Composite Materials for Skull Regeneration

Significance to VA: Defects of the craniomaxillofacial (CMF) skeleton are among the top reasons for Veterans seeking reconstructive surgery. CMF defects commonly occur in Veterans due to active combat as well as civilian life for etiologies spanning trauma, stroke, cancer, and cerebral aneurysms. Among CMF defects, the most devastating is the skull defect due to the necessity of an intact skull for cerebral protection, normal neurologic functioning, as well as psychological well-being and vocational opportunities, particularly when the defects are large and visible. The current clinically available materials for cranial defect reconstruction are limited by donor site morbidity for autologous bone and complications and cost for alloplastic materials, thereby providing an opportunity to develop strategies targeting skull regeneration. Innovation and Impact: This project introduces a novel anisotropic composite material consisting of nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) and a phosphate-eluting hydrogel (aMCGPh) to enhance osteogenesis and skull regeneration. This approach builds on extensive prior data on the base material MC-GAG combined with the observation that augmenting phosphate ion delivery in a temporospatially controlled manner can improve osteoprogenitor differentiation via the sodium phosphate cotransporters PiT-1 and PiT-2. The innovative materials-only strategy eliminates the need for growth factors or preloaded progenitor cells, offering a safe, cost-effective, and scalable option for cranial defect repair. Successful outcomes would provide Veterans with an off-the-shelf regenerative solution available at point-of- care in the operating room. Specific Aims 1. To evaluate the in vitro effects of aMCGPh on osteogenic differentiation of primary human mesenchymal stem cells (hMSCs). Objective: Characterize the contributions of phosphate dosage, diffusion, and mechanical properties of the respective hydrogels on the two aMCGPh variants on osteogenic gene expression and cell-mediated mineralization compared to MC-GAG. 2. To assess the in vivo safety and efficacy of aMCGPh in a rabbit calvarial defect model. Objective: Evaluate in vivo bone healing, biomechanics, inflammation, vascularization, and local and systemic safety of aMCGPh variants for calvarial regeneration. Methodology: Aim 1 will evaluate two dosages of aMCGPh with two different distances for phosphate diffusion, the necessity of PiT-1 and PiT-2 using knockdown studies, and the importance of mechanical properties of the hydrogel component to assess the impact of the phosphate-eluting hydrogel depot on hMSC osteogenic differentiation measured using gene expression, protein expression, and matrix mineralization studies. Aim 2 will assess efficacy of aMCGPh on in vivo rabbit cranial defect healing using radiographic, biomechanical, histologic studies as well as determine safety using bloodwork and distant tissue necropsy. In vivo comparison groups will include: unreconstructed defects, autologous bone-reconstructed defects, MC- GAG-reconstructed defects, and two dosages of aMCGPh-reconstructed defects. Path to Translation/Implementation: Our proposed studies are unified in the goal of delivering a useful, regenerative material for a common surgical problem in Veterans. Our preliminary work has outlined a promising composite material for skull defects, aMCGPh, for which we have already obtained a provisional patent (VA Invention ID 2023-139; Provisional Patent No. 63/503,824). This project will generate preclinical safety and performance data in preparation for an Investigational Device Exemption application to the FDA. Project Number: 1I01RD000539-01A2 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Justine Lee | Institution: VA GREATER LOS ANGELES HEALTHCARE SYSTEM, LOS ANGELES, CA | Activity Code: I01 | Study Section: Regenerative Rehabilitation[RRD0] View on NIH RePORTER: https://reporter.nih.gov/project-details/11243242