Concise Review: Injectable Biomaterials for the Treatment of Myocardial Infarction and Peripheral Artery Disease: Translational Challenges and Progress

This report summarizes the latest preclinical and clinical studies on injectable biomaterial therapies for myocardial infarction (MI) and peripheral artery disease (PAD). The study highlights the major challenges facing translation of these therapies to the clinic (e.g., regulatory, manufacturing, and delivery), with the purpose of increasing awareness of the barriers for translating novel biomaterial therapies for MI and PAD and facilitating more rapid translation of new biomaterial technologies.

Abstract

Recently, injectable biomaterial-based therapies for cardiovascular disease have been gaining attention, because they have shown therapeutic potential in preclinical models for myocardial infarction (MI) and peripheral artery disease (PAD). Naturally derived (e.g., alginate, hyaluronic acid, collagen, or extracellular matrix-based) or synthetic (e.g., peptide or polymer-based) materials can enhance stem cell survival and retention in vivo, prolong growth factor release from bulk hydrogel or particle constructs, and even stimulate endogenous tissue regeneration as a standalone therapy. Although there are many promising preclinical examples, the therapeutic potential of biomaterial-based products for cardiovascular disease has yet to be proved on a clinical and commercial scale. This review aims to briefly summarize the latest preclinical and clinical studies on injectable biomaterial therapies for MI and PAD. Furthermore, our overall goal is to highlight the major challenges facing translation of these therapies to the clinic (e.g., regulatory, manufacturing, and delivery), with the purpose of increasing awareness of the barriers for translating novel biomaterial therapies for MI and PAD and facilitating more rapid translation of new biomaterial technologies.

Introduction

Cardiovascular disease is the leading cause of morbidity and mortality in the U.S. [1]. Although approximately 83.6 million Americans experience the disease in some capacity, there is still no cure for some of the most common cardiovascular events such as myocardial infarction (MI) and peripheral artery disease (PAD). For MI, approximately 700,000 new cases occur each year in the U.S. [1], yet no therapies are available to prevent the negative left ventricular (LV) remodeling process that leads to heart failure, and the only effective options for patients with end stage heart failure are LV assist devices or heart transplants. PAD is a condition that afflicts 12%–20% of Americans older than 65 years [2]. Also caused by atherosclerosis, PAD causes pain in the lower limbs that can progress to critical limb ischemia (CLI), the most severe form of the disease. Currently, revascularization therapy is the only option for patients with PAD. However, because many patients are ineligible for revascularization therapy, the amputation rates for patients with CLI have remained largely unchanged for the past 30 years [3, 4].

In this review, we focus on recent developments in the field of injectable biomaterial scaffolds and related regenerative medicine therapies for preventing and/or treating heart failure after MI and PAD (Figure 1 provides a summary of the injectable biomaterial approaches for MI and PAD). We then investigate the main obstacles faced by investigators in translating their therapies to the clinic, including regulatory considerations, delivery concerns, and manufacturing-related challenges.

Figure 1.

Injectable therapies for myocardial infarction (MI) and peripheral artery disease (PAD). Current biomaterial-based regenerative medicine therapies for MI or PAD involve a material alone, material plus cells, or material plus other therapeutics (e.g., growth factors). For MI, large animal models and clinical trials use either transcatheter injection or a surgically based direct epicardial injection procedure. For PAD, most studies involve intramuscular injections directly to the site of ischemia. Adapted from [9] with permission from the Journal of the American College of Cardiology.

Current Biomaterial-Based Regenerative Medicine Approaches

Myocardial Infarction

The first reports on using injectable materials for treating MI (either alone, as a cell delivery vehicle [5–7], or as a growth factor delivery vehicle [8]) were published in 2003 and 2004, and the past decade has seen a significant increase in the number of reports in this area. Numerous comprehensive reviews have detailed the various studies in the field [9–14]. At this time, several injectable biomaterials have been shown to improve cardiac function and/or the delivery and efficacy of cells or other therapeutics. Although most studies continue to be in rodent models, many groups have moved toward designing injectable therapies for easier clinical translation and using more clinically relevant large animal models. Thus, in this review, we focus solely on preclinical studies that have been performed with large animal MI models (Table 1).

Table 1.

Selected injectable biomaterials for myocardial infarction

Cells and Material

Injectable hydrogels were first explored to increase poor cell retention and survival associated with cell transplantation in the heart [5, 7]. It is now largely acknowledged that injected cells, which have translated to the clinic, act via a paracrine mechanism of action, and the goal of adding a biomaterial scaffold is to improve survival by giving the cells a temporary extracellular matrix and, thereby, increase the positive paracrine signals over time. Numerous studies to date have been performed in small animals using either naturally derived materials, such as fibrin, alginate, collagen, or hyaluronic acid, or synthetic hydrogels, such as self-assembling peptides or polymer-based systems (see [10–15] for extensive reviews of these small animal studies). Although pluripotent stem cells, such as embryonic stem cell- and induced pluripotent stem cell-derived cardiomyocytes, have been explored, most studies have focused on more immediately translatable cell types, such as cardiosphere-derived cells and bone marrow-derived cells [14]. Limited studies have, however, been performed in large animal models, which more closely mimic the cardiac (patho)physiology of human patients. Lin et al. showed that cell retention improved by almost 10-fold after direct epicardial injection of bone marrow-derived mononuclear cells (BM-MNCs) in self-assembling peptide nanofibers in a porcine MI model [15]. Cell injection within the nanofibers led to improved systolic and diastolic cardiac function and capillary density, but cells alone only improved systolic function [15]. Ladage et al. showed for the first time in a large animal model the safety and feasibility of an intrapericardial injection method for delivering a cell and material therapy to infarcted porcine myocardium. They injected Gelfoam (a Food and Drug Administration [FDA]-approved gelatin-based material; Pfizer, New York, NY, http://www.pfizer.com) particles and either bone marrow-derived mesenchymal stem cells (MSCs) or adenoviral enhanced green fluorescent protein (eGFP) into the pericardial space and demonstrated myocardial localization of cells and expression of the eGFP gene [16]. Although this study did not measure the ability of intrapericardially delivered therapies to improve cardiac function after MI, it introduced a new potential delivery mechanism for translation of biomaterial-based therapies.

Other Therapeutics and Material

Early studies examined delivery of angiogenic growth factors in biomaterial microspheres [8, 17]. More recent studies in large animal models have investigated sustained release of growth factors or other therapeutics (drugs or biologics) from injectable scaffolds for preventing negative LV remodeling. Lin et al. showed that vascular endothelial growth factor (VEGF) release can be sustained for 2 weeks from self-assembling peptide nanofibers in vivo. The nanofibers ensured that VEGF activity was localized to the infarct area and did not have effects in other tissues, a major concern of bolus injections of VEGF. The nanofiber-VEGF system improved angiogenesis, fractional shortening, and infarct size following direct epicardial injection in a porcine MI model [18]. Similarly, Koudstaal et al. showed that release of insulin-like growth factor-1 and hepatocyte growth factor (HGF) from a pH sensitive ureidopyrimidinone hydrogel delivered via percutaneous transendocardial injections attenuated negative LV remodeling, improved recruitment of endogenous cardiac progenitor cells, and increased capillary density in the border zone in a porcine MI model [19]. Eckhouse et al. recently showed the attenuation of negative LV remodeling after sustained release (longer than 14 days) of recombinant tissue inhibitor of matrix metalloproteinase-3 (rTIMP-3) from a hyaluronic acid-based hydrogel delivered via direct epicardial injection. The sustained release of rTIMP-3 from the material led to significant improvements in several metrics of cardiac function at 2 weeks after MI in a porcine model, including LV ejection fraction (LVEF), LV end diastolic diameter and volume, wall stress, infarct area, and wall thickness and smooth muscle actin expression compared with saline and material-alone controls [20]. Another group used direct intrapericardial injection to deliver recombinant periostin peptide (rPN) in Gelfoam to the infarcted myocardium. They showed improved rPN release within 7 days by nonfibrotic fibrin encapsulation of the Gelfoam, which improved angiogenesis and cardiomyocyte proliferation in the infarct border zone in a porcine MI model [21].

Material Alone

Although biomaterials can be used to enhance delivery of therapeutics, such as those described above, injectable hydrogels have also been shown to improve cardiac function on their own. Several materials have now been studied in small animal models, including alginate, chitosan, fibrin, hyaluronic acid, collagen, Matrigel (BD Biosciences, San Jose, CA, www.bdbiosciences.com), keratin, decellularized extracellular matrix (ECM), and synthetic peptide- or polyethylene glycol-based systems. However, more limited large animal studies have been performed. Mukherjee et al. showed increased wall thickness and reduced infarction expansion after direct epicardial injection of a fibrin-alginate composite [22], and Leor et al. demonstrated decreases in LV volumes [23] after intracoronary infusion of alginate, both in porcine MI models. With the promising results from the alginate alone group, this material and delivery method transitioned into phase I and now phase II clinical trials [24, 25]. Another group has shown reduction of infarct size using hyaluronic acid (HA) hydrogels injected via direct epicardial injection in an ovine model [26]. Seif-Naraghi et al. presented the first large animal study of the regenerative capabilities of an injectable naturally derived decellularized material after MI [27]. The tissue specific myocardial ECM hydrogel, injected via a catheter-based transendocardial approach, improved LVEF, LV end diastolic and systolic volumes, and global wall motion index in a porcine MI model. Increased cardiac muscle was also observed at the endocardium, along with reduced infarct fibrosis compared with saline injected controls. Taken together, these results indicate that the hydrogel improved both LV geometries and contractility.

Peripheral Artery Disease

Although gene therapy, stem cells, and growth factors have all been studied for PAD, the use of biomaterials either to enhance these therapies or to act as a standalone treatment is just beginning to be explored. Thus, in this review we will cover both small and large animal preclinical studies of injectable biomaterials for PAD (Table 2).

Table 2.

Selected injectable biomaterials for peripheral artery disease

Cells and Material

Cell therapy for PAD, compared with MI, has a more singularly angiogenic focus because ischemia is the main etiology of PAD. Tang et al. first injected human umbilical vein endothelial cells (HUVECs) intramuscularly in HA, a proangiogenic ECM component. The addition of HA prolonged the degree of cell retention and enhanced the ability of HUVECs to survive and engraft into the endothelium and recruit host smooth muscle cells. The HA plus HUVEC combination also improved limb perfusion and angiogenesis compared with either cells or material alone at a 4-week point in a nude mouse hind limb ischemia model [28]. Wang et al. injected autologous bone marrow-derived MSCs seeded in a collagen hydrogel in a rabbit model of hind limb ischemia. Their cell-material constructs enhanced angiogenesis and improved hind limb perfusion as measured by oxygen saturation ratio after 8 weeks. Although collagen alone improved the capillary density, the MSC-collagen construct significantly improved mature vessel density and oxygen saturation compared with cell, material, and saline controls [29]. Another group used a synthetic hydroxyapatite nanoparticle system to deliver BM-MNCs into the murine ischemic limb; they showed increased angiogenesis, arteriogenesis, and cell survival after 7 days that correlated with increased VEGF and basic fibroblast growth factor (bFGF) protein levels in the tissue [30].

Other Therapeutics and Material

Perhaps because of the largely paracrine effects seen with many stem cell injections, many groups have looked to embedding growth factors in materials as a method to improve sustained release of angiogenic factors without the complication of using stem cells. The only biomaterial-based therapy currently in clinical trials for PAD involves such a sustained release system, using gelatin microspheres to deliver bFGF to ischemic tissue for prolonged periods [31]. Sustained release can improve with cross-linking, such as was seen with bFGF release for 10 days from glutaraldehyde-cross-linked gelatin microspheres in a canine hind limb ischemia model [32]. Naturally derived materials have also been shown to sustain release of factors. For example, Ruvinov et al. showed that alginate modified with sulfate improved affinity binding and thus allowed for more sustained release of HGF for 7 days, leading to improvements in limb perfusion and mature vessel formation [33]. Kuraitis et al. showed that a combination of two naturally derived materials, alginate microspheres within an injectable collagen hydrogel, prolonged the delivery of stem cell derived factor 1 (SDF-1) for 10 days to the ischemic murine hind limb, improving perfusion, arteriole density, and recruitment of GFP-labeled bone marrow progenitor cells. Although collagen alone also significantly improved perfusion and arteriole density compared with phosphate-buffered saline controls, the SDF-1/alginate/collagen system had higher trends in all metrics and a significantly higher arteriole lumen area and recruitment of GFP-labeled bone marrow cells [34]. Other groups have used a fragmin/protamine system to form microparticles that allow for sustained release of bFGF or platelet-rich plasma (PRP) [35]. For example, Fujita et al. showed improved collateral vessel formation and calf blood pressure in a rabbit model of hind limb ischemia using the PRP-loaded fragmin/protamine microparticles [36]. Furthermore, all three components of their system are currently used for other clinical applications, which would likely facilitate clinical translation. In a completely synthetic system, Kim et al. showed that self-assembling bioactive peptides sustained release of substance P, a neuropeptide involved in wound healing, to recruit host mesenchymal stem cells and improve limb perfusion in a mouse model of hind limb ischemia after 4 weeks [37]. Webber et al. also designed a synthetic system of peptide amphiphile structures engineered to display a VEGF-mimetic epitope [38]. The construct improved angiogenesis and limb perfusion after 3 weeks compared with all material controls. In other synthetic systems, groups have explored the loading of gold [39], poly(d,l-lactide-co-glycolide) (PLGA) [40], or dextran and gelatin [41] nano- or microparticles with VEGF. These particle systems all demonstrated sustained release of VEGF for 35, 20, or 12 days, respectively, into the ischemic hind limb and led to increased angiogenesis and limb perfusion.

Material Alone

Although a relatively new approach for the PAD field, injection of materials alone may show particular promise for translatability, because of the fewer issues without additional bioactive components such as cells or growth factors. Fan et al. injected fibrin particles intramuscularly in a rabbit model of hind limb ischemia and showed improved capillary and arteriole density, as well as improved perfusion measured via angiographic score and calf blood pressure ratio after 28 days [42]. In a more recent study, DeQuach et al. were the first group to develop a tissue-specific injectable matrix for hind limb ischemia [43]. This initial study showed that the naturally derived, decellularized skeletal muscle ECM hydrogel improved neovascularization and muscle cell infiltration into the material after 2 weeks.

Translating Injectable Biomaterials to the Clinic: Current Obstacles

Despite promising preclinical results, there are currently no FDA-approved injectable biomaterial products for treating MI, chronic heart failure, PAD, or CLI. The difficulty in bringing a therapy to the market is reflected in the small number of biomaterials currently undergoing clinical trials (Fig. 2). For the heart, only two injectable biomaterials are currently in clinical trials: both are alginate hydrogel systems, one delivered via transcoronary catheter infusion for acute MI [24, 25] and the other delivered via direct epicardial injection for dilated cardiomyopathy [44–46]. For PAD, there are several clinical trials for stem cell, growth factor, and gene therapy systems, but none have shown conclusively positive results [47], and only one involved a biomaterial scaffold [31]. This lack of transition from preclinical to clinical studies indicates a heightened need to consider strategies that will better enable translation of injectable biomaterial therapies for MI and PAD. In designing a material for clinical application, it is important to consider regulatory options, manufacturing strategies, and delivery methods throughout the development of the product. Although these design criteria are not always considered in early academic research, attention early on could minimize hurdles later in the path to the clinic.

Figure 2.

Translational pathway. The typical time, cost, relative number of publications, funding sources, and phases of the translational pathway for biomaterial-based therapies for cardiovascular disease are highlighted. ∗, number of studies in PubMed (preclinical) and ClinicalTrials.Gov (clinical) averaged per year for the past 5 years, using search terms “cell therapy,” “gene therapy,” “biomaterials,” “myocardial infarction,” and “peripheral artery disease.” The cost of each phase was drawn from [49] for preclinical and clinical phases, [62] for PAD market size, and [63] for MI market size. Abbreviations: AHA, American Heart Association; FDA, Food and Drug Administration; Gov’t, government; Med., medical; MI, myocardial infarction; mil, million; NSF, National Science Foundation; PAD, peripheral artery disease; Pharma, pharmaceutical; SBIR, Small Business Innovation Research.

Regulatory Challenges

A major obstacle in the translation of biomaterials for cardiovascular disease to the clinic is regulatory approval. Given the diversity of the biomaterial therapies described above, it is difficult to classify some products within just one of FDA’s regulatory arms. Thus, in 2011, the Office of Combination Products (OCP) at the FDA published a draft guidance document on classification issues to help resolve this confusion [48]. In it, they focus on the three regulatory classifications: drugs, devices, and biologic products. Although their definition of drug is very broad (i.e., any substance used to “affect the structure or any function of the body of man”), their classification of a device is limited to any product that does not “achieve its primary intended purposes through chemical action.” Historically, biomaterial only therapies have largely been classified as devices under this definition; however, in the guidance document, the OCP stresses that any therapy that “depends, even in part, on chemical action within or on the body of man to achieve any one of its primary intended purposes, would not be a device.” Therefore, many biomaterial products are now being designated as biologics in the U.S. Although a final guidance document has not been issued, the draft guidance document gives insight into the current thinking of OCP in regard to product classification. This will have an enormous effect on the translatability of a biomaterial therapy because of the drastically different regulatory pathways for each classification. Drugs, regulated through the Center for Drug Evaluation and Research, and biologics, regulated through the Center for Biologics Evaluation and Research, must undergo a three-phase, 5–10-year process costing hundreds of millions of dollars. In contrast, devices regulated by the Center for Devices and Radiological Health have a relatively shorter and less expensive pathway. See [49] for a good review of the different costs associated with these pathways. In addition, any product that involves a combination of components regulated by different centers could fall under the OCP, which determines the classification and center jurisdiction.

Most therapies described in this review could potentially fall under multiple classifications owing to their complex nature in combining biomaterial therapies with cells, growth factors, or other therapeutics. Although more components may have desirable synergistic effects, the addition of each component can add time, cost, and regulatory hurdles to getting that therapy to market. Combination therapies can require extensive preclinical testing examining each component of the product, including the recommended testing for cell and gene therapies [50], as well as assessing the safety of the biomaterial scaffold, which often involves assessing biocompatibility of the scaffold alone using ISO-10993 biocompatibility tests. Although biomaterial only therapies can be advantageous in this regard, the main mechanism of action of materials in the heart and ischemic limbs is still unclear, leading to ambiguity in regulatory classification. It is important for researchers to consider these regulatory hurdles as early as possible when designing a new therapy. Given the uncertainties with regulatory classification and its effect on product development, early interactions with the relevant centers at the FDA and, if necessary, submission of a “Request for Designation” to the OCP are recommended.

Delivery Challenges

Another translational concern is the delivery method of the biomaterial therapy. Specifically, how the biomaterial is delivered can affect the ease of obtaining regulatory approval and the likelihood of the therapy being adopted by hospitals into clinical workflows and protocols. For example, an injectable myocardial therapy that can be delivered during cardiac catheterization procedures, which would obviate the need for general anesthesia and reduce the risk to the patient, will likelier be easier to implement after MI than surgically based epicardial injections. However, many of the injectable materials that have been tested in rodents are not amenable to cardiac catheters and the multiple injections or intracoronary infusions that are required [10]. It is therefore important to consider these aspects when initially designing an injectable material. If a material is not compatible with current cardiac catheters (e.g., short gelation times), then, in addition to the regulatory challenges associated with a new biomaterial therapy, there will be an added burden of developing and obtaining FDA clearance for a new catheter device. Furthermore, injections via catheter are prone to leakage into the systemic circulation, and, therefore, hemocompatibility should also be evaluated. A more extensive review on the delivery challenges associated with injectable hydrogels for myocardial applications can be found in [10]. To facilitate more rapid clinical translation, these design constraints should be considered at the very early stages of biomaterial design and testing. Another factor that should be considered is the intended timing of delivery because needle-based injections are not generally regarded as safe for patients within the first few days after MI owing to the unstable acute infarct wall. In addition, delivery in a subacute infarct is quite different than that in a chronic MI scar. Appropriately mimicking this in preclinical models is critical to fully assess the therapeutic potential of a new technology, because efficacy outcomes are known to vary with the delivery point [51, 52].

In peripheral artery disease, delivery has its own set of challenges. Many groups inject intramuscularly adjacent to the site of femoral artery resection in animal models; however, in a human patient, the gradual onset of plaque buildup, claudication (pain), and ischemia means that there is no acute injury site to be targeted. Still, in clinical trials, most groups tend to inject cell therapies intramuscularly at many sites in the quadriceps or gastrocnemius muscles, intra-arterially, or intravenously [47]. The problems with intramuscular injections are the limited biodistribution of factors such as gene plasmids, growth factors, or biomaterials and limited knowledge about the most effective delivery locations within the muscle. Some populations of stem cells, such as endothelial progenitor cells, have been shown to migrate more extensively in ischemic tissue than in healthy tissue, specifically toward sites of ischemia [53]. However, multiple injection sites raises concerns regarding systemic exposure of the potential therapy, and intra-arterial and intravenous injections are not always an option for patients with severe vessel blockage. For this reason, the dosing and delivery mechanisms will be important questions to answer before any therapy for PAD can translate successfully to the clinic.

Manufacturing Challenges

Another concern with the translatability of biomaterials to the clinic is their ability to be scaled up to a current good manufacturing practice (cGMP) process. Specifically, naturally derived biomaterials and cell therapies can have issues with batch-to-batch variability, scaling up, and efficiencies. The material content and properties of a naturally derived biomaterial can depend on the tissue source for biomaterials derived from animal tissue. Although a certain composition is typically conserved from specimen to specimen, variability can be present owing to tissue species, age, or health status of the human or animal from which the tissue is derived. For example, human versus porcine myocardial matrices were found to have different material properties and compositions; specifically, the human matrices had high levels of patient-to-patient variability [54]. A study of human pericardium-derived matrices also showed this patient-to-patient variability in material characterization; however, the researchers concluded that this variability in vitro did not affect gelation in vivo, thus not denying its potential as an autologous biomaterial therapy [55]. Host age also has an effect on the mechanical properties of the biomaterial, because younger source tissue appears to facilitate a more constructive tissue remodeling response than older source tissue [56, 57].

Scaling up production from bench to manufacturing plant can also have large implications for any cell- or material-based therapy. A review of cGMP practices for cell therapies has been provided by Abbasalizadeh and Baharvand [58] and by Giancola et al. [59]. Scaling up a manufacturing process to a sufficient batch size and according to cGMP practice can take significantly longer than expected. The act of scaling up a manufacturing process can also have effects on yield efficiencies of sensitive processes such as cell encapsulation. For example, even at the bench level, some groups have trouble achieving encapsulation efficiencies greater than 20% [60]. Thus, any process with more stable components might be easier to scale up than components such as growth factors, which might have an unstable shelf life, and stem cells, which require intensive work to reach appropriate batch sizes for commercial and clinical applications. Moreover, the cost of scaling up a manufacturing process from bench to plant should not be neglected. Although having detailed knowledge about cGMP guidelines is outside the realm of most academic laboratories, a basic understanding of the differences between a laboratory bench and cGMP process could facilitate more rapid translation to the clinic.

Other Challenges

In terms of translatability, a challenge for developing new treatments for critical limb ischemia or MI will be the consensus of a working animal model. For critical limb ischemia, depending on the severity of the surgical procedure, the animal can heal significantly on its own. For this reason, studies in rats, mice, and rabbits could have more significantly positive results than what is actually seen in clinical trials (see [47] for an extensive review on the clinical trial landscape for PAD). For MI, large animal models might not accurately mimic the clinical pathologic features. For example, some models use permanent occlusion of major vessels, although most patients today have their vessels reperfused within hours of the acute ischemic event. Furthermore, the treatment timelines for MI and PAD preclinical models also typically mimic the acute or subacute stage of the disease instead of chronic heart failure or PAD, which are the more common indications to treat in clinical trials. This mismatch between animal model and clinical treatment timelines can give unrealistic results for the efficacy of an injectable biomaterial therapy.

Future Directions: Designing a Translatable Biomaterial

All these challenges are vital to clinical translation yet can be overlooked in academic settings. Often, attrition occurs when translating therapies between the bench to the clinic, called the “valley of death” (Fig. 2). In recent years, the valley of death has widened, because venture capitalists and strategic partners (i.e., large pharmaceutical or medical device companies) typically want to see patient data (often phase II data) before they are willing to invest in a new technology. Designing better preclinical studies in academic laboratories can facilitate bridging this gap. For example, designing studies that appropriately mimic the timing and delivery route of a material therapy, and developing technologies that can be readily translated to a cGMP process and current clinical delivery modalities can facilitate entering clinical trials. Although good laboratory practice (GLP) studies [61] in full compliance with 21 CFR [Code of Federal Regulations] 58 are difficult to accomplish in an academic setting, it is possible for academic laboratories to conduct studies in the “spirit of GLP” that can be FDA compliant [50], and have less documentation and no quality assurance oversight. Therefore, appropriately designing and documenting studies, in particular, large animal studies, can accelerate translation, decrease the amount of funding necessary to translate a therapy to patients, and give a technology a better chance at crossing the valley of death.

Although many novel approaches have been used in the field of regenerative medicine for cardiovascular disease in the past 10 years, we are still waiting for an effective treatment to reach patients. Initially, the field showed a trend toward using different variations of cell and gene or protein therapies. However, more recently, the potential of biomaterials to sustain release and prolong survival of factors and cells has been harnessed, with significant gains in preclinical treatment efficacies. Still, the complex nature of these therapies and the subsequent challenges in regulatory approval, manufacturing, and delivery have likely hindered biomaterial-based therapies from proceeding in large numbers to the clinic. The recent trend of standalone biomaterials that can act on endogenous cells avoids many of the regulatory complexities and could reduce some of the concerns with manufacturing and delivery mechanism. Despite these challenges, the field of injectable biomaterial-based regenerative medicine therapies for cardiovascular disease has significant potential to help a large number of patients, and, as the first injectable biomaterials progress through clinical trials, it is anticipated that more will soon advance through the translational pathway.

Author Contributions

J.L.U.: conception and design, manuscript writing; K.L.C.: conception and design, financial support, manuscript writing, final approval of manuscript.

Disclosure of Potential Conflicts of Interest

K.L.C. has compensated intellectual property owned by the University of California, San Diego, and a compensated consultancy with Ventrix, Inc. She is also cofounder, board member, and holds equity interest in Ventrix, Inc.