Development of Scar-Inhibiting Compliant Tissue Adhesive

抑制疤痕柔顺组织粘合剂的开发

• 批准号: 7789558
• 负责人: JIRO NAGATOMI
• 金额: $ 21.44万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789558
• 关键词: 3T3 Cells; Acrylamides; Address; Adhesiveness; Adhesives; Age; Animals; Biocompatible Materials; Biological; Biomechanics; Bladder; Bladder Injury; Bladder Tissue; Bolus Infusion; Businesses; Catheters; Cell surface; Cells; Chemicals; Cicatrix; Clinical Treatment; Complex; Complication; Crosslinker; Cultured Cells; Cyanoacrylates; Data; Development; Drug Controls; Drug Delivery Systems; Drug Formulations; Elasticity; Engineering; Equipment; Exhibits; Fibrin; Fibrin Tissue Adhesive; Fluorescence; Free Radicals; Funding; Gel; Gene Delivery; Gene Expression; Gene Silencing; Genes; Genetic Vectors; Glues; Goals; Healed; Health; Hydrogels; Hysterectomy; Immune response; In Vitro; Incidence; Injury; Kinetics; Laceration; Life; Liquid substance; MADH3 gene; Mechanics; Methods; Modeling; Modification; Molecular Weight; Nature; Nucleic Acids; Operating Rooms; Operative Surgical Procedures; Outcome; Patients; Phase; Plasmids; Polyethylene Glycols; Polymers; Population; Procedures; Property; Quality of life; Rattus; Reaction; Recovery; Relative (related person); Research; Research Personnel; Research Project Grants; Route; Safety; Signal Pathway; Small Business Innovation Research Grant; Solutions; Spottings; Stretching; Sulfhydryl Compounds; Surgical sutures; System; Technology; Therapeutic; Time; Tissue Adhesives; Tissues; Toxic effect; Transfection; Ultraviolet Rays; United States; Urine; Viral; Woman; Work; arm; base; biomaterial compatibility; bladder surgery; cohesion; controlled release; copolymer; crosslink; design; extracellular; healing; human MADH3 protein; implantation; in vivo; injury and repair; innovation; knock-down; mRNA Expression; novel; polymerization; pressure; public health relevance; repaired; small hairpin RNA; tissue glueing; urologic; vector

DESCRIPTION (provided by applicant): An estimated 22 million women in the United States have undergone hysterectomy; in 2004, 617,000 of these procedures were performed. Accidental laceration of the bladder during surgery is the most common (incidence of up to 8.3%) complication of hysterectomy. Most of these bladder injuries are repaired by suturing during the surgery, and the bladder is drained with a catheter postoperatively. However, these bladder injuries can result in scar tissue formation. The use of sutures and the formation of scar tissue are especially undesirable because either can compromise the proper distension of the bladder to store urine. In addition, the use of catheters and collecting bags during recovery can severely diminish patients' quality of life. To address these serious health issues, the proposed work will engineer a tissue adhesive that will eliminate the need for suture and will minimize scar formation. The main goal of the proposed research is to design a clinically applicable tissue adhesive that is easy to use (rapid curing, two-component solutions with long shelf life), conforms with stretching of the bladder wall (highly compliant), and degrades with controlled release of bioactive molecules that inhibit scar formation. The investigators will combine their expertise in polymer synthesis, controlled drug/gene delivery, and biomechanics to develop and assess a biodegradable tissue adhesive for repair of bladder tissue injuries using a high-strength, compliant hydrogel system currently in development. Specific aims of the proposed research are 1) To optimize mechanical properties of the bladder tissue adhesives ex vivo, 2) to optimize the scar-inhibiting function of the tissue adhesive ex vivo, and 3) to evaluate the efficacy of the selected scar-inhibiting tissue adhesive in vivo. Tasks involved in achieving these specific aims include, a) tuning the hydrogel tensile properties, cure time, and tissue adhesiveness by adjusting the chemical composition, concentration, molecular weights, and reaction conditions, b) evaluating degradation rate, release kinetics, and efficacy of nucleic acid therapeutics for antagonizing the expression of genes pertinent to scar formation in cultured cells, and c) evaluating the safety and efficacy of the newly designed hydrogel system by evaluating the host response in a rat bladder injury model. These initial in vivo data will be used for further modification of the design and will be the basis for advancing this research to a functional bladder injury model in larger animals. PUBLIC HEALTH RELEVANCE: In the United States, 1/3 of women can expect to have hysterectomy by age 60 and the most common (incidence of up to 8.3%) complication associated with this procedure is accidental nicking of the bladder during surgery. The main goal of the proposed research is to engineer a novel, biodegradable tissue glue for on-the-spot treatment of surgical bladder injuries. The new glue will not only eliminate the need for stitches, catheters, and collecting bags during recovery, but also release therapeutics to block unwanted scar tissues on the bladder during healing, and thus, will help increase the quality of life of many women.

描述（由申请人提供）：在美国，估计有2200万妇女接受了子宫切除术; 2004年，进行了617，000例此类手术。手术中膀胱意外撕裂是子宫切除术最常见的并发症（发生率高达8.3%）。大多数这些膀胱损伤在手术期间通过尿道修复，术后用导管引流膀胱。然而，这些膀胱损伤可导致瘢痕组织形成。使用缝线和形成疤痕组织是特别不希望的，因为任何一种都可能损害膀胱储存尿液的适当扩张。此外，在恢复期间使用导管和收集袋会严重降低患者的生活质量。为了解决这些严重的健康问题，拟议的工作将工程组织粘合剂，将消除缝合的需要，并将最大限度地减少疤痕的形成。 拟议研究的主要目标是设计一种临床适用的组织粘合剂，该粘合剂易于使用（快速固化，具有长保质期的双组分溶液），符合膀胱壁的拉伸（高度顺应性），并通过抑制瘢痕形成的生物活性分子的受控释放而降解。研究人员将联合收割机结合他们在聚合物合成、受控药物/基因递送和生物力学方面的专业知识，开发和评估一种可生物降解的组织粘合剂，用于使用目前正在开发的高强度、顺应性水凝胶系统修复膀胱组织损伤。 所提出的研究的具体目的是1）优化离体膀胱组织粘合剂的机械性能，2）优化离体组织粘合剂的瘢痕抑制功能，3）评价所选瘢痕抑制组织粘合剂的体内功效。实现这些特定目标所涉及的任务包括，a）通过调节化学组成、浓度、分子量和反应条件来调节水凝胶拉伸性能、固化时间和组织粘附性，B）评价降解速率、释放动力学和核酸治疗剂拮抗培养细胞中与瘢痕形成相关的基因表达的功效，和c）通过评价大鼠膀胱损伤模型中的宿主反应来评价新设计的水凝胶系统的安全性和有效性。这些初始的体内数据将用于进一步修改设计，并将成为将本研究推进到大型动物功能性膀胱损伤模型的基础。 公共卫生关系：在美国，1/3的女性在60岁时可能会接受子宫切除术，与此手术相关的最常见（发生率高达8.3%）并发症是手术期间膀胱意外切口。这项研究的主要目标是设计一种新型的、可生物降解的组织胶，用于外科膀胱损伤的现场治疗。这种新的胶水不仅可以在恢复过程中消除对缝线、导管和收集袋的需求，而且还可以在愈合过程中释放治疗剂来阻止膀胱上不需要的疤痕组织，从而有助于提高许多女性的生活质量。