Boes Matthew, Kain Michael, Kakar Sanjeev, Nicholls Fred, Cullinane Dennis, Gerstenfeld Louis, Einhorn Thomas A, Tornetta Paul
Department of Orthopaedics, Boston Medical Center, Dowling 2 North, 850 Harrison Avenue, Boston, MA 02118, USA.
J Bone Joint Surg Am. 2006 Apr;88(4):738-43. doi: 10.2106/JBJS.D.02648.
Heterotopic bone formation has been observed in patients with traumatic brain injury; however, an association between such an injury and enhanced fracture-healing remains unclear. To test the hypothesis that traumatic brain injury causes a systemic response that enhances fracture-healing, we established a reproducible model of traumatic brain injury in association with a standard closed fracture and measured the osteogenic response with an in vitro cell assay and assessed bone-healing with biomechanical testing.
A standard closed femoral fracture was produced in forty-three Sprague-Dawley rats. Twenty-three of the rats were subjected to additional closed head trauma that produced diffuse axonal injury similar to that observed in patients with a traumatic brain injury. Twenty-one days after the procedure, all animals were killed and fracture-healing was assessed by measuring callus size and by mechanical testing. Sera from the animals were used in subsequent in vitro experiments to measure mitogenic effects on established cell lines of committed osteoblasts, fibroblasts, and mesenchymal stem cells.
Biomechanical assessment demonstrated that the brain-injury group had increased stiffness (p = 0.02) compared with the fracture-only group. There was no significant difference in torsional strength between the two groups. Cell culture studies showed a significant increase in the proliferative response of mesenchymal stem cells after exposure to sera from the brain-injury group compared with the response after exposure to sera from the fracture-only group (p = 0.0002). This effect was not observed in fibroblasts or committed osteoblasts.
These results support data from previous studies that have suggested an increased osteogenic potential and an enhancement of fracture-healing secondary to traumatic brain injury. Our results further suggest that the mechanism for this enhancement is related to the presence of factors in the serum that have a mitogenic effect on undifferentiated mesenchymal stem cells.
创伤性脑损伤患者中已观察到异位骨形成；然而，这种损伤与骨折愈合增强之间的关联仍不明确。为了验证创伤性脑损伤会引发一种增强骨折愈合的全身反应这一假说，我们建立了一个与标准闭合性骨折相关的创伤性脑损伤可重复性模型，并通过体外细胞试验测量成骨反应，以及通过生物力学测试评估骨愈合情况。
对43只Sprague-Dawley大鼠造成标准的闭合性股骨骨折。其中23只大鼠还遭受了额外的闭合性颅脑创伤，导致弥漫性轴索损伤，类似于创伤性脑损伤患者所观察到的情况。术后21天，处死所有动物，通过测量骨痂大小和进行力学测试来评估骨折愈合情况。将动物的血清用于后续的体外实验，以测量对成熟成骨细胞、成纤维细胞和间充质干细胞系的促有丝分裂作用。
生物力学评估表明，与单纯骨折组相比，脑损伤组的刚度增加（p = 0.02）。两组之间的抗扭强度无显著差异。细胞培养研究显示，与暴露于单纯骨折组血清后的反应相比，间充质干细胞暴露于脑损伤组血清后的增殖反应显著增加（p = 0.0002）。在成纤维细胞或成熟成骨细胞中未观察到这种效应。
这些结果支持了先前研究的数据，即创伤性脑损伤继发的成骨潜能增加和骨折愈合增强。我们的结果进一步表明，这种增强的机制与血清中对未分化间充质干细胞有促有丝分裂作用的因子的存在有关。
