UCSF

Type 1 diabetes (T1D) is an autoimmune disease characterized by destroying insulin-producing beta cells within the pancreas, leading to high blood glucose levels and various complications. Cell encapsulation devices offer a promising approach to treating T1D by protecting insulin-producing cells from immune attack while restoring endogenous insulin production. However, their effectiveness is limited by inadequate cell survival due to the foreign body response that results in insufficient vasculature and inflammation at the implantation site. This thesis aims to improve the performance of cell encapsulation devices by addressing these challenges.

Chapter 1 discusses the foreign body response and fibrosis in response to implantable devices for diabetes treatment, providing insights into molecular mechanisms, cellular interactions, and strategies for long-term success. The thesis then examines techniques to optimize cell encapsulation devices for T1D. Chapter 2 focuses on developing an innovative encapsulation device designed to improve the survival of encapsulated stem cell-derived insulin-producing cells within the poorly vascularized subcutaneous space. The device features an internal compartment that steadily releases the essential nutrients alanine and glutamine over several weeks, increasing post-transplantation cell survival by 30% in the subcutaneous space.

Chapter 3 presents a novel, replenishable, pre-vascularized implantation methodology (RPVIM) aimed at promoting vascular integration around the implant and enhancing nutrient supply to encapsulated cells. The findings reveal that over 75% of RPVIM devices containing insulin-producing cells survive after 28 days of implantation in the subcutaneous space. Importantly, RPVIM devices outperform other implantation methodologies in terms of survivability and maintain the functionality of encapsulated insulin-producing beta cell clusters, which is a critical factor in successful T1D management.

Lastly, Chapter 4 explores the impact of surface topography on macrophage polarization in response to biomaterials used for cell encapsulation in T1D. Adjusting the surface topography of polycaprolactone (PCL)-based biomaterials can polarize macrophages towards the reparative phenotype, thus modulating the immune response and accelerating device engraftment. This study evaluates gene expression of the M1 inflammatory phenotype and M2 reparative phenotype in macrophages cultured on mineralized PCL thin films with nanoscale topography and micron-scaled topographic PCL thin films. These results offer valuable insights into tailoring biomaterial properties to improve cell encapsulation device success in treating T1D.

In conclusion, this thesis delves into the challenges cell encapsulation devices face for T1D treatment due to the foreign body response. Through the development of nutrient-supplementing devices, pre-vascularization techniques, and tailoring of biomaterial properties, this body of work aims to enhance the performance and long-term success of cell encapsulation devices in treating T1D.