Biomimetic Scaffold Delivering Osteogenic Molecules for Alveolar Bone Engineering

为牙槽骨工程输送成骨分子的仿生支架

• 批准号: 8302181
• 负责人: Min Lee
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302181
• 关键词: Adverse effects; Alginates; Alveolar; Alveolar Ridge Augmentation; Alveolar ridge; Apatites; Architecture; Biomimetics; Body Fluids; Bone Morphogenetic Proteins; Bone Regeneration; Calvaria; Cells; Chitosan; Clinical; Commit; Complex; Computer Assisted; Craniosynostosis; Custom; Cyst; Data; Defect; Dental Implants; Dose; Elements; Environment; Excision; Exhibits; Growth Factor; Human; Image; Immersion Investigative Technique; Implantation procedure; In Vitro; Kinetics; Laboratories; Malignant Neoplasms; Mandible; Marrow; Maxillary Sinus; Mechanics; Mediating; Methods; Minerals; Modeling; Natural regeneration; Nutritional Requirements; Osteogenesis; Patients; Periodontal Diseases; Physiological; Platelet-Derived Growth Factor; Polymers; Printing; Process; Property; Proteins; Protocols documentation; Rattus; Reconstructive Surgical Procedures; Research; Shapes; Signaling Molecule; Simulate; Site; Source; Spinal; Spinal Fusion; Stem cells; System; Techniques; Testing; Therapeutic; Tibial Fractures; Tissue Engineering; Tooth Loss; Tooth structure; Translations; Trauma; X-Ray Computed Tomography; alveolar bone; base; bone; bone engineering; bone healing; computer design; in vivo; meetings; novel; osteogenic; osteogenic protein; osteoinductive factor; platelet-derived growth factor BB; repaired; scaffold

DESCRIPTION (provided by applicant): Periodontal disease and malignant neoplasms are devastating complications often leading to the resection of large segments of the mandible. Various osteoinductive growth factor-based therapies have been developed in an attempt to find an effective and safer method of bone regeneration. In particular, bone morphogenetic proteins (BMPs) are currently approved for spinal fusion, tibial fracture repair, and alveolar ridge or maxillary sinus augmentation. However, BMPs are highly pleiotropic molecules and their supra-physiological high dose requirement leads to adverse side effects such as cyst formation, and inefficient bone formation. Thus, there is a need to develop alternative growth factor therapeutic strategies using osteoinductive factors with more specific osteogenic effects. Nell-1 (Nel-like protein-1) is a novel osteogenic protein originally identified in active bone forming sites of human craniosynostosis patients, and is believed to specifically target cells committed to the osteogenic lineage. To provide effective and safer bone regeneration for the repair of large, complex and structural defects, we propose a novel computer-designed, biomimetic scaffolding system for controlled local delivery of Nell-1. This system will consist of three-dimensional (3D) chitosan/alginate (Chi/Al) scaffolds with well-defined geometries on the macro- and micro-scales created from an indirect 3D printing technique in conjunction with biomimetic processing strategy to confer bone mineral-mimicking apatite microenvironment and osteogenic signaling molecules (Nell-1). To maximize bone regeneration, Nell-1 will be employed also in combination with platelet-derived growth factor-BB (PDGF-BB) in clinical use for the treatment of periodontal osseous defects. The specific hypothesis of this proposal is that controlled delivery of Nell-1+PDGF from computer-designed biomimetic scaffolds can enhance repair of alveolar bone defects. To investigate this hypothesis, we propose the following aims: 1) To develop biomimetic apatite-coated Chi/Al scaffolds with controlled architectures and delivery of osteogenic molecules (Nell-1+PDGF-BB); 2) To enhance alveolar bone regeneration by biomimetic scaffolds delivering Nell-1+PDGF-BB. Chi/Al scaffold architectures that facilitate mass transport and vessel ingrowth will be created from an indirect 3D printing technique. In this construct, we will create a biomimetic apatite coating and determine if apatite layer can increase Nell-1 and PDGF delivery efficiency. The bone formation efficacy of Nell-1 from the fabricated biomimetic scaffolds will be evaluated in a larger mandibular segmental defect model. In addition, we will also incorporate PDGF into the scaffolds and assess the effects of combined Nell-1+ PDGF on bone regeneration to maximize bone formation. The results from this proposal will be critical towards clinical translation of Nell-1 mediated therapeutics to augment alveolar bone regeneration while minimizing potential adverse effects of current osteoinductive therapeutics. PUBLIC HEALTH RELEVANCE: Loss of alveolar ridge due to periodontal disease, trauma, tooth loss or reconstructive surgery often leads to clinical situations exhibiting limited alveolar bone availability for dental implant placement. The proposed research provides effective and safer bone regeneration strategies combining a novel osteogenic protein with biomimetic scaffolding/delivery systems while minimizing potential adverse effects of current osteoinductive therapeutics.

描述(申请人提供)：牙周病和恶性肿瘤是破坏性的并发症，通常会导致下颌骨大段切除。各种基于骨诱导生长因子的治疗方法已经被开发出来，试图找到一种有效和安全的骨再生方法。特别是，骨形态发生蛋白(BMPs)目前被批准用于脊柱融合、胫骨骨折修复和牙槽突或上颌窦增高术。然而，BMP是高度多效性的分子，其超生理高剂量需求会导致不良副作用，如囊性形成和低效的骨形成。因此，有必要开发使用具有更特定成骨作用的骨诱导因子的替代生长因子治疗策略。Nell-1(Nel-like Protein-1)是一种新的成骨蛋白，最初发现于人类颅骨融合症患者活跃的骨形成部位，被认为是致力于成骨细胞系的特异性靶细胞。为了提供有效和安全的骨再生用于修复大的、复杂的和结构性的缺损，我们提出了一种新型的计算机设计的仿生支架系统，用于控制局部递送Nell-1。该系统将由三维(3D)壳聚糖/海藻酸盐(CHI/Al)支架组成，这些支架在宏观和微观尺度上具有明确的几何形状，通过间接3D打印技术结合仿生处理策略来提供类骨矿物磷灰石微环境和成骨信号分子(Nell-1)。为了最大限度地促进骨再生，Nell-1还将与血小板衍生生长因子-BB(PDGF-BB)联合用于临床治疗牙周骨缺损。这一建议的具体假设是，从计算机设计的仿生支架中受控输送Nell-1+PDGF可以促进牙槽骨缺损的修复。为了研究这一假说，我们提出了以下目标：1)开发具有可控结构和成骨分子输送的仿生磷灰石涂层CHI/Al支架(Nell-1+PDGF-BB)；2)通过输送Nell-1+PDGF-BB的仿生支架促进牙槽骨再生。将通过间接3D打印技术创建促进大众运输和血管嵌入的CHI/Al脚手架建筑。在这个结构中，我们将创建一种仿生磷灰石涂层，并确定磷灰石涂层是否可以提高Nell-1和PDGF的输送效率。我们将在一个更大的下颌骨节段性缺损区模型中评估Nell-1在仿生支架上的成骨效果。此外，我们还将把PDGF整合到支架中，并评估联合使用Nell-1+PDGF对骨再生的影响，以最大限度地促进骨形成。这一建议的结果将对临床转化Nell-1介导的治疗药物以促进牙槽骨再生，同时最大限度地减少当前骨诱导治疗的潜在不良影响至关重要。 公共卫生相关性：由于牙周病、创伤、牙齿脱落或重建手术导致的牙槽骨丢失通常会导致临床表现为牙槽骨受限。 种植体植入的骨可获得性。这项研究提供了一种新的成骨蛋白与仿生支架/输送系统相结合的有效和安全的骨再生策略，同时将现有骨诱导疗法的潜在不良影响降至最低。