Infection resistant surface for ventricular assist device (VAD) transcutaneous dr

描述（由申请人提供）：感染是与医疗植入物相关的常见且经常非常严重的并发症。人造材料，包括那些用于制造心室辅助装置（VAD）的材料，以两种方式损害人体对抗感染的能力。第一，通过经皮插管和传动线破坏皮肤，第二，通过引发异物反应，导致植入物表面附近的瘢痕形成，从而产生细菌可以在身体免疫系统范围外繁殖的环境。目前可用的抗感染材料通常依赖于抗菌物质的释放。虽然在短期内有效，但释放的药物可能会损害正常愈合，并加剧植入物表面与人体免疫防御隔离的问题。Ension提出开发一种抗感染表面，旨在促进心室辅助装置经皮传动系统的正常愈合。拟议的表面将采用三管齐下的方法来抵抗感染;旨在防止或阻碍微生物附着的低粘附表面，抗菌剂的受控释放，以及促进组织整合的天然胶原蛋白表面。该表面的创新在于超越急性抗菌剂释放的部分解决方案（例如VAD经皮传动系统应用中通常使用的银浸渍纱布），成为一种工程化表面，还可促进相邻组织的最佳愈合反应。靠近表面的正常愈合反应产生没有疤痕和慢性炎症的组织，确保正常的免疫反应，从而提高长期的抗感染能力。使用原型表面进行的初步体外测试表明，所提出的表面促进成纤维细胞粘附（正常愈合的一部分），抵抗细菌附着，并避免导致阻碍正常愈合的毒性。拟议的Fast Track项目将改进最有前途的原型表面，并将其应用于聚氨酯基材（I期特定目标1），制造和测试经优化表面处理的植入物在小鼠中的生物相容性（I期特定目标2和3），并对猪的抗感染性进行详细的体内评价（II期）。第二阶段在 体内试验将包括在植入时接受细菌挑战、植入后定期接受细菌挑战的猪组和“未挑战”对照组（II期特定目标2）。荧光标记和共聚焦显微镜将用于确定植入物表面或附近的细胞类型和数量及其空间分布（II期特定目标3）。这些方法还允许检测相同组织样品中的纤维蛋白和胶原蛋白。将获得的数据与对照组和正常愈合期间观察到的既定数据进行比较。预期该表面在愈合反应、细菌粘附、局部感染和全身感染体征方面显示出优于未处理对照的改善。快速通道项目计划的成功完成将使表面准备好进行资格测试，监管批准和随后的商业化。

DESCRIPTION (provided by applicant): Infection is a common and frequently very serious complication associated with medical implants. Man-made materials, including those used to fabricate ventricular assist devices (VADs), compromise the body's ability to fight infection in tw ways. First, by breaching skin with transcutaneous cannulae and drivelines, and second, by eliciting a foreign body reaction which results in scarring near the implant surface that creates an environment where bacteria can thrive outside the reach of the body's immune system. Currently available infection resistant materials typically rely on the release of antimicrobial substances. Though effective over the short-term, the released drugs can compromise normal healing and exacerbate the problem of isolating the implant surface from the body's immune defenses. Ension proposes development of an infection resistant surface designed to promote normal healing for application to the transcutaneous drivelines of ventricular assist devices. The proposed surface will incorporate a three-pronged approach to infection resistance; a low adhesion surface designed to prevent or hinder the attachment of microbes, controlled release of antimicrobial agents, and a natural collagen surface that promotes tissue integration. The innovation of the surface lies in going beyond the partial solution of acute antimicrobial release (such as the silver-impregnated gauze typically used in VAD transcutaneous driveline applications) to an engineered surface that also promotes optimal healing response of the adjacent tissue. The normal healing response near the surface generates tissue devoid of scarring and chronic inflammation, assuring a normal immune response and thus improving long-term infection resistance. Preliminary in vitro testing using prototype surfaces demonstrated that the proposed surface facilitates fibroblast adhesion (a part of normal healing), resists attachment of bacteria, and avoids causing toxicity that would hinder normal healing. The proposed Fast Track project will refine the most promising prototype surface and apply it to polyurethane substrate material (Phase I Specific Aim 1), fabricate and test implants treated with the optimized surface for biocompatibility in mice (Phase I Specific Aims 2 and 3), and perform detailed in vivo evaluation of infection resistance in pigs (Phase II). The Phase II in vivo testing will include groups of pigs implanted with bacterial challenge at implant, with periodic bacterial challenges following implant, and "unchallenged" controls (Phase II Specific Aim 2). Fluorescence labeling and confocal microscopy will be used to determine the types and numbers of cells at or near the implant surface and their spatial distribution (Phase II Specific Aim 3). These methods also allow detection of fibrin and collagen in the same tissue samples. The data obtained will be compared both to controls and to established data observed during normal healing. The surface is expected to show improvement over untreated controls with respect to healing response, bacterial adhesion, local infection and systemic signs of infection. Successful completion of the Fast Track project plan will result in a surface ready for qualification testing, regulatory approval, and subsequent commercialization.