BackgroundAutologous grafting, despite some disadvantages, is still considered the gold standard for reconstruction of maxillofacial bone defects. The aim of this study was to evaluate bone regeneration using bone marrow-derived mesenchymal stromal cells (MSCs) in a clinical trial, a less invasive approach than autologous bone grafting. This comprehensive clinical trial included subjects with severe mandibular ridge resorption.MethodsThe study included 11 subjects aged 52–79 years with severe mandibular ridge resorption. Bone marrow cells were aspirated from the posterior iliac crest and plastic adherent cells were expanded in culture medium containing human platelet lysate. The MSCs and biphasic calcium phosphate granules as scaffolds were inserted subperiosteally onto the resorbed alveolar ridge. After 4–6 months of healing, new bone formation was assessed clinically and radiographically, as were safety and feasibility. Bone at the implant site was biopsied for micro-computed topography and histological analyses and dental implants were placed in the newly regenerated bone. Functional outcomes and patient satisfaction were assessed after 12 months.ResultsThe bone marrow cells, expanded in vitro and inserted into the defect together with biphasic calcium phosphate granules, induced significant new bone formation. The regenerated bone volume was adequate for dental implant installation. Healing was uneventful, without adverse events. The patients were satisfied with the esthetic and functional outcomes. No side effects were observed.ConclusionsThe results of this comprehensive clinical trial in human subjects confirm that MSCs can successfully induce significant formation of new bone, with no untoward sequelae. Hence, this novel augmentation procedure warrants further investigation and may form the basis of a valid treatment protocol, challenging the current gold standard.Trial registrationEudraCT, 2012-003139-50. Registered on 21 August 2013. ClinicalTrials.gov, NCT 02751125. Registered on 26 April 2016.

Temporomandibular disorders (TMDs) are characterized by pain and dysfunction in the masticatory apparatus and the temporomandibular joint (TMJ). Previous trauma, stress symptoms, psychosocial impairment, and catastrophizing have been related to TMD. To assess if the hypothalamic-pituitary-adrenal (HPA) axis is upregulated in TMD patients, we performed a cross-sectional study with saliva from 44 TMD patients and 44 healthy sex- and age-matched controls for cortisol (F) and cortisone (E) with liquid chromatography-tandem mass spectrometry. Furthermore, we calculated the F/E ratio for the evaluation of 11β-hydroxysteroid dehydrogenase activity. We also assessed anxiety/depression and pain catastrophizing scores from a questionnaire that participants completed prior to the examination. We found that F (P=0.01), E (P=0.04), the F/E ratio (P=0.002), and the sum of glucocorticoids (E + E) in saliva (P=0.02) were significantly higher in the TMD group. Anxiety/depression and catastrophizing scores were also significantly higher in the TMD group (P < 0.0001). Our findings indicate that patients with TMDs may have an upregulated HPA axis with higher F secretion from the adrenal cortex. Anxiety/depression and pain catastrophizing scores were significantly higher in the TMD group, and psychological factors may contribute to chronic upregulation of the HPA axis.

Massage-like stroking induces acute antinociceptive effects that can be reversed by an oxytocin antagonist, indicating activation of oxytocin on endogenous pain controlling systems. We now demonstrate an increase in hindpaw withdrawal latencies (HWLs), in response to thermal and mechanical stimuli, which was present after six treatments of massage-like stroking every other day and which continued to increase through the remaining seven treatments. Repeated massage-like stroking also resulted in increased oxytocin-like immunoreactivity (oxytocin-LI) levels in plasma and periaquaductal grey matter (PAG). Furthermore, increases in HWLs were also present after injections of oxytocin into the PAG (0.1, 0.5 and 1.0 nmol). Intra-PAG oxytocin injection of 1 nmol followed by 1 or 20 nmol of naloxone attenuated the increments in HWL. Also, there was a dose-dependent attenuation of the oxytocin-induced antinociceptive effects following intra-PAG injection of the mu-opioid antagonist beta-funaltrexamine (beta-FNA) and the kappa-opioid antagonist nor-binaltorphimine (nor-BNI) but not the delta-antagonist naltrindole. The long-term antinociceptive effects of massage-like stroking may be attributed, at least partly, to the oxytocinergic system and its interaction with the opioid system, especially the mu- and the kappa-receptors in the PAG.

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