Hydrogel Platform for Localized and Sustained Delivery of Human IgG-Based Immunomodulatory Biologics

Abstract

Beta cell replacement therapy for type 1 diabetes (T1D) requires chronic systemic immunosuppression for long-term allograft survival. This causes general immunodeficiency and adverse events, which limits the applicability of these therapies. Therefore, I aimed to develop implantable IgG-capturing enzymatically degradable polyethylene glycol (PEG) hydrogels to deliver IgG-based immunomodulatory biologics locally in the cell transplant site in a sustained and prolonged manner (>1 month) to prevent allograft rejection with negligible systemic adverse effects. Here, I tested the effects of in vitro PEGMAL concentration, hydrogel degradability, crosslinking density, and drug-gel binding on drug release kinetics. Additionally, I investigated in vivo hydrogel degradation by implanting fluorescently labelled hydrogels and insulinoma cell cluster allografts in C57BL/6 mice and quantifying graft site fluorescence over time. I found faster FITC-IgG drug release from 5% PEGMAL hydrogels compared to 10% PEGMAL hydrogels, as well as from fully degradable versus half degradable hydrogels. Additionally, I found that hydrogels with passively loaded FITC-IgG follow a first-order burst drug release kinetics, while drug-gel binding hydrogels achieve a zero-order constant release kinetics with reduced burst release. Moreover, the gel binding of FITC-IgG via the MAL Fc-III peptide was also shown to reduce the burst release of FITC-IgG compared to passively loaded hydrogels with no Fc-III. Lastly, I found that in vivo hydrogel degradation occurs 3.2 months after implantation. These experiments suggest that PEG hydrogel degradation can be tuned by varying the polymer concentration, crosslinking density, and using drug-gel conjugation to achieve desired drug release kinetics. This enzymatically degradable drug-binding PEG hydrogel biomaterial platform could enable the sustained delivery of clinically effective IgG-based biologics locally within the transplant site to increase safety and efficacy of allogeneic cell transplant-based regenerative medicine therapies