(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.
|Kim, Yoon Kyung; Que, Richard; Wang, Szu-Wen et al. (2014) Modification of biomaterials with a self-protein inhibits the macrophage response. Adv Healthc Mater 3:989-94|
|Ueno, Norikiyo; Harker, Katherine S; Clarke, Elizabeth V et al. (2014) Real-time imaging of Toxoplasma-infected human monocytes under fluidic shear stress reveals rapid translocation of intracellular parasites across endothelial barriers. Cell Microbiol 16:580-95|
|Harker, Katherine S; Jivan, Elizabeth; McWhorter, Frances Y et al. (2014) Shear forces enhance Toxoplasma gondii tachyzoite motility on vascular endothelium. MBio 5:e01111-13|
|McWhorter, Frances Y; Wang, Tingting; Nguyen, Phoebe et al. (2013) Modulation of macrophage phenotype by cell shape. Proc Natl Acad Sci U S A 110:17253-8|