Tunable Mechano-Activated Microcapsules for Therapeutic Delivery

摘要 该项目寻求通过开发新的机械装置来推进受控药物输送系统。 机械负荷作用下的治疗用活化微囊(MAMCs)。而上一次 策略已经建立了具有各种触发释放机制(例如，pH、热、渗透)的微胶囊 肿胀)给药，大多数需要外部驱动，而生理反馈在 放手。该建议采用了使用机械加载环境的独特方法(例如，阐明 关节)以触发和控制治疗药物的释放。当破裂时，生物活性分子从 微胶囊(嵌入基质中)可以刺激合成代谢过程，导致细胞增殖， 分化、基质生物合成或许多其他反应，包括控制炎症。考虑到 释放的时间由机械载荷控制，可以根据 微胶囊的机械敏感性。例如，这些MAMC可以与 工程化组织，在康复过程中，在受控载荷下促进再生，或设计为启动 针对正常行走和锻炼，从而促进局部快速修复。在目标1中，我们将调查 修改键对生理性载荷下MAMCs结构释放特性的影响 制造参数，包括聚合物组成、壳体厚度与半径比和壳体 弹性/塑性。在目标2中，我们将描述嵌入在工程中的MAMCs的失效特性 作为制造参数、对局部环境的粘附性的函数的类似天然组织的基质，以及 装填。在目标3中，我们将评估植入工程化MAMCs的治疗性释放的效果 生理负荷刺激生长和促进修复的软骨 对伤害性负荷的反应。最后，在目标4中，我们将评估MAMCs在活体负载中的作用 软骨修复的负重动物模型。总而言之，这些目标将检验生理学上的假设 相关机械力可以在时间和空间上控制生物活性促生长物质的输送 对组织的形成和修复有积极影响的分子。这些目标的实现最终将是 在临床相关动物模型中验证MAMCs，并支持将其作为一种新的药物递送系统 在指导机械负载组织的再生和修复方面有广泛的应用。

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.