Bone fracture healing impairment related to mechanical problems has been largely corrected by advances in fracture management. Better protocols, more strict controls of time and function, and hardware and surgical technique evolution have contributed to better prognosis, even in complex fractures. However, atrophic nonunion persists in clinical cases where, for different reasons, the osteogenic capability is impaired. When this is the case, a better understanding of the basic mechanisms under bone repair and augmentation techniques may put in perspective the current possibilities and future opportunities. Among those, cell therapy particularly aims to correct this insufficient osteogenesis. However, the launching of safe and efficacious cell therapies still requires substantial amount of research, especially clinical trials. This review will envisage the current clinical trials on bone healing augmentation based on cell therapy, with the experience provided by the REBORNE Project, and the insight from investigator-driven clinical trials on advanced therapies towards the future. This article is part of a Special Issue entitled Stem Cells and Bone.

• Introduction • Bone fracture healing and healing problems • Biomaterial scaffolds and tissue engineering in bone formation ‐ Bone tissue engineering ‐ Biomaterial scaffolds ‐ Synthetic scaffolds ‐ Micro‐ and nanostructural properties of scaffolds ‐ Conclusion • Mesenchymal stem cells and osteogenesis ‐ Bone tissue ‐ Origin of osteoblasts ‐ Isolation and characterization of bone marrow derived MSC ‐ In vitro differentiation of MSC into osteoblast lineage cells ‐ In vivo differentiation of MSC into bone ‐ Factors and pathways controlling osteoblast differentiation of hMSC ‐ Defining the relationship between osteoblast and adipocyte differentiation from MSC ‐ MSC and sex hormones ‐ Effect of aging on osteoblastogenesis ‐ Conclusion • Embryonic, foetal and adult stem cells in osteogenesis ‐ Cell‐based therapies for bone ‐ Specific features of bone cells needed to be advantageous for clinical use ‐ Development of therapeutic biological agents ‐ Clinical application concerns ‐ Conclusion • Platelet‐rich plasma (PRP), growth factors and osteogenesis ‐ PRP effects in vitro on the cells involved in bone repair ‐ PRP effects on osteoblasts ‐ PRP effects on osteoclasts ‐ PRP effects on endothelial cells ‐ PRP effects in vivo on experimental animals ‐ The clinical use of PRP for bone repair ‐ Non‐union ‐ Distraction osteogenesis ‐ Spinal fusion ‐ Foot and ankle surgery ‐ Total knee arthroplasty ‐ Odontostomatology and maxillofacial surgery ‐ Conclusion • Molecular control of osteogenesis ‐ TGF‐β signalling ‐ FGF signalling ‐ IGF signalling ‐ PDGF signalling ‐ MAPK signalling pathway ‐ Wnt signalling pathway ‐ Hedgehog signalling ‐ Notch signalling ‐ Ephrin signalling ‐ Transcription factors regulating osteoblast differentiation ‐ Conclusion • Summary This invited review covers research areas of central importance for orthopaedic and maxillofacial bone tissue repair, including normal fracture healing and healing problems, biomaterial scaffolds for tissue engineering, mesenchymal and foetal stem cells, effects of sex steroids on mesenchymal stem cells, use of platelet‐rich plasma for tissue repair, osteogenesis and its molecular markers. A variety of cells in addition to stem cells, as well as advances in materials science to meet specific requirements for bone and soft tissue regeneration by addition of bioactive molecules, are discussed.

Background: Abundant literature regarding the use of intravenous tranexamic acid (TXA) in primary total knee replacement is available. Randomized controlled trials have confirmed the efficacy of topical TXA compared with placebo, but the comparison between topical and intravenous TXA is unclear. The present study was designed to verify noninferior efficacy and safety of topical intra-articular TXA compared with intravenous TXA in primary total knee replacement with cemented implants. Methods: A Phase-III, single-center, double-blind, randomized, controlled clinical trial was performed to compare topical intra-articular TXA (3 g of TXA in 100 mL of physiological saline solution) with two intravenous doses of TXA (15 mg/kg in 100 mL of physiological saline solution, one dose before tourniquet release and another three hours after surgery) in a multimodal protocol for blood loss prevention. The primary outcome was the blood transfusion rate, and the secondary outcomes included visible blood loss (as measured in the drain) at twenty-four hours postoperatively and invisible blood loss (as estimated from the Nadler formula) at forty-eight hours postoperatively. The sample size of seventy-eight patients was calculated to give a statistical power of 99% for demonstrating noninferiority. Thirty-nine patients each were allocated to receive topical intra-articular TXA (the experimental group) and intravenous TXA (the control group); there were no significant differences in demographics or preoperative laboratory values between the groups. Noninferiority was estimated by comparing the confidence intervals with a delta of 10%. Student t and Mann-Whitney tests were used to assess the significance of any differences. Results: The transfusion rate was zero in both groups; thus, noninferiority was demonstrated for the primary efficacy end point, suggesting equivalence. Noninferiority was also demonstrated for the secondary efficacy end points. Drain blood loss at twenty-four hours was 315.6 mL (95% confidence interval [CI], 248.5 to 382.7 mL) in the experimental group and 308.1 mL (95% CI, 247.6 to 368.5 mL) in the control group (p = 0.948, Mann-Whitney). Also, estimated blood loss at forty-eight hours was 1259.0 mL (95% CI, 1115.6 to 1402.3 mL) in the experimental group and 1317.9 mL (95% CI, 1175.4 to 1460.4 mL) in the control group (p = 0.837, Mann-Whitney). No significant safety differences were seen between groups. Conclusions: Topical administration of TXA according to the described protocol demonstrated noninferiority compared with intravenous TXA, with no safety concerns. This randomized controlled trial supports the topical intra-articular administration of TXA in primary total knee replacement with cemented implants. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

To improve the microbiological diagnosis of device-related osteoarticular infections, we have developed a protocol based on the sonication of device samples, followed by concentration and inoculation of the sonicate in a broad variety of media in a quantitative manner. Sixty-six samples from 31 patients were included in the study (17 of them with clinical diagnosis of infection). The sonication procedure had a sensitivity of 94.1%, which is better than that of conventional cultures (88.2%). One case of contamination and six cases of unexpected positive cultures were detected (specificity of 42.8%): two of these were considered to represent true infection, while the other four were considered to be nonsignificant (corrected specificity of 50%), although the clinical importance of these isolates is questionable. When we analyzed the number of CFU, no breakpoint between significant and nonsignificant isolates could be established. Based on our results, the procedure of sonication of retrieved implants is better than conventional cultures for the diagnosis of device-related infections. The significance of some isolates in patients without clinical infection remains uncertain. However, they may become pathogens and cannot be routinely considered to be contamination.