Cardiac and stem cell-cocooned hybrid microspheres: A multi factorial design approach

Cell therapy is a promising approach for the treatment of patients suffering from myocardial infarction. Most recent therapies involve direct injection of cells into the damaged heart tissue to induce regeneration and help restore its functions, however, anoikis and the harsh environment at the sight of injection limit the therapeutic efficacy of current techniques. Biopolymeric microspheres such as alginate have been widely used for cells encapsulation and delivery for cell therapy applications. However, majority of these techniques are not standardized that is a big challenge for translation into clinically-relevant treatment options. In addition, purely-alginate base microspheres are limited by poor biodegradability and lack of strong interaction between the encapsulated cells and their surrounding alginate matrix. In this work, we have shown that the addition of type I collagen into alginate microspheres, systematically optimized by a multivariate experimental design, improves the biocompatibility of the microspheres towards induced pluripotent stem cells (iPS), cardiomyocytes, and blood outgrowth endothelial cells (BOEC), whilst improving diffusion between outside environment and the inner sphere. The addition of collagen allows for multiple routes for sphere degradation leading to potentially greater control over cell release once delivered. Mathematical models were developed and utilized to effectively evaluate and predict the influence of various factors such as polymer ratios, micronization air flow rate, and air-gap distance on spheres size and shape, which play a key role in cell viability, degradation rate of microspheres, as well as controlled production of the cell cocoons toward clinically-relevant cell therapies for treatment of myocardial infarction.