A tissue engineering approach to regenerate the cranial suture skeletal stem cell niche with a multicompartment biomaterial scaffold

Abstract Craniosynostosis is a debilitating congenital anomaly characterized by the premature fusion of cranial sutures in the skull, resulting from the abnormal fate specification of critical skeletal stem cells. This leads to disrupted craniofacial development and dysmorphology. As an alternative to invasive cranial vault remodeling surgery, we propose a tissue engineering approach to effectively restore the damaged or absent suture stem cell niche using a biomaterial capable of regioselective stem cell maintenance, marking a significant paradigm shift. By harnessing the role of biomaterial scaffold pore design to direct cell fate, we developed a “bone-suture-bone” design within a triphasic scaffold. We demonstrate that this unique scaffold design maintains stemness in a central region while promoting osteogenic differentiation in the surrounding areas, replicating the interfaces and function of the native suture. The scaffold’s ability to reconstitute an engineered skeletal stem cell niche and facilitate the functional recovery of the craniosynostosis phenotype is validated in a caBmpr1a; Wnt1-Cre murine model of midline craniosynostosis, the most common nonsyndromic clinical presentation in humans. This work shows significant promise for improving patient outcomes through a rational tissue engineering strategy for reconstituting a native stem cell niche.