Remotely activated biomaterial scaffolds for flexibly directing the recruitment and differentiation of bone progenitor cells

骨组织的定向再生需要一系列不同的生物事件，首先需要炎症反应来避免感染，然后是祖细胞到损伤部位的招募，最后是祖细胞分化成骨特异性细胞类型。本提案的目标是开发一种生物材料支架，其中祖细胞募集和祖细胞分化因子的时间和序列被加载到磁脂质体中，可以通过远程应用磁指令来控制，这些指令已经被微调以选择性地响应不同幅度和频率的磁信号。所获得的结果将通过在骨组织工程中发现更优化的再生策略产生影响。开发的生物材料系统将广泛适用于研究分子表现的时间、顺序、浓度和空间方向性如何影响各种临床相关的生物过程（例如，再生其他组织、疼痛管理、糖尿病治疗、化疗和免疫治疗）。该研究将提供指导机会，并通过招聘、保留和提供本科生研究机会、课堂项目、顶点设计项目和增强多样性来加强本科教育和推广，并计划在当地小学和中学为少数民族学生组织/领导夏季讲习班。骨骼再生和其他再生过程由一系列复杂的生物分子输送来协调。植入式生物材料支架在提供这些输送来源以及新组织生长的机械框架方面显示出了希望。然而，目前骨组织工程中的生物材料策略无法提供具有灵活性的受控递送序列：1)通过实验研究这些生物分子呈现的序列和时间如何影响再生结果；2)根据患者病史和当前患者预后，根据具体情况实时修改治疗过程。因此，迫切需要可植入的生物材料系统，以灵活的方式控制多种生物分子递送的时间和顺序。这项研究的目的是开发一种生物材料支架，其中至少两个生物分子的时间和序列可以通过远程应用磁指令来控制。这种支架将被磁脂质体（MLs）浸透，磁脂质体装载骨祖细胞募集因子或分化因子。关键的是，这些MLs将被调谐以对不同幅度和频率的射频磁信号做出不同的响应。通过将MLs与不同大小、浓度和组成的纳米颗粒相结合，可以实现调谐。实验将进行，以1)验证磁性控制骨祖细胞募集和分化因子的时间和序列的能力，2)表征这些生长因子如何在支架范围内外传播，以及3)证明支架系统协调和优化关键再生事件（即骨祖细胞募集和分化）时间的能力。所提出的工作将通过在骨组织工程中发现更多优化的再生策略而具有重要意义，并将通过为临床实施优化策略提供材料手段来启动变革性的研究轨迹。提出的工作将提高患者的生活质量，通过生产的调查和临床工具，优化和实施改进的骨再生策略。这种生物材料系统将广泛适用于研究分子表现的时间、序列、浓度和空间方向性如何影响各种临床相关的生物过程（例如，再生其他组织、疼痛管理、糖尿病治疗、化疗和免疫治疗）。该研究将被用作指导和加强本科教育的工具，通过：1)为PI/ co -PI的生物材料和纳米工具课程的本科研究，课堂项目和顶点设计项目提供衬托；2)改善实施这些项目所需的基础设施/设备。在与学院多样性办公室的协调下，PI/ co -PI提出了通过招聘、保留和推广来提高多样性的长期举措。PI/Co-PI将提高专门招募的少数民族学生的研究、组织和领导技能，这些学生将在当地中小学进行研究和组织/领导暑期讲习班。

1603433-KennedyDirected regeneration of bone tissue requires a choreographed sequence of distinct biological events, beginning with the need for an inflammatory response to stave off infections, followed by the recruitment of progenitor cells to the injury site and ending with the differentiation of the progenitor cells into bone-specific cell types. The objective of this proposal is to develop a biomaterial scaffold where the timing and sequence of progenitor recruitment and progenitor differentiation factors, which are loaded into magneto-liposomes, can be controlled through remotely applied magnetic instructions that have been fine tuned to selectively respond to magnetic signals of different amplitudes and frequencies. Results obtained would have impact by enabling discovery of more optimized regenerative strategies in bone tissue engineering. The biomaterial system developed will be broadly adaptable for investigating how the timing, sequence, concentration, and spatial directionality of molecular presentations influence a wide variety of clinically relevant biological processes (e.g., regenerating other tissues, pain management, diabetes treatments, chemotherapies, and immunotherapies). The research will provide mentorship opportunities and enhance undergraduate education and outreach through recruitment, retention and providing undergraduate research opportunities, class projects, capstone designing projects and enhanced diversity, facilitated by plans to organize/lead summer workshops for minority students at local elementary and middle schoolsBone regeneration and other regenerative processes are coordinated by a complex sequence of biomolecular deliveries. Implantable biomaterial scaffolds have shown promise in providing a source of these deliveries as well as the mechanical framework for the growth of new tissues. However, current biomaterial strategies in bone tissue engineering are unable to provide controlled sequences of deliveries with the flexibility required to 1) experimentally investigate how the sequence and timing of these biomolecular presentations impact regenerative outcome and 2) modify the course of therapies on a case by case basis and in real-time as informed by patient history and current patient prognoses. Therefore, there is an urgent need for implantable biomaterial systems where the timing and sequence of multiple biomolecular deliveries can be controlled in a flexible manner. The objective of this proposed research is to develop a biomaterial scaffold where the timing and sequence of at least two biomolecules can be controlled through remotely applied magnetic instructions. This scaffold will be impregnated with magneto-liposomes (MLs) that are loaded with either bone progenitor recruitment factors or differentiation factors. Critically, these MLs will be tuned to differentially respond to RF magnetic signals of different amplitudes and frequencies. Tuning will be achieved by integrating MLs with nanoparticles of different sizes, concentrations, and compositions. Experiments will be conducted in order to 1) verify the ability to magnetically control the timing and sequence of bone progenitor recruitment and differentiation factors, 2) characterize how these growth factors propagate within and beyond the confines of the scaffold, and 3) demonstrate the scaffold system's ability to coordinate and optimize the timing of critical regenerative events (i.e., bone progenitor recruitment and differentiation). The proposed work will provide significance by enabling the discovery of more optimized regenerative strategies in bone tissue engineering and will initiate a transformative research trajectory by providing the material means to clinically implement optimized strategies. The proposed work will improve patient quality of life by producing both an investigative and clinical tool for optimizing and implementing improved bone regeneration strategies. This biomaterial system will be broadly adaptable for investigating how the timing, sequence, concentration, and spatial directionality of molecular presentations influence a wide variety of clinically relevant biological processes (e.g., regenerating other tissues, pain management, diabetes treatments, chemotherapies, and immunotherapies). The research will be utilized as a vehicle for mentorship and enhancing undergraduate education by: 1) providing a foil for undergraduate research, class project in the PI/Co-PIs' Biomaterials and Nano-Tool courses, and capstone design projects and 2) improving the infrastructure/equipment required to carry out these projects. In coordination with the college's diversity office, the PI/Co-PIs propose long-term initiatives to enhance diversity through recruitment, retention, and outreach. The PI/Co-PI will improve the research, organizational, and leadership skills of minority students specifically recruited to conduct research and organize/lead summer workshops at local elementary and middle schools.