Bioengineered artificial pancreas for diabetes treatment

Cell encapsulation has emerged as a strategy to protect transplanted cells from immune rejection in the treatment of endocrine disorders. Encapsulated cells are physically isolated from the immune system, thus overcoming the need for harsh immunosuppressant drugs. However, inadequate oxygen and nutrient supply is a major limiting factor of these systems. To address these issues, Dr. Alessandro Grattoni's group at the Houston Methodist Research Institute developed a dual-reservoir neovascularized implantable cell encapsulation and homing (NICHE) device, which integrates in situ prevascularization and local immunosuppressant delivery. The NICHE is 3D printed using biocompatible polyamide 2200 and the two independent cell and drug reservoirs are separated by a nanoporous membrane for sustained immunosuppressant release. The objective of this thesis was to improve the distribution of pancreatic islets within the NICHE cell reservoir by creating a U-shaped distribution to facilitate optimal space utilization. To achieve this goal, two alternative approaches were explored. The first approach involved integrating a catheter within the device to facilitate pancreatic islet administration after a six-week vascularization phase. Islets were injected through a needle inserted into the catheter lumen, which was simultaneously removed during a minimally invasive surgery. The second method utilized a thermoreversible hydrogel as spacekeeper that could be easily removed but remained stable within the device during the preconditioning period. The hydrogel was removed by reversing the gelation and washing it away with cold irrigation, leaving a vacant passage for subsequent cell injection. Modifications were made to the device, ensuring mechanical stability of the added anchor and appropriate sealing of the silicon plugs after catheter removal. Extensive in vitro and in vivo experiments were conducted using a rat model to evaluate device efficacy. The study demonstrated that the use of PNIPAm hydrogel as a spacekeeper yielded comparable results to standard injection methods. The use of a catheter showed promising results for pancreatic islet injection but revealed unsatisfactory outcomes for microsphere injection, potentially due to their smooth surface leading to possible leakage during the injection procedure. In conclusion, this research contributes to improving the distribution of pancreatic islets within the NICHE cell reservoir, offering potential procedures to maximize cell engraftment and function.