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Synthesis and High-Throughput In Vivo Characterization of Alginate Encapsulation Materials for Long-Term Islet

用于长期胰岛的海藻酸盐封装材料的合成和高通量体内表征

基本信息

批准号：
9982065
负责人：
Omid Veiseh
金额：
$ 77.51万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982065
关键词：
Address Alginates Allogenic Animal Model Bar Codes Biocompatible Materials Biological Assay Blood Glucose C57BL/6 Mouse Caliber Cells Chemicals Chemistry Chronic Disease Data Detection Diabetes Mellitus Diabetic Diet Diabetic mouse Disease Donor person Encapsulated Epidemic Evaluation Exhibits Failure Fibrosis Foreign Bodies Formulation Gene Frequency Generations Genetic Genomics Genotype Glucose Graft Rejection Graft Survival Histology Human Hydrogels Immune Immunologic Monitoring Immunosuppression Implant In Vitro Incidence Individual Inflammation Injections Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Isomerism Kinetics Lead Libraries Macaca Mediating Methods Modeling Modification Monkeys Mus Patients Performance Preclinical Testing Preparation Property Regimen Research Research Project Grants Rodent Rodent Model SNP genotyping Single Nucleotide Polymorphism Site Statistical Data Interpretation Structure Testing Tissues Transplantation Triazoles Validation analog base biomaterial compatibility capsule clinical application combinatorial density design genetic variant glucose monitor graft failure high throughput screening immunogenic implant material implantation improved in vitro testing in vivo insulin secretion islet next generation sequencing nonhuman primate novel response screening side effect standard of care subcutaneous theories treatment research volunteer

项目摘要

Diabetes remains a global epidemic afflicting more than 300 million people worldwide, with incidence only expected to rise. Despite decades of research the current standard of care for those suffering from type I diabetes (TID) remains a rigorous regimen of blood glucose monitoring together with daily administrations of exogenous insulin and diabetic diet, these individuals still are challenged with untoward side effects due to complications of the disease in part the result of daily compliance issues. Islet transplantation has tremendous potential, but serious technological limitations remain. The lack of suitable biomaterials used for cell encapsulation is one of the key obstacles to clinical application. Cell encapsulation materials used to date are immunogenic, and lead to tissue capsule formation and cell graft failure. To address this challenge, here we propose the synthesis of 7000 candidate immune modulatory alginate- based hydrogel capsule formulations for cell encapsulation and a high-throughput in vivo method for identification of novel materials which can enable long-term protection and viability of transplanted donor pancreatic islet cells. A first-generation screen of 774 alginate formulations guides our design of this proposed second generation 7000 analogue structures. To enable increased throughput of screening, we propose to implant mixtures of different materials in the same implantation site. To pair the material identity with the observed material function, we are developing a next-generation sequencing (NGS) assay to determine material identity via a single nucleotide polymorphism (SNP) genotype of co-encapsulated HuVEC cells. Preliminary results using a 84-plex SNP NGS panel on 23 volunteers indicate high confidence genomic identification using limited NGS reads. Thus, a typical implantation of 200 alginate beads (1.5mm diameter) allows the simultaneous evaluation of 20 different implanted materials, with still sufficient independent beads per material to allow statistical analysis. In the course of this research project, the PI will first synthesize the new analogue library compounds. Subsequently, the PI will screen these materials in vivo using a xenogeneic transplantation of islets/HuVEC mixtures into a profibrotic C57BL/6 model rodents, that enables us to simultaneously screen up to 20-fold more distinct materials formulations in a single rodent. Next, the PI will examine the ability of leads (5-10) formulations to protect transplanted islet and restore normoglycemia in a T1D rodent model for up to 100 days. Finally lead formulations will be further vetted in healthy non-human primate studies. We anticipate that upon completion of this project, lead alginate materials for encapsulating islet cells will be identified that succeed in two different animal models (C57BL/6 mouse and macaque monkeys) and will be ready for pre-clinical tests under GLP/GMP conditions in preparation for an FDA IND submission.

糖尿病仍然是一种全球性流行病，全世界有3亿多人受其影响，仅发病率而已