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）：压力性尿失禁 (SUI) 每年影响美国 1300 万人 [2]，一些研究表明至少 2% 的医疗费用是由尿失禁造成的 [3]。虽然不是危及生命的病症，但与该病症相关的个人费用以及成功治疗可能改善的生活质量，使其成为一种高度可解决的病症。此外，相对简单的治疗选择使得永久性治疗策略非常可取。最理想的是一种永久置换组织、恢复功能并避免复发的方法。用于治疗压力性尿失禁的有效组织填充剂应该是非免疫原性的、生物相容性的、无毒的和低过敏性的。它还必须表现出解剖学的完整性，与局部组织整合且炎症最小，保持其注射量，不会迁移到预期的填充区域之外，并且易于使用且具有成本效益。物理上使组织膨胀的可注射粘弹性材料将是理想的。该提案描述了适合组织膨胀的材料的持续开发，以治疗压力性尿失禁或大便失禁。现有的原理技术是一种新方法，利用现有的生物相容性材料，在不发生化学反应的情况下，将注射液形成水凝胶，从而使制剂具有惰性、真正的生物相容性和组织友好性。我们的具体目标将满足可注射聚（乙烯醇）（PVA）系统作为治疗压力性尿失禁和大便失禁的组织填充剂的以下要求： 1. 以液体预凝胶形式存在，可以通过窄规格针头安全注射； 2.在生理条件（温度、介质）下凝胶化； 3. 填补空间； 4. 抵制迁移； 5.炎症反应最小。具体目标 1：预凝胶的基本要求和性能将使用非胶凝 PVA 溶液来确定。具体目标 1 的结果将是目标应用的预凝胶流变特性的功能规格。具体目标 2：将考虑凝胶系统，特别是研究浓度、分子量和灭菌对一组水凝胶的凝胶动力学和粘度的影响。具体目标 2 的结果将是选择满足 SA1 功能规格并具有完全表征的流变响应的目标配方。具体目标 3：具体目标 2 中开发的最佳水凝胶配方将在伽马灭菌后进行可注射性、凝胶化和安全性的筛选。通过这些测试、可注射且在 400°C 凝胶的制剂将被考虑用于特定目标 4。特定目标 4：将选择具有合适凝胶动力学的 3-4 个生物相容性注射制剂用于台式空间填充、凝胶化和保留分析。将使用大鼠模型来验证至少 12 周的安全性。该项目的成果将是至少一种可注射 PVA 水凝胶配方，该配方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 中进行组织膨胀的机械标准。这里概述的制定和测试将为预期的第二阶段项目的未来工作奠定基础。公共健康相关性：压力性尿失禁困扰着美国约 1300 万人，并与不适和尴尬有关。这个问题会严重影响健康个体的生活质量，并且通常与相对容易解决的泌尿道周围肌肉功能障碍有关。目前可用的治疗选择包括用于恢复肌肉位置的组织填充剂，但目前可用的许多产品仅提供短期解决方案，需要反复注射和多次手术就诊，并且植入物寿命有限。这里提出的研究将进一步开发一种创新的可注射水凝胶材料，该材料具有生物相容性和不可降解性，可用作治疗压力性尿失禁的组织填充剂。