Development of a Novel Composite Surgical Mesh

描述（由申请人提供）：既往研究表明，1-6%的植入式医疗器械发生感染，1约占医院感染的45% 2。在腹疝修补术中，感染发生率为2- 10%（即开放手术的感染率为7-18%，腹腔镜手术的感染率为0-2%）。疝修补术是全世界普通外科医生最常进行的手术之一，在美国每年进行超过100万例腹壁修补术，其中770，000例是腹股沟修补术4-6。考虑到腹股沟疝和腹疝的流行病学意义，确定一种适当有效的疝修补方法是非常重要的。现有证据强烈支持在大多数患者中常规使用假体加固（补片）进行疝修补。与假体补片相关的三个主要难题是：1）其倾向于诱导慢性炎症和过度纤维化，导致植入部位的补片柔韧性丧失和刚度增加，2）补片植入后感染，以及3）聚酯补片材料降解。在本申请中，我们提出开发一类新的复合外科网片，其基于具有嵌入硅酮弹性体涂层的PET网片基底，所述嵌入硅酮弹性体涂层可被配制成包括一种或多种活性药剂，以便：1）增强网片生物相容性和生物稳定性，2）引导组织修复，以及3）降低装置对细菌定植、生物膜形成和感染的易感性。具体而言，我们提出以下目标：目标1。配制包含PET基材和UV固化硅酮封装涂层的无药物复合补片，通过迭代改善涂层均匀性和完整性来优化复合材料制造参数，并在皮下植入模型中评价优化复合材料的体内性能。目标2.制造包含两种单独活性药物成分抗菌剂的两种复合补片配置和各自包含二元抗菌剂系统的两种复合补片配置，并表征体外性能（细菌学、药物递送、生物相容性指数等）对比剂量，并选择两种最佳剂量/浓度配置，用于目标3中的详细体内评价。 目标3：评价目标2中开发的两种体外性能最佳的新型复合外科补片的体内性能。 作为这项拟议研究的结果，我们将开发出一种新型复合外科补片，该补片基于聚酯补片基材，具有嵌入式硅橡胶弹性体涂层，可配制成包含一种或多种API，以便：1）增强补片的生物相容性和生物稳定性，2）减少炎症和纤维化，和/或3）降低器械对细菌定植的敏感性，生物膜形成和感染。 公共卫生相关性：疝修补术是最常进行的手术之一，常规使用假体加固（补片）进行疝修补。与补片相关的主要难题是其诱导炎症、纤维化、补片植入后感染和聚酯补片材料降解的倾向。该提案的目标是开发一种新型复合外科补片，其配方旨在增强生物相容性和生物稳定性，减少炎症并降低对细菌定植和生物膜形成的敏感性。

DESCRIPTION (provided by applicant): Previous studies have demonstrated that 1-6% of implanted medical devices become infected, 1 and account for ~45% of nosocomial infections 2. In ventral hernia repair, infections occur in 2-10 % of the time (i.e. open surgery 7-18% and laparoscopic 0-2% infection rates) 3. Hernia repairs are among the most commonly performed operations by general surgeons throughout the world with over 1 million abdominal wall repairs performed each year in the U.S. Of these, 770,000 are inguinal repairs 4-6. Given the epidemiologic significance of inguinal and ventral hernias, determining an appropriate and effective means of hernia repair is very important. The existing evidence strongly supports routine use of prosthetic reinforcement (meshes) for the repair of hernias in most patients. Three of the major dilemmas associated with prosthetic meshes are 1) their propensity to induce chronic inflammation and excessive fibrosis, with resulting loss of mesh pliability and increased stiffness at the site of the implantation, 2) post mesh implantation infections, and 3) degradation of the mesh material in the case of polyester. In the present application we propose to develop a new class of composite surgical meshes based on a PET mesh substrate with intercalating silicone elastomer coatings that may be formulated to include one or more active pharmaceutical agents in order to: 1) enhance mesh biocompatibility and bio- stability, 2) guide tissue repair, and 3) decrease the susceptibility of the device to bacterial colonization, biofilm formation and infection. Specifically we propose to the following aims: Aim 1. Formulate a drug-free composite mesh comprising a PET substrate and a UV-curing silicone encapsulating coating, optimize the composite fabrication parameters by iteratively improving coating uniformity and integrity, and evaluate the in vivo performance of the optimized composite in a subcutaneous implant model. Aim 2. Fabricate two composite mesh configurations comprising two individual active pharmaceutical ingredient antimicrobial agents and two composite mesh configurations each comprising a binary antimicrobial agent system and characterize in vitro performance (bacteriology, drug delivery, biocompatibility index etc.) vs. dose, and choose the two optimal dose/concentration configurations for a detailed in vivo evaluation in Aim 3. Aim 3. Evaluate the in vivo performance of the top two in vitro performing novel composite surgical meshes developed in Aim 2. As a result of this proposed research we will have developed a new class of composite surgical meshes based on a polyester mesh substrate with intercalating silicone elastomer coatings that may be formulated to include one or more APIs in order to: 1) enhance mesh biocompatibility and bio-stability of the mesh, 2) decrease inflammation and fibrosis, and/or 3) decrease the susceptibility of the device to bacterial colonization, biofilm formation and infection. PUBLIC HEALTH RELEVANCE: Hernia repair is among the most commonly performed operations and routinely prosthetic reinforcement (meshes) is utilized for the repair of hernias. Major dilemmas associated with meshes are their propensity to induce inflammation; fibrosis, post mesh implantation infection and degradation of the polyester mesh material. The goal of this proposal is to develop a new class of composite surgical meshes, which are formulated to enhance biocompatibility and bio stability, decrease inflammation and decrease susceptibility to bacterial colonization and biofilm formation.