Injectable, biocompatible poly (vinyl alcohol) hydrogels for tissue bulking

用于组织膨胀的可注射、生物相容性聚（乙烯醇）水凝胶

• 批准号: 7747226
• 负责人: Gavin James Braithwaite
• 金额: $ 9.83万
• 依托单位: CAMBRIDGE POLYMER GROUP, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7747226
• 关键词: Address; Affect; Alcohols; Area; Biocompatible; Biocompatible Materials; Body Temperature; Complex; Coupled; Data; Dependence; Development; Drug Formulations; Exhibits; Fecal Incontinence; Foundations; Functional disorder; Future; Gel; Health Care Costs; Housing; Hydrogels; Implant; In Vitro; Individual; Inflammation; Inflammatory Response; Injectable; Injection of therapeutic agent; Investigation; Kinetics; Life; Liquid substance; Literature; Liver; Longevity; Measures; Mechanics; Methods; Modeling; Molecular Weight; Morphology; Muscle; Needles; Operative Surgical Procedures; Outcome; Phase; Physiological; Positioning Attribute; Property; Protocols documentation; Quality of life; Rattus; Recurrence; Research; Safety; Shapes; Solutions; Sterilization for infection control; Stress; Stress Urinary Incontinence; System; Technology; Temperature; Testing; Time; Tissue Model; Tissues; United States; Urinary Incontinence; Urinary tract; Viscosity; Visit; Work; base; chemical reaction; cost; cost effective; cytotoxicity; design; functional restoration; immunogenic; improved; in vivo; innovation; meetings; migration; novel; public health relevance; response; treatment strategy; urinary

DESCRIPTION (provided by applicant): Stress urinary incontinence (SUI) affects 13 million people in the United States per year [2], and some studies have suggested that at least 2% of healthcare costs result from urinary incontinence [3]. Although not a life- threatening condition, the personal cost associated with the condition, and quality-of-life improvement possible with successful treatment, make this a highly addressable condition. In addition, the relatively straightforward treatment options available, make permanent treatment strategies very desirable. Most desirable would be an approach that permanently displaces the tissue, restoring function and avoiding recurrence. An effective tissue-bulking agent for stress urinary incontinence should be non- immunogenic, biocompatible, non-toxic, and hypo-allergenic. It must also exhibit anatomical integrity, integrate with local tissues with minimal inflammation, maintain its injected volume, exhibit no migration outside of the intended bulking area, and be easy to use as well as cost effective. An injectable viscoelastic material that physically bulks the tissue would be ideal. This proposal describes the continued development of a material suitable for tissue bulking to treat stress urinary or fecal incontinence. The existing principle technology is a novel method that uses existing biocompatible materials to form a hydrogel from an injectable liquid without a chemical reaction thus making the formulation inert, truly biocompatible and tissue friendly. Our specific aims will address the following requirements for an injectable poly(vinyl alcohol) (PVA) system as a tissue-bulking agent for treatment of stress urinary incontinence and fecal incontinence: 1. to exist as a liquid pre-gel that can be injected safely through a narrow gauge needle; 2. to gel at under physiological conditions (temperature, medium); 3. to be space-filling; 4. to resist migration; 5. to have minimal inflammatory response. Specific Aim 1: The basic requirements and properties of the pre-gel will be determined using non-gelling PVA solutions. The outcomes of Specific Aim 1 will be functional specifications for the rheological properties of the pre-gel for the target application. Specific Aim 2: Gelling systems will be considered, specifically, investigation of the effects of concentration, molecular weight, and sterilization on the gelation kinetics and viscosity of a set of hydrogels. The outcome of Specific Aim 2 will be a selection of target formulations that meet the functional specifications of SA1 and that have fully characterized rheological responses. Specific Aim 3: Optimal hydrogel formulations developed in Specific Aim 2 will be screened after gamma sterilization for injectability, gelation and safety. Those formulations that pass these tests, are injectable and gel at 400C will be considered for use in Specific Aim 4. Specific Aim 4: 3-4 biocompatible, injectable formulations that possess suitable gelation kinetics will be selected for bench-top space-filling, gelation, and retention analysis. A rat model will be used to validate safety over the period of at least 12 weeks. The outcome from this project will be at least one formulation of injectable PVA hydrogel that is proven safe in short-term in vitro and in vivo tests and that has passed mechanical criteria sufficient for tissue bulking in SUI. The formulation and testing outlined here will provide a foundation for future work in an anticipated Phase II project. PUBLIC HEALTH RELEVANCE: Stress urinary incontinence afflicts approximately 13 million people in the U.S. and is associated with discomfort and embarrassment. This issue can severely impact the quality of life of otherwise healthy individuals, and is often associated with a relatively easily addressed dysfunction of the muscles surrounding the urinary tract. Current treatment options available today include tissue bulking agents to restore muscle position, but many of the products currently available provide only short term solutions that require recurrent injections and multiple surgical visits and have only a limited implant life. The research proposed here will further develop an innovative injectable hydrogel material that is both biocompatible and non-degradable for use as a tissue bulking agent to treat stress urinary incontinence.

描述（由申请人提供）：压力尿失禁（SUI）每年影响美国1300万人[2]，一些研究表明，至少有2％的医疗保健费用是由于尿失禁而导致的[3]。尽管不是威胁生命的状况，但与该状况相关的个人成本以及成功治疗的生活质量改善，但使这是一种高度可寻求的状况。此外，可用的相对简单的治疗方案，使永久治疗策略非常理想。最可取的是一种永久移动组织，恢复功能并避免复发的方法。应力尿失禁的有效组织膨胀剂应非免疫原性，生物相容性，无毒和低变应原性。它还必须表现出解剖完整性，与局部炎症最小的局部组织集成，保持其注入的体积，在预期的散装区域之外没有迁移，并且易于使用且具有成本效益。物理上散装组织的可注射粘弹性材料是理想的。该提案描述了一种持续开发一种适合组织散装的材料，以治疗应激尿路或粪便失禁。现有的原理技术是一种新颖的方法，它使用现有的生物相容性材料从没有化学反应的情况下从注射液中形成水凝胶，从而使配方惰性，真正的生物相容性和组织友好。我们的具体目的将解决以下对可注射聚（乙烯基醇）系统的需求，作为一种组织吊剂，用于治疗应激尿失禁和粪便尿失禁：1。以液态前凝胶的形式存在，可以通过狭窄的指针安全地注射； 2。在生理条件下（温度，培养基）处于凝胶； 3。要填充空间； 4。抵抗迁移； 5。具有最小的炎症反应。特定目的1：凝胶前的基本要求和特性将使用非胶合PVA溶液确定。特定目标1的结果将是目标应用前凝胶的流变特性的功能规范。具体目的2：胶凝系统将被特别研究，研究浓度，分子量和灭菌对一组水凝胶的凝胶化动力学和粘度的影响。特定目标2的结果将是符合SA1功能规范的目标配方的选择，并且具有完全表征的流变响应。特定目的3：在伽马灭菌后将筛选在特定目标2中开发的最佳水凝胶制剂，以进行注射性，凝胶化和安全性。那些通过这些测试的配方可注射，在400C时进行注射凝胶。特定目标4：3-4生物相容性，可注射的配方，具有合适的胶凝动力学，以用于台式空间填充空间填充，凝胶，凝胶和保留分析。大鼠模型将在至少12周内验证安全性。该项目的结果至少是一种可注射的PVA水凝胶的一种公式，在短期体外和体内测试中被证明是安全的，并且已经通过了足以在SUI中进行组织的机械标准。此处概述的配方和测试将为预期的II期项目中的未来工作提供基础。公共卫生相关性：在美国，压力尿失禁遭受了约1300万人的困扰，并与不适和尴尬有关。这个问题可能会严重影响其他健康个体的生活质量，并且通常与尿道周围肌肉的功能障碍相对较容易地相关。当前可用的当前治疗选择包括组织散装剂以恢复肌肉位置，但是当前可用的许多产品仅提供需要经常注射和多次手术就诊的短期解决方案，并且仅具有有限的植入寿命。此处提出的研究将进一步开发一种创新的注射水凝胶材料，该水凝胶材料既具有生物相容性且不可降解，又可以用作组织散装剂来治疗应激尿失禁。