Synthetic Immunomodulatory Biomaterials to Improve Islet Graft Survival

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Abstract

Introduction and Objective

Type 1 diabetes (T1D) is a chronic condition in which patients produce little to no insulin due to the progressive loss of betacells. While the disease can be managed via external insulin delivery, patients still experience a high incidence of mortality and development of chronic debilitating comorbidities. Islet transplantation has emerged as a potential strategy to restore a patient’s glycemic control, yet long-term rejection and the need for chronic immunosuppression present a major barrier. Herein, we engineered synthetic materials to provide biological cues locally and in a controlled manner to enhance vascularization and promote long-term islet graft survival.

Materials and Methods

Hydrogel particles (microgels, 200 μm diameter) were fabricated by reacting 5% w/v PEG-4MAL with 1.0 mM biotin-PEG-thiol, dispersed in a microfluidic device and cross-linked with an emulsion of dithiothreitol. Microgels were functionalized with a chimeric streptavidin and PD-L1 and used either in co-culture experiments or for co-transplantation with islets. Biotin-functionalized microgels without the engineered protein were used as controls. The effects of SA-PD-L1 functionalized microgels on pancreatic islet cultures were assessed in vitro by incubating pancreatic islets (500 IEQ) with 1000 microgels for 24 hr, after which samples were analyzed for metabolic activity, glucose stimulated insulin release (GSIR), and viability. For in vivo functional outcomes, syngeneic islets (600 IEQ) were mixed with 1200 SA-PD-L1-engineered or control microgels and transplanted in the epididymal fat pad of a chemically induced diabetic C57BL/6. Animals were monitored for blood glucose, and an intraperitoneal glucose tolerance test (IPGTT) was performed on day 30.

Results and Discussion

Co-incubation of SA-PD-L1 microgels with islets in vitro had no effects on islet function as the treatment group had stimulation index and insulin release profiles comparable to the free islet group. Moreover, the presence of functionalized microgels led to a reduction in the presence of proinflammatory cytokine IL-6 in culture as compared to controls. In vivo, islets co-transplanted with functionalized SA-PDL-1 microgels led to diabetes reversal in all transplanted animals. An IPGTT test performed 4 weeks post-transplantation demonstrated glucose clearance rates comparable to naïve animals of the same age.

Conclusion

These studies established the applicability of implementing synthetic materials to deliver immunological cues to islet transplants without hindering engraftment. As such, this approach has the potential not only to improve current strategies for islet transplantation, but also mitigate the need for chronic immunosuppression with a significant impact on clinical islet transplantation.

Conclusion

The authors acknowledge JDRF and NIH for support.

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