Tunable electroconductive decellularized extracellular matrix hydrogels for engineering human cardiac microphysiological systems

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer tremendous potential for use in engineering human tissues for regenerative therapy and drug screening.However, differentiated cardiomyocytes are phenotypically immature, reducing assay reliability when translating in vitro results to clinical studies and precluding hiPSC-derived cardiac tissues from therapeutic use in vivo. To address this, we have developed hybrid hydrogels comprised of decellularized porcine myocardial extracellular matrix (dECM) and reduced graphene oxide (rGO) to provide a more instructive microenvironment for proper cellular and tissue development. A tissue-specific protein profile was preserved post-decellularization, and through the modulation of rGO content and degree of reduction, the mechanical and electrical properties of the hydrogels could be tuned. Engineered heart tissues (EHTs) generated using dECM-rGO hydrogel scaffolds and hiPSC-derived cardiomyocytes exhibited significantly increased twitch forces at 14 days of culture and had increased the expression of genes that regulate contractile function. Similar improvements in various aspects of electrophysiological function, such as calcium-handling, action potential duration, and conduction velocity, were also induced by the hybrid biomaterial.We also demonstrate that dECM-rGO hydrogels can be used as a bioink to print cardiac tissues in a high-throughput manner, and these tissues were utilized to assess the proarrhythmic potential of cisapride. Action potential prolongation and beat interval irregularities was observed in dECM-rGO tissues at clinical doses of cisapride, indicating that the enhanced maturation of these tissues corresponded well with a capability to produce physiologically relevant drug responses.

Biomaterials-based Approaches for Cardiac Regeneration

“… 91) Three-dimensional myocardial matrix-graphene composite scaffolds that mimic the electrical, mechanical and biochemical environmental cues are currently in transition to injectable forms that would allow for testing in vivo. 92) Other approaches seek to activate beneficial cellular processes to improve cell viability and retention when deposited. In the past decade, injectable hydrogels have become increasingly investigated for clinical potential.…”

Bioengineering platforms for cell therapeutics derived from pluripotent and direct reprogramming

“…Recently, Tsui et al developed a hybrid hydrogel composed of decellularized myocardial ECM and reduced graphene oxide. 107 The mechanical and electrical properties of the hydrogel could be tuned. The engineered cardiac tissue with iPSC-CMs in this hydrogel system showed enhanced contractile function and improved electrophysiological function.…”

Recent Advances on Stimuli-Responsive Hydrogels Based on Tissue-Derived ECMs and Their Components: Towards Improving Functionality for Tissue Engineering and Controlled Drug Delivery

“…Therefore, the use of phenotypically immature precursors has been the most straightforward and cost-effective solution, as it eliminates the need of acquiring pluripotent stem cells and implementing precisely controlled differentiation regimes every time [ 139 ]. Accordingly, several electroconductive dECM-based hydrogels have been envisioned for improving the maturation of these tissues by promoting electrically active phenotypes in biomimetic microenvironments [ 49 ]. Tsui and colleagues, for instance, developed an rGO-embedded myocardial dECM hydrogel that showed high hiPSC-derived cardiomyocyte viability after 35 days and increased contractile and electrophysiological function by tuning rGO reduction degree and concentration within the bioink [ 49 ].…”

“…Accordingly, several electroconductive dECM-based hydrogels have been envisioned for improving the maturation of these tissues by promoting electrically active phenotypes in biomimetic microenvironments [ 49 ]. Tsui and colleagues, for instance, developed an rGO-embedded myocardial dECM hydrogel that showed high hiPSC-derived cardiomyocyte viability after 35 days and increased contractile and electrophysiological function by tuning rGO reduction degree and concentration within the bioink [ 49 ]. Alternatively, Roshanbinfar and colleagues developed an electroconductive hydrogel based on pericardial tissue-derived dECM and carbodihydrazide-functionalized multi-walled CNTs (MWCNTs) with embedded hiPSC-derived cardiomyocytes for engineering cardiac tissue [ 140 ].…”

“…To circumvent this, several studies have functionalized their surfaces with hydrophilic agents [48,132,133], controlled the reduction degree of graphene oxide (GO) by using weaker reducing agents [49], or included hydrophobic moieties within the hydrogels to promote hydrophobic or π-π stacking interactions with these nanostructured materials [129]. For instance, Shin and colleagues devised a catechol-functionalized HA hydrogel where CNTs were stably dispersed along with polypyrrole nanocomposites through hydrophobic interactions with the present catechol moieties [129].…”