Synergistic Molecule Delivery Using Hydrogels for BoneTissue Repair

使用水凝胶进行协同分子传递以修复骨组织

• 批准号: 8526634
• 负责人: Julianne Leigh Holloway
• 金额: $ 4.71万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526634
• 关键词: Acrylates; Adhesives; Autologous Transplantation; BMP2 gene; Bone Regeneration; Bone Tissue; Bone Transplantation; Cells; Cephalic; Clinic; Clinical; Collaborations; Defect; Disadvantaged; Disease; Dose; Engineering; Evaluation; Extracellular Matrix; Family; Gel; Gold; Growth Factor; Hyaluronic Acid; Hydrogels; Hydrolysis; In Vitro; Kinetics; Laboratories; Lead; Mediating; Metalloproteases; Mind; Modeling; Morbidity - disease rate; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Patients; Pennsylvania; Peptides; Process; Production; Publishing; Rattus; Reaction; Recovery; Reporting; Research; Signal Transduction; Site; Techniques; Therapeutic; Time; Tissue Engineering; Tissues; Trauma; United States; Universities; Work; base; bone; bone loss; bone morphogenic protein; cost; crosslink; density; design; improved; in vivo; insight; novel; prevent; public health relevance; repaired; scaffold; tissue repair

DESCRIPTION (provided by applicant): The use of bone morphogenic proteins (BMPs) shows promise as therapeutics for improving bone regeneration; however, high supraphysiological concentrations required for desired osteoinductive effect, costs, and patient variability have prevented the full advantages of BMP-based therapeutics from being realized. Thus, there is a clinical need to develop growth factor delivery strategies that will optimize release kinetics and overcome the need for non-physiologic high concentrations to promote bone repair. The proposed approach utilizes a matrix metalloprotease (MMP)-sensitive hyaluronic acid (HA)-based hydrogel scaffold as a cell-mediated delivery vehicle, where the remodeling of the gel releases the molecules. Scaffold degradation kinetics can be controlled through varying the MMP sensitivity of the proteolytic peptide and through cross-link density. Canonical Wnt signaling is known to promote osteoblastogenesis, osteoblast function, and bone regeneration and can be promoted using the R-spondin (Rspo) family of secreted molecules. Enhancing canonical Wnt signaling through the synergistic delivery of BMP2 and Rspo2 using an engineered synthetic HA-based hydrogel should allow for improved bone tissue repair. With these features in mind, the objective of this work is two-fold: (1) evaluate the influence of hydrogel remodeling and BMP2 growth factor release kinetics on in vivo tissue repair and (2) determine if the synergistic delivery of Rspo2 and BMP2 improves BMP2 induced osteogenesis. Growth factor release kinetics and bioactivity will be evaluated using in vitro characterization techniques. A cranial defect rat model will be used to determine the influence of both growth factor release profiles and the combined delivery of Rspo2 and BMP2 on bone tissue formation. Thus, the specific aims of the work are: (1) Determine the effect of BMP2 release kinetics on osteogenesis (a) in vitro and (b) in vivo using MMP-sensitive hydrogels of varying sensitivity and (2) Synergistic delivery of Rspo2 and BMP2 for improved bone tissue repair. Upon completion of this work, a more thorough understanding of BMP-based therapies will be obtained, as well as work towards a clinically translatable approach to improve the treatment of patients with bone loss.

描述（由申请人提供）：骨形态发生蛋白（BMP）的使用显示出作为改善骨再生的治疗方法的前景；然而，所需的骨诱导效果所需的高超生理浓度、成本和患者变异性阻碍了基于 BMP 的治疗的全部优势的实现。因此，临床需要开发生长因子递送策略，以优化释放动力学并克服非生理性高浓度的需要以促进骨修复。所提出的方法利用基质金属蛋白酶（MMP）敏感的透明质酸（HA）基水凝胶支架作为细胞介导的递送载体，其中凝胶的重塑释放分子。支架降解动力学可以通过改变蛋白水解肽的 MMP 敏感性和交联密度来控制。已知规范的 Wnt 信号传导可促进成骨细胞生成、成骨细胞功能和骨再生，并且可以使用分泌分子的 R-spondin (Rspo) 家族来促进。使用工程合成的基于 HA 的水凝胶通过协同传递 BMP2 和 Rspo2 来增强经典 Wnt 信号传导，应该可以改善骨组织修复。考虑到这些特征，这项工作的目标有两个：(1) 评估水凝胶重塑和 BMP2 生长因子释放动力学对体内组织修复的影响；(2) 确定 Rspo2 和 BMP2 的协同递送是否改善 BMP2 诱导的成骨作用。将使用体外表征技术评估生长因子释放动力学和生物活性。颅骨缺损大鼠模型将用于确定生长因子释放曲线以及 Rspo2 和 BMP2 联合递送对骨组织形成的影响。因此，这项工作的具体目标是：（1）使用不同敏感性的 MMP 敏感水凝胶（a）体外和（b）体内确定 BMP2 释放动力学对成骨的影响；（2）协同递送 Rspo2 和 BMP2 以改善骨组织修复。完成这项工作后，将获得对基于 BMP 的疗法的更透彻的了解，并致力于寻找可临床转化的方法来改善骨质流失患者的治疗。