Infection-Prevention Barriers for Osseointegrated Percutaneous Implants

描述(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。目前正在考虑使用经皮骨整合植入物将外假体连接到残肢上。为了使这一方法获得成功，必须在经皮穿刺器周围的组织处实现并维持无感染屏障。PI建议通过使用医用级微孔聚氨酯制造的生物兼容真皮下法兰来消除骨集成植入物的宿主-组织/经皮塔界面的感染。这种灵活的法兰可以机械地稳定皮肤到植入物，建立一个完整的真皮下屏障，机械地保护真皮屏障免受不可避免的冲击载荷，并从生物上加速软组织与经皮支架的整合，从而产生针对急性和慢性感染的卓越真皮下屏障。PI比较了两种设计的软组织整合法兰：(1)硬质微孔钛皮下法兰(基线对照)和(2)新型柔性微孔聚氨酯皮下法兰。此外，聚亚安酯法兰将装载一种临床上常见的多功能人类蛋白生长因子--血小板衍生生长因子β(PDGF-BB)，用于局部释放，作为一种已被证实的骨诱导、血管生成和皮肤愈合生物活性物质。在目标1中，创建了一种真皮下屏障，通过促进宿主软组织与连接到塔架上的创新的柔性微孔聚合物法兰的整合来阻止急性和慢性经皮感染。这在机械上稳定了软组织/经皮-支架界面的运动，允许继续生长、植入物-真皮密封和预防感染。将评估聚氨基甲酸酯与钛法兰装置的感染率、组织附着率、血管化率和组织率。目的2试图证明，聚氨基甲酸酯法兰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。受控冲击载荷将直接作用于体内的软组织/经皮-支架界面，装置留在原位进行愈合。随后的感染、组织再附着、愈合、再血管化和组织内生长将被测量。在目标3中，目前正在进行临床试验的人蛋白衍生生长因子(PDGF-BB)将被配方到聚合物法兰中，以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分析将用于最大限度地发挥药效学效应，并设计供体内使用的蛋白质释放策略。机械匹配的聚合物法兰与固有的组织整合和种植体的局部释放PDGF-BB相结合，将被用来加速塔架周围急性期组织的愈合，增强与种植体界面的机械耦合，增强局部组织抗创伤的稳定性，并保留与种植体相关的组织屏障，以防止感染问题。 公共卫生相关性：PIS建议通过使用由医用级微孔聚氨酯制造的生物兼容真皮下法兰来促进软组织与植入物塔架的整合和稳定，从而消除植入物/组织界面的感染。这种灵活的凸缘机械地将皮肤稳定到植入物上，建立了一个完整的真皮下感染屏障，机械地保护真皮屏障免受不可避免的冲击载荷，并从生物上加速了软组织与经皮支架的整合，从而产生了针对急性和慢性感染的出色的真皮下屏障。

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.