3D Encapsulation, Bioprinting and Controlled Delivery of Functionally Engineered EVs (FEEs)

摘要： 组织修复是一个复杂的过程，它涉及炎症和炎症之间微妙的时间平衡。 再生机制。在健康中，最初的炎症事件被再生过程取代 协调一致的方式。这一序列在疾病状态和复杂的损伤中被打乱。的目标是 再生医学是通过预防慢性/异常炎症和促进 以特定于组织的方式修复和再生。而干细胞和生长因子疗法一直是 传统上对此进行了探索，最近的研究强调了免疫调节和保护功能 间充质干细胞来源的细胞外小泡(MSC EVS)。尽管MSC电动汽车拥有多功能 属性，以参与组织特异性途径，并与翻译的精确医学目标相匹配 相关性，MSC电动汽车必须设计为增强特定路径的功能并在现场交付 以空间和时间受控的方式。在这项提案中，利用我们的初步结果和我们的 在肠道病毒生物学、免疫学和骨骼生物学方面的专业知识，我们假设：时空控制 免疫调节和再生途径可以通过选择性地掺入功能 3D打印脚手架中的工程电动汽车(费用)。使用骨再生作为模型系统，我们将测试这一点 三个具体目标的假设。在目标1中，我们将生成功能工程化的电动汽车(费用)，目标是 特定的骨诱导和免疫调节途径。在目标2中，我们将开发一种可光交联型 基于海藻酸盐的电动汽车载体和释放模体用于空间定位和时间定位的递送系统 目标1中开发的费用的受控交付。在目标3中，我们将利用3D打印技术来打印 限定的结构，封装了体内空间和时间受控两相给药的费用。这 该系统将在大鼠颅骨缺损模型中进行测试。根据建议的研究，我们将开发一个平台 可影响颅面和肌肉骨骼以外的再生医学领域的技术 系统。

Summary: Tissue repair is a complex process that involves a delicate temporal balance between inflammatory and regenerative mechanisms. In health, initial inflammatory events are replaced by regenerative processes in a coordinated manner. This sequence is disrupted in diseased states and complex injuries. The goal of regenerative medicine is to reestablish this balance by preventing chronic/aberrant inflammation and promoting repair and regeneration in a tissue-specific manner. While stem cell and growth factor therapies have been explored for this purpose traditionally, recent studies highlight the immunomodulatory and protective functions of mesenchymal stem cell derived extracellular vesicles (MSC EVs). Although MSC EVs possess versatile properties, to engage tissue-specific pathways and fit the goals of precision medicine with translational relevance, MSC EVs have to be engineered for enhanced pathway-specific functionality and delivered on site in a spatially and temporally controlled manner. In this proposal, leveraging our preliminary results and our expertise in EV biology, immunology and bone biology, we hypothesize that: Spatiotemporal control of immunomodulatory and regenerative pathways can be achieved by selective incorporation of Functionally Engineered EVs (FEEs)in 3D printed scaffolds. Using bone regeneration as a model system, we will test this hypothesis in three specific aims. In aim 1, we will generate functionally engineered EVs (FEEs) that target specific osteoinductive and immunomodulatory pathways. In aim 2, we will develop a photocrosslinkable alginate-based delivery system with EV carrier and release motifs for spatial localization and temporally controlled delivery of the FEEs developed in aim 1. In aim 3, we will utilize 3D printing technology to print defined structures encapsulating the FEEs for spatially and temporally controlled biphasic delivery in vivo. This system will be tested in a rat calvarial defect model. From the proposed studies, we will develop a platform technology that can impact the field of regenerative medicine beyond the craniofacial and musculoskeletal systems.