Chitosan as Functional Biomaterial for Designing Delivery Systems in Cardiac Therapies

Cardiovascular diseases are a leading cause of mortality across the globe, and transplant surgeries are not always successful since it is not always possible to replace most of the damaged heart tissues, for example in myocardial infarction. Chitosan, a natural polysaccharide, is an important biomaterial for many biomedical and pharmaceutical industries. Based on the origin, degree of deacetylation, structure, and biological functions, chitosan has emerged for vital tissue engineering applications. Recent studies reported that chitosan coupled with innovative technologies helped to load or deliver drugs or stem cells to repair the damaged heart tissue not just in a myocardial infarction but even in other cardiac therapies. Herein, we outlined the latest advances in cardiac tissue engineering mediated by chitosan overcoming the barriers in cardiac diseases. We reviewed in vitro and in vivo data reported dealing with drug delivery systems, scaffolds, or carriers fabricated using chitosan for stem cell therapy essential in cardiac tissue engineering. This comprehensive review also summarizes the properties of chitosan as a biomaterial substrate having sufficient mechanical stability that can stimulate the native collagen fibril structure for differentiating pluripotent stem cells and mesenchymal stem cells into cardiomyocytes for cardiac tissue engineering.

Graphene-Based Scaffolds: Fundamentals and Applications for Cardiovascular Tissue Engineering

Cardiac tissue engineering requires materials that can faithfully recapitulate and support the native in vivo microenvironment while providing a seamless bioelectronic interface. Current limitations of cell scaffolds include the lack of electrical conductivity and suboptimal mechanical properties. Here we discuss how the incorporation of graphene into cellular scaffolds, either alone or in combination with other materials, can affect morphology, function, and maturation of cardiac cells. We conclude that graphene-based scaffolds hold great promise for cardiac tissue engineering.

Cardiac Tissue Engineering for the Treatment of Myocardial Infarction

Poor cell engraftment rate is one of the primary factors limiting the effectiveness of cell transfer therapy for cardiac repair. Recent studies have shown that the combination of cell-based therapy and tissue engineering technology can improve stem cell engraftment and promote the therapeutic effects of the treatment for myocardial infarction. This mini-review summarizes the recent progress in cardiac tissue engineering of cardiovascular cells from differentiated human pluripotent stem cells (PSCs), highlights their therapeutic applications for the treatment of myocardial infarction, and discusses the present challenges of cardiac tissue engineering and possible future directions from a clinical perspective.

Abstract P359: Electroconductive Scaffolds To Mature Induced Pluripotent Stem Cell-derived Cardiomyocytes For Cardiac Tissue Engineering

Heart disease is the leading cause of death worldwide. Cardiac tissue engineering (CTE) aims to repair and replace heart tissue, offering a solution. Induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) could revolutionize CTE due to their theoretical ability to supply limitless patient-specific CMs. However, iPSC-CMs are electrophysiologically immature compared to functional adult CMs, and therefore incapable of sustaining a heartbeat. Thus, a scaffold capable of electrophysiologically maturing iPSC-CMs is needed. My research increases the electroconductivity of electrospun (ES) scaffolds by incorporating carbon nanotubes (CNTs), which I hypothesize will mature iPSC-CMs seeded onto them due to their excellent electroconductive properties. Morphological, biocompatibility, and electrical analyses have been performed on ES polycaprolactone (PCL) and gelatin scaffolds with CNTs incorporated via a ‘sandwich’ and dual deposition method in order to increase electroconductivity. Morphological analyses were performed via ImageJ on SEM images. Fiber diameter and pore size quantification confirmed the ability to exert morphological control by modifying solution properties and ES parameters, which is crucial to achieve biomimicry of the cardiac extracellular matrix. Live/dead assays and immunofluorescence revealed the CNT scaffolds offer high biocompatibility for NIH 3T3 fibroblasts, which attach, proliferate, and migrate well. Electrical analysis performed with a multimeter and two-probe resistance measurement confirms that inclusion of CNTs significantly increases scaffold conductivity, moreso for dual deposition scaffolds than ‘sandwich’ ones, and moreso parallel to the CNT arrays than orthogonally. These results prove the feasibility of using such scaffolds as a method for in vitro electrophysiological iPSC-CM maturation. Next steps include optimization of scaffolds, analysis of iPSC-CM biocompatibility and response, and recapitulation and manipulation of the electrophysiology of cardiac tissue, including quantification of markers for cardiac function and maturity, and assessment of iPSC-CM + scaffold response to electrical pacing.

Abstract P403: Three-dimensional Bioprinting Of Adhesive Cardiac Patch Systems

Rapid advancements in 3D bioprinting have enabled the design of functionalized bioinks to create scaffolds with robust adhesive properties. These constructs are of great interest in cardiac tissue engineering, where the integration of grafted patch with the host myocardium, through sutures, staples, or adhesives, faces risks such as bleeding, cytotoxicity, and infection. We introduce the first generation of functional adhesive bioinks that can be bioprinted through various modalities to fabricate patch structures with intrinsic adhesive properties. A dopamine-modified hyaluronic acid methacrylate (HAMA-Dopa) and gelatin methacrylate (gelMA) composite bioink is used to create the patch via air and embedded bioprinting. Constructs are crosslinked onto a collagen sheet substrate simulating the host cardiac tissue ( Figure 1A-C ). We developed novel in vitro methods to assess adhesion properties of printed patch under shear, tension, or dynamic loading ( Figure 1C ). Our approach allowed for steady and precise application of stress to the adhesion interface. Embedded-printed HAMA-Dopa/gelMA scaffold showed significantly enhanced adhesion strength (1025 Pa) compared to gelMA (495 Pa) and HAMA (477 Pa) control groups under tension, and under shear (548 Pa vs. 234 and 239 Pa). The adhesion strength of air-printed HAMA-Dopa/gelMA constructs was markedly higher (10,128 Pa) than the embedded ones, possibly due to the more effective, in-situ crosslinking. We also investigated the dynamic adhesive properties in aqueous environment using an ex vivo beating heart model. Air-printed HAMA-Dopa/gelMA showed the greatest adhesion under wet conditions, tolerating 345,600 cycles. We further characterized printing fidelity, mechanical properties, swelling, and biocompatibility of HAMA-Dopa/gelMA constructs, demonstrating adequate functionality of this bioprinted adhesive scaffold for cardiac tissue engineering applications. Figure 1 . Summary of workflow to develop bioprinted adhesive scaffolds. A: Embedded (top) or air (bottom) bioprinting was used to create 3D patch geometries. B: Printing fidelity assessment and optimization. C: Different adhesion mechanisms were assessed using novel customized tools and approaches to apply tensile ( C-i ), shear ( C-ii ), and dynamic ( C-iii ) loading.