(Provided by the applicant) Abstract: This project aims to develop biomaterials that will promote the long term implantation of encapsulated islets for treatment of diabetes by designing surfaces that directly modulate the function of local immune cells. Type I diabetes is caused by autoimmune attack on insulin- producing beta-cells within pancreatic islets, and affects nearly 3 million patients in the United States. While replacement of beta-cells with healthy donor tissue is a proven treatment modality, widespread clinical success has been limited by the sufficient availability of insulin- producing beta-cells. Transplantation of encapsulated xenograft islets remains a promising approach, but translation to the clinic has remained elusive primarily due to the failure of the encapsulating biomaterial to remain free of fibrosis over long periods of time. The objective of this work is to develop biomaterials that inhibit local immune cells, in order to prevent the inflammatory and ensuing fibrotic response to encapsulated cell therapies. I seek to mitigate the immune response by using a new approach to biomaterial design, where materials are decorated with immunomodulatory molecules that actively deliver tolerizing signals to local immune cells. I hypothesize that coating materials with immunomodulatory molecules will inhibit local inflammation and therefore reduce the host response that results from biomaterial implantation. To test this hypothesis, I will engineer surfaces to display a model immunomodulatory protein at physiologically relevant densities. In addition, I will identify immunomodulatory small molecular weight peptides using phage display screens against known immune cell receptors or directly to immune cells. Identified peptides will be used to modify encapsulation materials and tested in a combinatorial manner within a high throughput in vivo imaging model that allows the real-time evaluation of material biocompatibility within live animals. Identified peptide formulations will be further tested as coatings for encapsulation materials in a xenograft transplant model. This study will investigate an innovative strategy to biomaterial design, where surfaces are engineered to display immunomodulatory molecules that mitigate the host response. This approach may not only benefit cell encapsulation technologies, but also broadly impact the design of biomaterials for medical devices. Public Health Relevance: Transplantation of encapsulation pancreatic islets to treat type I diabetes remains a promising treatment modality, but is hindered by the host inflammatory response to the encapsulating material. This project will explore a new approach to biomaterial design, where materials are tailored to interact with specific receptors expressed on immune cells and inhibit their activation, therefore mitigating the host response to encapsulated islets fr treatment of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2DE023319-01
Application #
8358630
Study Section
Special Emphasis Panel (ZGM1-NDIA-C (01))
Program Officer
Drummond, James
Project Start
2012-09-30
Project End
2017-08-31
Budget Start
2012-09-30
Budget End
2017-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$2,302,500
Indirect Cost
$802,500
Name
University of California Irvine
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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