Fight Aging!

It remains challenging to produce large or thick sections of engineered tissue because there is no widely adopted, feasible approach to creating sufficient dense and structured blood vessel networks. A capillary network is needed to supply the inner sections of larger blocks of tissue, and without this networking cells die due to lack of nutrients and oxygen. While some very promising lines of work exist, such as that under development at Volumetric, they are not yet broadly employed in the research community. This state of affairs limits the applications of tissue engineering to cases in which thin sheets of tissue can be useful, such as the production of a patch for a damaged heart. Even in this type of application, however, and as demonstrated in today's research materials, being able to engineer some form of vascular network improves the outcome considerably.

Researchers have for a few years demonstrated the ability to apply patches of engineered tissue to an injured heart. Various attempts have varied from very simple biodegradable scaffolds that are only intended to increase the survival time of transplanted stem cells and heart muscle cells, to produce a better effect than direct injection of cells into cardiac tissue, to quite sophisticated pseudo-tissue structures, containing chemical cues and varied cell populations, that integrate into the vasculature of the heart. Applying such patches appears a fairly promising approach to increase survival and heart function following heart attack or other damage, but it has yet to make it to the clinic.

A patch that could help heal broken hearts

During a heart attack, or myocardial infarction (MI), a blocked artery and the resulting oxygen deprivation cause massive cardiac cell death, blood vessel impairment, and inflammation. To effectively treat MI, lost heart muscle tissue must regenerate and new blood vessels must form to restore oxygen and nutrients to cells. Scientists have tried to develop patches containing various therapeutic cells to treat MI, but so far most have been too cumbersome to make, or they don't restore both cardiac muscle and blood supply to the injured site. Researchers previously developed a relatively easy-to-make pre-vascularized cardiac patch, which contained engineered microvessels in a fibrin gel spiked with cardiac stromal cells. When implanted into rats after an MI, the cells in the patch secreted growth factors that made cardiac muscle and blood vessels regrow. Now, the researchers wanted to test the patch further in rats, as well as in pigs, which have cardiovascular systems more similar to humans than those of rodents.

The researchers implanted the cardiac patch in rats that recently had a heart attack. Four weeks later, rats that received the patch had less scar tissue, increased cardiac muscle, and improved cardiac pump function compared with untreated rats. The team observed similar effects in pigs that had undergone MI and were treated with the patches. The patch increased recruitment of the pigs' progenitor cells to the damaged area and enhanced the growth of new blood vessels, as well as decreased cardiac cell death and suppressed inflammation. Although prior studies have used blood vessel-forming cells or natural blood vessels to vascularize cardiac patches, this study is the first to demonstrate the success of pre-vascularized cardiac stromal cell patches using microengineered synthetic blood vessels for treating MI in a large animal model.

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

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.