PROJECT SUMMARY/ABSTRACT
Defects of the cranial skeleton occur frequently in trauma, stroke, cancer, and congenital anomalies resulting in
significant neurological, psychological, social, and vocational burdens. The limitations of current clinical options
for cranial defect reconstruction, such as tissue availability and donor site morbidity in autologous bone and
extrusion, infection, and cost in alloplastic materials, provide an impetus to develop methods that specifically
target calvarial bone regeneration. Despite decades of research, contemporary regenerative strategies
consisting of expanded stem cells and growth factor cocktails delivered by scaffolding materials have not
attained clinical translation secondary to the drawbacks of surgical impracticality, cost, time consumption, and
the untoward effects of supraphysiologic dosages of growth factors. With the increasing knowledge of the
instructive capabilities of the extracellular matrix, we previously demonstrated the efficacy of an extracellular
matrix-inspired material composed of nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) for
regeneration of massive calvarial defects without ex vivo progenitor cell expansion or exogenous growth factor
supplementation. We further showed that the mechanistic basis for MC-GAG induced osteogenic differentiation
was due to an autogenous activation of the bone morphogenetic protein receptor (BMPR) signaling pathway.
Our previous work established the concept of MC-GAG as a materials-only regenerative strategy. However,
three questions require further investigation. First, what are the properties of MC-GAG that induce
osteogenesis and can they be refined? Second, are there any untoward side effects with the usage of MC-
GAG? Third, as cerebral protection is paramount in clinically relevant defects and regeneration offers no
protection until healing is complete, would MC-GAG demonstrate the same amount of regeneration as a
composite with a clinically available resorbable material for cerebral protection? In Aim 1, we will determine the
contributions of calcium and phosphate-induced signaling and mechanical stiffness in MC-GAG-mediated
osteogenesis in human mesenchymal stem cells. We hypothesize that calcium and phosphate ion signaling
may be the primary triggers for osteogenic differentiation on MC-GAG, bridging the connection between the
material, autogenous BMPR signaling, matrix mineralization, and bone healing. In Aim 2, we will evaluate a
composite of MC-GAG with poly-D,L-lactide (PDLLA) mesh, a clinically available resorbable cranioplasty
material, in a rabbit calvarial defect model for biomechanical properties, vascularity, inflammation, bone
healing, and local and systemic safety. We hypothesize that MC-GAG/PDLLA composites would result in bone
regeneration equivalent to MC-GAG alone and add the dimension of cerebral protection during regeneration.
Our proposed studies are unified in the goal of calvarial regenerative technology development. The current
proposal will allow us to understand mechanistic interactions between MC-GAG and progenitor cells to further
refine the material and to generate preclinical safety and performance data for an IDE application to the FDA.
