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

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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.