Biomaterials For Cardiac Tissue Engineering Research Articles

MXene functionalized collagen biomaterials for cardiac tissue engineering driving iPSC-derived cardiomyocyte maturation

Electroconductive biomaterials are gaining significant consideration for regeneration in tissues where electrical functionality is of crucial importance, such as myocardium, neural, musculoskeletal, and bone tissue. In this work, conductive biohybrid platforms were engineered by blending collagen type I and 2D MXene (Ti3C2Tx) and afterwards covalently crosslinking; to harness the biofunctionality of the protein component and the increased stiffness and enhanced electrical conductivity (matching and even surpassing native tissues) that two-dimensional titanium carbide provides. These MXene platforms were highly biocompatible and resulted in increased proliferation and cell spreading when seeded with fibroblasts. Conversely, they limited bacterial attachment (Staphylococcus aureus) and proliferation. When neonatal rat cardiomyocytes (nrCMs) were cultured on the substrates increased spreading and viability up to day 7 were studied when compared to control collagen substrates. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were seeded and stimulated using electric-field generation in a custom-made bioreactor. The combination of an electroconductive substrate with an external electrical field enhanced cell growth, and significantly increased cx43 expression. This in vitro study convincingly demonstrates the potential of this engineered conductive biohybrid platform for cardiac tissue regeneration.

Progress in Biomaterials for Cardiac Tissue Engineering and Regeneration.

Cardiovascular diseases are one of the leading global causes of morbidity and mortality, posing considerable health and economic burden on patients and medical systems worldwide. This phenomenon is attributed to two main motives: poor regeneration capacity of adult cardiac tissues and insufficient therapeutic options. Thus, the context calls for upgrading treatments to deliver better outcomes. In this respect, recent research has approached the topic from an interdisciplinary perspective. Combining the advances encountered in chemistry, biology, material science, medicine, and nanotechnology, performant biomaterial-based structures have been created to carry different cells and bioactive molecules for repairing and restoring heart tissues. In this regard, this paper aims to present the advantages of biomaterial-based approaches for cardiac tissue engineering and regeneration, focusing on four main strategies: cardiac patches, injectable hydrogels, extracellular vesicles, and scaffolds and reviewing the most recent developments in these fields.

Recent Advances in Designing Electroconductive Biomaterials for Cardiac Tissue Engineering.

Implantable cardiac patches and injectable hydrogels are among the most promising therapies for cardiac tissue regeneration following myocardial infarction. Incorporating electrical conductivity into these patches and hydrogels is found to be an efficient method to improve cardiac tissue function. Conductive nanomaterials such as carbon nanotube, graphene oxide, gold nanorod, as well as conductive polymers such as polyaniline, polypyrrole, and poly(3,4-ethylenedioxythiophene):polystyrene sulfonate are appealing because they possess the electroconductive properties of semiconductors with ease of processing and have potential to restore electrical signaling propagation through the infarct area. Numerous studies have utilized these materials for regeneration of biological tissues that possess electrical activities, such as cardiac tissue. In this review, recent studies on the use of electroconductive materials for cardiac tissue engineering and their fabrication methods are summarized. Moreover, recent advances in developing electroconductive materials for delivering therapeutic agents as one of emerging approaches for treating heart diseases and regenerating damaged cardiac tissues are highlighted.

Stimuli-responsive biomaterials for cardiac tissue engineering and dynamic mechanobiology.

Since the term “smart materials” was put forward in the 1980s, stimuli-responsive biomaterials have been used as powerful tools in tissue engineering, mechanobiology, and clinical applications. For the purpose of myocardial repair and regeneration, stimuli-responsive biomaterials are employed to fabricate hydrogels and nanoparticles for targeted delivery of therapeutic drugs and cells, which have been proved to alleviate disease progression and enhance tissue regeneration. By reproducing the sophisticated and dynamic microenvironment of the native heart, stimuli-responsive biomaterials have also been used to engineer dynamic culture systems to understand how cardiac cells and tissues respond to progressive changes in extracellular microenvironments, enabling the investigation of dynamic cell mechanobiology. Here, we provide an overview of stimuli-responsive biomaterials used in cardiovascular research applications, with a specific focus on cardiac tissue engineering and dynamic cell mechanobiology. We also discuss how these smart materials can be utilized to mimic the dynamic microenvironment during heart development, which might provide an opportunity to reveal the fundamental mechanisms of cardiomyogenesis and cardiac maturation.

Natural Biomaterials for Cardiac Tissue Engineering: A Highly Biocompatible Solution.

Cardiovascular diseases (CVD) constitute a major fraction of the current major global diseases and lead to about 30% of the deaths, i.e., 17.9 million deaths per year. CVD include coronary artery disease (CAD), myocardial infarction (MI), arrhythmias, heart failure, heart valve diseases, congenital heart disease, and cardiomyopathy. Cardiac Tissue Engineering (CTE) aims to address these conditions, the overall goal being the efficient regeneration of diseased cardiac tissue using an ideal combination of biomaterials and cells. Various cells have thus far been utilized in pre-clinical studies for CTE. These include adult stem cell populations (mesenchymal stem cells) and pluripotent stem cells (including autologous human induced pluripotent stem cells or allogenic human embryonic stem cells) with the latter undergoing differentiation to form functional cardiac cells. The ideal biomaterial for cardiac tissue engineering needs to have suitable material properties with the ability to support efficient attachment, growth, and differentiation of the cardiac cells, leading to the formation of functional cardiac tissue. In this review, we have focused on the use of biomaterials of natural origin for CTE. Natural biomaterials are generally known to be highly biocompatible and in addition are sustainable in nature. We have focused on those that have been widely explored in CTE and describe the original work and the current state of art. These include fibrinogen (in the context of Engineered Heart Tissue, EHT), collagen, alginate, silk, and Polyhydroxyalkanoates (PHAs). Amongst these, fibrinogen, collagen, alginate, and silk are isolated from natural sources whereas PHAs are produced via bacterial fermentation. Overall, these biomaterials have proven to be highly promising, displaying robust biocompatibility and, when combined with cells, an ability to enhance post-MI cardiac function in pre-clinical models. As such, CTE has great potential for future clinical solutions and hence can lead to a considerable reduction in mortality rates due to CVD.

Silk-Based Biomaterials for Cardiac Tissue Engineering.

Cardiovascular diseases are one of the leading causes of death globally. Among various cardiovascular diseases, myocardial infarction is an important one. Compared with conventional treatments, cardiac tissue engineering provides an alternative to repair and regenerate the injured tissue. Among various types of materials used for tissue engineering applications, silk biomaterials have been increasingly utilized due to their biocompatibility, biological functions, and many favorable physical/chemical properties. Silk biomaterials are often used alone or in combination with other materials in the forms of patches or hydrogels, and serve as promising delivery systems for bioactive compounds in tissue engineering repair scenarios. This review focuses primarily on the promising characteristics of silk biomaterials and their recent advances in cardiac tissue engineering.

An Injectable Conductive Three-Dimensional Elastic Network by Tangled Surgical-Suture Spring for Heart Repair.

Designing scaffolds with persistent elasticity and conductivity to mimic microenvironments becomes a feasible way to repair cardiac tissue. Injectable biomaterials for cardiac tissue engineering have demonstrated the ability to restore cardiac function by preventing ventricular dilation, enhancing angiogenesis, and improving conduction velocity. However, limitations are still among them, such as poor mechanical stability, low conductivity, and complicated procedure. Here, we developed thermal plastic poly(glycolic acid) surgical suture and mussel-inspired conductive particle's adhesion into a highly elastic, conductive spring-like coils. The polypyrrole (PPy)-coated biospring acted as an electrode and then was assembled into a solid-state supercapacitor. After being injected through a syringe needle (0.33 mm inner diameter), the tangled coils formed an elastically conductive three-dimensional (3-D) network to modulate cardiac function. We found that cardiomyocytes (CMs) grew along the spring coils' track with elongated morphologies and formed highly oriented sarcomeres. The biospring enhanced the CMs' maturation in synchronous contraction accompanied by high expressions of cardiac-specific proteins, α-actinin, and connexin 43 (cx43). After the elastic, conductive biosprings were injected into the myocardial infarction (MI) area, the left ventricular fractional shortening was improved by about 12.6% and the infarct size was decreased by about 34%. Interestingly, the spring can be utilized as a sensor to measure the CMs' contractile force, which was 1.57 × 10-3 ± 0.26 × 10-3 mN (∼4.1 × 106 cells). Accordingly, this study highlights an injectable biospring to form a tangled conductive 3-D network in vivo for MI repair.

The rationale and emergence of electroconductive biomaterial scaffolds in cardiac tissue engineering.

The human heart possesses minimal regenerative potential, which can often lead to chronic heart failure following myocardial infarction. Despite the successes of assistive support devices and pharmacological therapies, only a whole heart transplantation can sufficiently address heart failure. Engineered scaffolds, implantable patches, and injectable hydrogels are among the most promising solutions to restore cardiac function and coax regeneration; however, current biomaterials have yet to achieve ideal tissue regeneration and adequate integration due a mismatch of material physicochemical properties. Conductive fillers such as graphene, carbon nanotubes, metallic nanoparticles, and MXenes and conjugated polymers such as polyaniline, polypyrrole, and poly(3,4-ethylendioxythiophene) can possibly achieve optimal electrical conductivities for cardiac applications with appropriate suitability for tissue engineering approaches. Many studies have focused on the use of these materials in multiple fields, with promising effects on the regeneration of electrically active biological tissues such as orthopedic, neural, and cardiac tissue. In this review, we critically discuss the role of heart electrophysiology and the rationale toward the use of electroconductive biomaterials for cardiac tissue engineering. We present the emerging applications of these smart materials to create supportive platforms and discuss the crucial role that electrical stimulation has been shown to exert in maturation of cardiac progenitor cells.

Native cardiac environment and its impact on engineering cardiac tissue.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) generally have an immature fetal-like phenotype when directly compared to isolated CMs from human hearts, despite significant advance in differentiation of human pluripotent stem cells (hPSCs) to multiple cardiac lineages. Therefore, hPSC-CMs may not accurately mimic all facets of healthy and diseased human adult CMs. During embryonic development, the cardiac extracellular matrix (ECM) experiences a gradual assembly of matrix proteins that transits along the maturation of CMs. Mimicking these dynamic stages may contribute to hPSC-CMs maturation in vitro. Thus, in this review, we describe the progressive build-up of the cardiac ECM during embryonic development, the ECM of the adult human heart and the application of natural and synthetic biomaterials for cardiac tissue engineering with hPSC-CMs.

Conductive biomaterials in cardiac tissue engineering

Conductive biomaterials (including conductive polymer, carbon-base materials, nanogold, and conductive silicon nanowires etc.) with prominent electrical conductivity, good cellular response, and promotion of cell-cell signaling transduction are possibly more suitable for cardiac tissue engineering. To date, their excellent properties catch more attention of the researchers to investigate their roles in life science research. Due to the limited therapeutic approaches of myocardial infarction (MI), engineered cardiac patches have received more attention in the treatment of MI. While, conductive biomaterial taken as a scaffold for cardiac tissue engineering is a promising strategy to repair infarct myocardium and improve the cardiac function. In this review, we summarized the fabrication of various conductive biomaterials for cardiac tissue engineering, and discuss the interaction between the conductive biomaterials and the cells [cardiomyocytes (CMs) and stem cells]. The advance of conductive biomaterials in tissue engineering, regenerative medicine and bio-sensing are also demonstrated.

Strategies for the chemical and biological functionalization of scaffolds for cardiac tissue engineering: a review.

The development of biomaterials for cardiac tissue engineering (CTE) is challenging, primarily owing to the requirement of achieving a surface with favourable characteristics that enhances cell attachment and maturation. The biomaterial surface plays a crucial role as it forms the interface between the scaffold (or cardiac patch) and the cells. In the field of CTE, synthetic polymers (polyglycerol sebacate, polyethylene glycol, polyglycolic acid, poly-l-lactide, polyvinyl alcohol, polycaprolactone, polyurethanes and poly(N-isopropylacrylamide)) have been proven to exhibit suitable biodegradable and mechanical properties. Despite the fact that they show the required biocompatible behaviour, most synthetic polymers exhibit poor cell attachment capability. These synthetic polymers are mostly hydrophobic and lack cell recognition sites, limiting their application. Therefore, biofunctionalization of these biomaterials to enhance cell attachment and cell material interaction is being widely investigated. There are numerous approaches for functionalizing a material, which can be classified as mechanical, physical, chemical and biological. In this review, recent studies reported in the literature to functionalize scaffolds in the context of CTE, are discussed. Surface, morphological, chemical and biological modifications are introduced and the results of novel promising strategies and techniques are discussed.

Biomaterials for cardiac tissue engineering

The heart is the first organ to start functioning in a human (at three weeks gestation), often before a mother knows she is expecting. It is also the last organ that remains functional, just before death. The first beats are relatively slow and irregular, peaking at 7 weeks gestation at around 3 Hz, more specifically 175 bpm, then decreasing gradually to 140–150 bpm before birth [1]. Subsequently, in the post-natal period, during childhood and into adulthood, the beating rate will further decrease gradually to reach the resting rate of 1 Hz, 60 bpm, on average, in an adult human. The heart will beat approximately 2.5–3.2 billion times and in a life-time [2] of an individual, pumping 175–224 millions of liters of blood throughout the body. This remarkable and truly unique function of the heart is afforded by a sub-set of unique cells in the heart muscle, termed cardiomyocytes, that have an ability to contract in response to electrical stimulation. Heart muscle, the myocardium, is a powerhouse that works to pump the blood throughout the body. The synchronous and integrated action of the myocardial cardiomyocytes is afforded by several structural characteristics: the cells are aligned in parallel with the orientation angle changing through the ventricular wall enabling the ventricle to twist as it contracts, in an attempt to push as much blood out as possible. Cardiomyocytes are intimately connected to one another, directly through gap junctions, enabling electrical impulses to travel around as well as through the cells contributing to the synchronous contractile response. Cardiomyocytes have limited ability to proliferate, as recent studies have conclusively shown that adult humans will replace at most of 50% of the cardiomyocytes they were born with during the average lifetime of 80 years, with an average proliferation rate less than 1% per year [3]. The vision of cardiac tissue engineering is to develop in the laboratory, high-fidelity mimics of native human tissue for modelling of physiology and disease, or ultimately to repair the damaged or impaired heart muscle. For this effort to be successful, one needs to carefully select the source of cardiomyocytes, develop biomaterials that will support the function and assembly of these cells, and often to cultivate these constructs in bioreactors that are focused on providing appropriate electromechanical stimulation. This special section is focused on biomaterials for cardiac tissue engineering. In general, the appropriate biomaterial for cardiac tissue engineering should be as unique as the heart itself: it should be highly flexible, elastic and capable of enduring millions of contraction cycles, while supporting the seeded cell viability and differentiated phenotype both in vitro and in vivo. The special section combines original research papers and review articles that present recent progress in development of cardiac tissue engineering biomaterials. It discusses potential cell sources in original papers [4, 5] and reviews [6]. The use of various hydrogels for cardiovascular tissue engineering is reviewed [7, 8] and original papers on development of brand new scaffold materials that incorporate architectural complexity of the native myocardium are presented [9, 10]. An approach to increase smooth muscle cell elastogenesis in vitro is presented, an important step towards increasing elasticity during matrix remodelling in engineered tissues [11]. The featured reviews present recent progress in assembling cells and matrix into functional tissues by 3D printing [12], and microfabrication for the purposes of personalization, disease modelling and drug discovery [6, 13]. Once the cells are injected or placed with a biomaterial matrix at the desired site in the heart, their fate needs to be tracked in vivo and this special section brings an original paper on in vivo tracking of angiogenic cells transplanted into rodent hearts [14]. Finally, the progress of in vivo pre-clinical studies with engineered cardiac tissues on biomaterial matrices are reviewed [15].