Quax PH, Hoefer IE, Pasterkamp G, The multifaceted functions of CXCL10 in cardiovascular disease, Biomed Res Int, 2014 (2014) 893106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [81].An R, Xi C, Xu J, Liu Y, Zhang S, Wang Y, Hao Y, Sun L, Intramyocardial Injection of Recombinant Adeno-Associated Viral Vector Coexpressing PR39/Adrenomedullin Enhances Angiogenesis and Reduces Apoptosis in a Rat Myocardial Infarction Model, Oxid Med Cell Longev, 2017 (2017) 1271670. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [82].Joki Y, Ohashi K, Yuasa D, Shibata R, Kataoka Y, Kambara T, Uemura Y, Matsuo K, Hayakawa S, Hiramatsu-Ito M, Kanemura N, Ito M, Ogawa H, Daida H, Murohara T, Ouchi N, Neuron-derived neurotrophic factor ameliorates adverse cardiac remodeling after experimental myocardial infarction, Circ Heart Fail, 8 (2015) 342–351. [DOI] [PubMed] [Google Scholar]
- [83].Zhu K, Wu M, Lai H, Guo C, Li J, Wang Y, Chen Y, Wang C, Shi J, Nanoparticle-enhanced generation of gene-transfected mesenchymal stem cells for in vivo cardiac repair, Biomaterials, 74 (2016) 188–199. [DOI] [PubMed] [Google Scholar]
- [84].Liu M, Li W, Wang H, Yin L, Ye B, Tang Y, Huang C, CTRP9 Ameliorates Atrial Inflammation, Fibrosis, and Vulnerability to Atrial Fibrillation in Post-Myocardial Infarction Rats, J Am Heart Assoc, 8 (2019) e013133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [85].Cui J, Deng Q, Zhou Q, Cao S, Jiang N, Wang Y, Chen J, Hu B, Tan T, Enhancement of Angiogenesis by Ultrasound-Targeted Microbubble Destruction Combined with Nuclear Localization Signaling Peptides in Canine Myocardial Infarction, Biomed Res Int, 2017 (2017) 9390565. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [86].Chen L, Zhang Y, Tao L, Yang Z, Wang L, Mesenchymal Stem Cells with eNOS Over-Expression Enhance Cardiac Repair in Rats with Myocardial Infarction, Cardiovasc Drugs Ther, 31 (2017) 9–18. [DOI] [PubMed] [Google Scholar]
- [87].Ishikawa K, Fish K, Aguero J, Yaniz-Galende E, Jeong D, Kho C, Tilemann L, Fish L, Liang L, Eltoukhy AA, Anderson DG, Zsebo K, Costa KD, Hajjar RJ, Stem cell factor gene transfer improves cardiac function after myocardial infarction in swine, Circ Heart Fail, 8 (2015) 167–174. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [88].Katz MG, Gubara SM, Hadas Y, Weber T, Kumar A, Eliyahu E, Bridges CR, Fargnoli AS, Effects of genetic transfection on calcium cycling pathways mediated by double-stranded adeno-associated virus in postinfarction remodeling, J Thorac Cardiovasc Surg, 159 (2020) 1809–1819 e1803. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [89].Fattah C, Nather K, McCarroll CS, Hortigon-Vinagre MP, Zamora V, Flores-Munoz M, McArthur L, Zentilin L, Giacca M, Touyz RM, Smith GL, Loughrey CM, Nicklin SA, Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction, J Am Coll Cardiol, 68 (2016) 2652–2666. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [90].Lee YS, Choi JW, Oh JE, Yun CO, Kim SW, Human relaxin gene expression delivered by bioreducible dendrimer polymer for postinfarct cardiac remodeling in rats, Biomaterials, 97 (2016) 164–175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [91].Gu X, Matsumura Y, Tang Y, Roy S, Hoff R, Wang B, Wagner WR, Sustained viral gene delivery from a micro-fibrous, elastomeric cardiac patch to the ischemic rat heart, Biomaterials, 133 (2017) 132–143. [DOI] [PubMed] [Google Scholar]
- [92].Liu N, Wang BJ, Broughton KM, Alvarez R, Siddiqi S, Loaiza R, Nguyen N, Quijada P, Gude N, Sussman MA, PIM1-minicircle as a therapeutic treatment for myocardial infarction, PLoS One, 12 (2017) e0173963. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [93].Meng X, Li J, Yu M, Yang J, Zheng M, Zhang J, Sun C, Liang H, Liu L, Transplantation of mesenchymal stem cells overexpressing IL10 attenuates cardiac impairments in rats with myocardial infarction, J Cell Physiol, 233 (2018) 587–595. [DOI] [PubMed] [Google Scholar]
- [94].Yin L, Liu MX, Li W, Wang FY, Tang YH, Huang CX, Over-Expression of Inhibitor of Differentiation 2 Attenuates Post-Infarct Cardiac Fibrosis Through Inhibition of TGF-beta1/Smad3/HIF-1alpha/IL-11 Signaling Pathway, Front Pharmacol, 10 (2019) 1349. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [95].Guenther CM, Brun MJ, Bennett AD, Ho ML, Chen W, Zhu B, Lam M, Yamagami M, Kwon S, Bhattacharya N, Sousa D, Evans AC, Voss J, Sevick-Muraca EM, Agbandje-McKenna M, Suh J, Protease-Activatable Adeno-Associated Virus Vector for Gene Delivery to Damaged Heart Tissue, Mol Ther, 27 (2019) 611–622. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [96].Lee S, Lee DH, Park BW, Kim R, Hoang AD, Woo SK, Xiong W, Lee YJ, Ban K, Park HJ, In vivo transduction of ETV2 improves cardiac function and induces vascular regeneration following myocardial infarction, Exp Mol Med, 51 (2019) 1–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [97].Kang K, Ma R, Cai W, Huang W, Paul C, Liang J, Wang Y, Zhao T, Kim HW, Xu M, Millard RW, Wen Z, Wang Y, Exosomes Secreted from CXCR4 Overexpressing Mesenchymal Stem Cells Promote Cardioprotection via Akt Signaling Pathway following Myocardial Infarction, Stem Cells Int, 2015 (2015) 659890. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [98].Magadum A, Singh N, Kurian AA, Sharkar MTK, Chepurko E, Zangi L, Ablation of a Single N-Glycosylation Site in Human FSTL 1 Induces Cardiomyocyte Proliferation and Cardiac Regeneration, Mol Ther Nucleic Acids, 13 (2018) 133–143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [99].Liu X, Liu Z, Chen J, Zhu L, Zhang H, Quan X, Yuan Y, Miao H, Huang B, Dong H, Zhang Z, Pigment Epithelium-Derived Factor Increases Native Collateral Blood Flow to Improve Cardiac Function and Induce Ventricular Remodeling After Acute Myocardial Infarction, J Am Heart Assoc, 8 (2019) e013323. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [100].Ma T, Chen Y, Chen Y, Meng Q, Sun J, Shao L, Yu Y, Huang H, Hu Y, Yang Z, Yang J, Shen Z, MicroRNA-132, Delivered by Mesenchymal Stem Cell-Derived Exosomes, Promote Angiogenesis in Myocardial Infarction, Stem Cells Int, 2018 (2018) 3290372. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [101].Yang J, Brown ME, Zhang H, Martinez M, Zhao Z, Bhutani S, Yin S, Trac D, Xi JJ, Davis ME, High-throughput screening identifies microRNAs that target Nox2 and improve function after acute myocardial infarction, Am J Physiol Heart Circ Physiol, 312 (2017) H1002–H1012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [102].Wang Y, Jin B, Chen Q, Yan B, Liu Z, MicroRNA-29b upregulation improves myocardial fibrosis and cardiac function in myocardial infarction rats through targeting SH2B3, European review for medical and pharmacological sciences, 23 (2019) 10115–10122. [DOI] [PubMed] [Google Scholar]
- [103].Kang JY, Park H, Kim H, Mun D, Park H, Yun N, Joung B, Human peripheral bloodderived exosomes for microRNA delivery, Int J Mol Med, 43 (2019) 2319–2328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [104].Wei Z, Qiao S, Zhao J, Liu Y, Li Q, Wei Z, Dai Q, Kang L, Xu B, miRNA-181a over-expression in mesenchymal stem cell-derived exosomes influenced inflammatory response after myocardial ischemia-reperfusion injury, Life Sci, 232 (2019) 116632. [DOI] [PubMed] [Google Scholar]
- [105].Liang Q, Li F, Li Y, Liu Y, Lan M, Wu S, Wu X, Ji Y, Zhang R, Yin L, Self-assisted membrane-penetrating helical polypeptides mediate anti-inflammatory RNAi against myocardial ischemic reperfusion (IR) injury, Biomater Sci, 7 (2019) 3717–3728. [DOI] [PubMed] [Google Scholar]
- [106].Ku SH, Hong J, Moon HH, Jeong JH, Mok H, Park S, Choi D, Kim SH, Deoxycholic acid-modified polyethylenimine based nanocarriers for RAGE siRNA therapy in acute myocardial infarction, Arch Pharm Res, 38 (2015) 1317–1324. [DOI] [PubMed] [Google Scholar]
- [107].Wang LL, Chung JJ, Li EC, Uman S, Atluri P, Burdick JA, Injectable and protease-degradable hydrogel for siRNA sequestration and triggered delivery to the heart, J Control Release, 285 (2018) 152–161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [108].Xu S, Xu Y, Cheng X, Huang C, Pan Y, Jin S, Xiong W, Zhang L, He S, Zhang Y, Inhibition of DRG-TRPV1 upregulation in myocardial ischemia contributes to exogenous cardioprotection, J Mol Cell Cardiol, 138 (2020) 175–184. [DOI] [PubMed] [Google Scholar]
- [109].Yao X, Liu Y, Gao J, Yang L, Mao D, Stefanitsch C, Li Y, Zhang J, Ou L, Kong D, Zhao Q, Li Z, Nitric oxide releasing hydrogel enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction, Biomaterials, 60 (2015) 130–140. [DOI] [PubMed] [Google Scholar]
- [110].Vunjak-Novakovic G, Tandon N, Godier A, Maidhof R, Marsano A, Martens TP, Radisic M, Challenges in cardiac tissue engineering, Tissue Eng Part B Rev, 16 (2010) 169–187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [111].Zebrowski DC, Vergarajauregui S, Wu CC, Piatkowski T, Becker R, Leone M, Hirth S, Ricciardi F, Falk N, Giessl A, Just S, Braun T, Weidinger G, Engel FB, Developmental alterations in centrosome integrity contribute to the post-mitotic state of mammalian cardiomyocytes, Elife, 4 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [112].Burchfield JS, Dimmeler S, Role of paracrine factors in stem and progenitor cell mediated cardiac repair and tissue fibrosis, Fibrogenesis Tissue Repair, 1 (2008) 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [113].Epstein JA, A Time to Press Reset and Regenerate Cardiac Stem Cell Biology, JAMA Cardiol, 4 (2019) 95–96. [DOI] [PubMed] [Google Scholar]
- [114].George JC, Stem cell therapy in acute myocardial infarction: a review of clinical trials, Transl Res, 155 (2010) 10–19. [DOI] [PubMed] [Google Scholar]
- [115].Kolata G, Harvard calls for retraction of dozens of studies by noted cardiac researcher, New York Times, 2018. [Google Scholar]
- [116].Kaiser J, Suspect science leads to pause in stem cell trial, Science, 362 (2018) 513. [DOI] [PubMed] [Google Scholar]
- [117].Chen CW, Wang LL, Zaman S, Gordon J, Arisi MF, Venkataraman CM, Chung JJ, Hung G, Gaffey AC, Spruce LA, Fazelinia H, Gorman RC, Seeholzer SH, Burdick JA, Atluri P, Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction, Cardiovasc Res, 114 (2018) 1029–1040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [118].Robich MP, Chu LM, Oyamada S, Sodha NR, Sellke FW, Myocardial therapeutic angiogenesis: a review of the state of development and future obstacles, Expert Rev Cardiovasc Ther, 9 (2011) 1469–1479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [119].Fan Z, Guan J, Antifibrotic therapies to control cardiac fibrosis, Biomater Res, 20 (2016) 13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [120].Ahmed Z, Bicknell R, Angiogenic signalling pathways, Methods Mol Biol, 467 (2009) 3–24. [DOI] [PubMed] [Google Scholar]
- [121].Yokoyama M, Hirase T, Harmonic interplay of angiogenic growth factors in the development of coronary blood vessels, Circ Res, 88 (2001) 1099–1101. [DOI] [PubMed] [Google Scholar]
- [122].Lugano R, Ramachandran M, Dimberg A, Tumor angiogenesis: causes, consequences, challenges and opportunities, Cell Mol Life Sci, 77 (2020) 1745–1770. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [123].Gerber HP, Condorelli F, Park J, Ferrara N, Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia, J Biol Chem, 272 (1997) 23659–23667. [DOI] [PubMed] [Google Scholar]
- [124].Gerhardt H, VEGF and Endothelial Guidance in Angiogenic Sprouting, 2000–2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [125].Brakenhielm E, Alitalo K, Cardiac lymphatics in health and disease, Nat Rev Cardiol, 16 (2019) 56–68. [DOI] [PubMed] [Google Scholar]
- [126].Henri O, Pouehe C, Houssari M, Galas L, Nicol L, Edwards-Levy F, Henry JP, Dumesnil A, Boukhalfa I, Banquet S, Schapman D, Thuillez C, Richard V, Mulder P, Brakenhielm E, Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction, Circulation, 133 (2016) 1484–1497; discussion 1497. [DOI] [PubMed] [Google Scholar]
- [127].Hinderer S, Schenke-Layland K, Cardiac fibrosis - A short review of causes and therapeutic strategies, Adv Drug Deliv Rev, 146 (2019) 77–82. [DOI] [PubMed] [Google Scholar]
- [128].Fan Z, Fu M, Xu Z, Zhang B, Li Z, Li H, Zhou X, Liu X, Duan Y, Lin PH, Duann P, Xie X, Ma J, Liu Z, Guan J, Sustained Release of a Peptide-Based Matrix Metalloproteinase-2 Inhibitor to Attenuate Adverse Cardiac Remodeling and Improve Cardiac Function Following Myocardial Infarction, Biomacromolecules, 18 (2017) 2820–2829. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [129].Rodell CB, Lee ME, Wang H, Takebayashi S, Takayama T, Kawamura T, Arkles JS, Dusaj NN, Dorsey SM, Witschey WR, Pilla JJ, Gorman JH 3rd, Wenk JF, Burdick JA, Gorman RC, Injectable Shear-Thinning Hydrogels for Minimally Invasive Delivery to Infarcted Myocardium to Limit Left Ventricular Remodeling, Circ Cardiovasc Interv, 9 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [130].Herum KM, Choppe J, Kumar A, Engler AJ, McCulloch AD, Mechanical regulation of cardiac fibroblast profibrotic phenotypes, Mol Biol Cell, 28 (2017) 1871–1882. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [131].Eckhouse SR, Purcell BP, McGarvey JR, Lobb D, Logdon CB, Doviak H, O'Neill JW, Shuman JA, Novack CP, Zellars KN, Pettaway S, Black RA, Khakoo A, Lee T, Mukherjee R, Gorman JH, Gorman RC, Burdick JA, Spinale FG, Local hydrogel release of recombinant TIMP-3 attenuates adverse left ventricular remodeling after experimental myocardial infarction, Sci Transl Med, 6 (2014) 223ra221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [132].Bombardini T, Myocardial contractility in the echo lab: molecular, cellular and pathophysiological basis, Cardiovasc Ultrasound, 3 (2005) 27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [133].Abraham TP, Laskowski C, Zhan WZ, Belohlavek M, Martin EA, Greenleaf JF, Sieck GC, Myocardial contractility by strain echocardiography: comparison with physiological measurements in an in vitro model, Am J Physiol Heart Circ Physiol, 285 (2003) H2599–2604. [DOI] [PubMed] [Google Scholar]
- [134].Frangogiannis NG, Regulation of the inflammatory response in cardiac repair, Circ Res, 110 (2012) 159–173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [135].Courties G, Moskowitz MA, Nahrendorf M, The innate immune system after ischemic injury: lessons to be learned from the heart and brain, JAMA Neurol, 71 (2014) 233–236. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [136].Farkona S, Diamandis EP, Blasutig IM, Cancer immunotherapy: the beginning of the end of cancer?, BMC Med, 14 (2016) 73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [137].Vishwakarma A, Bhise NS, Evangelista MB, Rouwkema J, Dokmeci MR, Ghaemmaghami AM, Vrana NE, Khademhosseini A, Engineering Immunomodulatory Biomaterials To Tune the Inflammatory Response, Trends Biotechnol, 34 (2016) 470–482. [DOI] [PubMed] [Google Scholar]
- [138].Smits AIPM, Bouten CVC, Tissue engineering meets immunoengineering: Prospective on personalized in situ tissue engineering strategies, Current Opinion in Biomedical Engineering, 6 (2018) 17–26. [Google Scholar]
- [139].Jung M, Ma Y, Iyer RP, DeLeon-Pennell KY, Yabluchanskiy A, Garrett MR, Lindsey ML, IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation, Basic Res Cardiol, 112 (2017) 33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [140].Wang Y, Dembowsky K, Chevalier E, Stuve P, Korf-Klingebiel M, Lochner M, Napp LC, Frank H, Brinkmann E, Kanwischer A, Bauersachs J, Gyongyosi M, Sparwasser T, Wollert KC, C-X-C Motif Chemokine Receptor 4 Blockade Promotes Tissue Repair After Myocardial Infarction by Enhancing Regulatory T Cell Mobilization and Immune-Regulatory Function, Circulation, 139 (2019) 1798–1812. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [141].Gerczuk PZ, Kloner RA, An update on cardioprotection: a review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials, J Am Coll Cardiol, 59 (2012) 969–978. [DOI] [PubMed] [Google Scholar]
- [142].Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Shay CM, Spartano NL, Stokes A, Tirschwell DL, VanWagner LB, Tsao CW, American E Heart Association Council on, C. Prevention Statistics, S. Stroke Statistics, Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association, Circulation, 141 (2020) e485–e507. [DOI] [PubMed] [Google Scholar]
- [143].Tong F, Liu S, Yan B, Li X, Ruan S, Yang S, Endogenous ornithine decarboxylase/polyamine system mediated the antagonist role of insulin/PEG-CMCS preconditioning against heart ischemia/reperfusion injury in diabetes mellitus, Int J Nanomedicine, 13 (2018) 2507–2520. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- [144].Zhang Z, Yao L, Yang J, Wang Z, Du G, PI3K/Akt and HIF1 signaling pathway in hypoxiaischemia (Review), Mol Med Rep, 18 (2018) 3547–3554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [145].Lu Z, Xu S, ERK1/2 MAP kinases in cell survival and apoptosis, IUBMB Life, 58 (2006) 621–631. [DOI] [PubMed] [Google Scholar]
- [146].Steele AN, Cai L, Truong VN, Edwards BB, Goldstone AB, Eskandari A, Mitchell AC, Marquardt LM, Foster AA, Cochran JR, Heilshorn SC, Woo YJ, A novel protein-engineered hepatocyte growth factor analog released via a shear-thinning injectable hydrogel enhances post-infarction ventricular function, Biotechnol Bioeng, 114 (2017) 2379–2389. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [147].Diao L, Meibohm B, Pharmacokinetics and pharmacokinetic-pharmacodynamic correlations of therapeutic peptides, Clin Pharmacokinet, 52 (2013) 855–868. [DOI] [PubMed] [Google Scholar]
- [148].Buganza Tepole A, Kuhl E, Systems-based approaches toward wound healing, Pediatr Res, 73 (2013) 553–563. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [149].Simons M, Bonow RO, Chronos NA, Cohen DJ, Giordano FJ, Hammond HK, Laham RJ, Li W, Pike M, Sellke FW, Stegmann TJ, Udelson JE, Rosengart TK, Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary, Circulation, 102 (2000) E73–86. [DOI] [PubMed] [Google Scholar]
- [150].Li C, Wang J, Wang Y, Gao H, Wei G, Huang Y, Yu H, Gan Y, Wang Y, Mei L, Chen H, Hu H, Zhang Z, Jin Y, Recent progress in drug delivery, Acta Pharm Sin B, 9 (2019) 1145–1162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [151].Hoffman AS, The origins and evolution of "controlled" drug delivery systems, J Control Release, 132 (2008) 153–163. [DOI] [PubMed] [Google Scholar]
- [152].Leong KW, Langer R, Polymeric controlled drug delivery, Advanced Drug Delivery Reviews, 1 (1988) 199–233. [Google Scholar]
- [153].Peppas NA, Historical perspective on advanced drug delivery: how engineering design and mathematical modeling helped the field mature, Adv Drug Deliv Rev, 65 (2013) 5–9. [DOI] [PubMed] [Google Scholar]
- [154].Christian DA, Hunter CA, Particle-mediated delivery of cytokines for immunotherapy, Immunotherapy, 4 (2012) 425–441. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [155].Rasheed T, Nabeel F, Raza A, Bilal M, Iqbal HMN, Biomimetic nanostructures/cues as drug delivery systems: a review, Materials Today Chemistry, 13 (2019) 147–157. [Google Scholar]
- [156].Hu X, Yang G, Chen S, Luo S, Zhang J, Biomimetic and bioinspired strategies for oral drug delivery, Biomater Sci, 8 (2020) 1020–1044. [DOI] [PubMed] [Google Scholar]
- [157].Fernandez-Yague MA, Abbah SA, McNamara L, Zeugolis DI, Pandit A, Biggs MJ, Biomimetic approaches in bone tissue engineering: Integrating biological and physicomechanical strategies, Adv Drug Deliv Rev, 84 (2015) 1–29. [DOI] [PubMed] [Google Scholar]
- [158].Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MDP, Acosta-Torres LS, Diaz-Torres LA, Grillo R, Swamy MK, Sharma S, Habtemariam S, Shin HS, Nano based drug delivery systems: recent developments and future prospects, J Nanobiotechnology, 16 (2018) 71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [159].Yu M, Wu J, Shi J, Farokhzad OC, Nanotechnology for protein delivery: Overview and perspectives, J Control Release, 240 (2016) 24–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [160].Paulis LE, Geelen T, Kuhlmann MT, Coolen BF, Schafers M, Nicolay K, Strijkers GJ, Distribution of lipid-based nanoparticles to infarcted myocardium with potential application for MRI-monitored drug delivery, J Control Release, 162 (2012) 276–285. [DOI] [PubMed] [Google Scholar]
- [161].Chang MY, Yang YJ, Chang CH, Tang AC, Liao WY, Cheng FY, Yeh CS, Lai JJ, Stayton PS, Hsieh PC, Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction, J Control Release, 170 (2013) 287–294. [DOI] [PubMed] [Google Scholar]
- [162].Barua S, Mitragotri S, Challenges associated with Penetration of Nanoparticles across Cell and Tissue Barriers: A Review of Current Status and Future Prospects, Nano Today, 9 (2014) 223–243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [163].Maeda H, Vascular permeability in cancer and infection as related to macromolecular drug delivery, with emphasis on the EPR effect for tumor-selective drug targeting, Proc Jpn Acad Ser B Phys Biol Sci, 88 (2012) 53–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [164].Danhier F, To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?, J Control Release, 244 (2016) 108–121. [DOI] [PubMed] [Google Scholar]
- [165].Wang AZ, EPR or no EPR? The billion-dollar question, Science Translational Medicine, 7 (2015) 294ec112–294ec112. [Google Scholar]
- [166].Dvir T, Bauer M, Schroeder A, Tsui JH, Anderson DG, Langer R, Liao R, Kohane DS, Nanoparticles targeting the infarcted heart, Nano Lett, 11 (2011) 4411–4414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [167].Hamilton A, Biganzoli L, Coleman R, Mauriac L, Hennebert P, Awada A, Nooij M, Beex L, Piccart M, Van Hoorebeeck I, Bruning P, de Valeriola D, EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx, Doxil) at a 6-week interval in patients with metastatic breast cancer. European Organization for Research and Treatment of Cancer, Ann Oncol, 13 (2002) 910–918. [DOI] [PubMed] [Google Scholar]
- [168].Rodriguez PL, Harada T, Christian DA, Pantano DA, Tsai RK, Discher DE, Minimal "Self" peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles, Science, 339 (2013) 971–975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [169].Parodi A, Quattrocchi N, van de Ven AL, Chiappini C, Evangelopoulos M, Martinez JO, Brown BS, Khaled SZ, Yazdi IK, Enzo MV, Isenhart L, Ferrari M, Tasciotti E, Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions, Nat Nanotechnol, 8 (2013) 61–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [170].Huang Z, Song Y, Pang Z, Zhang B, Yang H, Shi H, Chen J, Gong H, Qian J, Ge J, Targeted delivery of thymosin beta 4 to the injured myocardium using CREKA-conjugated nanoparticles, Int J Nanomedicine, 12 (2017) 3023–3036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [171].Siepmann F, Siepmann J, Microparticles Used as Drug Delivery Systems, Springer; (2006). [Google Scholar]
- [172].Hamoudi-Ben Yelles MC, Tran Tan V, Danede F, Willart JF, Siepmann J, PLGA implants: How Poloxamer/PEO addition slows down or accelerates polymer degradation and drug release, J Control Release, 253 (2017) 19–29. [DOI] [PubMed] [Google Scholar]
- [173].Saralidze K, Koole LH, Knetsch MLW, Polymeric Microspheres for Medical Applications, Materials, 3 (2010) 3537–3564. [Google Scholar]
- [174].Nihant N, Schugens C, Grandfils C, Jerome R, Teyssie P, Polylactide microparticles prepared by double emulsion/evaporation technique. I. Effect of primary emulsion stability, Pharm Res, 11 (1994) 1479–1484. [DOI] [PubMed] [Google Scholar]
- [175].Chen JL, Chiang CH, Yeh MK, The mechanism of PLA microparticle formation by water-in-oil-in-water solvent evaporation method, J Microencapsul, 19 (2002) 333–346. [DOI] [PubMed] [Google Scholar]
- [176].Rosca ID, Watari F, Uo M, Microparticle formation and its mechanism in single and double emulsion solvent evaporation, J Control Release, 99 (2004) 271–280. [DOI] [PubMed] [Google Scholar]
- [177].Deshmukh R, Wagh P, Naik J, Solvent evaporation and spray drying technique for micro- and nanospheres/particles preparation: A review, Drying Technology, 34 (2016) 1758–1772. [Google Scholar]
- [178].Li W, Zhang L, Ge X, Xu B, Zhang W, Qu L, Choi CH, Xu J, Zhang A, Lee H, Weitz DA, Microfluidic fabrication of microparticles for biomedical applications, Chem Soc Rev, 47 (2018) 5646–5683. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [179].Champion JA, Walker A, Mitragotri S, Role of particle size in phagocytosis of polymeric microspheres, Pharm Res, 25 (2008) 1815–1821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [180].Champion JA, Mitragotri S, Role of target geometry in phagocytosis, Proc Natl Acad Sci U S A, 103 (2006) 4930–4934. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [181].Natarajan JV, Nugraha C, Ng XW, Venkatraman S, Sustained-release from nanocarriers: a review, J Control Release, 193 (2014) 122–138. [DOI] [PubMed] [Google Scholar]
- [182].Sinha VR, Aggarwal A, Trehan A, Biodegradable PEGylated Microspheres and Nanospheres, American Journal of Drug Delivery, 2 (2004) 157–171. [Google Scholar]
- [183].Balmert SC, Zmolek AC, Glowacki AJ, Knab TD, Rothstein SN, Wokpetah JM, Fedorchak MV, Little SR, Positive Charge of "Sticky" Peptides and Proteins Impedes Release From Negatively Charged PLGA Matrices, J Mater Chem B, 3 (2015) 4723–4734. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [184].Putney SD, Burke PA, Improving protein therapeutics with sustained-release formulations, Nat Biotechnol, 16 (1998) 153–157. [DOI] [PubMed] [Google Scholar]
- [185].Wang H, Rodell CB, Lee ME, Dusaj NN, Gorman JH 3rd, Burdick JA, Gorman RC, Wenk JF, Computational sensitivity investigation of hydrogel injection characteristics for myocardial support, J Biomech, 64 (2017) 231–235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [186].Traverse JH, Henry TD, Dib N, Patel AN, Pepine C, Schaer GL, DeQuach JA, Kinsey AM, Chamberlin P, Christman KL, First-in-Man Study of a Cardiac Extracellular Matrix Hydrogel in Early and Late Myocardial Infarction Patients, JACC Basic Transl Sci, 4 (2019) 659–669. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [187].Frey N, Linke A, Suselbeck T, Muller-Ehmsen J, Vermeersch P, Schoors D, Rosenberg M, Bea F, Tuvia S, Leor J, Intracoronary delivery of injectable bioabsorbable scaffold (IK-5001) to treat left ventricular remodeling after ST-elevation myocardial infarction: a first-inman study, Circ Cardiovasc Interv, 7 (2014) 806–812. [DOI] [PubMed] [Google Scholar]
- [188].Bahram M, Mohseni N, Moghtader M, An Introduction to Hydrogels and Some Recent Applications, Emerging Concepts in Analysis and Applications of Hydrogels, IntechOpen, (2016). [Google Scholar]
- [189].Catoira MC, Fusaro L, Di Francesco D, Ramella M, Boccafoschi F, Overview of natural hydrogels for regenerative medicine applications, J Mater Sci Mater Med, 30 (2019) 115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [190].Samant PP, Prausnitz MR, Mechanisms of sampling interstitial fluid from skin using a microneedle patch, Proc Natl Acad Sci U S A, 115 (2018) 4583–4588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [191].Leor J, Tuvia S, Guetta V, Manczur F, Castel D, Willenz U, Petnehazy O, Landa N, Feinberg MS, Konen E, Goitein O, Tsur-Gang O, Shaul M, Klapper L, Cohen S, Intracoronary injection of in situ forming alginate hydrogel reverses left ventricular remodeling after myocardial infarction in Swine, J Am Coll Cardiol, 54 (2009) 1014–1023. [DOI] [PubMed] [Google Scholar]
- [192].Garbern JC, Minami E, Stayton PS, Murry CE, Delivery of basic fibroblast growth factor with a pH-responsive, injectable hydrogel to improve angiogenesis in infarcted myocardium, Biomaterials, 32 (2011) 2407–2416. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [193].Bao R, Tan B, Liang S, Zhang N, Wang W, Liu W, A pi-pi conjugation-containing soft and conductive injectable polymer hydrogel highly efficiently rebuilds cardiac function after myocardial infarction, Biomaterials, 122 (2017) 63–71. [DOI] [PubMed] [Google Scholar]
- [194].Wu CH, Sun MK, Shieh J, Chen CS, Huang CW, Dai CA, Chang SW, Chen WS, Young TH, Ultrasound-responsive NIPAM-based hydrogels with tunable profile of controlled release of large molecules, Ultrasonics, 83 (2018) 157–163. [DOI] [PubMed] [Google Scholar]
- [195].Wickremasinghe NC, Kumar VA, Shi S, Hartgerink JD, Controlled Angiogenesis in Peptide Nanofiber Composite Hydrogels, ACS Biomater Sci Eng, 1 (2015) 845–854. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [196].Li J, Mooney DJ, Designing hydrogels for controlled drug delivery, Nat Rev Mater, 1 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [197].Kai D, Wang QL, Wang HJ, Prabhakaran MP, Zhang Y, Tan YZ, Ramakrishna S, Stem cell-loaded nanofibrous patch promotes the regeneration of infarcted myocardium with functional improvement in rat model, Acta Biomater, 10 (2014) 2727–2738. [DOI] [PubMed] [Google Scholar]
- [198].Tang J, Wang J, Huang K, Ye Y, Su T, Qiao L, Hensley MT, Caranasos TG, Zhang J, Gu Z, Cheng K, Cardiac cell-integrated microneedle patch for treating myocardial infarction, Sci Adv, 4 (2018) eaat9365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [199].Lam MT, Wu JC, Biomaterial applications in cardiovascular tissue repair and regeneration, Expert Rev Cardiovasc Ther, 10 (2012) 1039–1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [200].American Heart Association, Cardiac Procedures and Surgeries. (https://www.heart.org/en/health-topics/heart-attack/treatment-of-a-heart-attack/cardiac-procedures-and-surgeries) accessed 6/4/2020).
- [201].San Bok J, Lee GD, Kim DK, Lim D, Joo SK, Choi S, Changes of pleural pressure after thoracic surgery, J Thorac Dis, 10 (2018) 4109–4117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [202].Habib RH, Zacharias A, Engoren M, Determinants of prolonged mechanical ventilation after coronary artery bypass grafting, The Annals of Thoracic Surgery, 62 (1996) 1164–1171. [DOI] [PubMed] [Google Scholar]
- [203].Mack M, Acuff T, Yong P, Jett G, Carter D, Minimally invasive thoracoscopically assisted coronary artery bypass surgery, European Journal of Cardio-Thoracic Surgery, 12 (1997) 20–24. [DOI] [PubMed] [Google Scholar]
- [204].Jutley RS, Waller DA, Loke I, Skehan D, Ng A, Stafford P, Chin D, Spyt TJ, Video-assisted thoracoscopic implantation of the left ventricular pacing lead for cardiac resynchronization therapy, Pacing Clin Electrophysiol, 31 (2008) 812–818. [DOI] [PubMed] [Google Scholar]
- [205].Kawel N, Turkbey EB, Carr JJ, Eng J, Gomes AS, Hundley WG, Johnson C, Masri SC, Prince MR, van der Geest RJ, Lima JA, Bluemke DA, Normal left ventricular myocardial thickness for middle-aged and older subjects with steady-state free precession cardiac magnetic resonance: the multi-ethnic study of atherosclerosis, Circ Cardiovasc Imaging, 5 (2012) 500–508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [206].Gyongyosi M, Pavo N, Lukovic D, Zlabinger K, Spannbauer A, Traxler D, Goliasch G, Mandic L, Bergler-Klein J, Gugerell A, Jakab A, Szankai Z, Toth L, Garamvolgyi R, Maurer G, Jaisser F, Zannad F, Thum T, Batkai S, Winkler J, Porcine model of progressive cardiac hypertrophy and fibrosis with secondary postcapillary pulmonary hypertension, J Transl Med, 15 (2017) 202. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [207].Mehlman E, Bright JM, Jeckel K, Porsche C, Veeramachaneni DN, Frye M, Echocardiographic evidence of left ventricular hypertrophy in obese dogs, J Vet Intern Med, 27 (2013) 62–68. [DOI] [PubMed] [Google Scholar]
- [208].McAdams RM, McPherson RJ, Dabestani NM, Gleason CA, Juul SE, Left ventricular hypertrophy is prevalent in Sprague-Dawley rats, Comp Med, 60 (2010) 357–363. [PMC free article] [PubMed] [Google Scholar]
- [209].Saito S, Masuda K, Mori Y, Nakatani S, Yoshioka Y, Murase K, Mapping of left ventricle wall thickness in mice using 11.7-T magnetic resonance imaging, Magn Reson Imaging, 36 (2017) 128–134. [DOI] [PubMed] [Google Scholar]
- [210].Filgueira CS, Igo SR, Wang DK, Hirsch M, Schulz DG, Bruckner BA, Grattoni A, Technologies for intrapericardial delivery of therapeutics and cells, Adv Drug Deliv Rev, 151–152 (2019) 222–232. [DOI] [PubMed] [Google Scholar]
- [211].Gao X, Serial echocardiographic assessment of left ventricular dimensions and function after myocardial infarction in mice, Cardiovascular Research, 45 (2000) 330–338. [DOI] [PubMed] [Google Scholar]
- [212].Curaj A, Simsekyilmaz S, Staudt M, Liehn E, Minimal invasive surgical procedure of inducing myocardial infarction in mice, J Vis Exp, (2015) e52197. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [213].Conrad C, Gupta R, Mohan H, Niess H, Bruns CJ, Kopp R, von Luettichau I, Guba M, Heeschen C, Jauch KW, Huss R, Nelson PJ, Genetically engineered stem cells for therapeutic gene delivery, Curr Gene Ther, 7 (2007) 249–260. [DOI] [PubMed] [Google Scholar]
- [214].Mali S, Delivery systems for gene therapy, Indian J Hum Genet, 19 (2013) 3–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [215].Amsbio, Viral Delivery Systems, pp. 1–15. (http://ams-resources.supremeclients.com/Catalog/Viral-Delivery-Systems.pdf)
- [216].Kotterman MA, Chalberg TW, Schaffer DV, Viral Vectors for Gene Therapy: Translational and Clinical Outlook, Annu Rev Biomed Eng, 17 (2015) 63–89. [DOI] [PubMed] [Google Scholar]
- [217].Pack DW, Hoffman AS, Pun S, Stayton PS, Design and development of polymers for gene delivery, Nat Rev Drug Discov, 4 (2005) 581–593. [DOI] [PubMed] [Google Scholar]
- [218].Mintzer MA, Simanek EE, Nonviral vectors for gene delivery, Chem Rev, 109 (2009) 259–302. [DOI] [PubMed] [Google Scholar]
- [219].Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG, Non-viral vectors for gene-based therapy, Nat Rev Genet, 15 (2014) 541–555. [DOI] [PubMed] [Google Scholar]
- [220].Fillmore HL, Shultz MD, Henderson SC, Cooper P, Broaddus WC, Chen ZJ, Shu CY, Zhang J, Ge J, Dorn HC, Corwin F, Hirsch JI, Wilson J, Fatouros PP, Conjugation of functionalized gadolinium metallofullerenes with IL-13 peptides for targeting and imaging glial tumors, Nanomedicine (Lond), 6 (2011) 449–458. [DOI] [PubMed] [Google Scholar]
- [221].Rogers RG, Ciullo A, Marban E, Ibrahim AG, Extracellular Vesicles as Therapeutic Agents for Cardiac Fibrosis, Front Physiol, 11 (2020) 479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [222].Yang L, Zhu J, Zhang C, Wang J, Yue F, Jia X, Liu H, Stem cell-derived extracellular vesicles for myocardial infarction: a meta-analysis of controlled animal studies, Aging (Albany NY), 11 (2019) 1129–1150. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [223].Hinkel R, Lange P, Petersen B, Gottlieb E, Ng JK, Finger S, Horstkotte J, Lee S, Thormann M, Knorr M, El-Aouni C, Boekstegers P, Reichart B, Wenzel P, Niemann H, Kupatt C, Heme Oxygenase-1 Gene Therapy Provides Cardioprotection Via Control of Post-Ischemic Inflammation: An Experimental Study in a Pre-Clinical Pig Model, J Am Coll Cardiol, 66 (2015) 154–165. [DOI] [PubMed] [Google Scholar]
- [224].Yang Y, Yang J, Liu XW, Ding JW, Li S, Guo X, Yang CJ, Fan ZX, Wang HB, Li Q, Wang HM, Yang J, Down-Regulation of miR-327 Alleviates Ischemia/Reperfusion-Induced Myocardial Damage by Targeting RP105, Cell Physiol Biochem, 49 (2018) 1049–1063. [DOI] [PubMed] [Google Scholar]
- [225].Lai NC, Gao MH, Giamouridis D, Suarez J, Miyanohara A, Parikh J, Hightower S, Guo T, Dillmann W, Kim YC, Diaz-Juarez J, Hammond HK, Intravenous AAV8 Encoding Urocortin-2 Increases Function of the Failing Heart in Mice, Hum Gene Ther, 26 (2015) 347–356. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [226].Yang K, Xu C, Zhang Y, He S, Li D, Sestrin2 Suppresses Classically Activated Macrophages-Mediated Inflammatory Response in Myocardial Infarction through Inhibition of mTORC1 Signaling, Front Immunol, 8 (2017) 728. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [227].Tian A, Yang C, Zhu B, Wang W, Liu K, Jiang Y, Qiao Y, Fu H, Li Z, Polyethylene-glycol-coated gold nanoparticles improve cardiac function after myocardial infarction in mice, Can J Physiol Pharmacol, 96 (2018) 1318–1327. [DOI] [PubMed] [Google Scholar]
- [228].Mao S, Wang L, Chen P, Lan Y, Guo R, Zhang M, Nanoparticle-mediated delivery of Tanshinone IIA reduces adverse cardiac remodeling following myocardial infarctions in a mice model: role of NF-kappaB pathway, Artif Cells Nanomed Biotechnol, 46 (2018) S707–S716. [DOI] [PubMed] [Google Scholar]
- [229].Shao M, Yang W, Han G, Protective effects on myocardial infarction model: delivery of schisandrin B using matrix metalloproteinase-sensitive peptide-modified, PEGylated lipid nanoparticles, Int J Nanomedicine, 12 (2017) 7121–7130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [230].Yang MJ, Ku SH, Kim D, Kim WJ, Mok H, Kim SH, Kwon IC, Enhanced Cytoplasmic Delivery of RAGE siRNA Using Bioreducible Polyethylenimine-based Nanocarriers for Myocardial Gene Therapy, Macromol Biosci, 15 (2015) 1755–1763. [DOI] [PubMed] [Google Scholar]
- [231].Solhjou Z, Uehara M, Bahmani B, Maarouf OH, Ichimura T, Brooks CR, Xu W, Yilmaz M, Elkhal A, Tullius SG, Guleria I, McGrath MM, Abdi R, Novel Application of Localized Nanodelivery of Anti-Interleukin-6 Protects Organ Transplant From Ischemia-Reperfusion Injuries, Am J Transplant, 17 (2017) 2326–2337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [232].Fujiwara M, Matoba T, Koga JI, Okahara A, Funamoto D, Nakano K, Tsutsui H, Egashira K, Nanoparticle incorporating Toll-like receptor 4 inhibitor attenuates myocardial ischaemia-reperfusion injury by inhibiting monocyte-mediated inflammation in mice, Cardiovasc Res, 115 (2019) 1244–1255. [DOI] [PubMed] [Google Scholar]
- [233].Ishikita A, Matoba T, Ikeda G, Koga J, Mao Y, Nakano K, Takeuchi O, Sadoshima J, Egashira K, Nanoparticle-Mediated Delivery of Mitochondrial Division Inhibitor 1 to the Myocardium Protects the Heart From Ischemia-Reperfusion Injury Through Inhibition of Mitochondria Outer Membrane Permeabilization: A New Therapeutic Modality for Acute Myocardial Infarction, J Am Heart Assoc, 5 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [234].Nguyen MM, Carlini AS, Chien MP, Sonnenberg S, Luo C, Braden RL, Osborn KG, Li Y, Gianneschi NC, Christman KL, Enzyme-Responsive Nanoparticles for Targeted Accumulation and Prolonged Retention in Heart Tissue after Myocardial Infarction, Adv Mater, 27 (2015) 5547–5552. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [235].Ferreira MPA, Ranjan S, Kinnunen S, Correia A, Talman V, Makila E, Barrios-Lopez B, Kemell M, Balasubramanian V, Salonen J, Hirvonen J, Ruskoaho H, Airaksinen AJ, Santos HA, Drug-Loaded Multifunctional Nanoparticles Targeted to the Endocardial Layer of the Injured Heart Modulate Hypertrophic Signaling, Small, 13 (2017). [DOI] [PubMed] [Google Scholar]
- [236].Albrecht-Schgoer K, Barthelmes J, Schgoer W, Theurl M, Nardin I, Lener D, Gutmann C, Dunnhaupt S, Bernkop-Schnurch A, Kirchmair R, Nanoparticular delivery system for a secretoneurin derivative induces angiogenesis in a hind limb ischemia model, J Control Release, 250 (2017) 1–8. [DOI] [PubMed] [Google Scholar]
- [237].Hao H, Hu S, Chen H, Bu D, Zhu L, Xu C, Chu F, Huo X, Tang Y, Sun X, Ding BS, Liu DP, Hu S, Wang M, Loss of Endothelial CXCR7 Impairs Vascular Homeostasis and Cardiac Remodeling After Myocardial Infarction: Implications for Cardiovascular Drug Discovery, Circulation, 135 (2017) 1253–1264. [DOI] [PubMed] [Google Scholar]
- [238].Wang J, Seo MJ, Deci MB, Weil BR, Canty JM, Nguyen J, Effect of CCR2 inhibitor-loaded lipid micelles on inflammatory cell migration and cardiac function after myocardial infarction, Int J Nanomedicine, 13 (2018) 6441–6451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [239].Varanko A, Saha S, Chilkoti A, Recent trends in protein and peptide-based biomaterials for advanced drug delivery, Advanced Drug Delivery Reviews, (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [240].Jacques E, Hosoyama K, Biniam B, Eren Cimenci C, Sedlakova V, Steeves AJ, Variola F, Davis DR, Stewart DJ, Suuronen EJ, Alarcon EI, Collagen-Based Microcapsules As Therapeutic Materials for Stem Cell Therapies in Infarcted Myocardium, ACS Biomaterials Science & Engineering, (2020). [DOI] [PubMed] [Google Scholar]
- [241].Daly AC, Riley L, Segura T, Burdick JA, Hydrogel microparticles for biomedical applications, Nature Reviews Materials, 5 (2019) 20–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [242].Formiga FR, Garbayo E, Diaz-Herraez P, Abizanda G, Simon-Yarza T, Tamayo E, Prosper F, Blanco-Prieto MJ, Biodegradation and heart retention of polymeric microparticles in a rat model of myocardial ischemia, Eur J Pharm Biopharm, 85 (2013) 665–672. [DOI] [PubMed] [Google Scholar]
- [243].Cannon GJ, Swanson JA, The macrophage capacity for phagocytosis, J Cell Sci, 101 ( Pt 4) (1992) 907–913. [DOI] [PubMed] [Google Scholar]
- [244].Teng CJ, Luo J, Chiu RC, Shum-Tim D, Massive mechanical loss of microspheres with direct intramyocardial injection in the beating heart: implications for cellular cardiomyoplasty, J Thorac Cardiovasc Surg, 132 (2006) 628–632. [DOI] [PubMed] [Google Scholar]
- [245].Gao SQ, Maeda T, Okano K, Palczewski K, A microparticle/hydrogel combination drug-delivery system for sustained release of retinoids, Invest Ophthalmol Vis Sci, 53 (2012) 6314–6323. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [246].Lee J, Lee KY, Local and sustained vascular endothelial growth factor delivery for angiogenesis using an injectable system, Pharm Res, 26 (2009) 1739–1744. [DOI] [PubMed] [Google Scholar]
- [247].Lee J, Bhang SH, Park H, Kim BS, Lee KY, Active blood vessel formation in the ischemic hindlimb mouse model using a microsphere/hydrogel combination system, Pharm Res, 27 (2010) 767–774. [DOI] [PubMed] [Google Scholar]
- [248].Sah H, Stabilization of proteins against methylene chloride/water interface-induced denaturation and aggregation, Journal of Controlled Release, 58 (1999) 143–151. [DOI] [PubMed] [Google Scholar]
- [249].Black KA, Priftis D, Perry SL, Yip J, Byun WY, Tirrell M, Protein Encapsulation via Polypeptide Complex Coacervation, ACS Macro Letters, 3 (2014) 1088–1091. [DOI] [PubMed] [Google Scholar]
- [250].Boopathy AV, Martinez MD, Smith AW, Brown ME, Garcia AJ, Davis ME, Intramyocardial Delivery of Notch Ligand-Containing Hydrogels Improves Cardiac Function and Angiogenesis Following Infarction, Tissue Eng Part A, 21 (2015) 2315–2322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [251].Kim D, Hong J, Moon HH, Nam HY, Mok H, Jeong JH, Kim SW, Choi D, Kim SH, Anti-apoptotic cardioprotective effects of SHP-1 gene silencing against ischemia-reperfusion injury: use of deoxycholic acid-modified low molecular weight polyethyleneimine as a cardiac siRNA-carrier, J Control Release, 168 (2013) 125–134. [DOI] [PubMed] [Google Scholar]
- [252].Huang Q, Zou Y, Arno MC, Chen S, Wang T, Gao J, Dove AP, Du J, Hydrogel scaffolds for differentiation of adipose-derived stem cells, Chem Soc Rev, 46 (2017) 6255–6275. [DOI] [PubMed] [Google Scholar]
- [253].Bahlmann LC, Fokina A, Shoichet MS, Dynamic bioengineered hydrogels as scaffolds for advanced stem cell and organoid culture, MRS Communications, 7 (2017) 472–486. [Google Scholar]
- [254].Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, Ratajczak MZ, Janowska-Wieczorek A, Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases, Stem Cells, 24 (2006) 1254–1264. [DOI] [PubMed] [Google Scholar]
- [255].Lau TT, Wang DA, Stromal cell-derived factor-1 (SDF-1): homing factor for engineered regenerative medicine, Expert Opin Biol Ther, 11 (2011) 189–197. [DOI] [PubMed] [Google Scholar]
- [256].Ullah M, Liu DD, Thakor AS, Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement, iScience, 15 (2019) 421–438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [257].Rocca DG, Willenberg BJ, Qi Y, Simmons CS, Rubiano A, Ferreira LF, Huo T, Petersen JW, Ruchaya PJ, Wate PS, Wise EA, Handberg EM, Cogle CR, Batich CD, Byrne BJ, Pepine CJ, An injectable capillary-like microstructured alginate hydrogel improves left ventricular function after myocardial infarction in rats, Int J Cardiol, 220 (2016) 149–154. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [258].Bayer EA, Jordan J, Roy A, Gottardi R, Fedorchak MV, Kumta PN, Little SR, (*) Programmed Platelet-Derived Growth Factor-BB and Bone Morphogenetic Protein-2 Delivery from a Hybrid Calcium Phosphate/Alginate Scaffold, Tissue Eng Part A, 23 (2017) 1382–1393. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [259].Tengood JE, Ridenour R, Brodsky R, Russell AJ, Little SR, Sequential delivery of basic fibroblast growth factor and platelet-derived growth factor for angiogenesis, Tissue Eng Part A, 17 (2011) 1181–1189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [260].Tengood JE, Kovach KM, Vescovi PE, Russell AJ, Little SR, Sequential delivery of vascular endothelial growth factor and sphingosine 1-phosphate for angiogenesis, Biomaterials, 31 (2010) 7805–7812. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [261].Brudno Y, Ennett-Shepard AB, Chen RR, Aizenberg M, Mooney DJ, Enhancing microvascular formation and vessel maturation through temporal control over multiple pro-angiogenic and pro-maturation factors, Biomaterials, 34 (2013) 9201–9209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [262].Nakamura T, Matsumoto K, Mizuno S, Sawa Y, Matsuda H, Nakamura T, Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyopathic hamster hearts, Am J Physiol Heart Circ Physiol, 288 (2005) H2131–2139. [DOI] [PubMed] [Google Scholar]
- [263].Taniyama Y, Morishita R, Aoki M, Hiraoka K, Yamasaki K, Hashiya N, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T, Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy, Hypertension, 40 (2002) 47–53. [DOI] [PubMed] [Google Scholar]
- [264].Ohashi K, Enomoto T, Joki Y, Shibata R, Ogura Y, Kataoka Y, Shimizu Y, Kambara T, Uemura Y, Yuasa D, Matsuo K, Hayakawa S, Hiramatsu-Ito M, Murohara T, Ouchi N, Neuron-derived neurotrophic factor functions as a novel modulator that enhances endothelial cell function and revascularization processes, J Biol Chem, 289 (2014) 14132–14144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [265].Hu C, Yong X, Li C, Lu M, Liu D, Chen L, Hu J, Teng M, Zhang D, Fan Y, Liang G, CXCL12/CXCR4 axis promotes mesenchymal stem cell mobilization to burn wounds and contributes to wound repair, J Surg Res, 183 (2013) 427–434. [DOI] [PubMed] [Google Scholar]
- [266].Miao C, Lei M, Hu W, Han S, Wang Q, A brief review: the therapeutic potential of bone marrow mesenchymal stem cells in myocardial infarction, Stem Cell Res Ther, 8 (2017) 242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [267].Wojakowski W, Kucia M, Milewski K, Machalinski B, Halasa M, Buszman P, Klimeczek P, Kazmierski M, Pasowicz M, Ratajczak MZ, Tendera M, The role of CXCR4/SDF-1, CD117/SCF, and c-met/HGF chemokine signalling in the mobilization of progenitor cells and the parameters of the left ventricular function, remodelling, and myocardial perfusion following acute myocardial infarction, European Heart Journal Supplements, 10 (2008) K16–K23. [Google Scholar]
- [268].Torrieri G, Fontana F, Figueiredo P, Liu Z, Ferreira MPA, Talman V, Martins JP, Fusciello M, Moslova K, Teesalu T, Cerullo V, Hirvonen J, Ruskoaho H, Balasubramanian V, Santos HA, Dual-peptide functionalized acetalated dextran-based nanoparticles for sequential targeting of macrophages during myocardial infarction, Nanoscale, 12 (2020) 2350–2358. [DOI] [PubMed] [Google Scholar]
- [269].Ong SB, Hernandez-Resendiz S, Crespo-Avilan GE, Mukhametshina RT, Kwek XY, Cabrera-Fuentes HA, Hausenloy DJ, Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities, Pharmacol Ther, 186 (2018) 73–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [270].Glowacki AJ, Yoshizawa S, Jhunjhunwala S, Vieira AE, Garlet GP, Sfeir C, Little SR, Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes, Proc Natl Acad Sci U S A, 110 (2013) 18525–18530. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [271].Ratay ML, Glowacki AJ, Balmert SC, Acharya AP, Polat J, Andrews LP, Fedorchak MV, Schuman JS, Vignali DAA, Little SR, Treg-recruiting microspheres prevent inflammation in a murine model of dry eye disease, J Control Release, 258 (2017) 208–217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [272].Legler DF, Thelen M, New insights in chemokine signaling, F1000Res, 7 (2018) 95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [273].Zhou H, Tan W, Qiu Z, Song Y, Gao S, A bibliometric analysis in gene research of myocardial infarction from 2001 to 2015, PeerJ, 6 (2018) e4354. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [274].Gupta AS, Nanomedicine approaches in vascular disease: a review, Nanomedicine, 7 (2011) 763–779. [DOI] [PubMed] [Google Scholar]
- [275].Saleh B, Dhaliwal HK, Portillo-Lara R, Shirzaei Sani E, Abdi R, Amiji MM, Annabi N, Local Immunomodulation Using an Adhesive Hydrogel Loaded with miRNA-Laden Nanoparticles Promotes Wound Healing, Small, 15 (2019) e1902232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [276].Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH, Multilineage cells from human adipose tissue: implications for cell-based therapies, Tissue Eng, 7 (2001) 211–228. [DOI] [PubMed] [Google Scholar]
- [277].Gimble JM, Katz AJ, Bunnell BA, Adipose-derived stem cells for regenerative medicine, Circ Res, 100 (2007) 1249–1260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [278].Rasmussen JG, Frobert O, Holst-Hansen C, Kastrup J, Baandrup U, Zachar V, Fink T, Simonsen U, Comparison of human adipose-derived stem cells and bone marrow-derived stem cells in a myocardial infarction model, Cell Transplant, 23 (2014) 195–206. [DOI] [PubMed] [Google Scholar]
- [279].Adolfsson E, Helenius G, Friberg O, Samano N, Frobert O, Johansson K, Bone marrow- and adipose tissue-derived mesenchymal stem cells from donors with coronary artery disease; growth, yield, gene expression and the effect of oxygen concentration, Scand J Clin Lab Invest, 80 (2020) 318–326. [DOI] [PubMed] [Google Scholar]
- [280].Raghavan R, Benzaquen BS, Rudski L, Timing of bypass surgery in stable patients after acute myocardial infarction, Canadian Journal of Cardiology, 23 (2007) 976–982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [281].Erak M, Bellmann-Sickert K, Els-Heindl S, Beck-Sickinger AG, Peptide chemistry toolbox - Transforming natural peptides into peptide therapeutics, Bioorg Med Chem, 26 (2018) 2759–2765. [DOI] [PubMed] [Google Scholar]
- [282].Mueller LK, Baumruck AC, Zhdanova H, Tietze AA, Challenges and Perspectives in Chemical Synthesis of Highly Hydrophobic Peptides, Front Bioeng Biotechnol, 8 (2020) 162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [283].Gracia SR, Gaus K, Sewald N, Synthesis of chemically modified bioactive peptides: recent advances, challenges and developments for medicinal chemistry, Future Med Chem, 1 (2009) 1289–1310. [DOI] [PubMed] [Google Scholar]
- [284].Bertinchant JP, Polge A, Juan JM, Oliva-Lauraire MC, Giuliani I, Marty-Double C, Burdy JY, Fabbro-Peray P, Laprade M, Bali JP, Granier C, de la Coussaye JE, Dauzat M, Evaluation of cardiac troponin I and T levels as markers of myocardial damage in doxorubicin-induced cardiomyopathy rats, and their relationship with echocardiographic and histological findings, Clinica Chimica Acta, 329 (2003) 39–51. [DOI] [PubMed] [Google Scholar]
- [285].Kanki S, Jaalouk DE, Lee S, Yu AY, Gannon J, Lee RT, Identification of targeting peptides for ischemic myocardium by in vivo phage display, J Mol Cell Cardiol, 50 (2011) 841–848. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [286].McGuire MJ, Samli KN, Johnston SA, Brown KC, In vitro selection of a peptide with high selectivity for cardiomyocytes in vivo, J Mol Biol, 342 (2004) 171–182. [DOI] [PubMed] [Google Scholar]
- [287].Pelouch V, Dixon IM, Golfman L, Beamish RE, Dhalla NS, Role of extracellular matrix proteins in heart function, Mol Cell Biochem, 129 (1993) 101–120. [DOI] [PubMed] [Google Scholar]
- [288].Torrieri G, Ferreira MP, Shahbazi M-A, Talman V, Carvalho C, Karhu T, Pinto JF, Hirvonen J, Ruskoaho HJ, Balasubramanian V, Santos HA, Abstract 221: Tannic Acid Coated Nanoparticles for Cardiac Regeneration, Circulation Research, 127 (2020). [Google Scholar]
- [289].Creemers EE, Cleutjens JP, Smits JF, Daemen MJ, Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure?, Circ Res, 89 (2001) 201–210. [DOI] [PubMed] [Google Scholar]
- [290].Judd J, Ho ML, Tiwari A, Gomez EJ, Dempsey C, Van Vliet K, Igoshin OA, Silberg JJ, Agbandje-McKenna M, Suh J, Tunable protease-activatable virus nanonodes, ACS Nano, 8 (2014) 4740–4746. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [291].Nyman JS, Lynch CC, Perrien DS, Thiolloy S, O'Quinn EC, Patil CA, Bi X, Pharr GM, Mahadevan-Jansen A, Mundy GR, Differential effects between the loss of MMP-2 and MMP-9 on structural and tissue-level properties of bone, J Bone Miner Res, 26 (2011) 1252–1260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [292].Corbel M, Boichot E, Lagente V, Role of gelatinases MMP-2 and MMP-9 in tissue remodeling following acute lung injury, Braz J Med Biol Res, 33 (2000) 749–754. [DOI] [PubMed] [Google Scholar]
- [293].Nascimento Dda C, Durigan Rde C, Tibana RA, Durigan JL, Navalta JW, Prestes J, The response of matrix metalloproteinase-9 and - 2 to exercise, Sports Med, 45 (2015) 269–278. [DOI] [PubMed] [Google Scholar]
- [294].Gonzalez-Santamaria J, Villalba M, Busnadiego O, Lopez-Olaneta MM, Sandoval P, Snabel J, Lopez-Cabrera M, Erler JT, Hanemaaijer R, Lara-Pezzi E, Rodriguez-Pascual F, Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction, Cardiovasc Res, 109 (2016) 67–78. [DOI] [PubMed] [Google Scholar]
- [295].Mauri E, Chincarini GMF, Rigamonti R, Magagnin L, Sacchetti A, Rossi F, Modulation of electrostatic interactions to improve controlled drug delivery from nanogels, Mater Sci Eng C Mater Biol Appl, 72 (2017) 308–315. [DOI] [PubMed] [Google Scholar]
- [296].Pakulska MM, Elliott Donaghue I, Obermeyer JM, Tuladhar A, McLaughlin CK, Shendruk TN, Shoichet MS, Encapsulation-free controlled release: Electrostatic adsorption eliminates the need for protein encapsulation in PLGA nanoparticles, Sci Adv, 2 (2016) e1600519. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [297].Dobaczewski M, Bujak M, Zymek P, Ren G, Entman ML, Frangogiannis NG, Extracellular matrix remodeling in canine and mouse myocardial infarcts, Cell Tissue Res, 324 (2006) 475–488. [DOI] [PubMed] [Google Scholar]
- [298].Ai H, Jones SA, Lvov YM, Biomedical Applications of Electrostatic Layer-by-Layer Nano-Assembly of Polymers, Enzymes, and Nanoparticles, Cell Biochemistry and Biophysics, 39 (2003) 23–44. [DOI] [PubMed] [Google Scholar]
- [299].Itakura S, Hama S, Matsui R, Kogure K, Effective cytoplasmic release of siRNA from liposomal carriers by controlling the electrostatic interaction of siRNA with a charge-invertible peptide, in response to cytoplasmic pH, Nanoscale, 8 (2016) 10649–10658. [DOI] [PubMed] [Google Scholar]
- [300].Salek-Ardakani S, Arrand JR, Shaw D, Mackett M, Heparin and heparan sulfate bind interleukin-10 and modulate its activity, Blood, 96 (2000) 1879–1888. [PubMed] [Google Scholar]
- [301].Kreuger J, Spillmann D, Li JP, Lindahl U, Interactions between heparan sulfate and proteins: the concept of specificity, J Cell Biol, 174 (2006) 323–327. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [302].Gorsi B, Stringer SE, Tinkering with heparan sulfate sulfation to steer development, Trends Cell Biol, 17 (2007) 173–177. [DOI] [PubMed] [Google Scholar]
- [303].Chu H, Johnson NR, Mason NS, Wang Y, A [polycation:heparin] complex releases growth factors with enhanced bioactivity, J Control Release, 150 (2011) 157–163. [DOI] [PubMed] [Google Scholar]
- [304].Awada HK, Johnson NR, Wang Y, Dual delivery of vascular endothelial growth factor and hepatocyte growth factor coacervate displays strong angiogenic effects, Macromol Biosci, 14 (2014) 679–686. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [305].Dunnhaupt S, Barthelmes J, Thurner CC, Waldner C, Sakloetsakun D, Bernkop-Schnurch A, S-protected thiolated chitosan: synthesis and in vitro characterization, Carbohydr Polym, 90 (2012) 765–772. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [306].Auton M, Bolen DW, Predicting the energetics of osmolyte-induced protein folding/unfolding, Proc Natl Acad Sci U S A, 102 (2005) 15065–15068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [307].Maity H, Muttathukattil AN, Reddy G, Salt Effects on Protein Folding Thermodynamics, J Phys Chem Lett, 9 (2018) 5063–5070. [DOI] [PubMed] [Google Scholar]
- [308].Jiang Z, Guan J, Qian J, Zhan C, Peptide ligand-mediated targeted drug delivery of nanomedicines, Biomater Sci, 7 (2019) 461–471. [DOI] [PubMed] [Google Scholar]
- [309].Gonda A, Kabagwira J, Senthil GN, Wall NR, Internalization of Exosomes through Receptor-Mediated Endocytosis, Mol Cancer Res, 17 (2019) 337–347. [DOI] [PubMed] [Google Scholar]
- [310].Cupic KI, Rennick JJ, Johnston AP, Such GK, Controlling endosomal escape using nanoparticle composition: current progress and future perspectives, Nanomedicine (Lond), 14 (2019) 215–223. [DOI] [PubMed] [Google Scholar]
- [311].Chien KR, Zangi L, Lui KO, Synthetic chemically modified mRNA (modRNA): toward a new technology platform for cardiovascular biology and medicine, Cold Spring Harb Perspect Med, 5 (2014) a014035. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [312].Raposo G, Stoorvogel W, Extracellular vesicles: exosomes, microvesicles, and friends, J Cell Biol, 200 (2013) 373–383. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [313].Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, Baty CJ, Gibson GA, Erdos G, Wang Z, Milosevic J, Tkacheva OA, Divito SJ, Jordan R, Lyons-Weiler J, Watkins SC, Morelli AE, Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes, Blood, 119 (2012) 756–766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [314].Suzuki E, Fujita D, Takahashi M, Oba S, Nishimatsu H, Therapeutic Effects of Mesenchymal Stem Cell-Derived Exosomes in Cardiovascular Disease, Adv Exp Med Biol, 998 (2017) 179–185. [DOI] [PubMed] [Google Scholar]
- [315].Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z, Mesenchymal Stem Cell-Derived Exosomes Improve the Microenvironment of Infarcted Myocardium Contributing to Angiogenesis and Anti-Inflammation, Cell Physiol Biochem, 37 (2015) 2415–2424. [DOI] [PubMed] [Google Scholar]
- [316].Phinney DG, Pittenger MF, Concise Review: MSC-Derived Exosomes for Cell-Free Therapy, Stem Cells, 35 (2017) 851–858. [DOI] [PubMed] [Google Scholar]
- [317].Ghorbani S, Talebi F, Chan WF, Masoumi F, Vojgani M, Power C, Noorbakhsh F, MicroRNA-181 Variants Regulate T Cell Phenotype in the Context of Autoimmune Neuroinflammation, Front Immunol, 8 (2017) 758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [318].Batrakova EV, Kim MS, Using exosomes, naturally-equipped nanocarriers, for drug delivery, J Control Release, 219 (2015) 396–405. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [319].Wang Y, Ding N, Guan G, Liu G, Huo D, Li Y, Wei K, Yang J, Cheng P, Zhu C, Rapid Delivery of Hsa-miR-590-3p Using Targeted Exosomes to Treat Acute Myocardial Infarction Through Regulation of the Cell Cycle, J Biomed Nanotechnol, 14 (2018) 968–977. [DOI] [PubMed] [Google Scholar]
- [320].Reiner AT, Witwer KW, van Balkom BWM, de Beer J, Brodie C, Corteling RL, Gabrielsson S, Gimona M, Ibrahim AG, de Kleijn D, Lai CP, Lotvall J, Del Portillo HA, Reischl IG, Riazifar M, Salomon C, Tahara H, Toh WS, Wauben MHM, Yang VK, Yang Y, Yeo RWY, Yin H, Giebel B, Rohde E, Lim SK, Concise Review: Developing Best-Practice Models for the Therapeutic Use of Extracellular Vesicles, Stem Cells Transl Med, 6 (2017) 1730–1739. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [321].Szatanek R, Baj-Krzyworzeka M, Zimoch J, Lekka M, Siedlar M, Baran J, The Methods of Choice for Extracellular Vesicles (EVs) Characterization, Int J Mol Sci, 18 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [322].Zhou R, Geiger RC, Dean DA, Intracellular trafficking of nucleic acids, Expert Opin Drug Deliv, 1 (2004) 127–140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [323].Opanasopit P, Rojanarata T, Apirakaramwong A, Ngawhirunpat T, Ruktanonchai U, Nuclear localization signal peptides enhance transfection efficiency of chitosan/DNA complexes, Int J Pharm, 382 (2009) 291–295. [DOI] [PubMed] [Google Scholar]
- [324].Tran EJ, King MC, Corbett AH, Macromolecular transport between the nucleus and the cytoplasm: Advances in mechanism and emerging links to disease, Biochim Biophys Acta, 1843 (2014) 2784–2795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [325].Duvshani-Eshet M, Baruch L, Kesselman E, Shimoni E, Machluf M, Therapeutic ultrasound-mediated DNA to cell and nucleus: bioeffects revealed by confocal and atomic force microscopy, Gene Ther, 13 (2006) 163–172. [DOI] [PubMed] [Google Scholar]
- [326].Mehier-Humbert S, Bettinger T, Yan F, Guy RH, Plasma membrane poration induced by ultrasound exposure: implication for drug delivery, J Control Release, 104 (2005) 213–222. [DOI] [PubMed] [Google Scholar]
- [327].deGruyter JN, Malins LR, Baran PS, Residue-Specific Peptide Modification: A Chemist's Guide, Biochemistry, 56 (2017) 3863–3873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [328].Khoshnejad M, Brenner JS, Motley W, Parhiz H, Greineder CF, Villa CH, Marcos-Contreras OA, Tsourkas A, Muzykantov VR, Molecular engineering of antibodies for site-specific covalent conjugation using CRISPR/Cas9, Sci Rep, 8 (2018) 1760. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [329].Schwinn MK, Machleidt T, Zimmerman K, Eggers CT, Dixon AS, Hurst R, Hall MP, Encell LP, Binkowski BF, Wood KV, CRISPR-Mediated Tagging of Endogenous Proteins with a Luminescent Peptide, ACS Chem Biol, 13 (2018) 467–474. [DOI] [PubMed] [Google Scholar]
- [330].Devoldere J, Dewitte H, De Smedt SC, Remaut K, Evading innate immunity in nonviral mRNA delivery: don't shoot the messenger, Drug Discov Today, 21 (2016) 11–25. [DOI] [PubMed] [Google Scholar]
- [331].Sultana N, Magadum A, Hadas Y, Kondrat J, Singh N, Youssef E, Calderon D, Chepurko E, Dubois N, Hajjar RJ, Zangi L, Optimizing Cardiac Delivery of Modified mRNA, Mol Ther, 25 (2017) 1306–1315. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [332].Oliveira PH, Prather KJ, Prazeres DM, Monteiro GA, Structural instability of plasmid biopharmaceuticals: challenges and implications, Trends Biotechnol, 27 (2009) 503–511. [DOI] [PubMed] [Google Scholar]
- [333].Huang M, Chen Z, Hu S, Jia F, Li Z, Hoyt G, Robbins RC, Kay MA, Wu JC, Novel minicircle vector for gene therapy in murine myocardial infarction, Circulation, 120 (2009) S230–237. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [334].Eichmann A, Yuan L, Breant C, Alitalo K, Koskinen PJ, Developmental expression of pim kinases suggests functions also outside of the hematopoietic system, Oncogene, 19 (2000) 1215–1224. [DOI] [PubMed] [Google Scholar]
- [335].Selvam C, Mutisya D, Prakash S, Ranganna K, Thilagavathi R, Therapeutic potential of chemically modified siRNA: Recent trends, Chem Biol Drug Des, 90 (2017) 665–678. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [336].Keeney M, Jiang XY, Yamane M, Lee M, Goodman S, Yang F, Nanocoating for biomolecule delivery using layer-by-layer self-assembly, J Mater Chem B, 3 (2015) 8757–8770. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [337].Gottipati A, Chelvarajan L, Peng H, Kong R, Cahall CF, Li C, Tripathi H, Al-Darraji A, Ye S, Elsawalhy E, Abdel-Latif A, Berron BJ, Gelatin Based Polymer Cell Coating Improves Bone Marrow-Derived Cell Retention in the Heart after Myocardial Infarction, Stem Cell Rev Rep, 15 (2019) 404–414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [338].Ludwinski FE, Patel AS, Damodaran G, Cho J, Furmston J, Xu Q, Jayasinghe SN, Smith A, Modarai B, Encapsulation of macrophages enhances their retention and angiogenic potential, NPJ Regen Med, 4 (2019) 6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [339].Fang RH, Kroll AV, Gao W, Zhang L, Cell Membrane Coating Nanotechnology, Adv Mater, 30 (2018) e1706759. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [340].Don CW, Murry CE, Improving survival and efficacy of pluripotent stem cell-derived cardiac grafts, J Cell Mol Med, 17 (2013) 1355–1362. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [341].Schirone L, Forte M, Palmerio S, Yee D, Nocella C, Angelini F, Pagano F, Schiavon S, Bordin A, Carrizzo A, Vecchione C, Valenti V, Chimenti I, De Falco E, Sciarretta S, Frati G, A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling, Oxid Med Cell Longev, 2017 (2017) 3920195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [342].Guzman E, Mateos-Maroto A, Ruano M, Ortega F, Rubio RG, Layer-by-Layer polyelectrolyte assemblies for encapsulation and release of active compounds, Adv Colloid Interface Sci, 249 (2017) 290–307. [DOI] [PubMed] [Google Scholar]
- [343].Dow J, Simkhovich BZ, Kedes L, Kloner RA, Washout of transplanted cells from the heart: a potential new hurdle for cell transplantation therapy, Cardiovasc Res, 67 (2005) 301–307. [DOI] [PubMed] [Google Scholar]
- [344].Chen MH, Chung JJ, Mealy JE, Zaman S, Li EC, Arisi MF, Atluri P, Burdick JA, Injectable Supramolecular Hydrogel/Microgel Composites for Therapeutic Delivery, Macromol Biosci, 19 (2019) e1800248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [345].Vinnakota KC, Bassingthwaighte JB, Myocardial density and composition: a basis for calculating intracellular metabolite concentrations, Am J Physiol Heart Circ Physiol, 286 (2004) H1742–1749. [DOI] [PubMed] [Google Scholar]
- [346].Annabi N, Tamayol A, Uquillas JA, Akbari M, Bertassoni LE, Cha C, Camci-Unal G, Dokmeci MR, Peppas NA, Khademhosseini A, 25th anniversary article: Rational design and applications of hydrogels in regenerative medicine, Adv Mater, 26 (2014) 85–123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [347].Zhang YS, Khademhosseini A, Advances in engineering hydrogels, Science, 356 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [348].El-Shazly M, El-Shafiey H, Soft versus hard implants in dorsal nasal augmentation: a comparative clinical study, Aesthetic Plast Surg, 36 (2012) 1019–1027. [DOI] [PubMed] [Google Scholar]
- [349].Julier Z, Park AJ, Briquez PS, Martino MM, Promoting tissue regeneration by modulating the immune system, Acta Biomater, 53 (2017) 13–28. [DOI] [PubMed] [Google Scholar]
- [350].Jhunjhunwala S, Raimondi G, Glowacki AJ, Hall SJ, Maskarinec D, Thorne SH, Thomson AW, Little SR, Bioinspired controlled release of CCL22 recruits regulatory T cells in vivo, Adv Mater, 24 (2012) 4735–4738. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [351].Sands RW, Verbeke CS, Ouhara K, Silva EA, Hsiong S, Kawai T, Mooney D, Tuning cytokines enriches dendritic cells and regulatory T cells in the periodontium, J Periodontol, (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [352].Chen B, Frangogiannis NG, Chemokines in Myocardial Infarction, J Cardiovasc Transl Res, (2020). [DOI] [PubMed] [Google Scholar]
- [353].Kim YC, Park JH, Prausnitz MR, Microneedles for drug and vaccine delivery, Adv Drug Deliv Rev, 64 (2012) 1547–1568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [354].Shi H, Xue T, Yang Y, Jiang C, Huang S, Yang Q, Lei D, You Z, Jin T, Wu F, Zhao Q, Ye X, Microneedle-mediated gene delivery for the treatment of ischemic myocardial disease, Sci Adv, 6 (2020) eaaz3621. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [355].Whyte W, Roche ET, Varela CE, Mendez K, Islam S, O'Neill H, Weafer F, Shirazi RN, Weaver JC, Vasilyev NV, McHugh PE, Murphy B, Duffy GP, Walsh CJ, Mooney DJ, Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir, Nat Biomed Eng, 2 (2018) 416–428. [DOI] [PubMed] [Google Scholar]
- [356].Gu Z, Gu L, Eils R, Schlesner M, Brors B, circlize Implements and enhances circular visualization in R, Bioinformatics, 30 (2014) 2811–2812. [DOI] [PubMed] [Google Scholar]
- [357].Community BO, Blender - a 3D modelling and rendering package, Stichting Blender Foundation, Amsterdam, (2019) Retrieved from http://www.blender.org [Google Scholar]
- [358].Fujimoto KL, Ma Z, Nelson DM, Hashizume R, Guan J, Tobita K, Wagner WR, Synthesis, characterization and therapeutic efficacy of a biodegradable, thermoresponsive hydrogel designed for application in chronic infarcted myocardium, Biomaterials, 30 (2009) 4357–4368. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [359].Bogart S, Sankeymatic, http://sankeymatic.com/build/ 9.14.20 accessed, 7.25.18 last updated. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.