Infection-Prevention Barriers for Osseointegrated Percutaneous Implants

描述（由申请人提供）：肢体截肢与日常功能和生活质量的毁灭性丧失有关。目前正在考虑采用经皮骨整合种植体将外假体附着在残肢上。为了使该方法取得成功，必须在经皮肾塔周围的组织中建立并保持无感染屏障。pi建议通过利用医用级微孔聚氨酯制造的生物相容性真皮下法兰来消除骨整合植入物宿主组织/经皮桥架界面的感染。这种灵活的法兰在机械上稳定皮肤，以建立一个完整的皮下屏障，在机械上保护皮肤屏障免受不可避免的冲击载荷，并在生物上加速软组织与经皮桥的整合，从而形成一个抵抗急性和慢性感染的优质皮下屏障。PIs比较了猪模型胫骨骨整合植入物上两种软组织整合法兰的设计：(1)刚性微孔钛合金皮下法兰（基线对照）和(2)新型柔性微孔聚氨酯皮下法兰。此外，聚氨酯法兰将装载临床常见的多能人蛋白生长因子-血小板衍生生长因子β (PDGF-BB)，作为一种经证实的骨诱导、血管生成和皮肤愈合生物活性剂，用于局部释放。在Aim 1中，通过创新的柔性微孔聚合物凸缘附着在桥架上，促进宿主软组织的整合，创造了一个皮下屏障，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-塔界面的运动，允许生长，植入物-真皮密封和感染预防。将评估聚氨酯法兰装置与钛法兰装置的感染率、组织附着、血管化和组织。目的2旨在证明聚氨酯法兰可以更好地保护软组织/经皮界面免受创伤，特别是对周围软组织的冲击损伤。受控的冲击载荷将被定向到体内的软组织/经皮-桥塔界面，设备留在原位愈合。随后的感染、组织重新附着、愈合、血管重建和组织生长将被测量。在Aim 3中，一种目前处于临床试验的人类蛋白衍生生长因子（PDGF-BB）将被制成聚合物法兰，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试验将用于最大化药效学效应和设计体内使用的蛋白质释放策略。机械匹配的聚合物法兰与内在组织整合和PDGF-BB从种植体局部释放的组合将被用于加速塔周围急性期组织愈合，增强与种植体界面的机械耦合，增强局部组织对创伤的稳定性，并保留种植体相关组织屏障以防止感染问题。

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.