File(s) under embargo

1

year(s)

6

month(s)

25

day(s)

until file(s) become available

Oligomeric Collagen Encapsulation Design and Mechanism of Protection for Beta-cell Replacement Therapy

thesis
posted on 28.04.2022, 19:22 authored by Rachel Alena MorrisonRachel Alena Morrison

Type 1 Diabetes Mellitus (T1D), a chronic disease affecting over 1.5 million Americans, is characterized by the autoimmune destruction of insulin-producing β-cells within pancreatic islets. Islet/β-cell replacement therapies, where replenishable β-cell sources are implanted within protective microenvironments, have the potential to provide a long-term solution for individuals with T1D by restoring glucose-sensitive, insulin release and overall glycemic control. However, most conventional encapsulation materials elicit an immune reaction, known as a foreign body response (FBR), which compromises β-cell health and function. In this dissertation, we designed and evaluated various formulations of a polymerizable collagen, namely type I oligomeric collagen (Oligomer), as encapsulation materials for minimally invasive, subcutaneous delivery of replacement β-cells. Preclinical validation in chemically-induced diabetic mice demonstrated rapid (within 24 hours) reversal of diabetes for beyond 90 days with no signs of rejection or FBR after subcutaneous delivery of both allogeneic and xenogeneic (rat) islets. To further define this uncommon mechanism of protection, the tissue response to Oligomer, in comparison to commercial synthetic and collagen-based materials, was evaluated following subcutaneous implantation within rats, a well-established biocompatibility model. Histological and transcriptomics analyses were used to define the immune response at both cellular and molecular levels. Interestingly, Oligomer showed minimal and transient activation of innate immune cells similar to the sham surgical control, with no evidence of foreign body giant cell formation, inflammatory-mediated bioresorption, or fibrosis. Overall, this work evaluates preclinical efficacy and demonstrates mechanistic understanding of immune tolerance for Oligomer materials for β-cell replacement therapy and other regenerative medicine applications.

Funding

National Science Foundation Graduate Research Fellowship DGE-1333468

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) T32 Indiana Bioengineering Interdisciplinary Training for Diabetes Research Program Grant T32 DK-101000

Generous gift funds from the McKinley Family Foundation

History

Degree Type

Doctor of Philosophy

Department

Biomedical Engineering

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Sherry Voytik-Harbin

Advisor/Supervisor/Committee co-chair

Jenna Rickus

Additional Committee Member 2

Raghavendra Mirmira

Additional Committee Member 3

Robert V. Considine

Additional Committee Member 4

Kinam Park