Silicon, a Novel Antioxidant Role in Bone Healing

硅，一种新的抗氧化剂，在骨愈合中发挥作用

• 批准号: 8772006
• 负责人: Venu Gopal Varanasi
• 金额: $ 11.47万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772006
• 关键词: Adhesions; Adverse effects; American; Antioxidants; Architecture; Ascorbic Acid; Binding; Biomedical Engineering; Biopolymers; Bone Density; Bone Diseases; Bone Regeneration; Bone Substitutes; Calvaria; Chemicals; Chemistry; Collagen; Defect; Deposition; Development; Devices; Disease; Dose; Drug Delivery Systems; Enzymes; FDA approved; Figs - dietary; Fracture; Fracture Healing; General Population; Genetic Transcription; Geometry; Goals; Healed; Health; Health Care Costs; Hydrogen Peroxide; Hydroxyapatites; Hypoxia; Implant; In Vitro; Incidence; Inflammation; Ischemia; Lead; Life Expectancy; Metals; Methods; Mission; Modeling; Mus; Nanostructures; Nanotechnology; Natural regeneration; Necrosis; Nitrogen; Osteoblasts; Osteocalcin; Osteogenesis; Oxidases; Oxidative Stress; Oxygen; Patient Care; Patients; Pharmaceutical Preparations; Play; Polymers; Process; Property; Rattus; Reactive Oxygen Species; Reagent; Reporting; Research; Role; Silicon; Silicon Dioxide; Site; Superoxide Dismutase; Surface; Testing; Time; Tooth Loss; Trauma; Vascularization; Water; age related; base; biomaterial development; biomineralization; bone; bone healing; bone loss; clinically relevant; craniofacial; crosslink; density; design; effective therapy; healing; improved; in vivo; innovation; lithography; nano; nanostructured; novel; novel strategies; osteoblast differentiation; osteogenic; osteoporosis with pathological fracture; repaired; vapor

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.

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，这些并发症是由骨病、颅面外伤或牙齿脱落引起的。由于显着的骨量损失、脉管系统损失以及导致氧化应激的严重炎症，这些骨折很难愈合。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 活性并促进正常愈合。抗氧化酶，如超氧化物歧化酶 (SOD1)，很重要，因为它们参与促进骨再生过程中的成骨转录、胶原蛋白合成和强度。因此，能够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。尽管合成材料用于治愈这些骨折，但它们要么愈合时间长并且没有报道的抗氧化特性（例如金属），要么它们太弱而无法支撑周围的骨骼（例如聚合物）。因此，我们的目标是合成新型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表达和胶原蛋白形成。此外，我们发现将氮掺入 SiOx-(Si(ON)x 器件中可以维持 Si4+ 的释放，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。在本提案中，我们的首要目标是确定效果Si4+ 对 SOD1 表达以及体外胶原基质合成和强度的影响 在这项研究中，在 Si4+ 剂量和对照抗氧化剂（维生素 C）治疗之前，将向成骨细胞施用过量的 ROS。 Si4+ 剂量增加，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 修饰的生物医学设备材料（金属）的效果。基于纳米技术的方法（化学气相沉积、光刻）用于骨再生，以在生物医学设备材料上形成 3D 结构。与未修改的装置相比，可促进羟基磷灰石的快速形成，从而实现体外快速生物矿化，并促进体内关键尺寸缺陷的快速骨形成。当目标实现时，这项研究将为使用 SiOX 改性的生物医学设备提供创新转变，以在骨折愈合过程中提供结构和抗氧化支持。因此，这些发现的意义在于发现Si4+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概念开发，该设备可调节氧化应激并对骨愈合产生强大影响，这符合 NIH 的使命，即利用纳米技术来理解和控制骨过程康复。