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

用于心室辅助装置 (VAD) 经皮手术的抗感染表面

• 批准号: 8892504
• 负责人: Patrick Thomas Cahalan
• 金额: $ 88.07万
• 依托单位: ENSION, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892504
• 关键词: Acute; Adherence; Adhesions; Animal Model; Bacteria; Bacterial Adhesion; Blood; Blood Platelets; Body Surface; Caliber; Cannulas; Cell Count; Cells; Chemicals; Chronic; Cicatrix; Collagen; Complication; Confocal Microscopy; Control Groups; Coupling; Data; Detection; Development; Devices; Dimensions; Engineering; Environment; Evaluation; Family suidae; Fibrin; Fibroblasts; Fluorescence; Foreign-Body Reaction; Gentamicins; Healed; Health; Histocompatibility; Hydrogels; Immune; Immune response; Immune system; Immunofluorescence Microscopy; Implant; In Vitro; Infection; Inflammation; Inflammatory; Inorganic Sulfates; Label; Length; Leukocytes; Life; Measures; Medical Device; Methods; Microbe; Modeling; Monitor; Mus; Performance; Pharmaceutical Preparations; Phase; Polyurethanes; Process; Public Health; Research; Resistance; Resistance to infection; Silver; Skin; Solutions; Spatial Distribution; Structure of parenchyma of lung; Surface; Systemic infection; Testing; Tissue Sample; Tissues; Toxic effect; Treatment Step; Unspecified or Sulfate Ion Sulfates; antimicrobial; antimicrobial drug; base; biomaterial compatibility; commercialization; controlled release; design; fighting; healing; implant material; improved; in vitro testing; in vivo; inflammatory marker; innovation; man; medical implant; meetings; mouse model; prevent; prototype; response; ventricular assist device; von Willebrand Factor

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.

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，包括用于制造心室辅助装置 (VAD) 的材料，会以两种方式损害人体抵抗感染的能力。首先，通过经皮插管和传动系统破坏皮肤，其次，通过引发异物反应，导致植入物表面附近形成疤痕，从而创造出细菌可以在人体免疫系统范围之外繁殖的环境。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系统隔离的问题。 Ension 建议开发一种抗感染表面，旨在促进正常愈合，应用于心室辅助装置的经皮传动系统。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了急性抗菌剂释放的部分解决方案（例如通常用于 VAD 经皮传动系统应用的银浸纱布），转而采用工程化表面，该表面还可以促进邻近组织的最佳愈合反应。表面附近的正常愈合反应会产生没有疤痕和慢性炎症的组织，确保正常的免疫反应，从而提高长期的感染抵抗力。使用原型表面进行的初步体外测试表明，所提出的表面有利于成纤维细胞粘附（正常愈合的一部分），抵抗细菌附着，并避免引起阻碍正常愈合的毒性。拟议的快速通道项目将完善最有前途的原型表面并将其应用于聚氨酯基材（第一阶段特定目标1），制造和测试经过优化表面处理的植入物以实现小鼠生物相容性（第一阶段特定目标2和3），并对猪的感染抵抗力进行详细的体内评估（第二阶段）。第二阶段在 体内测试将包括在植入时接受细菌挑战的猪群、植入后定期进行细菌挑战以及“未受到挑战”的对照（第二阶段具体目标2）。荧光标记和共聚焦显微镜将用于确定种植体表面或附近的细胞类型和数量及其空间分布（第二阶段具体目标 3）。这些方法还可以检测同一组织样本中的纤维蛋白和胶原蛋白。获得的数据将与对照以及正常愈合过程中观察到的既定数据进行比较。预计该表面在愈合反应、细菌粘附、局部感染和全身感染迹象方面比未处理的对照表现出改善。快速通道项目计划的成功完成将为资格测试、监管审批和后续商业化做好准备。