Zosteric Acid Integrated Thermo-reversible Gels for Preventing Surgical Adhesions

用于预防手术粘连的 Zosteric Acid 集成热可逆凝胶

基本信息

批准号：
8232885
负责人：
Bi-min Newby
金额：
$ 37.64万
依托单位：
UNIVERSITY OF AKRON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8232885
关键词：
Abdomen Acids Adhesions Adhesives Animals Anti-Adhesion Agent Area Behavior Binding Biological Factors Biomaterials Research Biomedical Research Cell Culture Techniques Cells Chemicals Cicatrix Clinical Clinical Trials Collaborations Collagen Communities Complex Complication Data Deposition Development Drug Compounding Drug Controls Drug Delivery Systems Effectiveness Encapsulated Engineering Ensure Expenditure Family suidae Fibrin Fibroblasts Film Funding Gel Glycolic-Lactic Acid Polyester Goals Grant Guidelines Health Health system Hospitalization Hour Human Human Activities Hydrogels Hydroxyl Radical In Vitro Infertility Inflammatory Institutes Journals Knowledge Laparoscopic Surgical Procedures Lead Learning Liquid substance Mammalian Oviducts Marines Mass Spectrum Analysis Medical Mentors Methods Methylcellulose Modeling Morbidity - disease rate Mus Nature Nuclear Magnetic Resonance Operative Surgical Procedures Organ Organism Pain Paper Patients Pelvis Pharmaceutical Preparations Phase Pluronics Prevention Production Property Proteins Publications Research Research Personnel Safety Science Scientist Site Solid Students Surface Surgical Management System Techniques Technology Time Tissue Engineering Tissues Toxic effect Training United States National Institutes of Health Universities Variant Water Work Zostera base biodegradable polymer career cell growth chemical synthesis clinical practice controlled release cytotoxicity design dosage drug synthesis graduate student high school in vivo insight meetings nanoparticle next generation pre-clinical prevent programs rhamnolipid scale up skills success symposium tissue culture

项目摘要

DESCRIPTION (provided by applicant): The development of adhesions following surgery represents a significant, costly morbidity typically expressed as pain and infertility in the patient. Availability of a reliable method to decrease occurrence of adhesions would constitute a beneficial advance in current surgical practice. However, the efficacy and utility in both open and laparoscopic surgery of currently approved standard adhesion barriers is limited. The goal of the proposed project is a delivery system that allows an initial burst of the anti-adhesion agent, zosteric acid (ZA), followed by a sustained release of the agent. Zosteric acid, a natural product extracted from eelgrass Zostera Marina, shows an extremely low toxicity but effectiveness in preventing adhesion formation of various organisms. It will be directly integrated, along with its nanoparticle-encapsulated form, into a thermo-reversible gel made of Pluronic(R) F-127 and Hydroxyl propyl methyl cellulose, which can then be easily applied in both open and laparoscopic surgeries to prevent adhesion development. The specific tasks include: (1) to successfully scale up the production of highly purified ZA; {(2) to assess the collagen deposition and fibroblast activities of human and mouse fibroblast cells using free form of ZA; (3)} to encapsulate ZA into micro/nanoparticles of a relatively rapid biodegradable polymer, poly(lactide-co-glycolide); (4) following encapsulation, we will first conduct in vitro culture studies to determine viability {of the thermo- reversible gel containing free form and micro/nanoparticle encapsulated ZA and} then in vivo studies. If cell culturing does not provide evidence of cell growth inhibition, we will repeat the encapsulation step utilizing an alternative drug (e.g. rhamnolipids) with the appropriate properties. When tissue culturing provides evidence of cell growth inhibition {and non-cytotoxic}, we will then determine the efficacy of the dual-delivery system in preventing adhesions in a swine model. While not to be included in this project, the next phase, following successful animal results, would be to pursue FDA approval and clinical trials. The proposed tasks have been designed to train and engage a team of a graduate, undergraduate and high school students. The involvement of undergraduate (via Tiered Mentoring) and high school students (via Project Lead the Way) are intended to promote and encourage careers in science, technology and engineering, an on-going effort that the PI has been actively participating in. The graduate student will not only be challenged to conduct research related to biomedicine, but also will be provided the opportunity to mentor underclassmen. Through informal discussion and weekly project meetings with the PIs, attending regional or national scientific meetings, and journal publications, the students trained in traditional chemical and material engineering will be given opportunities to explore the biomedical community. If funded, the proposed project would be one of the first NIH-funded researches in the Department of Chemical and Biomolecular Engineering at The University of Akron, a department on the rise in biomaterial research. PUBLIC HEALTH RELEVANCE: This AREA project is to develop a drug delivery system that allows an initial burst followed with a slow release of an anti-adhesive agent, zosteric acid, for the prevention of surgical adhesions. The Department of Chemical and Biomolecular Engineering at the University of Akron is developing focused research in the area of tissue engineering, drug delivery and biofouling based on an established research area, mainly contributed by PI, in biofouling/antifouling,. The program calls for a strong collaborative effort between our University and regional medical institutes, such as Summa Health System and NEOUCOM, and this AREA grant, if funded, will allow for such collaboration to expand and for the exposure of students to various health related research.

描述（由申请人提供）：手术后发生粘连代表着一种显着且昂贵的发病率，通常表现为患者的疼痛和不孕。减少粘连发生的可靠方法的可用性将构成当前外科实践的有益进步。然而，目前批准的标准粘连屏障在开放式和腹腔镜手术中的功效和实用性是有限的。拟议项目的目标是建立一种递送系统，该系统允许抗粘连剂大叶甾酸（ZA）最初爆发，然后持续释放该药物。大叶藻酸是从大叶藻大叶藻中提取的天然产物，毒性极低，但能有效防止各种生物体的粘附形成。它将与其纳米颗粒封装形式一起直接集成到由 Pluronic(R) F-127 和羟丙基甲基纤维素制成的热可逆凝胶中，然后可以轻松应用于开腹和腹腔镜手术中以防止粘连发展。具体任务包括：（1）成功实现高纯度ZA的规模化生产； {(2)使用游离形式的ZA评估人类和小鼠成纤维细胞的胶原沉积和成纤维细胞活性； (3)}将ZA封装到相对快速的可生物降解聚合物聚(丙交酯-共-乙交酯)的微米/纳米颗粒中； (4)封装后，我们将首先进行体外培养研究以确定{含有游离形式和微/纳米粒子封装的ZA的热可逆凝胶的活力，然后}进行体内研究。如果细胞培养没有提供细胞生长抑制的证据，我们将使用具有适当特性的替代药物（例如鼠李糖脂）重复封装步骤。当组织培养提供细胞生长抑制（且无细胞毒性）的证据时，我们将确定双重递送系统在猪模型中预防粘连的功效。虽然不包括在该项目中，但在动物实验取得成功后，下一阶段将寻求 FDA 批准和临床试验。拟议的任务旨在培训和吸引研究生、本科生和高中生团队。本科生（通过分层指导）和高中生（通过“引领道路”项目）的参与旨在促进和鼓励科学、技术和工程领域的职业生涯，这是 PI 一直积极参与的一项持续努力。学生不仅将面临进行生物医学相关研究的挑战，还将有机会指导低年级学生。通过与 PI 的非正式讨论和每周项目会议、参加地区或国家科学会议以及期刊出版物，接受传统化学和材料工程培训的学生将有机会探索生物医学界。如果获得资助，拟议的项目将成为阿克伦大学化学与生物分子工程系首批由美国国立卫生研究院资助的研究之一，该系在生物材料研究方面正在兴起。公共健康相关性：该领域项目旨在开发一种药物输送系统，该系统可在初始爆发后缓慢释放抗粘连剂（大叶酸），以预防手术粘连。阿克伦大学化学与生物分子工程系正在以主要由 PI 贡献的生物污损/防污研究领域为基础，在组织工程、药物输送和生物污损领域开展重点研究。该计划要求我们的大学和地区医疗机构（例如 Summa Health System 和 NEOUCOM）之间进行强有力的合作，而这笔 AREA 赠款如果获得资助，将允许扩大这种合作，并使学生有机会接触各种健康相关的研究。