Optimizing Therapeutic Revascularization by Endothelial Cell_Transplantation

Yale University, New Haven CT

Investigators

Abstract

Project Summary This diversity supplement will support the work of Sadiyah Parveen, a PhD candidate in biomedical engineering, to develop innovative drug delivery materials for controlled release of proteins and nucleic acids, tested within our 3D bioprinted engineered skin model. The primary objective of the parent grant is to create systems capable of safely and reliably releasing growth factors and mRNA. While the initial focus was on using alginate and poly(amine-co-esters) (PACE) materials, recent discoveries of the new material, poly(PEGMA), will offer enhanced functionality, including prolonged and triggered release. Specifically, alginate microparticles, although biocompatible, often exhibit burst release kinetics, whereas poly(PEGMA), with its stable chemical cross-linking and tunable properties, offers a promising alternative for sustained protein release. Additionally, current cationic polymer-based systems (i.e., PACE) provide sustained mRNA release but require further optimization for extended delivery. Poly(PEGMA) microparticles, with their hydrogel-like properties and controlled degradation, can potentially maintain therapeutic mRNA levels for longer durations, thereby promoting better vascularization and tissue regeneration. In aim 1, we will engineer microparticles composed of poly(PEGMA), a synthetic brush-type polymer with pendant polyethylene glycol (PEG) ligands, to encapsulate and release vascular endothelial growth factor (VEGF) in a sustained manner. These poly(PEGMA) microparticles will be compared to alginate microparticles from the parent grant. We hypothesize that poly(PEGMA) microparticles will provide superior control over protein release kinetics compared to alginate, resulting in improved vascularization within 3D bioprinted human skin constructs. In aim 2, we will focus on developing poly(PEGMA) microparticles that enable controlled or triggered release of mRNA polyplexes to transfect endothelial cells (ECs), promoting vascular growth and maturation. These new systems will be evaluated for their ability to slowly release mRNA encoding Bcl2, an anti-apoptotic protein, and will be compared to the PACE nanoparticle systems studied in the parent grant. We hypothesize that poly(PEGMA) microparticles loaded with mRNA polyplexes will achieve efficient and controlled delivery of Bcl2 mRNA, enhancing EC viability and functionality within 3D bioprinted skin constructs. Overall, this project leverages the synergistic expertise of our team to advance the development of non- immunogenic, engineered tissue systems. By focusing on new drug delivery materials, we aim to enhance the therapeutic potential of 3D bioprinted skin constructs, addressing critical needs in tissue engineering and regenerative medicine.