We propose newly developed electrospun chitosan guided bone regeneration (GBR) membranes for local delivery of simvastatin (SMV), an alternative to BMP-2, and raspberry ketone (RK), an anti- inflammatory/pro-healing agent, as a novel adjunctive therapy to heal grafted dental/craniomaxillofacial defects. GBR membranes are widely used in dental/craniomaxillofacial applications to protect bone grafted spaces from invasion by soft tissues and by providing an osteogenic environment for enhancing bone regeneration. Our chitosan GBR membranes overcome limitations of current GBR membranes by providing predictable degradation, and biomimetic nanofiber structure with an interconnected porosity that that is cell occlusive but allows exchange of fluids and signals between healing bone and epithelial compartments. The nanofiber structure also provides high surface area that is advantageous for drug loading and delivery. Our goal is to synergize our chitosan GBR membranes with local delivery of RK and SMV, to create novel bioactive GBR membranes that promote healing by stimulating the transition of the macrophage phenotype from pro-inflammation to pro-healing and promoting osteogenesis that significantly augments healing of grafted dental/craniomaxillofacial defects, especially large traumatic defects. Innovation of this work arises from our unique strategies that stabilize nanofiber structure of the electrospun chitosan and in the local delivery of SMV, an economical alternative to BMP-2 for stimulating bone formation, and the novel RK compound, to provide anti- inflammatory/pro-healing characteristics. Delivery of these agents from our GBR membranes will result in adjunctive implants that afford surgeons flexibility in choice of graft materials to be used with the GBR membrane in accordance with graft availability, clinician and patient factors, and may serve as a platform for overcoming inflammation and stimulating healing in other tissue engineering applications. In this work we will first, investigate individual delivery of RK (aim 1) and SMV (aim 2) from membranes, and effects on macrophage phenotype and osteogenesis in vitro and in rat calvarial models. We will then (aim 3) investigate dual release for synergistic/antagonistic effects on cells and healing of grafted site as compared to commercial GBR membrane in rat models. Finally (aim 4) the dual loaded bioactive chitosan GBR membranes will be investigated in a pre-clinical porcine model as compared to commercial devices. This work will have a large impact in augmenting dental/craniomaxillofacial bone regeneration especially in challenging traumatic bone injuries and lead to improved restoration of facial esthetics and subsequent dental/craniofacial implant therapies. These membranes may also find application in augmenting treatments in challenging large segmental orthopedic defects
Patients with craniomaxillofacial injuries, periodontal disease, and or requiring dental implant procedures often experience bone loss resulting in complications of masticatory function, speech and altered aesthetics that affect health and the ability to function in society. Guided bone regeneration membranes are widely used in these applications to augment bone healing/regeneration by protecting bone grafted sites, but current membranes are not ideal and suffer high complication rates. The work described in this proposal is an innovative bioactive membrane based on electrospun chitosan loaded with raspberry ketone, a natural anti- inflammatory/pro-healing agent, and simvastatin, a member of the statin class of pharmaceuticals that also stimulates bone healing. This novel membrane will then be able to provide superior protection, and augment healing by reducing inflammation and stimulating bone formation that will significant improve healing in dental/craniomaxillofacial defects, especially large traumatic defects.
