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Effects of Poly(ethylene glycol) Immunogenicity on Implant Biocompatibility

聚乙二醇免疫原性对植入物生物相容性的影响

基本信息

批准号：
10504301
负责人：
Daniel Alge
金额：
$ 41.78万
依托单位：
TEXAS ENGINEERING EXPERIMENT STATION
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10504301
关键词：
Acrylamides Address Adhesives Affect Alkynes Animal Model Animals Antibodies Azides Biocompatible Materials Blood Tests Cell Adhesion Cells Chemistry Complement Activation Cosmetics Drug Delivery Systems Enzymes Esters Exposure to Flow Cytometry Foreign Bodies Formulation Funding Future Histology Hydrogels Immune Immune response Immunize Immunohistochemistry Immunologics Immunology Implant Individual Inflammation Inflammatory Infusion procedures Intravenous Investigation Knowledge Ligands Longitudinal Studies Magnetic Resonance Imaging Medical Device Modulus Mus Outcome Peptides Pharmaceutical Preparations Pharmacologic Substance Polymers Population Predisposition Property Proteins Reporting Research Risk Safety Study of magnetics Sulfhydryl Compounds Testing Therapeutic United States National Institutes of Health Variant Work adaptive immune response base biomaterial compatibility chemical property crosslink design ethylene glycol experimental study immunogenic immunogenicity implantation in vivo in vivo evaluation inflammatory marker interest methacrylamide non-invasive imaging patient screening physical property response subcutaneous

项目摘要

PROJECT SUMMARY Poly(ethylene glycol) (PEG) based hydrogels are widely used in medical devices and are being studied for the delivery of protein and cellular therapeutics. While these biomaterials are widely regarded as biologically inert, concerns over PEG’s immunogenicity have emerged in recent years. It has been estimated that 20-30% of the population has antibodies against PEG due to exposure via pharmaceuticals, cosmetics, and other PEG- containing products. While an anti-PEG immune response has been found to reduce the efficacy of intravenously administered PEGylated drugs, the impact on the biocompatibility of PEG hydrogels has not previously been studied and is currently unknown. To address this knowledge gap, this project has two Specific Aims that encompass comprehensive in vivo testing to evaluate the host response to PEG hydrogels of varying physical and chemical properties. In these experiments, PEG hydrogels will be implanted subcutaneously in mice, and the host response will be evaluated at early, intermediate, and late timepoints using histology, immunohistochemistry, flow cytometry, and blood testing. The key comparison in these experiments will be between animals conditioned to mount an anti-PEG response and immunologically naïve controls. The project has two Specific Aims. Aim 1 focuses on PEG hydrogel formulations that lack hydrolytically and enzymatically cleavable linkers. Hydrogels that differ in modulus, crosslinking chemistry, and functionalization with cell-adhesive peptides will be systematically studied. Aim 2 focuses on PEG hydrogel formulations that contain hydrolytically and enzymatically degradable linkers. In addition to evaluating the host response, the impact of the anti-PEG immune response on the in vivo degradation rate of these hydrogels will be investigated via non-invasive imaging in a longitudinal study. The results of this project will either alleviate concerns over PEG immunogenicity for biomaterial implants or motivate future investigations on strategies to mitigate its effects.

项目总结聚乙二醇基水凝胶在医疗器械中有着广泛的应用，目前正在研究中。提供蛋白质和细胞疗法。虽然这些生物材料被广泛认为是生物惰性的，近年来，人们开始关注聚乙二醇的免疫原性。据估计，20%-30%的人群因接触药物、化妆品和其他聚乙二醇组分而产生抗聚乙醇组抗体。包含产品。虽然已经发现抗聚乙二醇胺免疫反应降低了静脉注射聚乙二醇化药物对聚乙二醇水凝胶的生物相容性没有影响以前曾被研究过，目前尚不清楚。为了解决这一知识鸿沟，这个项目有两个具体目标包括全面的体内测试，以评估宿主对聚乙二醇水凝胶的反应具有不同的物理和化学性质。在这些实验中，将植入聚乙二醇水凝胶在小鼠皮下注射，宿主的反应将在早、中、晚时间点进行评估采用组织学、免疫组织化学、流式细胞术和血液检测。这其中的关键比较实验将介于有条件的动物和免疫幼稚的动物之间控制。该项目有两个具体目标。目标1专注于缺乏聚乙二醇水凝胶配方可水解性和可酶解性连接物。不同模数、不同交联度的水凝胶和将系统地研究细胞粘附肽的功能化。目标2专注于聚乙二醇水凝胶含有可水解性和酶降解性连接物的制剂。除了评估主机反应，抗聚乙二醇免疫反应对这些水凝胶体内降解率的影响将在纵向研究中通过非侵入性成像进行研究。这个项目的结果要么是缓解对生物材料植入物的聚乙二醇免疫原性的担忧或推动未来研究策略减轻其影响。