Silicon, a Novel Antioxidant Role in Bone Healing

描述(申请人提供)：近1/4的美国人患有骨折后的并发症，这些并发症是由骨病、颅面创伤或牙齿脱落引起的。这些骨折很难愈合，因为严重的骨体积丢失、血管丢失和导致氧化应激的严重炎症。氧化应激包括活性氧物种(ROS，即过氧化氢)的积累，它压倒了骨骼自身的抗氧化酶，降低了ROS的活性，促进了正常的愈合。抗氧化酶，如超氧化物歧化酶(SOD1)，是重要的，因为它们参与促进成骨转录和胶原合成和强度在骨再生。因此，能够增强抗氧化剂表达和活性的骨修复策略可以减少ROS的负面影响，刺激骨愈合。虽然合成材料被用来治疗这些骨折，但它们要么愈合时间长，而且没有抗氧化性的报道(例如金属)，要么它们太弱而不能支撑周围的骨骼(例如聚合物)。因此，我们的目标是合成新的生物医学装置材料和设计，为加速骨再生提供结构和抗氧化支持。最近，我们发现无定形二氧化硅(SiOx)溶解的产物Si4+能促进成骨细胞分化过程中SOD1的表达和胶原的形成。此外，我们还发现，在SiOx-(Si(On)x)器件中掺入氮可以在3-4周内阻止Si4+的释放，迅速形成具有生物活性的羟基磷灰石，并促进生物矿化。在这项建议中，我们的第一个目标是确定Si4+对SOD1表达的影响，以及体外胶原基质的合成和强度。在这项研究中，过量的ROS将在Si4+剂量和对照抗氧化剂(维生素C)治疗之前被给予成骨细胞。随着Si4+剂量的增加，预计胶原基质合成和强度的增加是由于增加了SOD的表达和降低了ROS的活性。在我们的第二个目标中，我们将确定硅(ON)x修饰的生物医学装置材料(金属、生物聚合物)在体内对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)将被用来在生物医学装置材料上形成3D结构。我们期望与未修饰的装置相比，Si(On)x修饰的装置能够促进羟基磷灰石的快速形成，从而在体外快速生物矿化，并在体内关键尺寸的缺损处快速成骨。当这些目标实现时，这项研究将为使用SiOx修饰的生物医学设备在骨折愈合过程中提供结构和抗氧化支持提供创新的转变。因此，这些发现的意义将是发现Si4+在骨愈合过程中起到抗氧化作用。这项研究的影响是可持续的、概念性的开发硅(ON)x修饰的生物工程设备，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使用纳米技术了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.