Friday, April 4, 2025
4/4/2025
Bone-like organoids to understand factors controlling local bone immune response and regeneration - PROJECT SUMMARY Large craniofacial bone defect repairs are a frequent surgical procedure, yet limited regenerative options exist that do not require a secondary surgical site. Clinical outcomes remain difficult to predict, limiting intervention strategies to improve healing. Newly developed bone-like organoids have the potential to both serve as a patient specific screening platform for drug dosing and therapeutics, as well as a regenerative alternative for bone grafting. Additionally, the local and systemic immune response has been implicated as both a biomarker for successful bone healing in long bone trauma models and a potential therapeutic target to improve bone regeneration. Yet these strategies have yet to be applied in craniofacial bone, where bone defects can be exposed to the oral cavity and microbiome, which may further perturb the local and systemic immune response. The overall objective of this application is to further characterize the bone-like organoid as a model of bone healing and to determine the local and systemic immune response during bone healing for prediction of healing outcomes in a clinically relevant craniofacial defect model (mentored phase), then further develop the bone-like organoid to be both patient specific and have the added complexity of vascular and immune cells (independent phase). To achieve this goal, an experienced advisory team was assembled including Dr. Robert Guldberg (primary mentor), Dr. Luiz Bertassoni (co-mentor), Dr. Danielle Benoit, Dr. Niki Moutsopoulos (collaborators), Dr. Tamara Alliston, and Dr. Paul Krebsbach (consultants). Aim 1 will characterize the differentiation of the bone-like organoids as compared to native bone healing gene expression. Aim 2 will test the ability of the organoids to promote repair of OAC defects, characterize the local and systemic immune response, and create predictive models of bone healing. Aim 3 will develop an adipose derived, patient specific bone-like organoid model containing vessel fragments and immune cells for drug screening of immunomodulatory therapies as well as a regenerative strategy. The career development plan details steps to gain new scientific and professional skills to build a research portfolio in bioengineering, craniofacial sciences, and osteoimmunology with aspects of commercialization of biotechnologies. Together, these studies will fully characterize the newly developed bone-like organoid, as well as the local and systemic immune response during healing of a clinically relevant craniofacial defect model for identification of therapeutics to improve healing and for creation of patient specific predictive models for healing outcomes. This work will serve as a foundation for a robust, multi-faceted research program that pushes the boundaries of our understanding of osteoimmunology in craniofacial bone repair and organoid platforms.
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