Silicon, a Novel Antioxidant Role in Bone Healing

描述（由申请人提供）：近四分之一的美国人患有骨折后的并发症，这是由骨病、颅面创伤或牙齿脱落引起的。这些骨折具有愈合的挑战性，因为显著的骨体积损失、血管损失和导致氧化应激的严重炎症。氧化应激涉及活性氧物质（ROS，即，H2 O2），其压倒了骨骼自身的抗氧化酶，以降低ROS活性并促进正常愈合。抗氧化酶，如超氧化物歧化酶（SOD 1），是重要的，因为它们参与促进骨再生过程中的成骨转录和胶原合成和强度。因此，可以增强抗氧化剂表达和活性的骨愈合策略可以减少ROS的负面影响并刺激骨愈合。虽然合成材料被用来愈合这些骨折，但它们要么愈合时间长，要么没有报道抗氧化性能（例如，金属）或者它们太弱而不能支撑周围的骨头（例如，聚合物）。因此，我们的目标是合成新的生物医学设备材料和设计，为加速骨再生提供结构和抗氧化支持。最近，我们发现Si 4+，一种无定形二氧化硅（SiOx）溶解的产物，在成骨细胞分化过程中增强SOD 1表达和胶原形成。此外，我们发现氮掺入到SiOx-（Si（ON）x）装置中维持Si 4+释放，快速形成生物活性羟基磷灰石，并在3-4周内增强生物矿化。在这个提议中，我们的第一个目标将是确定Si 4+对SOD 1表达的影响，以及体外胶原基质合成和强度。在本研究中，在Si 4+剂量和对照抗氧化剂（维生素C）处理之前，将向成骨细胞施用过量的ROS。随着Si 4+剂量的增加，预计由于SOD表达增加和ROS活性降低，胶原基质合成和强度增加。在我们的第二个目标中，我们将确定Si（ON）x改性的生物医学设备材料（金属，生物聚合物）对体内快速骨折愈合的骨再生的影响。基于纳米技术的方法（化学气相沉积，光刻）将用于在生物医学设备材料上形成3D架构。我们预计Si（ON）x改性的器械与未改性的器械相比，可促进体外快速生物矿化的羟基磷灰石快速形成和体内关键尺寸缺损的快速骨形成。当目标实现时，这项研究将为SiOX改性生物医学设备的使用提供创新的转变，以在骨折愈合期间提供结构和抗氧化支持。因此，这些发现的意义将是发现Si 4+在骨愈合过程中发挥抗氧化作用。这项研究的影响是Si（ON）x改性生物工程设备的可持续性，概念性发展，这些设备调节氧化应激并对骨愈合产生强大影响，这符合NIH的使命，即使用纳米技术来理解和控制骨愈合过程。

DESCRIPTION (provided by applicant): 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.