Human Bone Engineering and Resorption in a Novel Mineralized Collagen Scaffold

 描述（由申请人提供）： 颅面骨骼和四肢的大缺陷经常发生在我们的退伍军人，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骼缺损的金标准，但可能会导致严重的供体部位发病率，包括慢性疼痛、感染、重复手术和长期住院，因此对替代骨骼置换方法的需求很大。 骨再生组织工程的成功取决于支架技术、生长因子和细胞材料以可交付的方式的最佳相互作用。真正的临床转化的两个障碍是外源性生长因子的可变副作用概况， 高浓度和宿主环境对实验室制造的骨的接受。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，但不良反应，如软组织肿胀，异位骨形成，邻近骨的吸收，以及对上颌骨生长的长期影响都有报道。我们的实验室先前已经证明，间充质干细胞可以诱导进行三维支架上的成骨。无论种属（小鼠、兔或人）或间充质干细胞来源（骨髓或脂肪），均刺激骨生成。此外，携带成骨细胞的支架可用于修复兔颅骨骨骼的临界尺寸的缺损。然而，与其他研究者的研究相似，工程化骨植入后的长期稳定性受到随时间推移的吸收的限制。 在本申请中，我们专注于描绘一种新型的纳米颗粒矿化胶原糖胺聚糖支架的成骨机制，该支架在没有额外的骨形态发生蛋白刺激的情况下赋予原代兔骨髓基质细胞和原代人间充质干细胞有效的成骨作用。我们建议通过体外和体内颅骨缺损研究来研究该系统中骨生成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.