Cardiac Stromal Cell Patch Integrated with Engineered Microvessels Improves Recovery from Myocardial Infarction in Rats and Pigs

Abstract

The vascularized cardiac patch strategy is promising for ischemic heart repair after myocardial infarction (MI), but current fabrication processes are quite complicated. Vascularized cardiac patches that can promote concurrent restoration of both the myocardium and vasculature at the injured site in a large animal model remain elusive. The safety and therapeutic benefits of a cardiac stromal cell patch integrated with engineered biomimetic microvessels (BMVs) were determined for treating MI. By leveraging a microfluidic method employing hydrodynamic focusing, we constructed the endothelialized microvessels and then encapsulated them together with therapeutic cardiosphere-derived stromal cells (CSCs) in a fibrin gel to generate a prevascularized cardiac stromal cell patch (BMV–CSC patch). We showed that BMV–CSC patch transplantation significantly promoted cardiac function, reduced scar size, increased viable myocardial tissue, promoted neovascularization, and suppressed inflammation in rat and porcine MI models, demonstrating enhanced therapeutic efficacy compared to conventional cardiac stromal cell patches. BMV–CSC patches did not increase renal and hepatic toxicity or exhibit immunogenicity. We noted a significant increase in endogenous progenitor cell recruitment to the peri-infarct region of the porcine hearts treated with BMV–CSC patch as compared to those that received control treatments. These findings establish the BMV–CSC patch as a novel engineered-tissue therapeutic for ischemic tissue repair.

Bioengineering Technologies for Cardiac Regenerative Medicine

“…The cellular patches are generated through seeding of different live cells into various 3D scaffolds. To enhance the survival of the transplanted live cells, the patches have been engineered with mimetic blood vessels ( Su et al, 2018a , 2020 ) or cocultured with ECs ( Shadrin et al, 2017 ). For better integration, the scaffold has been engineered with microneedles ( Tang et al, 2018b ).…”

Exosomes derived from MSC pre‐treated with oridonin alleviates myocardial IR injury by suppressing apoptosis via regulating autophagy activation

“…Moreover, apart from exosomes, some other cell‐based therapeutic approaches have been investigated. For example, it has been reported that the pre‐vascularized cardiac stromal cell patch generated from therapeutic cardiosphere‐derived stromal cells integrated with engineered micro‐vessels evidently improved the process of recovery from myocardial infarction in animal models 30,31 . Moreover, other methods including bispecific antibody inhalation therapy, platelet‐inspired nanocell injection and nanogel‐encapsulated human cardiac stem cell injection were also reported 32‐35 …”

Tunable biomaterials for myocardial tissue regeneration: promising new strategies for advanced biointerface control and improved therapeutic outcomes

“…156 Pre-vascularization of cardiac patches has been proposed as a promising strategy allowing the fabrication of thicker patches without compromising cell viability. For instance, Su et al 157 encapsulated microengineered endothelialized microvessels with an inner and outer diameter of approximately 250 and 550 μm, respectively, in a fibrin gel containing therapeutic cardiospherederived stromal cells (CSCs). The resulting patch released paracrine factors in a sustained manner with levels comparable to that produced during the co-culture of human CSCs and human umbilical vein endothelial cells (HUVECs).…”