Human Bone Engineering and Resorption in a Novel Mineralized Collagen Scaffold

 描述(由申请人提供)： 在退伍军人中，颅面部骨骼和四肢的巨大缺陷经常发生，并可能导致功能缺陷，需要广泛的重建。虽然自体骨移植是目前重建骨缺损的黄金标准，但可能会出现严重的供体SIT并发症，包括慢性疼痛、感染、重复手术和长时间住院，因此对替代骨替代方法的需求很大。组织工程学用于骨再生的成功依赖于支架技术、生长因子和细胞材料的最佳相互作用。真正的临床转化的两个障碍是外源生长因子在 高浓度和宿主环境对实验室人工骨的接受性。临床上，超生理剂量的成骨生长因子，如骨形态发生蛋白-2，被用作骨移植手术的补充或替代。虽然骨愈合可以在一定程度上完成，但软组织肿胀、异位骨形成、邻近骨吸收以及对上颌骨生长的长期影响等不良反应都已有报道。本实验室此前已证实，间充质干细胞可以在三维支架上诱导成骨。不分物种(小鼠、兔或人)或间充质干细胞来源(骨髓或脂肪)均可刺激成骨。此外，携带成骨细胞的支架可用于修复兔颅骨的临界大小的缺损。然而，与其他研究人员的研究类似，工程化骨植入后的长期稳定性受到时间吸收的限制。在这一应用中，我们重点描述了一种新型的纳米颗粒矿化胶原糖胺聚糖支架的成骨机制，这种支架可以在不增加骨形态发生蛋白刺激的情况下，有效地诱导原代兔骨髓基质细胞和原代人骨髓间充质干细胞成骨。我们建议通过体外和体内的颅骨缺损研究来研究该系统中成骨和破骨细胞生成的耦合。

 DESCRIPTION (provided by applicant): Large defects of the craniofacial skeleton and extremities occur frequently in our Veterans and may result in functional deficits that require extensive reconstruction. Although autologous bone grafting is the current gold standard for reconstruction of skeletal defects, significant donor sit morbidity including chronic pain, infection, repeated surgeries, and prolonged hospital stays may ensue thus creating a significant need for alternative methods of skeletal replacement. The success of tissue engineering for bone regeneration depends on the optimal interplay of scaffold technology, growth factors, and cellular material in a deliverable fashion. Two barriers to true clinical translation are the variable side effect profiles of exogenous growth factors delivered at high concentrations and the acceptance of laboratory fabricated bone by the host environment. Clinically, supraphysiologic doses of osteogenic growth factors, such as bone morphogenetic protein-2, are utilized as a supplement or replacement for bone grafting procedures. Although bone healing can be accomplished to a certain degree, untoward effects such as soft tissue swelling, ectopic bone formation, resorption of adjacent bone, and long term effects on maxillary growth have all been reported. Our laboratory has previously demonstrated that mesenchymal stem cells can be induced to undergo osteogenesis on three-dimensional scaffolds. Osteogenesis was stimulated regardless of species (mouse, rabbit, or human) or the source of mesenchymal stem cells (bone marrow or adipose). In addition, scaffolds carrying osteogenic cells can be utilized to heal critical sized defects of the rabbit cranial skeleton. However, similr to studies from other investigators, the long term stability of engineered bone after implantation is limited by resorption over time. In this application, we focus on delineating the osteogenic mechanism of a novel, nanoparticulate mineralized collagen glycosaminoglycan scaffolds that imparts efficient osteogenesis of both primary rabbit bone marrow stromal cells and primary human mesenchymal stem cells without additional bone morphogenetic protein stimulation. We propose to investigate the coupling of osteogenesis and osteoclastogenesis in this system with both in vitro and in vivo cranial defect studies.