Nearly 1 in 4 Americans suffer from complications following bone fractures, which result from bone disease, craniofacial trauma or tooth loss. These fractures are challenging to heal because of the significant bone volume loss, vasculature loss, and severe inflammation that lead to oxidative stress. Oxidative stress involves the accumulation of reactive oxygen species (ROS, i.e., H2O2) that overwhelm the bone's own antioxidant enzymes to reduce ROS activity and promote normal healing. Antioxidant enzymes, such as superoxide dismutase (SOD1), are important because they are involved in promoting osteogenic transcription and collagen synthesis and strength during bone regeneration. Thus, bone healing strategies that can enhance antioxidant expression and activity can reduce the negative impact of ROS and stimulate bone healing. Although synthetic materials are used to heal these fractures, they either have long healing times and no reported antioxidant properties (e.g., metals) or they are too weak to support the surrounding bone (e.g., polymers). Therefore, our goal is to synthesize novel biomedical device materials and designs that provide structural and antioxidant support for accelerated bone regeneration. Recently, we found that Si4+, a product of amorphous silica (SiOx) dissolution, enhances SOD1 expression and collagen formation during osteoblast differentiation. Moreover, we found that the incorporation of nitrogen into SiOx-(Si(ON)x devices sustain Si4+ release, rapidly form bioactive hydroxyapatite, and enhance biomineralization within 3-4 weeks. In this proposal, our first aim will be to determine the effect of Si4+ on SOD1 expression, and collagen matrix synthesis and strength in vitro. In this study, excessive ROS will be administered to osteoblasts prior to Si4+ dose and control antioxidant (Vitamin C) treatments. As Si4+ dose increases, it is expected that increased collagen matrix synthesis and strength occurs as a result of increased SOD expression and decreased ROS activity. In our second aim, we will determine the effect of Si(ON) x-modified biomedical device materials (metals, biopolymers) on bone regeneration for rapid bone fracture healing in vivo. Nanotechnology-based methods (chemical vapor deposition, lithography) will be used to form 3D architectures onto biomedical device materials. We expect that Si(ON) x-modified devices to promote rapid hydroxyapatite formation for rapid biomineralization in vitro and rapid bone formation in critical size defects in vivo versus un-modified devices. When the aims are achieved, this research will provide an innovative shift for the use of SiOX-modified biomedical devices to provide structural and antioxidant support during bone fracture healing. Therefore, the significance of these findings will be the discovery that Si4+ plays an antioxidant role during bone healing. The impact of this research is the sustainable, conceptual development of Si(ON)x-modified, bioengineered devices that regulate oxidative stress and exert a powerful influence on bone healing, which fits within NIH's mission to use nanotechnology to understand and control processes in bone healing.
The benefits of this research to the general public include the development of biomaterials that can be used as effective therapies in promoting faster or more improved methods of healing bone. This could potentially lead to improved healing, shortened healing times, and reduced health care costs associated with bone healing.
