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Conditioned media from hypoxic-cultured human dental pulp cells promotes bone healing during distraction osteogenesis.

ABSTRACT: Distraction osteogenesis (DO) is a surgical procedure used to correct various skeletal disorders. Improving the technique by reducing the healing time would be of clinical relevance. The aim of this study was to determine the angiogenic and regenerative potential of conditioned media (CMs) collected from human dental pulp cells (hDPCs) grown under different culture conditions. CM collected from cells under hypoxia was used to improve bone healing and the DO procedure in vivo. The angiogenic potentials of CMs collected from hDPCs grown under normoxic (-Nor) and hypoxic (-Hyp) conditions were evaluated by quantitative PCR (VEGF-A, angiopoietin-1, angiopoietin-2, interleukin-6 (IL-6) and CXCL12), ELISA assays (VEGF-A, Ang-2), tube-formation and wound-healing assays, using human umbilical vein endothelial cells. The results demonstrated that hypoxic CM had significantly higher angiogenic potential than normoxic CM. Human fetal osteoblasts (hFOBs) were exposed to CM, followed by alizarin red staining, to assess the osteogenic potential. It was found that CM did not enhance the mineralization capacity of hFOBs. DO was performed in the tibiae of 30 mice, followed by a local injection of 20?µl CM (CM-Nor and CM-Hyp groups) or serum-free DMEM (control group) into the distraction zone every second day. The mice were sacrificed at days 13 and 27. The CM-Hyp treatment revealed a higher X-ray density than the control group (p?

SUBMITTER: Fujio M

PROVIDER: S-EPMC5516172 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Conditioned media from hypoxic-cultured human dental pulp cells promotes bone healing during distraction osteogenesis.

Fujio Masahito M Xing Zhe Z Sharabi Niyaz N Xue Ying Y Yamamoto Akihito A Hibi Hideharu H Ueda Minoru M Fristad Inge I Mustafa Kamal K

Journal of tissue engineering and regenerative medicine 20151127 7

Distraction osteogenesis (DO) is a surgical procedure used to correct various skeletal disorders. Improving the technique by reducing the healing time would be of clinical relevance. The aim of this study was to determine the angiogenic and regenerative potential of conditioned media (CMs) collected from human dental pulp cells (hDPCs) grown under different culture conditions. CM collected from cells under hypoxia was used to improve bone healing and the DO procedure in vivo. The angiogenic pote ...[more]

PMID: 26612624

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Project description:During lower limb lengthening, poor bone regeneration is a devastating complication. Several local or systemic applications have been used to promote osteogenesis, and biologic stimulations are gaining attention, but their utility has not been proven in this setting.In patients undergoing bilateral tibial lengthening, we compared those receiving an osteotomy site injection of autologous bone marrow aspirate concentrate (BMAC) plus platelet-rich plasma (PRP) with those not receiving such an injection in terms of external fixator index (time in external fixation divided by amount of lengthening), full weightbearing index (time until a patient was permitted to do full weightbearing divided by amount of lengthening), four cortical healing indexes (time until each cortical union divided by amount of lengthening), and callus shape and type.Twenty-two patients (44 tibias) undergoing bilateral tibial lengthening enrolled in this randomized trial. Two patients were excluded, one due to insufficient radiographic evaluation and one who was lost to followup, leaving 20 patients (40 segments) for inclusion. Ten patients (20 segments) received BMAC combined with PRP injection (treatment group) and 10 patients (20 segments) received no injection (control group). All patients underwent stature lengthening for familial short stature with the lengthening over nail technique. Autologous BMAC combined with PRP was injected at the tibial osteotomy site at the end of the index surgery. Mean distraction rates were similar between groups (0.75 mm/day in the treatment group versus 0.72 mm/day in the control group; p = 0.24). Full weightbearing was permitted when we observed radiographic evidence of healing at two cortices; this assessment was made by the surgeon who was blinded to the treatment each patient received. Minimum followup was 24 months (mean, 28 months; range, 24-34 months).There was no difference in mean external fixator index between groups. However, mean cortical healing indexes (anterior/posterior/medial/lateral) were 1.14/0.81/0.96/0.88 months/cm in the treatment group and 1.47/1.26/1.42/1.22 months/cm in the control group (all p < 0.001), showing faster healing in the treatment group at each cortex. Full weightbearing was permitted earlier in the treatment group than in the control group (index: 0.99 months/cm and 1.38 months/cm, respectively, p < 0.001). Callus shape and type were not different between groups.Autologous BMAC combined with PRP injection at the osteotomy site helped improve bone healing in distraction osteogenesis of the tibia, although the effect size was small.Level I, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Project description:Background: Interfragmentary movements have benefits in the improvement of bone formation during distraction osteogenesis (DO). Although several clinical studies reported positive outcomes regarding the application of the cyclic distraction-compression (CDC) dynamization technique in cases with poor bone formation during DO, they are mostly anecdotal without a detailed description. The purpose of this study was to investigate the effectiveness and potential mechanism of different amplitudes and rates of the CDC technique on bone regeneration in a rat femur DO model. Methods: A total of 60 adult male Sprague-Dawley rats underwent right femoral mid-diaphysis transverse osteotomy and were randomly and evenly divided into Control (no manipulation), Group1 (CDC therapy), Group2 (CDC therapy with larger amplitude), and Group3 (CDC therapy with a slower rate) after distraction. The CDC technique was performed during the middle phase of the consolidation period according to different protocols. Animals were sacrificed after 4 and 6 weeks of consolidation. The process of bone formation was monitored by digital radiographs, and the regenerate bone was evaluated by micro-computed tomography (micro-CT), biomechanical test, and histological analysis. The serum contents of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunosorbent assay (ELISA). Results: Bone regeneration after the CDC technique was improved significantly during DO. The digital radiograph, micro-CT, histomorphological analysis, and biomechanical evaluation showed better effects regarding volume, continuity, and mechanical properties of the regenerate bone in Group2 and Group3 when compared to Group1. The angiogenic and osteogenic markers were more highly expressed in Group2 and Group3 than in Group1 according to the immunohistochemical analysis. As for ELISA, the serum contents of HIF-1α and VEGF were also increased after the CDC technique, especially in Group2 and Group3. Conclusion: The CDC dynamization technique has benefits on the improvement of bone formation during DO, and the mechanism may be due to tissue hypoxia activating the HIF pathway followed by the augmentation of osteogenic-angiogenic coupling. Better outcomes may be achieved by moderately increasing the amplitude and slowing down the rate of the CDC technique.

Project description:BackgroundHypoxia is the critical driving force for angiogenesis and can trigger the osteogenic-angiogenic coupling followed by the enhancement of bone regeneration. While lots of studies showed that hypoxia administration can accelerate bone formation during distraction osteogenesis (DO), the therapeutic timing for the osteogenic purpose was concentrated on the distraction phase. The outcomes of hypoxia administration in the consolidation phase stay uncertain. The purpose of this study was to determine the osteogenic effectiveness of hypoxia therapy during the consolidation phase, if any, to enhance bone regeneration in a rat femoral DO model.MethodsA total of 42 adult male Sprague-Dawley rats underwent right femoral mid-diaphysis transverse osteotomy and were randomly divided into Control (NS administration, n = 21) and Group1 (deferoxamine therapy, n = 21) after distraction. During the consolidation phase, Group1 was treated with local deferoxamine (DFO) injection into the distraction zone, while the Control underwent the same dosage of NS. Animals were sacrificed after 2, 4, and 6 weeks of consolidation. The process of bone formation and remodeling was monitored by digital radiographs, and the regenerated bone was evaluated by micro-computed tomography (micro-CT), biomechanical test, and histological analysis. The serum content of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) were measured by enzyme linked immunosorbent assay (ELISA) for further analysis.ResultsBone regeneration was significantly enhanced after hypoxia therapy during the consolidation phase. The digital radiograph, micro-CT, and biomechanical evaluation showed better effects regarding volume, continuity, and mechanical properties of the regenerated bone in Group1. The histomorphological evaluation also revealed the hypoxia treatment contributed to accelerate bone formation and remodeling during DO. The higher positive expression of angiogenic and osteogenic markers were observed in Group1 after hypoxia administration according to the immunohistochemical analysis. The serum content of HIF-1α and VEGF was also increased after hypoxia therapy as evidenced from ELISA.ConclusionHypoxia administration during the consolidation phase of distraction osteogenesis has benefits in enhancing bone regeneration, including accelerates the bone formation and remodeling.

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Conditioned media from hypoxic-cultured human dental pulp cells promotes bone healing during distraction osteogenesis.

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Conditioned media from hypoxic-cultured human dental pulp cells promotes bone healing during distraction osteogenesis.

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