The impact of large cranial and facial bone defects from birth defects or trauma can result in devastating functional impairment and physical changes, yet craniomaxillofacial (CMF) reconstruction is one of the most challenging areas for bone regeneration. It requires modulated repair that leads to bone tissue regeneration while maintaining or recapitulating facial structure and enabling adaptive growth remodeling in pediatric cases. Current approaches rely on the use of patient or donor bone and present issues of insufficient bone availability, morbidity at the bone donor site, or incompatibility of donated bone. The ability to gain healthy, highly vascularized and well developed bone tissue over reasonable timeframes remains limited. New synthetic or hybrid materials designed for bone regeneration often lack either the mechanical properties or conformability to shape new tissue to the contours of the face, or the ability to controllably release bioactive agents at rates that hel generate new bone tissue. The release of growth factors that regulate the differentiation of the patient's native stem cells to bone, and enable vascularization of the bone tissue offers great potential for this area, but most existing systems act as depots that release the proteins with a large bolus and need unusually high loadings. The result is a greatly lowered efficacy due to clearance of much of the protein from the local region of interest, and the risk of undesired side effects from large systemic exposure of the factors. In this work, we seek to release these potent bioactive agents in physiologically appropriate dose levels from degradable scaffolds to recruit native bone precursor cells to the healing site, and achieve full integration of new and native bone. This approach does not require the co-implantation of stem cells from the patient or a donor, which can require painful and expensive bone marrow extraction and relies on the health, availability and/or compatibility of the patient or donor. In the proposed work, we use a modular cell-free system that isolates the properties of the mechanical scaffold from the bioactive release system. Nanoscale electrostatic layers carrying active growth factors that elute over readily adapted time scales to recapitulate the wound healing cascade and induce rapid bone repair are used to coat a porous degradable polymer membrane. The rigidity or flexibility of the scaffold can be adapted through the choice of underlying polymer substrate. Growth factors and active agents are eluted from the nanolayered coating, which is thin, well- adhered and highly conformal to the features of the substrate. Because release from these systems is slow but sustained, clearance is limited and small amounts of growth factor can be used to induce significant increases in bone formation. The system is modular, enabling the incorporation of single or dual growth factors introduced with different release characteristics, such as an angiogenic factor followed by an osteoinductive factor. We investigate the potential of this approach and evaluate it with a rat mandibular defect model as a tunable, off-the-shelf, cell-free option for craniomaxillofacial bone tissue repair and restoration.
Large bone defects in the skull, face and jaw derived from birth defects, severe physical trauma from accidents or battlefield trauma can result in devastating functional impairment and physical disfigurement. This proposal investigates new synthetic materials that can be used to reconstruct the face and skull. These materials, which can be shaped to facial contours and implanted in surgery, slowly degrade away while the appropriate growth factor proteins are released in the correct amount and order to recruit the native stem cells in the patient and generate new healthy vascularized bone in the shape and place of the scaffold.
