Human BioMolecular Research Institute, San Diego, California, USA.
Department of Orthopedic Surgery, University of California, San Diego, San Diego, California, USA.
Tissue Eng Part C Methods. 2020 Nov;26(11):577-589. doi: 10.1089/ten.TEC.2020.0217. Epub 2020 Nov 13.
Despite considerable research effort, there is a significant need for safe agents that stimulate bone formation. Treatment of large or complex bone defects remains a challenge. Implantation of small molecule-induced human bone marrow-derived mesenchymal stromal cells (hBMSCs) on an appropriate tricalcium phosphate (TCP) scaffold offers a robust system for noninvasive therapy for spinal fusion. To show the efficacy of this approach, we identified a small molecule curcuminoid that when combined with TCP ceramic in the presence of hBMSCs selectively induced growth of bone cells: after 8- or 25-day incubations, alkaline phosphatase was elevated. Treatment of hBMSCs with curcuminoid 1 and TCP ceramic increased osteogenic target gene expression (i.e., and ) over time. In the presence of curcuminoid 1 and TCP ceramic, osteogenesis of hBMSCs, including proliferation, differentiation, and mineralization, was observed. No evidence of chondrogenic or adipogenic potential using this protocol was observed. Transplantation of curcuminoid 1-treated hBMSC/TCP mixtures into the spine of immunodeficient rats showed that it achieved spinal fusion and provided greater stability of the spinal column than untreated hBMSC-TCP implants or TCP alone implants. On the basis of histological analysis, greater bone formation was associated with curcuminoid 1-treated hBMSC implants manifested as contiguous growth plates with extensive hematopoietic territories. Stimulation of hBMSCs by administration of small molecule curcuminoid 1 in the presence of TCP ceramic afforded an effective noninvasive strategy that increased spinal fusion repair and provided greater stability of the spinal column after 8 weeks in immunodeficient rats. Impact statement Bone defects only slowly regenerate themselves in humans. Current procedures to restore spinal defects are not always effective. Some have side effects. In this article, a new method to produce bone growth within 8 weeks in rats is presented. In the presence of tricalcium phosphate ceramic, curcuminoid-1 small molecule-stimulated human bone marrow-derived mesenchymal stromal cells showed robust bone cell growth . Transplantation of this mixture into the spine showed efficient spinal fusion in rats. The approach presented herein provides an efficient biocompatible scaffold for delivery of a potentially clinically useful system that could be applicable in patients.
尽管已经进行了大量研究，但仍迫切需要安全的能够刺激骨形成的药物。治疗大或复杂的骨缺损仍然是一个挑战。将小分子诱导的人骨髓间充质基质细胞（hBMSC）植入合适的磷酸三钙（TCP）支架上为脊柱融合的非侵入性治疗提供了一个强大的系统。为了证明这种方法的有效性，我们鉴定出一种小分子姜黄素，当它与 TCP 陶瓷一起存在于 hBMSC 中时，可以选择性地诱导骨细胞生长：在 8 天或 25 天孵育后，碱性磷酸酶升高。用姜黄素 1 和 TCP 陶瓷处理 hBMSC 会随着时间的推移增加成骨靶基因的表达（即和）。在姜黄素 1 和 TCP 陶瓷存在的情况下，观察到 hBMSC 的成骨作用，包括增殖、分化和矿化。使用该方案没有观察到软骨形成或脂肪形成的潜力。将姜黄素 1 处理的 hBMSC/TCP 混合物移植到免疫缺陷大鼠的脊柱中表明，它实现了脊柱融合，并为脊柱柱提供了比未经处理的 hBMSC-TCP 植入物或 TCP 单独植入物更高的稳定性。基于组织学分析，与未经处理的 hBMSC-TCP 植入物或 TCP 单独植入物相比，与姜黄素 1 处理的 hBMSC 植入物相关的更大骨形成表现为连续的生长板和广泛的造血区域。在 TCP 陶瓷存在的情况下，用小分子姜黄素 1 刺激 hBMSC 提供了一种有效的非侵入性策略，可增加脊柱融合修复，并在免疫缺陷大鼠中 8 周后提供脊柱柱更高的稳定性。影响声明人类骨骼缺陷自身再生缓慢。目前恢复脊柱缺陷的程序并不总是有效。有些有副作用。在本文中，提出了一种在 8 周内在大鼠体内产生骨生长的新方法。在磷酸三钙陶瓷存在的情况下，姜黄素-1 小分子刺激人骨髓间充质基质细胞表现出强大的骨细胞生长。将这种混合物移植到脊柱中，在大鼠中显示出有效的脊柱融合。本文提出的方法为递送一种潜在临床有用的系统提供了有效的生物相容性支架，该系统可适用于患者。
