Tunable Mechano-Activated Microcapsules for Therapeutic Delivery

用于治疗传递的可调谐机械激活微胶囊

• 批准号: 10017663
• 负责人: George R. Dodge
• 金额: $ 34.28万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017663
• 关键词: 3-Dimensional; Address; Adhesions; Anabolic Agents; Anabolism; Animal Model; Autologous; Behavior; Biocompatible Materials; Biological; Biological Assay; Biological Factors; Biology; Cartilage; Cell Proliferation; Cells; Characteristics; Chondrocytes; Clinical; Confocal Microscopy; Cues; Defect; Degenerative polyarthritis; Development; Drug Delivery Systems; Elasticity; Encapsulated; Engineering; Environment; Exercise; Exposure to; Failure; Feedback; Fostering; Functional disorder; Goals; Growth; Hydrogels; Implant; In Situ; In Vitro; Individual; Inflammation; Joints; Lesion; Light; Mechanical Stimulation; Mechanics; Mesenchymal Differentiation; Mesenchymal Stem Cells; Methods; Microcapsules drug delivery system; Miniature Swine; Modality; Modeling; Modification; Motion; Musculoskeletal System; Natural regeneration; Pathology; Physiological; Play; Polymers; Process; Property; Radial; Rattus; Rehabilitation therapy; Research Personnel; Role; Running; Rupture; Structure; Swelling; System; Technology; Testing; Therapeutic; Therapeutic Effect; Thick; Tissue Engineering; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Validation; Variant; Walking; Weight-Bearing state; attenuation; base; capsule; cartilage repair; clinically relevant; crosslink; design; implantation; in vivo; innovation; joint loading; mechanical force; mechanical load; mechanical properties; new technology; novel; novel therapeutics; prevent; release factor; repaired; response; restoration; statistics; subcutaneous; three dimensional cell culture; tissue regeneration; tissue repair; tool; transforming growth factor beta3

Abstract This project seeks to advance controlled drug delivery systems via the development of novel mechanically activated microcapsules (MAMCs) for therapeutic delivery in response to mechanical load. While previous strategies have established microcapsules with various triggered release mechanisms (e.g., pH, heat, osmotic swelling) for drug delivery, most require external actuation, and physiological feedback plays little role in release. This proposal takes the unique approach of using mechanically loaded environments (e.g., articulating joints) to trigger and control release of therapeutics. Upon rupture, bioactive molecules released from microcapsules (embedded within matrices), can stimulate anabolic processes leading to cell proliferation, differentiation, matrix biosynthesis, or a host of other responses including control of inflammation. Given that the timing of release is controlled by mechanical load, it is possible to tune the release of factors based on the mechano-sensitivity of the microcapsules. For example, these MAMCs may be used in conjunction with engineered tissues to foster regeneration under controlled loading during rehabilitation, or designed to actuate in response to normal walking and exercise, so as to promote rapid local repair. In Aim 1 we will investigate the structure-release properties of the MAMCs under physiologic loading scenarios by modifying key fabrication parameters, including polymer composition, shell thickness-to-radius ratio, and shell elasticity/plasticity. In Aim 2 we will characterize failure properties of MAMCs embedded in engineered matrices analogous to native tissue as a function of fabrication parameters, adhesion to local environment, and load. In Aim 3 we will evaluate the effect of therapeutic release from MAMCs embedded within engineered cartilage for the purpose of stimulating growth in response to physiologic loading and promoting repair in response to injurious loading. Finally, in Aim 4, we will assess the actuation of MAMCs in an in vivo load bearing animal model of cartilage repair. Collectively these Aims will test the hypothesis that physiologically relevant mechanical forces can temporally and spatially control the delivery of bioactive growth promoting molecules that positively impact tissue formation and repair. Completion of these Aims will culminate with validation of MAMCs in a clinically relevant animal model and support this as a novel drug delivery system with broad applications in directing regeneration and repair in mechanically loaded tissues.

抽象的 该项目旨在通过机械开发小说来推进受控的药物输送系统 激活的微胶囊（MAMC）用于响应机械负荷的治疗递送。以前 策略已经建立了具有各种触发释放机制的微胶囊（例如，pH，热，渗透 肿胀）用于药物输送，大多数需要外部致动，生理反馈在 发布。该建议采用使用机械加载环境的独特方法（例如，阐明 关节）触发和控制治疗学的释放。破裂后，从 微胶囊（嵌入矩阵中）可以刺激导致细胞增殖的合成代谢过程， 分化，基质生物合成或许多其他反应，包括控制炎症。鉴于 释放的时间由机械负载控制，可以根据该因素的释放来调整因子的释放 微胶囊的机械敏感性。例如，这些MAMC可以与 在康复过程中，工程组织以在受控的负载下促进再生，或者旨在促进 响应正常的步行和运动，以促进局部快速修复。在目标1中，我们将调查 通过修改键 制造参数，包括聚合物组成，壳厚度 - 拉迪乌斯比和壳 弹性/可塑性。在AIM 2中，我们将表征嵌入在工程中的MAMC的故障属性 类似于天然组织的矩阵与制造参数的函数，对局部环境的粘附以及 加载。在AIM 3中，我们将评估嵌入工程中的MAMC的治疗释放的效果 软骨是为了刺激生长的生长，以应对生理负荷和促进修复 对伤害负荷的反应。最后，在AIM 4中，我们将评估MAMC在体内负载中的致动 软骨修复的动物模型。这些目标总的来说将检验以下假设 相关的机械力可以在时间和空间上控制生物活性生长的促进的传递 积极影响组织形成和修复的分子。这些目标的完成将达到顶峰 在临床相关的动物模型中对MAMC的验证，并将其作为一种新型药物输送系统的支持 在机械载荷组织中指导再生和修复方面的广泛应用。