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

描述（由申请人提供）：压力性尿失禁（SUI）在美国每年影响1300万人[1]，一些研究表明，尿失禁至少占医疗费用的2%[1]。虽然不是一种危及生命的疾病，但与这种疾病相关的个人成本，以及成功治疗可能改善的生活质量，使这种疾病成为一种高度可解决的疾病。此外，相对直接的治疗选择，使永久治疗策略非常可取。最理想的方法是永久置换组织，恢复功能并避免复发。治疗压力性尿失禁的有效组织膨胀剂应该是非免疫原性的、生物相容性的、无毒的、低过敏性的。它还必须具有解剖完整性，与局部组织结合，炎症最小，保持其注射体积，不会迁移到预定的填充区域之外，并且易于使用且具有成本效益。理想的是一种可注射的粘弹性材料，它可以使组织物理膨胀。本提案描述了一种适合用于治疗压力性尿失禁或粪便失禁的组织膨胀材料的持续发展。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可注射液体中形成水凝胶，而不发生化学反应，从而使配方具有惰性，真正的生物相容性和组织友好性。我们的具体目标是针对可注射聚乙烯醇（PVA）系统作为治疗压力性尿失禁和大便失禁的组织膨胀剂的以下要求：注射，注射：作为液体预凝胶存在，可以通过细针安全注射；2. 凝胶：在生理条件下（温度、介质）形成凝胶；3. 填满空间；4. 抵制迁移；5. 有最小的炎症反应。具体目标1：预凝胶的基本要求和性能将使用非凝胶化的PVA溶液来确定。特异性目标1的结果将是针对目标应用的预凝胶的流变特性的功能规格。具体目标2：胶凝系统将被考虑，具体来说，研究浓度、分子量和灭菌对一组水凝胶的胶凝动力学和粘度的影响。特异性目标2的结果将是选择符合SA1功能规格并具有充分表征流变反应的靶制剂。特异性目标3：特异性目标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，凝胶性和安全性筛选。那些通过这些测试的配方，在400C下是可注射和凝胶的，将被考虑用于特异性Aim 4。特异性目标4:3 -4具有合适凝胶动力学的生物相容性可注射制剂将被选择用于台式空间填充、凝胶和保留分析。将使用大鼠模型来验证至少12周的安全性。该项目的结果将是至少一种可注射的PVA水凝胶配方，该配方在短期体外和体内试验中被证明是安全的，并且已经通过了足以用于SUI组织膨胀的机械标准。这里概述的配方和测试将为预期的第二期项目的未来工作奠定基础。公共卫生相关性：在美国，压力性尿失禁折磨着大约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，并且通常与泌尿道周围肌肉的相对容易解决的功能障碍有关。目前可用的治疗方案包括组织膨胀剂来恢复肌肉位置，但目前可用的许多产品只能提供短期解决方案，需要反复注射和多次手术就诊，并且植入物寿命有限。本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，可作为组织膨胀剂用于治疗压力性尿失禁。

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.