Tunable Human Myocardium Derived Decellularized Extracellular Matrix for 3D Bioprinting and Cardiac Tissue Engineering

Abstract

The generation of 3D tissue constructs with multiple cell types and matching mechanical properties remains a challenge in cardiac tissue engineering. Recently, 3D bioprinting has become a powerful tool to achieve these goals. Decellularized extracellular matrix (dECM) is a common scaffold material due to providing a native biochemical environment. Unfortunately, dECM’s low mechanical stability prevents usage for bioprinting applications alone. In this study, we developed bioinks composed of decellularized human heart ECM (dhECM) with either gelatin methacryloyl (GelMA) or GelMA-methacrylated hyaluronic acid (MeHA) hydrogels dual crosslinked with UV light and microbial transglutaminase (mTGase). We characterized the bioinks’ mechanical, rheological, swelling, printability, and biocompatibility properties. Composite GelMA–MeHA–dhECM (GME) hydrogels demonstrated improved mechanical properties by an order of magnitude compared to the GelMA–dhECM (GE) hydrogels. All hydrogels were extrudable and compatible with human induced pluripotent stem cell derived cardiomyocytes (iCMs) and human cardiac fibroblasts (hCFs). Tissue-like beating of the printed constructs with striated sarcomeric alpha-actinin and connexin 43 expression was observed. The order of magnitude difference between the elastic modulus of these hydrogel composites offers applications in in vitro modeling of the myocardial infarct boundary. Here, as a proof of concept, we created an infarct boundary region with control over the mechanical properties along with the cellular and macromolecular content through printing iCMs with GE bioink and hCFs with GME bioink.

Extracellular Matrix-Based Biomaterials for Cardiovascular Tissue Engineering

“…The constructs exhibited contractile function. Cardiac tissue-derived ECM has also been shown to promote in vitro differentiation and maturation of cardiomyocytes derived from human embryonic stem cells or human induced pluripotent stem cells [78,79]. Bosara et al developed hydrogels using decellularized human myocardium-derived ECM with gelatin methacryloyl (GelMA) or GelMA-methacrylated hyaluronic acid (MeHA).…”

Bioengineering Systems for Modulating Notch Signaling in Cardiovascular Development, Disease, and Regeneration

“…The extrusion-based method is commonly used in bioprinting due to superior print speed [87]. Bioprinting ushers' advantages, including patient-derived anatomical shape via computed tomography (CT) images, forming complex organization structure of desired tissue, manipulating cell distribution in a printed construct (Figure 2I,j) [88][89][90]. Furthermore, the effect of Notch signaling inhibition on a bioprinted cardiac patch was studied.…”

Cardiac Tissue Engineering for the Treatment of Myocardial Infarction

“…In recent years, the rapid development of 3D printing technology enabled the construction of hydrogels and myocardial patches into highly precise and repeatable nanoscale 3D structures using multiple cell types. Biomaterials that are used for the 3D printing of myocardial tissue include alginate [93,94], fibrin [94], collagen [95,96], gelatin [97][98][99], hyaluronic acid [98], hydroxypropyl chitin [100], thixotropic magnesium phosphate [101], gellan gum [99], and decellularized ECM scaffolds [102][103][104]. Maiullari et al manufactured a vascularized heart tissue using human umbilical vein endothelial cell (HUVEC) and miPSC-CMs using alginate and PEG/fibrin hydrogel extruded through a microfluidic printing head [94].…”

“…This tissue-specific bioink may provide crucial cues for improving cell engraftment, survival, and function. Bioinks composed of decellularized human heart tissue with either gelatin methacryloyl (GelMA) or GelMA-methacrylated hyaluronic acid (MeHA) hydrogels were developed [104]. It was observed that all bioinks were compatible with hiPSC-CMs and human cardiac fibroblasts.…”