# Establishing immunoprivileged scaffolds for transplantation of immature beta cells

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $193,750

## Abstract

Summary
Exogenous insulin treatment is the standard of care for Type 1 diabetes (T1D), which negatively affects the
quality of life and is also often ineffective in preventing recurrent hyperglycemia episodes and its chronic
complications. Recent studies show that human islet allografts can restore normoglycemia and insulin
independence long-term, protect from severe hypoglycemia, and slow progression of microvascular lesions in
immunosuppressed type 1 diabetic recipients. However, there are at least 3 critical barriers to the progress in
the field of clinical islet transplantation; i) a limited supply of donor islets, ii) transplantation into the liver, which
compromises immediate post-graft islet engraftment as well as long-term survival, and iii) immune rejection,
precipitated by both innate and adaptive immune responses, despite chronic use of immunosuppression with
the associated various short- and long-term complications. This proposal investigates microporous polymer
scaffolds as a platform for the transplantation of human pluripotent stem cell (hPSC) derived immature beta
cells into an extrahepatic and clinically translational site. The scaffolds will be modified to positionally display
on their surface two recombinant immunological ligands for the signal regulatory protein alpha (SIRPa) and
Fas receptor with demonstrated function for the modulation of innate, adaptive, and regulatory immune
responses. Our central hypothesis is that the immobilized SIRPa and Fas receptor ligands will block both
innate and adaptive immune responses, respectively, while initiating a regulatory circuit locally within the graft
that will enhance immature beta cell maturation and achieve sustained graft survival and function in the
absence of chronic immunosuppression. The overall objective will be accomplished by testing our central
hypothesis through two Specific Aims. Studies under Aim 1 will engineer PLG scaffolds with the immunologic
ligands, load the engineered scaffolds with hPSC-derived beta cells, and assess the efficacy of this platform to
block innate immune responses and enhance beta cells maturation and engraftment in vivo in an animal model
with a restricted adaptive and competent innate immune system. Aim 2 will investigate in a humanized mouse
model competent for both innate and adaptive immune responses the efficacy of immunologic ligands-
engineered scaffolds to support sustained survival and function of beta cells transplanted into epididymal fat
pad, the equivalent of the great omentum in humans, as a clinically relevant site in the absence of chronic
immunosuppression. We are well prepared to undertake the proposed research because of the combined
expertise of our teams in biomaterial engineering, immunology, and hPSC-derived beta cells. If successful, this
approach will overcome the three aforementioned major barriers for wide-spread use of beta cells as a cure for
the treatment of type 1 diabetes.

## Key facts

- **NIH application ID:** 9968026
- **Project number:** 5R21AI147677-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lonnie D Shea
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,750
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968026

## Citation

> US National Institutes of Health, RePORTER application 9968026, Establishing immunoprivileged scaffolds for transplantation of immature beta cells (5R21AI147677-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9968026. Licensed CC0.

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