Objective
The objective of this proposal is to develop fully degradable biomaterials that promote host-implant interactions and immune tolerance in a subcutaneous site to allow for insulin producing cell therapy without the need for chronic antirejection therapy.
Background Rationale
Restoration of endogenous insulin production through cell replacement therapy is a clinically successful approach to treat T1D. However, long-term efficacy has been elusive due to the need for chronic systemic immunosuppression, significant cell loss due to inhospitable sites for transplantation, and detrimental host responses to the implant material in extrahepatic transplantation approaches. In this proposal, we seek to address these challenges by engineering devices that can hasten direct host interaction, can regulate local immune cell infiltration responses, and are fully degradable allowing for the long-term engraftment of a material-free and immunosuppression-free implant.
Description of Project
The development of devices for the delivery of insulin-producing cell-based therapies, which can provide physiological regulation of sugars, is necessary for transplantation into extrahepatic sites that provide easier access, and ease of monitoring such as the subcutaneous space. However, no current strategy has addressed the challenge of vascularization, immunosuppression and material mediated fibrosis for subcutaneous transplants. In here, we aim to engineer a modular material approach that can provide a three-dimensional structure to house insulin-producing cells under the subcutaneous space, allows for direct interaction between blood vessels and the cells, enhances tissue integration, and can promote cell survival long-term without the need for chronic antirejection therapy. Yet, the device can fully degrade with time allowing for a material free dynamic environment permissive to the survival and long-term function of insulin-producing cells.
Anticipated Outcome
We anticipate that the development of a degradable highly porous material presenting immunomodulatory agents in a subcutaneous site can induce immune tolerance and promote the long-term function of insulin-producing cell transplants. Specifically, we expect that the synergistic presentation of two immunomodulatory agents in a highly porous material will improve cell infiltration, and immune cell modulation for local tolerance induction. Moreover, we expect that the full degradation of the material will prevent unexpected long-term fibrotic complications that can alter the localized immune responses to the cell therapy.
Relevance to T1D
This project is of high relevance for the T1D community as transplantation of insulin producing cells for endogenous regulation of blood glucose can significantly improve the quality of life and reduce disease associated complications. However, the advent of stem-cell derived products and the need for chronic systemic immunosuppression, skews the risk to benefit ratio of cell replacement therapies and warrants the development of transplantation sites with a clearer safety profile. Herein, we seek to develop a novel biomaterial approach for the local control of immune responses towards insulin producing cell transplanted in the subcutaneous space. This approach allows for immune cell control in an accessible site with the goal of achieving an immunosuppression-free, and long-term material-free cell therapy.