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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：
10798522
负责人：
Daniel Alge
金额：
$ 2.97万
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/10798522
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.

项目摘要基于聚（乙二醇）（PEG）的水凝胶广泛用于医疗装置中，并且正在研究其用途。递送蛋白质和细胞治疗剂。虽然这些生物材料被广泛认为是生物惰性的，近年来出现了对PEG免疫原性的关注。据估计，20-30%的人群由于通过药物、化妆品和其他PEG接触而产生抗PEG抗体，包含产品。虽然已经发现抗PEG免疫应答降低了免疫治疗的功效，静脉内施用PEG化药物，对PEG水凝胶的生物相容性的影响没有以前被研究过，现在还不知道。为了解决这一知识差距，该项目有两个具体目的包括全面的体内试验，以评价宿主对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，PEG水凝胶将被植入小鼠皮下注射，并在早期、中期和晚期时间点评价宿主反应使用组织学、免疫组织化学、流式细胞术和血液测试。关键的比较实验将在适应于产生抗PEG应答的动物和免疫学上未处理的动物之间进行对照该项目有两个具体目标。目的1集中于PEG水凝胶制剂，其缺乏水解和酶促可裂解的接头。水凝胶在模量、交联化学和生物相容性方面不同，将系统地研究细胞粘附肽的功能化。目标2关注PEG水凝胶含有水解和酶可降解的连接体的制剂。除了评估主机响应，抗PEG免疫响应对这些水凝胶的体内降解速率的影响将在纵向研究中通过非侵入性成像进行研究。该项目的结果要么会缓解对生物材料植入物的PEG免疫原性的担忧或促使未来研究策略，减轻其影响。