Infection-Prevention Barriers for Osseointegrated Percutaneous Implants

描述（由申请人提供）：截肢与日常功能和生活质量的毁灭性丧失有关。经皮骨整合植入物目前正在考虑将外假体连接到残肢。为了使这种方法成功，必须在经皮支架周围的组织处实现并保持无感染屏障。PI建议通过利用由医用级微孔聚氨酯制成的生物相容性皮下凸缘来消除骨整合植入物的宿主组织/经皮pylon界面处的感染。该柔性凸缘机械地稳定皮肤至植入物，从而建立完整的皮下屏障，机械地保护真皮屏障免受不可避免的冲击载荷，并且生物地加速软组织与经皮支架的整合，从而产生抵抗急性和慢性感染的上级皮下屏障。PI比较了在猪模型胫骨中使用经皮外架的骨整合植入物上的两种软组织整合凸缘设计：（1）刚性微孔钛皮下凸缘（基线对照）和（2）新型柔性微孔聚氨酯皮下凸缘。此外，聚氨酯凸缘将装载临床上熟悉的多能人类蛋白质生长因子-血小板衍生生长因子β（PDGF-BB）-作为经证实的骨诱导、血管生成和皮肤愈合生物活性剂进行局部释放。在目标1中，通过促进宿主软组织与连接到支架的创新柔性微孔聚合物凸缘的整合，创建皮下屏障以阻止急性和慢性经皮感染。这在机械上稳定了软组织/经皮支架界面处的运动，允许生长、植入物-真皮密封和感染预防。将评估聚氨酯与钛凸缘器械内的感染率、组织附着率、血管形成率和组织发生率。目的2旨在证明聚氨酯凸缘将更好地保护软组织/经皮界面免受创伤，特别是对周围软组织的冲击损伤。受控冲击载荷将被引导至体内软组织/经皮支架界面，器械留在原位愈合。将测量后续感染、组织再附着、愈合、血运重建和组织向内生长。在目标3中，目前在临床试验中的人蛋白衍生生长因子（PDGF-BB）将被配制到聚合物凸缘中，用于控制释放到局部组织以增强愈合反应。体外细胞生长和迁移试验将用于最大化药效学效应，并设计体内使用的蛋白释放策略。将利用机械匹配的聚合物凸缘与内在组织整合和PDGF-BB从植入物局部释放的组合来加速支架周围的急性期组织愈合，增强与植入物界面的机械耦合，增强局部组织抗创伤的稳定性，并保留植入物相关的组织屏障以防止感染问题。 公共卫生相关性：PI建议通过使用由医用级微孔聚氨酯制成的生物相容性皮下凸缘促进软组织与植入物支架的整合和稳定，消除植入物/组织界面处的感染。这种柔性凸缘以机械方式将皮肤稳定在植入物上，建立完整的皮下感染屏障，以机械方式保护真皮屏障免受不可避免的冲击载荷，并在生物学上加速软组织与经皮支架的整合，从而形成针对急性和慢性感染的上级皮下屏障。

DESCRIPTION (provided by applicant): Limb amputation is associated with a devastating loss of everyday function and quality of life. Percutaneous osseointegrated implants are currently being considered to attach the exoprosthesis to the residual limb. For this methodology to succeed, an infection-free barrier must be achieved and maintained at the tissues surrounding the percutaneous pylon. The PIs propose to eliminate infections at the host-tissue/percutaneous pylon interface of osseointegrated implants by exploiting a biocompatible subdermal flange manufactured from medical grade microporous polyurethane. This flexible flange mechanically stabilizes skin to implant establishing an integral subdermal barrier, mechanically protecting the dermal barrier from inevitable impact loads, and biologically accelerating the integration of soft tissue to the percutaneous pylon, resulting in a superior subdermal barrier against both acute and chronic infections. The PIs compare two designs of soft tissue-integrating flanges on osseointegrated implants with percutaneous pylons into the tibia of a porcine model: (1) a rigid microporous titanium subcutaneous flange (baseline control), and (2) a novel flexible microporous polyurethane subcutaneous flange. Additionally, the polyurethane flange will be loaded with a clinically familiar pluripotent human protein growth factor - platelet derived growth factor beta (PDGF-BB) - for local release as a proven osteoinductive, angiogenic and dermal healing bioactive agent. In Aim 1, a subdermal barrier is created to hinder both acute and chronic percutaneous infections by promoting integration of host soft tissues with an innovative flexible microporous polymer flange attached to the pylon. This mechanically stabilizes the motion at the soft-tissue/percutaneous-pylon interface, allowing on-growth, implant-dermis sealing and infection prevention. Rates of infection, tissue attachment, vascularization, and tissue within polyurethane versus titanium flange devices will be assessed. Aim 2 seeks to demonstrate that polyurethane flanges will better protect the soft-tissue/percutaneous interface from trauma, specifically impact damage to the surrounding soft tissue. Controlled impact loads will be directed to soft- tissue/percutaneous-pylon interfaces in vivo, with the device left in situ to heal. Subsequent infection, tissue re-attachment, healing, re-vascularization, and tissue in-growth will be measured. In Aim 3, a human protein derived growth factor (PDGF-BB) currently in clinical trials will be formulated into the polymer flange for controlled release to local tissues to enhance healing responses. In vitro cell growth and migration assays will be used to maximize pharmacodynamic effects and design the protein release strategy for in vivo use. Combinations of mechanically matched polymer flanges with intrinsic tissue integration and local release of PDGF-BB from the implant will be exploited to accelerate acute phase tissue healing around the pylon, enhance the mechanical coupling to the implant interface, enhance local tissue stability against trauma, and preserve implant-associated tissue barriers to preclude infection issues. Public Health Relevance: The PIs propose to eliminate infections at the implant/tissue interface through promoting the integration and stabilization of the soft tissues to the implant pylon using a biocompatible subdermal flange manufactured from medical grade microporous polyurethane. This flexible flange mechanically stabilizes the skin to the implant establishing an integral subdermal barrier to infection, mechanically protecting the dermal barrier from inevitable impact loads, and biologically accelerating the integration of soft tissue to the percutaneous pylon, resulting in a superior subdermal barrier against both acute and chronic infections.