Development of a Novel Composite Surgical Mesh

描述（申请人提供）：以往的研究表明，1-6%的植入医疗器械发生感染1，占院内感染的~45% 2。在腹疝修补术中，感染发生率为2- 10%（即开放手术7-18%，腹腔镜手术0-2%）。疝修补术是全世界普通外科医生最常做的手术之一，在美国每年有超过100万例腹壁修补术，其中77万例是腹股沟修补4-6。考虑到腹股沟疝和腹疝的流行病学意义，确定一种合适有效的疝修补方法是非常重要的。现有的证据强烈支持常规使用假体加固（网）修补疝在大多数患者。与假体网相关的三个主要难题是：1)它们容易引起慢性炎症和过度纤维化，导致植入部位的网状物柔韧性丧失和刚度增加；2)网状物植入后感染；3)涤纶网状物材料的降解。在目前的应用中，我们建议开发一种基于PET网基板的新型复合手术网片，该网片具有嵌入有机硅弹性体涂层，该涂层可以配制成包括一种或多种活性药物，以便：1)增强网片的生物相容性和生物稳定性，2)引导组织修复，以及3)降低设备对细菌定植，生物膜形成和感染的敏感性。具体而言，我们提出以下目标：目标1。制备一种由PET基材和紫外光固化硅酮封装涂层组成的无药复合网状物，通过迭代提高涂层均匀性和完整性来优化复合材料的制备参数，并在皮下植入模型中评估优化后的复合材料的体内性能。目标2。制备两种复合网状结构，包括两种单独的活性药物成分抗菌剂和两种分别包括二元抗菌剂系统的复合网状结构，并表征体外性能（细菌学，药物传递，生物相容性指数等）与剂量的关系，并选择两种最佳剂量/浓度配置，在Aim 3中进行详细的体内评估。目标3。评估前两名在体外执行Aim 2中开发的新型复合手术网的体内性能。作为这项研究的结果，我们将开发一种新型的复合手术网片，基于聚酯网片基片，嵌入有机硅弹性体涂层，可以配制成包括一种或多种api，以便：1)增强网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)降低设备对细菌定植，生物膜形成和感染的敏感性。

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.