Vascularization of critical-sized craniomaxillofacial defects

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Project Summary Lack of proper vascularization leads to the ultimate failure in treatment of critical-sized craniomaxillofacial defects. The large size of the defect obstructs penetration of blood components from the surrounding environment into the inner parts of the defect, and thus hinders vascularity. In such situations, vascular endothelial growth factor (VEGF) is the most effective factor that can reestablish the oxygen supply to tissues. While applying external VEGF is a key means for blood vessel formation in critical-sized defects, its slight uncontrolled administration is risky and can be tumorigenic. Thus, conventional methods cannot be used for encapsulation and delivery of VEGF. In this proposal, we will develop a new on-chip method for delivery of VEGF with precise and sustained release capabilities using a microfluidic platform. Our novel design allows making monodispersed particles in a highly controllable and reproducible manner, providing us with the ability to fine- tune the size, microstructure, loading capacity and release rate of particles, in addition to balancing the pH and maintaining the VEGF bioactivity. Release of VEGF must not be only controlled and sustained, but also highly localized in the region of the defect as moving the VEGF-loaded particles into unwanted areas is not favorable and can be risky. Thus, in another strategy, the VEGF-loaded particles will be immobilized onto a new 3D-printed scaffold specifically designed for critical-sized defects. The design of this novel scaffold (filed for patent) is inspired by reinforced concrete, in which reinforcing Rebars are embedded in the host material to enhance the mechanical properties of the scaffold (100-375 times improvement). In other words, it is a hybrid scaffold, made of two components: 1) Skeleton Rebars: non-porous and slowly-biodegradable constituent undertaking mechanical necessities of the scaffold, and 2) Host Component: porous and rapidly-biodegradable constituent undertaking biological necessities of the scaffold. Although the mechanical strength of Rebars is the property that makes the scaffold appropriate for critical-sized defects, another functionality of the Rebar, which is its slow degradability (6 months), makes the design a perfect choice for the VEGF delivery purpose. Rebars will provide us with the opportunity to immobilize VEGF-loaded particles on a solid surface and not let the particles move elsewhere. The immobilization process itself is a new method developed in our lab that can firmly attach these particles to the rebars of the scaffolds. The VEGF-loaded scaffold will undergo a detailed in vitro analysis and release adjustment inside a bioreactor, which can mimic the body condition. The VEGF release profiles will be adjusted to reach the target value (1.2 ng/ml per day per cm3 of scaffold), and the comprehensive in vitro analyses will evaluate the osteogenesis and angiogenesis characters of the construct. The optimized VEGF-loaded scaffold will undergo a detailed in vivo study using critical-sized alveolar bone defects in New Zealand white rabbits. The new bone formation and angiogenesis will be fully studied to assess the functionality of the VEGF-loaded scaffold in comparison with a VEGF-free scaffold, as well as defects treated with a current therapeutic modality.