Improving Biomaterial Implant Tolerance with Damage-Associated Molecular Pathway (DAMP) Molecule Attachment

项目摘要 生物材料植入物成功的一个关键决定因素是它与宿主免疫系统的相互作用， 通常决定生物材料是否存活和/或为宿主提供任何益处。每一种生物材料 植入引发不同强度的创伤环境，并且宿主免疫的激活依赖于 通过细胞表面上的模式识别受体（PRR）刺激白细胞。PRR承认外国 病原体相关分子模式（PAMPs），在微生物上常见（信号感染）， 细胞应激、损伤或死亡（感染）引起的损伤相关分子模式（DAMP 独立）。由于它们在非病理性组织反应中的作用，我们认为植入物的表面处理 与DAMP分子结合可以极大地减少纤维化生物植入物反应， 更多的炎性PAMP分子。我们发明了一种具有高度可调表面的生物材料平台 化学（允许DAMP附着）和极低的固有纤维化生物材料反应，称为 微孔退火颗粒（MAP）支架。我们将使用MAP注射-植入的小鼠模型 支架，以识别指导有效伤口愈合和/或限制负面后果的DAMP PAMP介导的生物材料排斥反应。这将对我们理解 伤口愈合环境，并代表了可以利用的工具的原理实验的证明， 改善伤口愈合、诱导疤痕重塑和限制生物植入部位的负性免疫应答。

PROJECT SUMMARY A key determinant of the success of a biomaterial implant is its interactions with the host immune system, which often determines whether the biomaterial will survive and/or provide any benefit to the host. Every biomaterial implantation initiates a wound environment of varying intensity and activation of host immunity is dependent on leukocyte stimulation via pattern recognition receptors (PRRs) on the cell surface. PRRs recognize both foreign pathogen-associated molecular patterns (PAMPs) that are common on microorganisms (signaling infection) and damage-associated molecular patterns (DAMPs) that arise from cell stress, damage, or death (infection independent). Due to their role in a non-pathological tissue response, we believe surface treatment of implants with DAMP molecules can greatly diminish fibrotic bioimplant response and can even counteract the signaling of more inflammatory PAMP molecules. We have invented a biomaterial platform with highly tunable surface chemistry (to allow DAMP attachment) and an extremely low inherent fibrotic biomaterial response called Microporous Annealed Particle (MAP) scaffolding. We will use a murine model of injection-implant of the MAP scaffolding to identify DAMPs that instruct productive wound healing and/or limit the negative consequences PAMP-mediated biomaterial rejection. This will have important consequences for our understanding of the wound healing environment and represent proof of principle experiments for a tool that can be harnessed to improve wound healing, induce scar remodeling, and limit negative immune responses at bioimplant sites.