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.