Novel Osteoinductive Protein Synthesizing Implant System

新型骨诱导蛋白合成植入系统

• 批准号: 6487918
• 负责人: KYUMIN WHANG
• 金额: $ 7.29万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6487918
• 关键词: biodegradable product; bioengineering /biomedical engineering; biomaterial compatibility; biomaterial development /preparation; bone marrow; bone morphogenetic proteins; bone regeneration; cell differentiation; cell growth regulation; cell population study; cell proliferation; developmental genetics; drug delivery systems; gene expression; histochemistry /cytochemistry; implant; laboratory rat; lovastatin; medical implant science; morphometry; osteoblasts; osteogenesis; polymers; simvastatin; spectrometry; stem cell transplantation

DESCRIPTION: (provided by applicant) Therapies to aid healing of bone wounds and defects are major needs. Recently, small molecules that can induce expression of the bone morphogenetic protein (BMP)-2 gene in osteoblasts and bone marrow (BM) cells have been identified, such as the statins (e.g. lovastatin, simvastatin). However, their use in bone formation is limited due to a lack of suitable delivery vehicles. The long-range goal of this work is to develop optimized delivery devices for tissue engineering. The objective for this application is to determine the effect of different strategies for delivering statins from resorbable polymer scaffolds on bone regeneration in vitro and in vivo: diffusion-controlled delivery of statins, the slow degradation-controlled delivery of OG-PLG, and the continued in vivo stimulation of seeded BM cells to produce native BMP-2 using a novel Osteoinductive Protein Synthesizing Implant System (OPSIS). We have developed the strategy of an OPSIS to combat the problem of poor delivery. This system consists of OG-PLG fabricated into a three-dimensional scaffold using the emulsion freeze-drying (EFD) process, and seeded with BM cells. OG-PLG is synthesized by grafting simvastatin to the end of biodegradable poly[lactide-co-glycolide] (PLG) polymers. Preliminary in vitro studies showed that constant delivery of small amounts of lovastatin (2.5 ug/day) from EFD scaffolds enhanced the efficacy of the drug to form new bone by approximately two orders of magnitude over local subcutaneous injections. However, no bone was found inside the scaffolds because lovastatin is not chemotactic and bone cells were not recruited into the scaffold, and localized cytotoxicity was observed at high doses. Thus, the concept of the OPSIS was developed to continually stimulate BM cells seeded in OG-PLG scaffolds to synthesize native BMP-2 in vivo and stimulate both seeded BM cells and surrounding host cells to form bone. OG-PLG synthesis was confirmed using contact angle measurements, Attenuated Total Reflectance-FTIR and UV-Vis spectroscopy. The hypothesis to be tested is that osteoinduction is enhanced by slow degradation-controlled release of OG-PLG for interaction with seeded BM cells to induce synthesis of BMP-2 in the OPSIS. Two specific aims are proposed: 1) to determine the effects of binding statin onto PLG on osteoinduction in vitro and 2) to determine the effects of binding statin onto PLG and BM cell transnlantation on osteoinduction in vivo. Results will bridge the gap between basic research and clinical application because statins are as potent as the most powerful bone growth factors not yet FDA approved for clinical use and substantially (16,000-fold) cheaper to synthesize, and with an optimized delivery system even large, critical or nonunion defects will be treated effectively and efficiently.

描述：（由申请人提供）辅助骨伤口愈合的疗法 和缺陷是主要需求。最近，小分子可以诱导 骨形态发生蛋白（BMP）-2基因在成骨细胞中的表达， 已经鉴定了骨髓（BM）细胞，例如他汀类药物（例如， 洛伐他汀、辛伐他汀）。然而，它们在骨形成中的使用受到限制， 缺乏合适的运输工具。这项工作的长期目标是 开发用于组织工程的优化输送装置。年的目标 本申请旨在确定不同策略的效果， 从可吸收聚合物支架中释放他汀类药物对骨再生的影响 体外和体内：他汀类药物的扩散控制递送，缓慢的 OG-PLG的降解控制递送，以及持续的体内 使用一种新的方法刺激接种的BM细胞产生天然BMP-2， 骨诱导蛋白合成植入系统（OPSIS）。我们已经开发 解决执行情况不佳问题的战略。该系统 由OG-PLG组成，使用 乳液冷冻干燥（EFD）过程，并接种BM细胞。OG-PLG是 通过将辛伐他汀接枝到可生物降解的 聚[丙交酯-共-乙交酯]（PLG）聚合物。初步的体外研究显示， 从EFD中持续输送少量洛伐他汀（2.5 μ g/天） 支架增强了药物形成新骨的功效， 比局部皮下注射高两个数量级。然而，没有骨头 因为洛伐他汀不是趋化性的， 细胞没有被募集到支架中，并且局部细胞毒性被抑制。 在高剂量下观察到。因此，发展了战略问题信息系统的概念， 持续刺激接种在OG-PLG支架中的BM细胞合成天然的 BMP-2在体内并刺激接种的BM细胞和周围的宿主细胞， 形成骨头。使用接触角测量确认OG-PLG合成， 衰减全反射-FTIR和UV-Vis光谱。假设是 测试的是，骨诱导是通过缓慢的降解控制增强， 释放OG-PLG，用于与接种的BM细胞相互作用，以诱导 骨形态发生蛋白-2提出了两个具体目标：1）确定影响 在体外骨诱导中将他汀类药物结合到PLG上，以及2）确定 他汀类药物结合PLG和BM细胞转染对细胞增殖的影响 体内骨诱导。结果将弥合基础研究和 临床应用，因为他汀类药物与最强大的骨骼一样有效 FDA尚未批准用于临床使用的生长因子， (16 000倍）合成成本更低，并且通过优化的输送系统， 大的、严重的或骨不连的缺损将得到有效治疗， 有效地