Regenerative Integration of Percutaneous Implants

描述（由申请人提供）：经皮医疗器械，如中心静脉导管、腹膜透析导管和骨内植入物在现代医疗保健中普遍存在，尽管存在很大的感染风险。将合成器械与人体结合以减少感染负担是一个长期目标，这将大大提高采用经皮植入物的价值。利用组织再生策略将导致稳定的组织-器械界面，因此将起到稳健的免疫隔离屏障的作用。生物可降解弹性体将用作经皮植入物的主体材料，因为它能够使聚合物的机械性能与天然皮肤相匹配。目前的一个假说是皮肤再生可以通过调节巨噬细胞表型来实现。恢复性巨噬细胞群体的上调可导致增强的角质形成细胞迁移、细胞外基质沉积和稳定的血管形成。损伤性反应如炎症和瘢痕形成可以通过减少炎性巨噬细胞的数量来抑制。这一假设将通过完成本提案所述的具体目标来检验。简言之，将合成可生物降解的弹性体并用作药物洗脱经皮植入物。将设计一种两相控释系统，以递送小分子激动剂，从而在6周时间内诱导恢复性巨噬细胞。通过流式细胞术、荧光显微镜和细胞因子分析评估，将通过在体外将单核细胞分化为恢复性巨噬细胞来验证该系统。释放动力学、巨噬细胞表型和总体组织重塑将在体内相关。将阐明修复性巨噬细胞与炎症性巨噬细胞在血管重塑中的相对作用。该提案的完成将有助于验证使用小分子信号传导分子控制巨噬细胞表型来控制大规模伤口修复和组织生成的一般概念。这种方法可以应用于广泛的其他组织模型，并可能被采用作为一种新的策略，在组织工程和再生医学。此外，从这项拟议的研究中获得的知识将阐明单核细胞和巨噬细胞在组织修复和再生中的新作用。

DESCRIPTION (provided by applicant): Percutaneous medical devices such as central venous catheters, peritoneal dialysis catheters, and intraosseointegrated implants are ubiquitous in modern healthcare despite the fact that there is a large risk of infection. The integration of synthetic devices with the human body in order to reduce the infection burden is a long-term goal that will vastly improve the value in employing percutaneous implants. Leveraging tissue regeneration strategies will lead to stable tissue-device interfaces and therefore will function as robust immunoisolation barriers. Biodegradable elastomers will be used as the bulk material in percutaneous implants because of the ability to match the mechanical properties of the polymer with the native skin. One current hypothesis is that cutaneous regeneration can be achieved by modulating macrophage phenotype. The upregulation of restorative macrophage populations may lead to enhanced keratinocyte migration, extracellular matrix deposition, and stable vascularization. Injurious responses such as inflammation and scarring in can be suppressed by reducing the population of inflammatory macrophages. This hypothesis will be tested by completing the specific aims described in this proposal. Briefly, biodegradable elastomers will be synthesized and used as drug-eluting percutaneous implants. A two-phase controlled release system will be designed to deliver small molecule agonists to induce restorative macrophages over a 6-week time period. This system will be validated by differentiating monocytes into restorative macrophages in vitro as assessed by flow cytometry, fluorescence microscopy, and cytokine profiling. The release kinetics, macrophage phenotypes, and gross tissue remodeling will be correlated in vivo. The relative roles of restorative versus inflammatory macrophages in vascular remodeling will be elucidated. The completion of this proposal will be instrumental in validating the general concept of controlling broad scale wound repair and tissue generation using small molecule signaling molecules to control macrophage phenotype. This approach could be applied to a wide range of other tissue models and could potentially be adopted as a novel strategy in tissue engineering and regenerative medicine. Furthermore, the knowledge gained from this proposed research will elucidate the emerging role of monocytes and macrophages in tissue repair and regeneration.