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Backgroundand objectives Inflammation of the bone microenvironment in arthritic conditions leads to extensive infiltration of immune cells causing destruction of articular cartilage and bone. Similarities characterise bone fracture. Here, sustained inflammation leads to synthesis of bone and cartilage, massive infiltration of hematopoietic cells and controlled tissue resorption terminating into net bone formation. Thus, to better understand how bone inflammation leads to successful repair instead of autoimmunity, the authors have drawn a comprehensive cellular study of post-fracture bone regeneration by confocal microscopy and other histological techniques. Materials and methods Experimental closed femoral fracture was used to induce bone regeneration in C57BL/six mice and congenic RAG −/− KO (lymphopenic), TCR βδ chain −/− KO (T cell deficient) and JHT −/− KO (B cell deficient) mice. Confocal microscopy was used to detect the presence of T, B, macrophages, eosinophils, activated osteoclasts, osteogenic precursors and osteblasts in the fracture callus. Histomorphometry was used to quantify bone regeneration. Cell culture was used to measure mineralisation capacity at steady state of bone marrow derived osteogenic precursors in WT and lymphopenic mice. Results Our data show that during fracture repair the majority of lymphocytes, macrophages and eosinophils appear late upon ensuing endochondral bone formation. Interestingly, lymphopenic mice had the capacity to mineralise cartilage and undergo subsequent resorption earlier than WT controls in vivo. Accordingly, by histomorphometric comparison of fracture repair in different immunodeficient animal models, the authors found that the speed of endochondral bone formation is T cell dependent. Confocal microscopy also showed that accelerated mineralisation in RAG mice occurred well before lymphocytes could be detected within the callus of WT animals. However, the authors clearly visualised in the callus of RAG and normal mice the concomitant immigration of osteogenic precursors from surrounding tissues. Remarkably, bone marrow osteogenic cells from RAG mice, taken in normal conditions, displayed abnormal mineralisation capacity than normal controls upon cell culture. This suggests that lymphocytes control bone regeneration by programming the basal activity and capacity to respond to damage of osteoblast precursors. Conclusions Bone repair involves the migration of bone marrow osteogenic precursors into the bloodstream to reach fracture sites. Immune cells infiltrate the fracture callus during the mid-late stages of bone regeneration and they consist mainly of B lymphocytes. T cells control the velocity of endochondral bone formation by programming the mineralisation capacity of osteogenic cells. more...

This review aims to address the current limitations in biomaterial scaffold-based treatment strategies for bone defect healing and suggests new, alternative approaches that merit further investigation. The question of whether the biomaterial scaffold properties should mimic the natural extracellular matrix of mature tissue or some phase of the dynamic range of tissues observed during the healing process is discussed. Additionally, the authors advocate for a biomimetic approach, which uses the endogenous secondary fracture healing processes to inform the design of scaffold constructs. In particular, the mechanical environment is emphasized as an important factor influencing the clinical success of these constructs. The authors stress the need for a scaffolds design that provides an optimal mechanical environment for cell fate, supplies necessary signals and nutrition to the cells and, thus, more closely mimics the natural healing cascade. more...

The interest on applying mesenchymal stromal cells (MSCs) in orthopedic disorders has risen tremendously in the last years due to scientific successes in preclinical in vitro and animal model studies. In a wide range of diseases and injuries of the musculoskeletal system, MSCs are currently under evaluation, but so far have found access to clinical use only in few cases. The current assignment is to translate the acquired knowledge into clinical practice. Therefore, this review aims at presenting a synopsis of the up-to-date status of the use of MSCs and MSC related cell products in musculoskeletal indications. Clinical studies were included, whereas preclinical and animal study data not have been considered. Most studies published so far investigate the final outcome applying bone marrow derived MSCs. In fewer trials the use of adipose tissue derived MSCs and allogenic MSCs was investigated in different applications. Although the reported results are equivocal in the current literature, the vast majority of the studies shows a benefit of MSC based therapies depending on the cell sources and the indication in clinical use. In summary, the clinical use of MSCs in patients in orthopedic indications has been found to be safe. Standardized protocols and clear definitions of the mechanisms of action and the mode and timing of application as well as further coordinated research efforts will be necessary for finally adding MSC based therapies in standard operating procedures and guidelines for the clinicians treating orthopedic disorders. more...

This study reports that treatment of osseous defects with different growth factors initiates distinct rates of repair. We developed a new method for monitoring the progression of repair, based upon measuring the in vivo mechanical properties of healing bone. Two different members of the bone morphogenetic protein (BMP) family were chosen to initiate defect healing: BMP-2 to induce osteogenesis, and growth-and-differentiation factor (GDF)-5 to induce chondrogenesis. To evaluate bone healing, BMPs were implanted into stabilised 5 mm bone defects in rat femurs and compared to controls. During the first two weeks, in vivo biomechanical measurements showed similar values regardless of the treatment used. However, 2 weeks after surgery, the rhBMP-2 group had a substantial increase in stiffness, which was supported by the imaging modalities. Although the rhGDF-5 group showed comparable mechanical properties at 6 weeks as the rhBMP-2 group, the temporal development of regenerating tissues appeared different with rhGDF-5, resulting in a smaller callus and delayed tissue mineralisation. Moreover, histology showed the presence of cartilage in the rhGDF-5 group whereas the rhBMP-2 group had no cartilaginous tissue. Therefore, this study shows that rhBMP-2 and rhGDF-5 treated defects, under the same conditions, use distinct rates of bone healing as shown by the tissue mechanical properties. Furthermore, results showed that in vivo biomechanical method is capable of detecting differences in healing rate by means of change in callus stiffness due to tissue mineralisation. more...