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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：
10697334
负责人：
Daniel Alge
金额：
$ 35.91万
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/10697334
关键词：
Acrylamides Address Adhesives Affect Alkynes Animal Model Animals Antibodies Azides Biocompatible Materials Blood Tests Cell Adhesion Cell Therapy Cell secretion 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 Investigation Knowledge Ligands Longitudinal Studies Magnetic Resonance Imaging Marketing 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 biomaterial compatibility chemical property crosslink design ethylene glycol experimental study immunogenic immunogenicity implantation in vivo in vivo evaluation inflammatory marker interest intravenous administration 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.

项目概要聚乙二醇（PEG）基水凝胶广泛应用于医疗器械，目前正在研究其性能蛋白质和细胞疗法的递送。虽然这些生物材料被广泛认为具有生物惰性，近年来，人们开始担心 PEG 的免疫原性。据估计，20-30% 由于通过药物、化妆品和其他 PEG 接触，人群具有针对 PEG 的抗体包含产品。虽然已发现抗 PEG 免疫反应会降低功效静脉注射聚乙二醇化药物时，对聚乙二醇水凝胶的生物相容性没有影响之前已被研究过，目前未知。为了解决这一知识差距，该项目有两个具体目标包括全面的体内测试，以评估宿主对 PEG 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 PEG 水凝胶小鼠皮下注射，并在早期、中期和晚期时间点评估宿主反应使用组织学、免疫组织化学、流式细胞术和血液检测。关键的比较就在这些实验将在经过调节以产生抗 PEG 反应的动物和免疫学上未处理过的动物之间进行控制。该项目有两个具体目标。目标 1 重点关注缺乏的 PEG 水凝胶配方可水解和酶裂解的连接体。模量、交联化学性质不同的水凝胶将系统地研究细胞粘附肽的功能化。目标 2 重点关注 PEG 水凝胶含有可水解和酶降解的连接基的制剂。除了评价楼主反应，抗 PEG 免疫反应对这些水凝胶体内降解率的影响将通过纵向研究中的非侵入性成像进行调查。该项目的结果将缓解对生物材料植入物的 PEG 免疫原性的担忧或激发未来对策略的研究减轻其影响。