Effects of Poly(ethylene glycol) Immunogenicity on Implant Biocompatibility

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。该项目的结果要么将缓解 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。

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.