Nanotechnology: The Future for Diagnostic and Therapeutic Intervention in Cardiovascular Diseases is Here

Abstract

With advances in technology and medicine over the last 3 decades, cardiovascular medicine has evolved tremendously. Nanotechnology provides a promising future in personalized precision medicine. In this review, we delve into the current and prospective applications of nanotechnology and nanoparticles in cardiology. Nanotechnology has allowed for point-of-care testing such as high-sensitivity troponins, as well as more precise cardiac imaging. This review is focused on 3 diseases within cardiology: coronary artery disease, heart failure, and valvular heart disease. The use of nanoparticles in coronary stents has shown success in preventing in-stent thrombosis, as well as using nanosized drug delivery medications to prevent neointimal proliferation in a way that spares systemic toxicity. In addition, by using nanoparticles as drug delivery systems, nanotechnology can be utilized in the delivery of goal-directed medical therapy in heart failure patients. It has also been shown to improve cell therapy in this patient population by helping in cell retention of grafts. Finally, the use of nanoparticles in the manufacturing of bioprosthetic valves provides a promising future for the longevity and success of cardiac valve repair and replacement.

In a world heading toward individualized precision medicine, nanotechnology is at the forefront of this advancement. Nanotechnology refers to structures in the 1–100 nm size regime.¹ These molecules are engineered to serve various purposes, including diagnostic imaging, drug delivery, and therapeutics (Fig. 1). Their use is not limited to medicine. In fact, they include engineering, chemistry, biology, and computer science.¹ Although nanotechnology is a term that few are familiar with, nanotechnology has been used in the manufacturing of sunscreen products using titanium dioxide and zinc oxide to make them last longer. Nanoparticles (NPs) have been used in the manufacturing of our scrubs and lab coats for decades. They have even been used in manufacturing tennis balls to make them bounce longer.²

FIGURE 1.

The World of Nanoparticles. Nanomicelles are multiple nanosized drug delivery agents that are listed here. Polymeric micelles are used for drug delivery and are more effective because of their long half-life and low toxicity. Liposomal nanoparticles are also used for drug delivery. Carbon nanotubes are hollow tubes of graphene sheets and are used for targeted drug delivery and nerve cell regeneration. Magnetic nanoparticles are a class of nanoparticles that are manipulated by magnetic fields that make them ideal for drug-targeted delivery. Drug conjugates covalently link drugs to synthetic molecule carriers; a drug carrying a monoclonal antibody for specific drug targeting. Metallic nanoparticles are made up of elements such as gold, cobalt, cadmium, iron, zinc, nickel, or iron, which can be used as drug delivery targets, but also used as sensors, for imaging and protection against bacterial infections. Polymersomes are synthetic amphiphilic copolymers that can carry and release drugs for targeted delivery. Lipid nanoparticles are made up of lipids as the name suggests, making it an ideal pharmaceutical drug delivery system. Gold nanoparticles have a role in detecting biomarkers in diagnosing cardiovascular diseases, cancer, and microbial agents.

Cardiologists are familiar with the current applications of nanotechnology in the field. The evolution of high-sensitivity troponins has used nanotechnology to develop rapid, fast, and sensitive testing that has revolutionized the diagnosis of acute coronary syndromes. In addition, it has been used in nuclear imaging, including positron emission tomography (PET) scans used to determine the amount of inflammation in the coronary arteries. Nanotechnology has become a major area of interest and research for expanded use in cardiology. In this review, we will address the history of nanotechnology and its implications for the future of the diagnosis and treatment of cardiovascular disease.

HISTORY OF NANOTECHNOLOGY

Nano is a Greek prefix that refers to exceedingly small particles. Nanotechnology is the study of these particles and their application in modern science.³ The roots of nanoscience trace back to the 5th century, in the time of the Greeks and Democritus, when philosophers began to wonder if matter could be further divided into small, essential objects that we now know as atoms.⁴ This topic was re-introduced by Richard Feynman, who is now considered the father of nanotechnology. In 1959, Feynman made the hypothesis “Why can’t we write the entire 24 volumes of the Encyclopedia Britannica on the head of a pin?.”⁵ This question, at the time, was merely hypothetical. However, in 1986, Eric Drexler published the first book on nanotechnology and pioneered the field of molecular engineering.⁶ Thanks to the innovation of these scientists, nanotechnology is now being used in various fields, including medicine.

APPLICATION OF NANOTECHNOLOGY IN MEDICINE

Since 1986, the use of nanotechnology in medicine continued to grow. From simple things such as wound dressings, scientists are developing smart band-aids that contain NPs with antibiotic therapies, wound healing properties, infection detection features, and coagulation profiles.⁷ In addition, their specificity enables them to be ideal medication delivery systems, which can deliver antibiotics or anticancer therapy to limit side effects.^8,9 Nanotechnology can also be utilized in diagnostic imaging, which can focus on in-vivo imaging, which is more specific than our current in-vitro imaging.¹⁰ Due to its various implications, we will focus this review on nanotechnology in the diagnosis and treatment of cardiovascular disease.

NANOTECHNOLOGY IN CARDIOVASCULAR MEDICINE

Cardiovascular disease (CVD) remains the leading cause of death, resulting in a high societal and financial burden. It led to 17.9 million deaths in 2019 alone, which quantifies 32% of global deaths.¹¹ Despite major advancements in research in CVD, there have been only minor improvements in the toll of CVD on our societies.¹² When compared with cancer, CVD has not made as many advancements in nanotechnology. In 2022 alone, there were more articles published about nanotechnology in cancer than all the articles found in PubMed about nanotechnology in CVD.¹³ CVD would be the ideal field that nanotechnology will thrive in due to its complexity of diseases, high patient population, and various diagnostic and therapeutic modalities. In this review, we will discuss the implications of nanotechnology in 3 fields of cardiology seen in Figure 2: coronary artery disease (CAD), heart failure, and valvular heart disease and various diagnostic and therapeutic modalities.

FIGURE 2.

Nanotechnology in cardiovascular medicine. Three domains are currently addressed by nanotechnology: coronary artery disease, valvular heart disease, and heart failure.

Coronary Artery Disease

Diagnosis

Nanotechnology is used for the detection and management of CAD. Early diagnosis of CAD is critical to improve cardiovascular outcomes. Biomarkers such as cardiac troponins (cTns), myoglobin, creatinine kinase MB, C-reactive protein, and certain miRNAs are released into the bloodstream when the heart is damaged or stressed.¹⁴ Developing precise and rapid blood analysis methods for these biomarkers is essential for early CAD diagnosis. While mass spectrometry is commonly used for biomarker identification, its sensitivity and specificity are limited due to low biomarker levels in plasma. To overcome these limitations, combining nanotechnologies with biosensors shows promise in diagnosing early-stage CADs. Nanomaterials offer high affinity binding to target molecules and reduce nonspecific adsorption, while biosensors consist of a sensing element and a transducer for data conversion.¹⁵ Various biosensing methods, including electrochemistry, electrochemiluminescence, fluorescence, colorimetry, surface-enhanced Raman scattering, and surface plasmon resonance technology (SPR), are used to quantitatively detect protein targets.^16,17 Surface-enhanced Raman scattering is a promising tool for biomarker detection; SPR quantitatively measures binding events of protein–protein interactions and can study antigen-antibody analysis. Nanomaterials with excellent optoelectronic properties significantly enhance detection sensitivity. For example, a label-free electrochemistry biosensor decorated with zinc stannate (ZnSnO₃) perovskite nanomaterials achieved subfemtomolar detection sensitivity for troponin T.¹⁸ ZnSnO₃ is a stable chemical used in solar cells, batteries, and supercapacitors with an efficient storage capacity for energy. Another approach involved a gold triangular nanoprism-based localized SPR biosensor that detected cardiac troponin T in plasma, serum, and urine at an attomolar limit of detection, making it at least 50 times more sensitive than other label-free techniques.¹⁹

Recent advancements in nanotechnology have led to the development of multimodal and point-of-care testing (POCT) assays for detecting biomarkers related to CAD. These assays offer improved accuracy, speed, and convenience in assessing the disease process. Studies have shown that ratiometric electrochemiluminescence can enhance measurement precision by eliminating environmental interference.²⁰ Researchers have utilized gold nanoparticle-modified carbon nitride nanosheets as donors, paired with graphene oxide/polyethylenimine-loaded gold NPs as acceptors, demonstrating high stability and low limits of detection.²¹ Additionally, microfluidic paper-based devices have been designed for the simultaneous detection of different biomarkers at various stages of acute myocardial infarction (MI). POCT methods utilizing paper-based or microfluidic portable devices, along with signal amplification by nanomaterials, have shown promise in rapidly detecting CAD biomarkers in less than 20 minutes. However, current POCT methods still have limits of detection in the ng/mL range, necessitating further improvement.²²

In addition to protein biomarkers, noncoding RNAs, particularly microRNAs such as miR-133a and miR-499, are being investigated as novel biomarkers for myocardial injury. Notably, Li’s laboratory has developed a hemin-bridged metal-organic framework to enhance the payload and catalysis of G-quadruplex (G4) DNAzymes for the rapid detection of miRNAs associated with CADs. This methodology exhibits significantly higher sensitivity and longer duration for chemiluminescent miRNA imaging compared with previous smartphone-based methods.^14,23 In summary, nanomaterial-based biosensors offer precise, specific, simple, and rapid detection strategies for various CAD biomarkers, potentially revolutionizing CAD diagnosis. However, further work is needed for the clinical translation of nano-biosensors.

Nanotechnology is also crucial in improving the diagnostic quality of various imaging techniques in CAD. The diagnosis of atherosclerosis aims to differentiate between “vulnerable plaques” prone to rupture and stable plaques. Current imaging methods focus on plaque anatomy but often fail to identify high-risk lesions. Molecular imaging targets such as macrophages and annexin V for apoptosis have been explored for better characterization of atherosclerotic plaques.²⁴ For instance, 18F PET imaging can evaluate inflammation and macrophage load in symptomatic arteries.²⁵ Other techniques involve the use of NPs for targeted imaging, such as cross-linked iron oxide NPs and 19F perfluorocarbon NPs.²⁶ Furthermore, imaging of apoptotic cells, adhesion molecules, angiogenesis, and thrombosis stages provides insights into plaque vulnerability. Various imaging modalities, including PET, single-photon emission computed tomography, and magnetic resonance imaging (MRI), combined with specific molecular probes, offer promising avenues for the accurate detection and characterization of high-risk atherosclerotic lesions.²⁷ Magneto-photo-acoustic imaging emerges as a valuable tool for assessing NP delivery and endocytosis within cells, contributing to our understanding of targeted nanoparticle-based therapies for atherosclerosis.

In the pursuit of a highly accurate diagnosis for CAD, researchers aim to integrate complementary information from various imaging techniques. However, differences in penetration depth and resolution among these methods can lead to interpretation challenges. Dual imaging strategies, utilizing a single technique and system, offer significant advantages. For instance, ultrasmall magnetic dual-contrast iron oxide nanoparticles serve as efficient positive and negative dual-contrast agents for MRI, highlighting thrombi with contrasting signals.²⁸ Similarly, cyclic RGD-functionalized liposomes encapsulating contrast agents enable active thrombi binding and potentially allow monitoring of rupture-prone atherosclerotic lesions.²⁹ Optical imaging, with its high spatial resolution and sensitivity, is promising for atherosclerotic plaque and clot imaging. Near-infrared fluorescence imaging reduces tissue autofluorescence and scattering, enhancing lesion identification at the molecular level.³⁰ Radionuclide-based molecular imaging offers high sensitivity and quantification, making it widely used for atherosclerosis diagnosis. Multimodal fusion, combining multiple imaging modalities, provides complementary diagnostic information, enhancing sensitivity and accuracy. Nanoparticle-based PET/MRI dual-modal imaging, for example, offers high resolution from MRI and deep tissue penetration from PET, enabling comprehensive assessment of CAD.³¹ This approach can provide insights into macrophage biology and immune responses in ischemic heart disease. Integrating MRI and optical imaging for dual-modal imaging can mitigate their respective limitations, promising improved diagnostic capabilities.

Drug delivery systems

Nanomaterials serve as intelligent carriers for drug delivery, typically consisting of 2 essential components: targeting moieties and therapeutic agents. These targeting moieties, such as peptides, antibodies, ligands, or cell membranes, guide the nanocarriers to specific locations within the body, particularly lesion microenvironments, where they can interact with target molecules of interest. Due to their customizable nature and high loading capacity, nanocarriers have been effectively utilized to encapsulate a wide range of therapeutic drugs, including chemicals, proteins, peptides, and nucleic acids. Small-molecule drugs, exemplified by statins, are commonly prescribed medications for mitigating the risks associated with CADs.³² However, their systemic administration often leads to dose-dependent adverse effects such as liver toxicity and muscle-related complications. To circumvent these challenges, various nanocarrier systems have been developed to specifically deliver small-molecule drugs to atherosclerotic plaques or thrombi, thereby enhancing their therapeutic efficacy while minimizing systemic side effects.³³ For instance, NPs incorporating hyaluronan (HA) with atorvastatin cores (HA-ATV-NPs) were engineered to selectively bind to CD44 receptors overexpressed on cells within atherosclerotic plaques. These HA-ATV-NPs demonstrated significantly enhanced anti-inflammatory effects compared with free atorvastatin, both in vitro and in vivo. Similarly, simvastatin was loaded into core/shell NPs (CSNPs) composed of methyl-β-cyclodextrin (core) and phospholipids (shell). By exploiting the higher affinity of cyclodextrin for cholesterol than for statins, these CSNPs could effectively target atherosclerotic plaques, release statins, and scavenge cholesterol through cargo-switching mechanisms, thereby improving their therapeutic efficacy.³⁴

As advancements in atherosclerosis research progress, novel chemical drugs in the form of molecular inhibitors or agonists have emerged. Monocytes/macrophages have been identified as pivotal players in the progression of atherosclerotic plaques, contributing to processes such as monocyte recruitment to the vessel wall, macrophage accumulation, phenotypic alterations, and inflammatory cytokine secretion.³⁵ Therefore, targeting monocytes/macrophages efficiently using nanocarriers to deliver molecular inhibitors or agonists holds promise for attenuating the progression of atherosclerosis. Utilizing their natural affinity to macrophages, innovative reconstituted high-density lipoprotein NPs were developed to transport a small-molecule inhibitor (SMI 6877002).³⁶ These inhibitors demonstrated the ability to moderate CD40-CD40 ligand signaling in monocytes and macrophages by obstructing the interaction between CD40 and tumor necrosis factor receptor-associated factor 6.³⁷ Tang et al³⁸ engineered a diverse library of 17 high-density lipoprotein-mimicking hybrid NPs, optimizing their physicochemical properties to enhance the targeting capability of a liver X receptor agonist (GW3965). Among these, a nanoparticle with a dominant phospholipid composition ofPOPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), prolonged blood half-life, and small size exhibited favorable characteristics, effectively mitigating GW3965-induced liver toxicity while retaining efficacy against atherosclerotic plaque macrophages.³⁸ Further modification with a collagen IV targeting ligand enhanced the specific accumulation of GW3965 at atherosclerotic lesion sites, leading to reduced macrophage content without inducing hepatic lipid biosynthesis or hyperlipidemia in mice.³⁹

Coronary stent innovation

Coronary in-stent restenosis remains a significant challenge in maintaining the long-term effectiveness of coronary artery stent placement, which is a common procedure in the treatment of blocked coronary arteries. Initially, bare-metal stents were utilized for percutaneous coronary intervention. However, the occurrence of in-stent restenosis often necessitates additional interventions. To address this issue, drug-eluting stents (DES) were introduced, incorporating antiproliferative drugs within the stent to inhibit restenosis. Nonetheless, the use of DES led to late-stent thrombosis attributed to polymer hypersensitivity and impaired reendothelialization. Emerging evidence suggests that a combination of biofunctionalized polymers and antibody/peptide motifs could mitigate thrombosis while promoting in situ endothelialization. The integration of nanotechnology has enabled advanced techniques such as layer-by-layer self-assembly and localized delivery of drugs and genes using NPs.

One of the earliest nanoporous ceramic coatings used to DES was nanoporous aluminum oxide (Al₂O₃), which was recently acquired by Abbott Vascular’s subsidiary Jomed International. To guarantee adequate adhesion of the coating to the base metal, 316L stainless steel stents were first coated inside and out with a thin layer of aluminum using a physical vapor deposition approach during the surface production process. Next, using a 2% oxalic acid in the water bath, the metallic layer was electrochemically transformed into a nanoporous ceramic (Al₂O₃). The resulting surface’s pore density and diameter were reported to be 10⁹ pores/cm² and 5–15 nm, respectively.⁴⁰ To deliver tacrolimus to rabbit carotid arteries in vivo, the antirestenosis drug was applied by dipping the stents into a defined solution of tacrolimus and subsequent drying steps. However, the clinical performance of this system in present trials was disappointing since the coating “flaked off” the stent surface and the resulting particulate debris led to a proinflammatory response producing a thicker neointima.⁴¹

A range of medications, including gene products and small molecules, have been delivered using NPs to stop arterial stenosis. A liposomal nanoparticle containing bisphosphonate, a strong inhibitor of macrophages and monocytes, is one such instance. Because bisphosphonate has poor cell membrane permeability and requires high systemic dosages, its therapeutic usage has been limited. Bisphosphonates, on the other hand, are easily absorbed by monocytes or macrophages when they are enclosed in liposomes, which effectively renders the cells inactive and prevents their growth. Danenberg et al⁴² postulated that because severe inflammation is usually the cause of eventual restenosis, it may be possible to reduce it by temporarily deactivating macrophages at the site of vascular injury with liposomal bisphosphonates. According to the study, neointimal development and artery stenosis were significantly reduced when liposomal alendronate, a powerful bisphosphonate, was administered at the time of stent implantation in a lipid-fed rabbit model. There is presently a phase II, dose-finding, randomized, multicenter, prospective, double-blind trial underway to assess liposomal alendronate formulations.⁴³

Since targeted systemic nanoparticle delivery of medications can concentrate pharmaceuticals at the site of disease while limiting systemic toxicity, it has been shown to be an appealing goal for treating specific vascular damage sites. Potential targets for injured endothelium have been identified as several indicators, including v 3 integrin, vascular adhesion molecule-1, tissue factor, and subendothelial extracellular matrix proteins such as collagen IV or chondroitin sulfate proteoglycans.⁴⁴ To target chondroitin sulfate proteoglycans, Joner et al⁴⁵ created a novel liposomal formulation encapsulating prednisolone. They also showed that medicines preferentially localized to the locations of stent-induced damage, which led to a decrease in restenosis in atherosclerotic rabbits.⁴⁵ Alternatively, stents themselves can serve as a target for nanoparticle-assisted drug delivery. A biocompatible, paclitaxel-loaded magnetic nanoparticle that is attracted to the stent struts and adjacent arterial tissues in the presence of a magnetic field was developed, facilitating the localization of NPs and effective inhibiting of in-stent restenosis.⁴⁶

There are treatments available with nanotechnology to promote endothelialization. A self-assembling nanofibrous matrix that resembles the extracellular matrix seen in endothelium was created by Kushwaha et al.⁴⁷ In this work, a nanofibrous matrix was engineered to draw endothelial cells and act as a stand-in source of nitrogen oxide (NO), a crucial cytokine that inhibits platelet adhesion and smooth muscle cell proliferation while promoting reendothelialization. The matrix was made up of biomimetic scaffolds made of peptide amphiphiles, a peptide ligand that adheres to endothelial cells, a polylysine group that donates NO and acts as a reservoir for it, and a metalloprotease-2-mediated cleavage site that slowly breaks down the nanofibrous matrix to help release NO continuously. This NO-releasing nanofibrous matrix successfully suppressed smooth muscle cell growth and platelet cell adhesion in vitro, leading to a marked improvement in endothelialization.⁴⁷ Ceylan et al⁴⁸ conjugated peptide amphiphile nanofibers with 2 molecules to create a bioactive stent coating: (1) a REDV epitope that favors endothelial cell adhesion and spreading over smooth muscle cells and platelets, and (2) a Dopa molecule that solidifies a strong hydrogen bond with the hydrophilic surface of stainless steel, securely immobilizing the nanofiber on the stent surface. When compared with a bare stent, Ceylan demonstrated better endothelial cell adherence, spreading, and proliferation on a nanofiber-coated stent. These extracellular cell matrix-mimicking nanofibrous matrices may offer an effective platform for bioactive stent construction, encouraging endothelial cell recovery on a stent surface, while further research is required to evaluate their in-vivo application.⁴⁸

Heart Failure

Drug delivery

The focused and continuous delivery of biomolecules or medications to the site of injury is the primary objective of an effective and safe pharmacological treatment. Targeted NPs have demonstrated potential in effectively delivering medications to cardiac tissue by utilizing certain targeting moieties.⁴⁹ One of the targeted locations used in the therapy of heart failure is the angiotensin II type 1 (AT1) receptor.⁵⁰ The creation of nanoliposomes functionalized with AT1 receptor-targeting ligands showed extremely effective adhesion to AT1 receptor-expressing cells in the infarcted region. Other biomolecules, such as matrix metalloproteinase (MMP) enzymes (MMP2 and MMP9), were used to produce targeted NPs. They are involved in physiologic and pathologic remodeling with an active role in fibrosis and hypertrophy. For instance, rat model MI infarcted tissue was able to hold and localize MMP-responsive spherical micellar NPs.⁵¹

It is well known that N-acetylglucosamine (GlcNAc) has a strong affinity and propensity to be absorbed by cardiomyocytes. Consequently, this sugar molecule’s conjugation to the nanoparticle surface may enhance cardiomyocyte uptake of the cardioprotective chemical. To investigate this theory, p38-inhibiting polyketal NPs loaded with SB239063 were functionalized with GlcNAc and injected into a rat model of MI. The findings showed that by preserving the stunned cardiomyocytes, the accumulation of NPs in the heart significantly enhanced cardiac regeneration and function.⁵² In failing cardiac myocytes, aberrant calcium release and unregulated calcium signaling exacerbated cardiac contractility problems and arrhythmias.^53,54 The proteins (e.g., SERCA2a, PLB, RyR2, and STIM1) involved in calcium regulation were bound by the S100A1 protein and N-acetylglucosamine.^55,56 S100A1 expression levels in cardiac tissue appeared to be significantly downregulated in end-stage heart failure. A first-generation adenovirus used for intracoronary delivery of the human S100A1 gene decreased the amount of S100A1 in a chronic heart failure rat model, saving the failing myocardium’s Ca2+ cycling as well as contractile function.⁵⁷ GlcNAc NPs containing S100A1 protein have been shown by Maxwell et al⁵⁸ to regulate calcium signaling pathways and reduce erratic calcium release in failing heart cells. By altering proteins involved in signaling pathways, these bioactive NPs not only effectively administered the therapeutics to the failing heart cells but also had an extra therapeutic effect.⁵⁸

Insulin-like growth factor-1, increases the survival of cardiomyocytes following MI. Consequently, its safe administration at high concentrations to heart-infarcted regions may enhance cardiac remodeling and function.^59,60 This approach was used by Chang et al⁶¹ to demonstrate how, in a mouse model of MI, insulin-like growth factor-1-loaded poly lactic-co-glycolic acid/polyethyleneimine NPs significantly reduced the left ventricular diastolic/systolic dimensions and the infarct size, as well as increased fractional shortening, following injection into the border district of the infarcted part.^61,62 Strong endogenous antioxidant Coenzyme Q10 (CoQ10) has been thoroughly studied for potential application in the management of cardiovascular disease, specifically HF and CAD. It was discovered that giving CoQ10-loaded liposomes to rabbits with an experimental MI extended the intracellular transport of CoQ10 and, as a result, decreased the percentage of the permanently damaged myocardium.⁶³

Apart from pharmaceuticals, DNA and RNA can be delivered by nanotechnology to enhance heart function by altering the expression of cardiac genes and the ensuing release of proteins.⁶⁴ Despite the widespread use of plasmid and viral vectors for gene transfection, these in-vivo research findings have not been verified in human subjects.⁶⁵ For instance, therapeutic genes injected intravenously into heart tissue by viral vectors are dispersed to neighboring organs instead of correctly localizing in the infarcted areas.⁶⁶ Viral vectors encoding genes involved in heart regeneration are injected intramyocardially into the injured area to maximize their efficiency.⁶⁷ However, patients with acute cardiac illness may experience significant side effects from this invasive administration technique. Thus, there is a lot of interest in the creation of substitute carriers for RNA delivery. Cardiovascular illness is among the many diseases that can be treated with DNA and RNA delivered safely and effectively via NPs.

Cell therapy

Cell therapy is the transplantation of therapeutic cells into the myocardium to enable therapeutic myocardial regeneration and/or improvement in cardiac function. These cells include patient-specific cardiomyocytes and bone marrow-derived mesenchymal stem cells, which are primarily obtained by reprogramming human cells to become induced pluripotent cells that differentiate into induced cardiomyocytes.⁶⁸ It is significant to remember that cell therapy is still in its initial stages of development, is undergoing preliminary clinical trials, and is not yet generally accessible for use in clinical settings. A systematic evaluation and meta-analysis conducted in 2014 looked at 23 randomized controlled studies, including adult bone marrow-derived stem cells that were administered to 1255 patients with HF and chronic ischemic heart disease.⁶⁹ Based on data from 8 studies with 494 people, this review showed only low-quality evidence suggesting benefits for mortality at a minimum time of 12 months. Low-quality evidence based on data from 21 trials with 1138 participants suggested that 12-month mortality was not significantly improved. At less than 12 months and at 12 months or more, moderate-quality evidence for improvements in the left ventricular ejection fraction and the New York Heart Association functional class was discovered. There were rarely negative outcomes, and no reports of depressing long-term effects were made.⁶⁹

One of the most popular therapeutic strategies for healing damaged heart tissue and regaining heart function after heart failure is cell replacement. However, due to coronary vein washout, limited cell engraftment and retention are the primary restrictions to cell transplantation.⁷⁰ Reduction of the transplanted therapeutic cell retention is mostly dependent on the immune system. Almost 95–99% of cells that are directly injected into the myocardium often disappear in less than 80 hours.⁷¹ Numerous nanotechnology-based strategies have been created to address the predetermined low cell retention and engraftment problems. These strategies include:

• 1)Safely magnetizing therapeutic cells using magnetic NPs and delivering them to the distressed myocardium by applying an external magnetic field.⁷²
• 2)Developing dual antibody-targeted NPs can be conjugated to the markers on the surface of both therapeutic cells and injured cardiac cells. These types of NPs can connect therapeutic cells to injured cells, facilitating their retention, and improving their therapeutic efficacy.⁷³
• 3)Reducing particles that trigger inflammatory responses after MI to improve cell retention.⁷⁴
• 4)Creating a microenvironment using nanofibrous materials to improve therapeutic cell retention.⁷⁵

Valvular Heart Disease

An in-depth knowledge and comprehension of the mechanical and surface properties of the materials used in heart valve design is necessary for the creation of circulatory heart valves. Therefore, the creation of a replacement heart valve that functions precisely like the native heart valves continues to be a monumental task for biomedical engineers to solve. Securing materials appropriate for replacing soft tissue is a critical component for the creation of artificial heart valves. Not only does the material need to have mechanical characteristics that are comparable to the heart valve it is replacing, but it also needs to have better longevity, biocompatibility, low thrombogenicity, and minimal calcification.⁷⁶

Materials created by combining constituents at the nanoscale are known as nanocomposites. They consist of at least 2 main materials, known as the host or matrix, and an additional supporting element, the guest or nanofiller. Materials for nanocomposite structures might have an organic, inorganic, or hybrid makeup.⁷⁷ Although heart valves can have several problems, the most common one is heart valve failure brought on by mechanical stress, calcification of the heart valve, and problems with blood compatibility.⁷⁸ The severity of the heart valve failure issue and the necessity for more advancements in valve substitutes are highlighted by the National Institutes of Health’s estimate that the 10-year death rate for valve replacements still ranges from 30 to 55%.⁷⁹

Due to their superior qualities, polyhedral oligomeric silsesquioxane-poly (carbonate-urea) urethane (POSS-PCU), bacterial cellulose (BC) with polyvinyl alcohol, carbon nanotubes, graphene oxide, and nano-hydroxyapatite nanocomposites have become increasingly popular as potential biomaterial options for the cardiovascular industry.⁸⁰ POSS-PCU, the result of adding POSS NPs to PCU, was created for various surgical implant applications. PCU’s special nanoscale POSS moieties serve as a cross-linking agent and modify the physicochemical characteristics of this polymer nanocomposite in contrast to its conventional constituents. Numerous essential biological applications, including the first artificial trachea in history, lacrimal duct conduits, and lower limb bypass grafts—all of which are soon to go into clinical trials—were made possible by POSS-PCU.^81–83 As a result, the POSS-PCU nanocomposite’s potential uses for heart valve formation can be expanded.

BC is a viable, sustainable, and biodegradable nanofibrous material. The diameter of BC fibers ranges from 40 to 70 nm and these fibers are very pure and have a better degree of polymerization and excellent crystallinity, thereby giving them a high strength and modulus.⁸⁴ The smaller fiber diameter of BC confers a higher surface area, and its porous structures facilitate the retention of a large amount of water. BC is thermally stable and highly degradable. BC is used in a wide range of applications, such as artificial bones, skin, blood vessels, etc.⁸⁵ BC fibers are strong and ideal for the development of cardiovascular heart valves. Their results indicate that there would be the formation of new networks and fibers with a smaller diameter, resulting in a good increase in the mechanical strength of the resultant nanocomposite. Thus, this nanocomposite with properties mimicking cardiovascular tissues can be a synthetic replacement of cardiovascular tissues such as heart valves.⁸⁶

Another major issue with valves is calcification, a prime factor in the failure of bioprosthetic heart valves.⁸⁷ It increases the heart valve’s susceptibility to cusp tears and structural failure. The process known as “bioprosthesis calcification” occurs when circulating calcium ions and phospholipids with aldehyde groups react chemically to deposit crystalline calcium phosphate and other calcium minerals on the surface of the heart valve.⁸⁷ The commissural and basal regions of cusps, where mechanical stress exposure in heart valves is greatest, are the typical locations for calcific deposition.⁸⁸ Furthermore, it is discovered that several physiological factors also have a role in the calcification of heart valves.⁸⁹ The problem has not yet been fully solved, despite numerous studies being conducted to create a method to reduce the rate of calcification on heart valves. One potential solution to the problem of heart valve calcification is the use of nanocomposites.

Ghanbari et al⁹⁰ investigated the silsesquioxane nanocomposite polymer’s ability to prevent calcification. In this work, an in-vitro technique was used to generate and evaluate POSS-PCU, a new nanocomposite polymeric material. A calcium solution was applied to thin sheets of nanocomposite, PU, and bovine pericardium (BP) that had been fixed with glutaraldehyde. An in-vitro physiological pulsatile pressure device was used to accelerate the calcium solution for 31 days and 4 × 107 cycles. Following that, the samples underwent chemical analysis, x-ray analysis, and microscopy procedures to check for calcification. Stress-strain behavior experiments were used to determine the mechanical and surface properties. Hydrophobicity and surface morphology were also investigated. The extent of calcification varied between the nanocomposite, glutaraldehyde-fixed BP, and PU, according to the data. Although there was a noticeable calcium accumulation on glutaraldehyde-fixed BP and PU, it was not very noticeable on the nanocomposite. When comparing the calcified BP to the periphery areas close to the clamping site, it was found that the maximum calcification occurred in the areas of maximum mechanical stress. It was observed that there was no calcium deposition in the POSS-PCU nanocomposite sample. Nevertheless, the quantitative investigation revealed that the extracted solution had little calcium. However, x-ray and confocal microscopy examinations showed that the PU samples exhibited higher levels of calcium accumulation. The PU sample’s quantitative examination revealed that the extracted solution’s calcium content was higher than the POSS-PCU sample’s (P< 0.05). This finding could be seen as evidence that the PU was more resistant to calcification because it included POSS moieties. Furthermore, it is hypothesized that the POSS NPs modify calcium mobilization and crystallization to change surface calcium binding.⁹⁰ The above is a testament of the advancements in the use of nanotechnology in the field of valvular heart disease.

CONCLUSIONS

We can thank nanotechnology for rapid point-of-care testing with high-sensitivity troponins, that reduce time to diagnosis and treatment. With groundbreaking research in nanotechnology-based coronary stents, patients are expected to have longer-lasting stents with markedly reduced risk of restenosis. In addition, safer cell therapy will revolutionize the management of heart failure patients. Nanotechnology-based novel heart valves are less likely to calcify and resemble native valves in their mechanical properties. We can expect less re-operation as more patients outlive their valves. The future of cardiovascular medicine is brighter than ever, and nanotechnology will be at the forefront of this change.