Engineered platforms for mimicking cardiac development and drug screening.

Congenital heart defects are associated with significant health challenges, demanding a deep understanding of the underlying biological mechanisms and, thus, better devices or platforms that can recapitulate human cardiac development. The discovery of human pluripotent stem cells has substantially reduced the dependence on animal models. Recent advances in stem cell biology, genetic editing, omics, microfluidics, and sensor technologies have further enabled remarkable progress in the development of in vitro platforms with increased fidelity and efficiency. In this review, we provide an overview of advancements in in vitro cardiac development platforms, with a particular focus on technological innovation. We categorize these platforms into four areas: two-dimensional solid substrate cultures, engineered substrate architectures that enhance cellular functions, cardiac organoids, and embryos/explants-on-chip models. We conclude by addressing current limitations and presenting future perspectives.

Electroactive Nanomaterials for the Prevention and Treatment of Heart Failure: From Materials and Mechanisms to Applications.

Heart failure (HF) represents a cardiovascular disease that significantly threatens global well-being and quality of life. Electroactive nanomaterials, characterized by their distinctive physical and chemical properties, emerge as promising candidates for HF prevention and management. This review comprehensively examines electroactive nanomaterials and their applications in HF intervention. It presents the definition, classification, and intrinsic characteristics of conductive, piezoelectric, and triboelectric nanomaterials, emphasizing their mechanical robustness, electrical conductivity, and piezoelectric coefficients. The review elucidates their applications and mechanisms: 1) early detection and diagnosis, employing nanomaterial-based sensors for real-time cardiac health monitoring; 2) cardiac tissue repair and regeneration, providing mechanical, chemical, and electrical stimuli for tissue restoration; 3) localized administration of bioactive biomolecules, genes, or pharmacotherapeutic agents, using nanomaterials as advanced drug delivery systems; and 4) electrical stimulation therapies, leveraging their properties for innovative pacemaker and neurostimulation technologies. Challenges in clinical translation, such as biocompatibility, stability, and scalability, are discussed, along with future prospects and potential innovations, including multifunctional and stimuli-responsive nanomaterials for precise HF therapies. This review encapsulates current research and future directions concerning the use of electroactive nanomaterials in HF prevention and management, highlighting their potential to innovating in cardiovascular medicine.

Latest progress of self-healing hydrogels in cardiac tissue engineering.

Cardiovascular diseases represent a significant public health challenge and are responsible for more than 4 million deaths annually in Europe alone (45% of all deaths). Among these, coronary-related heart diseases are a leading cause of mortality, accounting for 20% of all deaths. Cardiac tissue engineering has emerged as a promising strategy to address the limitations encountered after myocardial infarction. This approach aims to improve regulation of the inflammatory and cell proliferation phases, thereby reducing scar tissue formation and restoring cardiac function. In cardiac tissue engineering, biomaterials serve as hosts for cells and therapeutics, supporting cardiac restoration by mimicking the native cardiac environment. Various bioengineered systems, such as 3D scaffolds, injectable hydrogels, and patches play crucial roles in cardiac tissue repair. In this context, self-healing hydrogels are particularly suitable substitutes, as they can restore structural integrity when damaged. This structural healing represents a paradigm shift in therapeutic interventions, offering a more native-like environment compared to static, non-healable hydrogels. Herein, we sharply review the most recent advances in self-healing hydrogels in cardiac tissue engineering and their potential to transform cardiovascular healthcare.

Enhanced Drug Classification Using Machine Learning with Multiplexed Cardiac Contractility Assays.

Cardiac screening of newly discovered drugs remains a longstanding challenge for the pharmaceutical industry. While therapeutic efficacy and cardiotoxicity are evaluated through preclinical biochemical and animal testing, 90% of lead compounds fail to meet safety and efficacy benchmarks during human clinical trials. A preclinical model more representative of the human cardiac response is needed; heart tissue engineered from human pluripotent stem cell derived cardiomyocytes offers such a platform. In this study, three functionally distinct and independently validated engineered cardiac tissue assays are exposed to increasing concentrations of known compounds representing 5 classes of mechanistic action, creating a robust electrophysiology and contractility dataset. Combining results from six individual models, the resulting ensemble algorithm can classify the mechanistic action of unknown compounds with 86.2% predictive accuracy. This outperforms single-assay models and offers a strategy to enhance future clinical trial success align with the recent FDA Modernization Act 2.0.

Insights into the prospects of nanobiomaterials in the treatment of cardiac arrhythmia.

Cardiac arrhythmia, a disorder of abnormal electrical activity of the heart that disturbs the rhythm of the heart, thereby affecting its normal function, is one of the leading causes of death from heart disease worldwide and causes millions of deaths each year. Currently, treatments for arrhythmia include drug therapy, radiofrequency ablation, cardiovascular implantable electronic devices (CIEDs), including pacemakers, defibrillators, and cardiac resynchronization therapy (CRT). However, these traditional treatments have several limitations, such as the side effects of medication, the risks of device implantation, and the complications of invasive surgery. Nanotechnology and nanomaterials provide safer, effective and crucial treatments to improve the quality of life of patients with cardiac arrhythmia. The large specific surface area, controlled physical and chemical properties, and good biocompatibility of nanobiomaterials make them promising for a wide range of applications, such as cardiovascular drug delivery, tissue engineering, and the diagnosis and therapeutic treatment of diseases. However, issues related to the genotoxicity, cytotoxicity and immunogenicity of nanomaterials remain and require careful consideration. In this review, we first provide a brief overview of cardiac electrophysiology, arrhythmia and current treatments for arrhythmia and discuss the potential applications of nanobiomaterials before focusing on the promising applications of nanobiomaterials in drug delivery and cardiac tissue repair. An in-depth study of the application of nanobiomaterials is expected to provide safer and more effective therapeutic options for patients with cardiac arrhythmia, thereby improving their quality of life.

Development of a bacterial cellulose-gelatin composite as a suitable scaffold for cardiac tissue engineering.

PURPOSE: Cardiac tissue engineering is suggested as a promising approach to overcome problems associated with impaired myocardium. This is the first study to investigate the use of BC and gelatin for cardiomyocyte adhesion and growth. METHODS: Bacterial cellulose (BC) membranes were produced by Komagataeibacter xylinus and coated or mixed with gelatin to make gelatin-coated BC (BCG) or gelatin-mixed BC (mBCG) scaffolds, respectively. BC based-scaffolds were characterized via SEM, FTIR, XRD, and AFM. Neonatal rat-ventricular cardiomyocytes (nr-vCMCs) were cultured on the scaffolds to check the capability of the composites for cardiomyocyte attachment, growth and expansion. RESULTS: The average nanofibrils diameter in all scaffolds was suitable (~ 30-65 nm) for nr-vCMCs culture. Pore diameter (≥ 10 µm), surface roughness (~ 182 nm), elastic modulus (0.075 ± 0.015 MPa) in mBCG were in accordance with cardiomyocyte requirements, so that mBCG could better support attachment of nr-vCMCs with high concentration of gelatin, and appropriate surface roughness. Also, it could better support growth and expansion of nr-vCMCs due to submicron scale of nanofibrils and proper elasticity (~ 0.075 MPa). The viability of nr-vCMCs on BC and BCG scaffolds was very low even at day 2 of culture (~ ≤ 40%), but, mBCG could promote a metabolic active state of nr-vCMCs until day 7 (~ ≥ 50%). CONCLUSION: According to our results, mBCG scaffold was the most suitable composite for cardiomyocyte culture, regarding its physicochemical and cell characteristics. It is suggested that improvement in mBCG stability and cell attachment features may provide a convenient scaffold for cardiac tissue engineering.

Application of Nanomaterials in Stem Cell-Based Therapeutics for Cardiac Repair and Regeneration.

Cardiovascular disease is a leading cause of disability and death worldwide. Although the survival rate of patients with heart diseases can be improved with contemporary pharmacological treatments and surgical procedures, none of these therapies provide a significant improvement in cardiac repair and regeneration. Stem cell-based therapies are a promising approach for functional recovery of damaged myocardium. However, the available stem cells are difficult to differentiate into cardiomyocytes, which result in the extremely low transplantation efficiency. Nanomaterials are widely used to regulate the myocardial differentiation of stem cells, and play a very important role in cardiac tissue engineering. This study discusses the current status and limitations of stem cells and cell-derived exosomes/micro RNAs based cardiac therapy, describes the cardiac repair mechanism of nanomaterials, summarizes the recent advances in nanomaterials used in cardiac repair and regeneration, and evaluates the advantages and disadvantages of the relevant nanomaterials. Besides discussing the potential clinical applications of nanomaterials in cardiac therapy, the perspectives and challenges of nanomaterials used in stem cell-based cardiac repair and regeneration are also considered. Finally, new research directions in this field are proposed, and future research trends are highlighted.

Advancing cardiac regeneration through 3D bioprinting: methods, applications, and future directions.

Cardiovascular diseases (CVDs) represent a paramount global mortality concern, and their prevalence is on a relentless ascent. Despite the effectiveness of contemporary medical interventions in mitigating CVD-related fatality rates and complications, their efficacy remains curtailed by an array of limitations. These include the suboptimal efficiency of direct cell injection and an inherent disequilibrium between the demand and availability of heart transplantations. Consequently, the imperative to formulate innovative strategies for cardiac regeneration therapy becomes unmistakable. Within this context, 3D bioprinting technology emerges as a vanguard contender, occupying a pivotal niche in the realm of tissue engineering and regenerative medicine. This state-of-the-art methodology holds the potential to fabricate intricate heart tissues endowed with multifaceted structures and functionalities, thereby engendering substantial promise. By harnessing the prowess of 3D bioprinting, it becomes plausible to synthesize functional cardiac architectures seamlessly enmeshed with the host tissue, affording a viable avenue for the restitution of infarcted domains and, by extension, mitigating the onerous yoke of CVDs. In this review, we encapsulate the myriad applications of 3D bioprinting technology in the domain of heart tissue regeneration. Furthermore, we usher in the latest advancements in printing methodologies and bioinks, culminating in an exploration of the extant challenges and the vista of possibilities inherent to a diverse array of approaches.

Carboxymethyl cellulose-alginate interpenetrating hydroxy ethyl methacrylate crosslinked polyvinyl alcohol reinforced hybrid hydrogel templates with improved biological performance for cardiac tissue engineering.

Cardiac tissue engineering is an emerging approach for cardiac regeneration utilizing the inherent healing responses elicited by the surviving heart using biomaterial templates. In this study, we aimed to develop hydrogel scaffolds for cardiac tissue regeneration following myocardial infarction (MI). Two superabsorbent hydrogels, CAHA2A and CAHA2AP, were developed employing interpenetration chemistry. CAHA2A was constituted with alginate, carboxymethyl cellulose, (hydroxyethyl) methacrylate, and acrylic acid, where CAHA2AP was prepared by interpenetrated CAHA2A with polyvinyl alcohol. Both hydrogels displayed superior physiochemical characteristics, as determined by attenuated total reflection infrared spectroscopy spectral analysis, differential scanning calorimetry measurements, tensile testing, contact angle, water profiling, dye release, and conductivity. In vitro degradation of the hydrogels displayed acceptable weight composure and pH changes. Both hydrogels were hemocompatible, and biocompatible as evidenced by direct contact and MTT assays. The hydrogels promoted anterograde and retrograde migration as determined by the z-stack analysis using H9c2 cells grown with both gels. Additionally, the coculture of the hydrogels with swine epicardial adipose tissue cells and cardiac fibroblasts resulted in synchronous growth without any toxicity. Also, both hydrogels facilitated the production of extracellular matrix by the H9c2 cells. Overall, the findings support an appreciable in vitro performance of both hydrogels for cardiac tissue engineering applications.

Insight into Heart-Tailored Architectures of Hydrogel to Restore Cardiac Functions after Myocardial Infarction.

With permanent heart muscle injury or death, myocardial infarction (MI) is complicated by inflammatory, proliferation and remodeling phases from both the early ischemic period and subsequent infarct expansion. Though in situ re-establishment of blood flow to the infarct zone and delays of the ventricular remodeling process are current treatment options of MI, they fail to address massive loss of viable cardiomyocytes while transplanting stem cells to regenerate heart is hindered by their poor retention in the infarct bed. Equipped with heart-specific mimicry and extracellular matrix (ECM)-like functionality on the network structure, hydrogels leveraging tissue-matching biomechanics and biocompatibility can mechanically constrain the infarct and act as localized transport of bioactive ingredients to refresh the dysfunctional heart under the constant cyclic stress. Given diverse characteristics of hydrogel including conductivity, anisotropy, adhesiveness, biodegradability, self-healing and mechanical properties driving local cardiac repair, we aim to investigate and conclude the dynamic balance between ordered architectures of hydrogels and the post-MI pathological milieu. Additionally, our review summarizes advantages of heart-tailored architectures of hydrogels in cardiac repair following MI. Finally, we propose challenges and prospects in clinical translation of hydrogels to draw theoretical guidance on cardiac repair and regeneration after MI.

Neonatal rat ventricular myocytes interfacing conductive polymers and carbon nanotubes.

Carbon nanotubes (CNTs) have become promising advanced materials and a new tool to specifically interact with electroresponsive cells. Likewise, conductive polymers (CP) appear promising electroactive biomaterial for proliferation of cells. Herein, we have investigated CNT blends with two different conductive polymers, polypyrrole/CNT (PPy/CNT) and PEDOT/CNT to evaluate the growth, survival, and beating behavior of neonatal rat ventricular myocytes (NRVM). The combination of CP/CNT not only shows excellent biocompatibility on NRVM, after 2 weeks of culture, but also exerts functional effects on networks of cardiomyocytes. NRVMs cultured on CNT-based substrates exhibited improved cellular function, i.e., homogeneous, non-arrhythmogenic, and more frequent spontaneous beating; particularly PEDOT/CNT substrates, which yielded to higher beating amplitudes, thus suggesting a more mature cardiac phenotype. Furthermore, cells presented enhanced structure: aligned sarcomeres, organized and abundant Connexin 43 (Cx43). Finally, no signs of induced hypertrophy were observed. In conclusion, the combination of CNT with CP produces high viability and promotes cardiac functionality, suggesting great potential to generate scaffolding supports for cardiac tissue engineering.

Advances in nanobased platforms for cardiovascular diseases: Early diagnosis, imaging, treatment, and tissue engineering.

Cardiovascular diseases (CVDs) present a significant threat to health, with traditional therapeutics based treatment being hindered by inefficiencies, limited biological effects, and resistance to conventional drug. Addressing these challenges requires advanced approaches for early disease diagnosis and therapy. Nanotechnology and nanomedicine have emerged as promising avenues for personalized CVD diagnosis and treatment through theranostic agents. Nanoparticles serve as nanodevices or nanocarriers, efficiently transporting drugs to injury sites. These nanocarriers offer the potential for precise drug and gene delivery, overcoming issues like bioavailability and solubility. By attaching specific target molecules to nanoparticle surfaces, controlled drug release to targeted areas becomes feasible. In the field of cardiology, nanoplatforms have gained popularity due to their attributes, such as passive or active targeting of cardiac tissues, enhanced sensitivity and specificity, and easy penetration into heart and artery tissues due to their small size. However, concerns persist about the immunogenicity and cytotoxicity of nanomaterials, necessitating careful consideration. Nanoparticles also hold promise for CVD diagnosis and imaging, enabling straightforward diagnostic procedures and real-time tracking during therapy. Nanotechnology has revolutionized cardiovascular imaging, yielding multimodal and multifunctional vehicles that outperform traditional methods. The paper provides an overview of nanomaterial delivery routes, targeting techniques, and recent advances in treating, diagnosing, and engineering tissues for CVDs. It also discusses the future potential of nanomaterials in CVDs, including theranostics, aiming to enhance cardiovascular treatment in clinical practice. Ultimately, refining nanocarriers and delivery methods has the potential to enhance treatment effectiveness, minimize side effects, and improve patients' well-being and outcomes.

Recent Advances in Generation of In Vitro Cardiac Organoids.

Cardiac organoids are in vitro self-organizing and three-dimensional structures composed of multiple cardiac cells (i.e., cardiomyocytes, endothelial cells, cardiac fibroblasts, etc.) with or without biological scaffolds. Since cardiac organoids recapitulate structural and functional characteristics of the native heart to a higher degree compared to the conventional two-dimensional culture systems, their applications, in combination with pluripotent stem cell technologies, are being widely expanded for the investigation of cardiogenesis, cardiac disease modeling, drug screening and development, and regenerative medicine. In this mini-review, recent advances in cardiac organoid technologies are summarized in chronological order, with a focus on the methodological points for each organoid formation. Further, the current limitations and the future perspectives in these promising systems are also discussed.

Chitosan-Based Scaffolds for the Treatment of Myocardial Infarction: A Systematic Review.

Cardiovascular diseases (CVD), such as myocardial infarction (MI), constitute one of the world's leading causes of annual deaths. This cardiomyopathy generates a tissue scar with poor anatomical properties and cell necrosis that can lead to heart failure. Necrotic tissue repair is required through pharmaceutical or surgical treatments to avoid such loss, which has associated adverse collateral effects. However, to recover the infarcted myocardial tissue, biopolymer-based scaffolds are used as safer alternative treatments with fewer side effects due to their biocompatibility, chemical adaptability and biodegradability. For this reason, a systematic review of the literature from the last five years on the production and application of chitosan scaffolds for the reconstructive engineering of myocardial tissue was carried out. Seventy-five records were included for review using the "preferred reporting items for systematic reviews and meta-analyses" data collection strategy. It was observed that the chitosan scaffolds have a remarkable capacity for restoring the essential functions of the heart through the mimicry of its physiological environment and with a controlled porosity that allows for the exchange of nutrients, the improvement of the electrical conductivity and the stimulation of cell differentiation of the stem cells. In addition, the chitosan scaffolds can significantly improve angiogenesis in the infarcted tissue by stimulating the production of the glycoprotein receptors of the vascular endothelial growth factor (VEGF) family. Therefore, the possible mechanisms of action of the chitosan scaffolds on cardiomyocytes and stem cells were analyzed. For all the advantages observed, it is considered that the treatment of MI with the chitosan scaffolds is promising, showing multiple advantages within the regenerative therapies of CVD.

Mechanical response of cardiac microtissues to acute localized injury.

After a myocardial infarction (MI), the heart undergoes changes including local remodeling that can lead to regional abnormalities in mechanical and electrical properties, ultimately increasing the risk of arrhythmias and heart failure. Although these responses have been successfully recapitulated in animal models of MI, local changes in tissue and cell-level mechanics caused by MI remain difficult to study in vivo. Here, we developed an in vitro cardiac microtissue (CMT) injury system that through acute focal injury recapitulates aspects of the regional responses seen following an MI. With a pulsed laser, cell death was induced in the center of the microtissue causing a loss of calcium signaling and a complete loss of contractile function in the injured region and resulting in a 39% reduction in the CMT's overall force production. After 7 days, the injured area remained void of cardiomyocytes (CMs) and showed increased expression of vimentin and fibronectin, two markers for fibrotic remodeling. Interestingly, although the injured region showed minimal recovery, calcium amplitudes in uninjured regions returned to levels comparable with control. Furthermore, overall force production returned to preinjury levels despite the lack of contractile function in the injured region. Instead, uninjured regions exhibited elevated contractile function, compensating for the loss of function in the injured region, drawing parallels to changes in tissue-level mechanics seen in vivo. Overall, this work presents a new in vitro model to study cardiac tissue remodeling and electromechanical changes after injury.NEW & NOTEWORTHY We report an in vitro cardiac injury model that uses a high-powered laser to induce regional cell death and a focal fibrotic response within a human-engineered cardiac microtissue. The model captures the effects of acute injury on tissue response, remodeling, and electromechanical recovery in both the damaged region and surrounding healthy tissue, modeling similar changes to contractile function observed in vivo following myocardial infarction.

Human Heart Anoxia and Reperfusion Tissue (HEART) Model for the Rapid Study of Exosome Bound miRNA Expression As Biomarkers for Myocardial Infarction.

Current biomarkers for myocardial infarction (MI) diagnosis are typically late markers released upon cell death, incapable of distinguishing between ischemic and reperfusion injury and can be symptoms of other pathologies. Circulating microRNAs (miRNAs) have recently been proposed as alternative biomarkers for MI diagnosis; however, detecting the changes in the human cardiac miRNA profile during MI is extremely difficult. Here, to study the changes in miRNA levels during acute MI, a heart-on-chip model with a cardiac channel, containing human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes in human heart decellularized matrix and collagen, and a vascular channel, containing hiPSC-derived endothelial cells, is developed. This model is exposed to anoxia followed by normoxia to mimic ischemia and reperfusion, respectively. Using a highly sensitive miRNA biosensor that the authors developed, the exact same increase in miR-1, miR-208b, and miR-499 levels in the MI-on-chip and the time-matched human blood plasma samples collected before and after ischemia and reperfusion, is shown. That the surface marker profile of exosomes in the engineered model changes in response to ischemic and reperfusion injury, which can be used as biomarkers to detect MI, is also shown. Hence, the MI-on-chip model developed here can be used in biomarker discovery.

A deep dive into the darning effects of biomaterials in infarct myocardium: current advances and future perspectives.

Myocardial infarction (MI) occurs due to the obstruction of coronary arteries, a major crux that restricts blood flow and thereby oxygen to the distal part of the myocardium, leading to loss of cardiomyocytes and eventually, if left untreated, leads to heart failure. MI, a potent cardiovascular disorder, requires intense therapeutic interventions and thereby presents towering challenges. Despite the concerted efforts, the treatment strategies for MI are still demanding, which has paved the way for the genesis of biomaterial applications. Biomaterials exhibit immense potentials for cardiac repair and regeneration, wherein they act as extracellular matrix replacing scaffolds or as delivery vehicles for stem cells, protein, plasmids, etc. This review concentrates on natural, synthetic, and hybrid biomaterials; their function; and interaction with the body, mechanisms of repair by which they are able to improve cardiac function in a MI milieu. We also provide focus on future perspectives that need attention. The cognizance provided by the research results certainly indicates that biomaterials could revolutionize the treatment paradigms for MI with a positive impact on clinical translation.

Electrospun electroconductive constructs of aligned fibers for cardiac tissue engineering.

Myocardial infarction remains the leading cause of death in the western world. Since the heart has limited regenerative capabilities, several cardiac tissue engineering (CTE) strategies have been proposed to repair the damaged myocardium. A novel electrospun construct with aligned and electroconductive fibers combining gelatin, poly(lactic-co-glycolic) acid and polypyrrole that may serve as a cardiac patch is presented. Constructs were characterized for fiber alignment, surface wettability, shrinkage and swelling behavior, porosity, degradation rate, mechanical properties, and electrical properties. Cell-biomaterial interactions were studied using three different types of cells, Neonatal Rat Ventricular Myocytes (NRVM), human lung fibroblasts (MRC-5) and induced pluripotent stem cells (iPSCs). All cell types showed good viability and unique organization on construct surfaces depending on their phenotype. Finally, we assessed the maturation status of NRVMs after 14 days by confocal images and qRT-PCR. Overall evidence supports a proof-of-concept that this novel biomaterial construct could be a good candidate patch for CTE applications.

A Change of Heart: Human Cardiac Tissue Engineering as a Platform for Drug Development.

PURPOSE OF REVIEW: Human cardiac tissue engineering holds great promise for early detection of drug-related cardiac toxicity and arrhythmogenicity during drug discovery and development. We describe shortcomings of the current drug development pathway, recent advances in the development of cardiac tissue constructs as drug testing platforms, and the challenges remaining in their widespread adoption. RECENT FINDINGS: Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been used to develop a variety of constructs including cardiac spheroids, microtissues, strips, rings, and chambers. Several ambitious studies have used these constructs to test a significant number of drugs, and while most have shown proper negative inotropic and arrhythmogenic responses, few have been able to demonstrate positive inotropy, indicative of relative hPSC-CM immaturity. Several engineered human cardiac tissue platforms have demonstrated native cardiac physiology and proper drug responses. Future studies addressing hPSC-CM immaturity and inclusion of patient-specific cell lines will further advance the utility of such models for in vitro drug development.

Progress in Bioengineering Strategies for Heart Regenerative Medicine.

The human heart has the least regenerative capabilities among tissues and organs, and heart disease continues to be a leading cause of mortality in the industrialized world with insufficient therapeutic options and poor prognosis. Therefore, developing new therapeutic strategies for heart regeneration is a major goal in modern cardiac biology and medicine. Recent advances in stem cell biology and biotechnologies such as human pluripotent stem cells (hPSCs) and cardiac tissue engineering hold great promise for opening novel paths to heart regeneration and repair for heart disease, although these areas are still in their infancy. In this review, we summarize and discuss the recent progress in cardiac tissue engineering strategies, highlighting stem cell engineering and cardiomyocyte maturation, development of novel functional biomaterials and biofabrication tools, and their therapeutic applications involving drug discovery, disease modeling, and regenerative medicine for heart disease.