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并发症，这是由骨病，颅面创伤或牙齿脱落引起的。这些骨折的愈合具有挑战性，因为显著的骨体积损失、脉管系统损失和严重的炎症导致氧化应激。氧化应激涉及活性氧（ROS，即H2O2）的积累，它会压倒骨骼自身的抗氧化酶，从而降低ROS活性，促进正常愈合。抗氧化酶，如超氧化物歧化酶（SOD1），很重要，因为它们在骨再生过程中参与促进成骨转录、胶原合成和强度。因此，增强抗氧化表达和活性的骨愈合策略可以减少ROS的负面影响并促进骨愈合。虽然人工合成材料被用于治疗这些骨折，但它们要么愈合时间长，而且没有抗氧化性能（如金属），要么太弱，无法支撑周围的骨头（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Si4+，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SOD1的表达和胶原的形成。此外，我们发现氮进入SiOx-(Si(ON)x装置可以维持Si4+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。在这个提案中，我们的第一个目标将是确定Si4+对SOD1表达，胶原基质合成和强度的影响。在本研究中，在Si4+剂量和控制抗氧化（维生素C）治疗之前，将过量的ROS给予成骨细胞。随着Si4+剂量的增加，预计由于SOD表达增加和ROS活性降低，胶原基质的合成和强度会增加。在我们的第二个目标中，我们将确定Si(ON) x修饰的生物医学设备材料（金属，生物聚合物）对骨再生的影响，以实现体内骨折的快速愈合。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结构。我们期望Si(ON) x修饰的装置与未修饰的装置相比，能够促进羟基磷灰石的快速形成，以实现体外快速生物矿化和体内临界尺寸缺陷的快速骨形成。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Si4+在骨愈合过程中起抗氧化作用。这项研究的影响是硅（ON）x修饰的生物工程设备的可持续的、概念性的发展，这些设备可以调节氧化应激并对骨愈合产生强大的影响，这符合NIH使用纳米技术来理解和控制骨愈合过程的使命。

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.