Bone regeneration and repair are crucial to ambulation and quality of life. Factors such as poor general health, serious medical comorbidities, chronic inflammation, and ageing can lead to delayed healing and nonunion of fractures, and persistent bone defects. Bioengineering strategies to heal bone often involve grafting of autologous bone marrow aspirate concentrate (BMAC) or mesenchymal stem cells (MSCs) with biocompatible scaffolds. While BMAC shows promise, variability in its efficacy exists due to discrepancies in MSC concentration and robustness, and immune cell composition. Understanding the mechanisms by which macrophages and lymphocytes – the main cellular components in BMAC – interact with MSCs could suggest novel strategies to enhance bone healing. Macrophages are polarized into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, and influence cell metabolism and tissue regeneration via the secretion of cytokines and other factors. T cells, especially helper T1 (Th1) and Th17, promote inflammation and osteoclastogenesis, whereas Th2 and regulatory T (Treg) cells have anti-inflammatory pro-reconstructive effects, thereby supporting osteogenesis. Crosstalk among macrophages, T cells, and MSCs affects the bone microenvironment and regulates the local immune response. Manipulating the proportion and interactions of these cells presents an opportunity to alter the local regenerative capacity of bone, which potentially could enhance clinical outcomes.

Cite this article: Bone Joint Res 2024;13(9):462–473.

Aims

To explore the efficacy of extracorporeal shockwave therapy (ESWT) in the treatment of osteochondral defect (OCD), and its effects on the levels of transforming growth factor (TGF)-β, bone morphogenetic protein (BMP)-2, -3, -4, -5, and -7 in terms of cartilage and bone regeneration.

Aims

This study aimed to explore the biological and clinical importance of dysregulated key genes in osteoarthritis (OA) patients at the cartilage level to find potential biomarkers and targets for diagnosing and treating OA.

Aims

This study aimed to evaluate the effectiveness of the induced membrane technique for treating infected bone defects, and to explore the factors that might affect patient outcomes.

Osteoarthritis (OA) is mainly caused by ageing, strain, trauma, and congenital joint abnormalities, resulting in articular cartilage degeneration. During the pathogenesis of OA, the changes in subchondral bone (SB) are not only secondary manifestations of OA, but also an active part of the disease, and are closely associated with the severity of OA. In different stages of OA, there were microstructural changes in SB. Osteocytes, osteoblasts, and osteoclasts in SB are important in the pathogenesis of OA. The signal transduction mechanism in SB is necessary to maintain the balance of a stable phenotype, extracellular matrix (ECM) synthesis, and bone remodelling between articular cartilage and SB. An imbalance in signal transduction can lead to reduced cartilage quality and SB thickening, which leads to the progression of OA. By understanding changes in SB in OA, researchers are exploring drugs that can regulate these changes, which will help to provide new ideas for the treatment of OA.

Cite this article: Bone Joint Res 2023;12(9):536–545.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive cartilage degradation, synovial membrane inflammation, osteophyte formation, and subchondral bone sclerosis. Pathological changes in cartilage and subchondral bone are the main processes in OA. In recent decades, many studies have demonstrated that activin-like kinase 3 (ALK3), a bone morphogenetic protein receptor, is essential for cartilage formation, osteogenesis, and postnatal skeletal development. Although the role of bone morphogenetic protein (BMP) signalling in articular cartilage and bone has been extensively studied, many new discoveries have been made in recent years around ALK3 targets in articular cartilage, subchondral bone, and the interaction between the two, broadening the original knowledge of the relationship between ALK3 and OA. In this review, we focus on the roles of ALK3 in OA, including cartilage and subchondral bone and related cells. It may be helpful to seek more efficient drugs or treatments for OA based on ALK3 signalling in future.

Tendon is a bradytrophic and hypovascular tissue, hence, healing remains a major challenge. The molecular key events involved in successful repair have to be unravelled to develop novel strategies that reduce the risk of unfavourable outcomes such as non-healing, adhesion formation, and scarring. This review will consider the diverse pathophysiological features of tendon-derived cells that lead to failed healing, including misrouted differentiation (e.g. de- or transdifferentiation) and premature cell senescence, as well as the loss of functional progenitors. Many of these features can be attributed to disturbed cell-extracellular matrix (ECM) or unbalanced soluble mediators involving not only resident tendon cells, but also the cross-talk with immigrating immune cell populations. Unrestrained post-traumatic inflammation could hinder successful healing. Pro-angiogenic mediators trigger hypervascularization and lead to persistence of an immature repair tissue, which does not provide sufficient mechano-competence. Tendon repair tissue needs to achieve an ECM composition, structure, strength, and stiffness that resembles the undamaged highly hierarchically ordered tendon ECM. Adequate mechano-sensation and -transduction by tendon cells orchestrate ECM synthesis, stabilization by cross-linking, and remodelling as a prerequisite for the adaptation to the increased mechanical challenges during healing. Lastly, this review will discuss, from the cell biological point of view, possible optimization strategies for augmenting Achilles tendon (AT) healing outcomes, including adapted mechanostimulation and novel approaches by restraining neoangiogenesis, modifying stem cell niche parameters, tissue engineering, the modulation of the inflammatory cells, and the application of stimulatory factors.

Cite this article: Bone Joint Res 2022;11(8):561–574.

Aims

Acquired heterotopic ossification (HO) is a debilitating disease characterized by abnormal extraskeletal bone formation within soft-tissues after injury. The exact pathogenesis of HO remains unknown. It was reported that BRD4 may contribute to osteoblastic differentiation. The current study aims to determine the role of BRD4 in the pathogenesis of HO and whether it could be a potential target for HO therapy.

Transforming growth factor-beta2 (TGF-β2) is recognized as a versatile cytokine that plays a vital role in regulation of joint development, homeostasis, and diseases, but its role as a biological mechanism is understood far less than that of its counterpart, TGF-β1. Cartilage as a load-resisting structure in vertebrates however displays a fragile performance when any tissue disturbance occurs, due to its lack of blood vessels, nerves, and lymphatics. Recent reports have indicated that TGF-β2 is involved in the physiological processes of chondrocytes such as proliferation, differentiation, migration, and apoptosis, and the pathological progress of cartilage such as osteoarthritis (OA) and rheumatoid arthritis (RA). TGF-β2 also shows its potent capacity in the repair of cartilage defects by recruiting autologous mesenchymal stem cells and promoting secretion of other growth factor clusters. In addition, some pioneering studies have already considered it as a potential target in the treatment of OA and RA. This article aims to summarize the current progress of TGF-β2 in cartilage development and diseases, which might provide new cues for remodelling of cartilage defect and intervention of cartilage diseases.

Aims. The aim of this study was to identify the risk factors for adverse events following the surgical correction of cervical spinal deformities in adults. Methods. We identified adult patients who underwent corrective cervical spinal surgery between 1 January 2007 and 31 December 2015 from the MarketScan database. The baseline comorbidities and characteristics of the operation were recorded. Adverse events were defined as the development of a complication, an unanticipated deleterious postoperative event, or further surgery. Patients aged < 18 years and those with a previous history of tumour or trauma were excluded from the study. Results. A total of 13,549 adults in the database underwent primary corrective surgery for a cervical spinal deformity during the study period. A total of 3,785 (27.9%) had a complication within 90 days of the procedure, and 3,893 (28.7%) required further surgery within two years. In multivariate analysis, male sex (odds ratio (OR) 0.90 (95% confidence interval (CI) 0.8 to 0.9); p = 0.019) and a posterior approach (compared with a combined surgical approach, OR 0.66 (95% CI 0.5 to 0.8); p < 0.001) significantly decreased the risk of complications. Osteoporosis (OR 1.41 (95% CI 1.3 to 1.6); p < 0.001), dyspnoea (OR 1.48 (95% CI 1.3 to 1.6); p < 0.001), cerebrovascular accident (OR 1.81 (95% CI 1.6 to 2.0); p < 0.001), a posterior approach (compared with an anterior approach, OR 1.23 (95% CI 1.1 to 1.4); p < 0.001), and the use of bone morphogenic protein (BMP) (OR 1.22 (95% CI 1.1 to 1.4); p = 0.003) significantly increased the risks of 90-day complications. In multivariate regression analysis, preoperative dyspnoea (OR 1.50 (95% CI 1.3 to 1.7); p < 0.001), a posterior approach (compared with an anterior approach, OR 2.80 (95% CI 2.4 to 3.2; p < 0.001), and postoperative dysphagia (OR 2.50 (95% CI 1.8 to 3.4); p < 0.001) were associated with a significantly increased risk of further surgery two years postoperatively. A posterior approach (compared with a combined approach, OR 0.32 (95% CI 0.3 to 0.4); p < 0.001), the use of BMP (OR 0.48 (95% CI 0.4 to 0.5); p < 0.001) were associated with a significantly decreased risk of further surgery at this time. Conclusion. The surgical approach and intraoperative use of BMP strongly influence the risk of further surgery, whereas the comorbidity burden and the characteristics of the operation influence the rates of early complications in adult patients undergoing corrective cervical spinal surgery. These data may aid surgeons in patient selection and surgical planning. Cite this article: Bone Joint J 2021;103-B(4):734–738

Aims

The purpose of this study was to: review the efficacy of the induced membrane technique (IMT), also known as the Masquelet technique; and investigate the relationship between patient factors and technique variations on the outcomes of the IMT.

MicroRNAs (miRNAs) are a class of small non-coding RNAs that have emerged as potential predictive, prognostic, and therapeutic biomarkers, relevant to many pathophysiological conditions including limb immobilization, osteoarthritis, sarcopenia, and cachexia. Impaired musculoskeletal homeostasis leads to distinct muscle atrophies. Understanding miRNA involvement in the molecular mechanisms underpinning conditions such as muscle wasting may be critical to developing new strategies to improve patient management. MicroRNAs are powerful post-transcriptional regulators of gene expression in muscle and, importantly, are also detectable in the circulation. MicroRNAs are established modulators of muscle satellite stem cell activation, proliferation, and differentiation, however, there have been limited human studies that investigate miRNAs in muscle wasting. This narrative review summarizes the current knowledge as to the role of miRNAs in the skeletal muscle differentiation and atrophy, synthesizing the findings of published data.

Cite this article: Bone Joint Res 2020;9(11):798–807.

Aims

The lack of disease-modifying treatments for osteoarthritis (OA) is linked to a shortage of suitable biomarkers. This study combines multi-molecule synovial fluid analysis with machine learning to produce an accurate diagnostic biomarker model for end-stage knee OA (esOA).

Aims

Osteopetrosis (OP) is a rare hereditary disease that causes reduced bone resorption and increased bone density as a result of osteoclastic function defect. Our aim is to review the difficulties, mid-term follow-up results, and literature encountered during the treatment of OP.

A balanced inflammatory response is important for successful fracture healing. The response of osteoporotic fracture healing is deranged and an altered inflammatory response can be one underlying cause. The objectives of this review were to compare the inflammatory responses between normal and osteoporotic fractures and to examine the potential effects on different healing outcomes. A systematic literature search was conducted with relevant keywords in PubMed, Embase, and Web of Science independently. Original preclinical studies and clinical studies involving the investigation of inflammatory response in fracture healing in ovariectomized (OVX) animals or osteoporotic/elderly patients with available full text and written in English were included. In total, 14 articles were selected. Various inflammatory factors were reported; of those tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 are two commonly studied markers. Preclinical studies showed that OVX animals generally demonstrated higher systemic inflammatory response and poorer healing outcomes compared to normal controls (SHAM). However, it is inconclusive if the local inflammatory response is higher or lower in OVX animals. As for clinical studies, they mainly examine the temporal changes of the inflammatory stage or perform comparison between osteoporotic/fragility fracture patients and normal subjects without fracture. Our review of these studies emphasizes the lack of understanding that inflammation plays in the altered fracture healing response of osteoporotic/elderly patients. Taken together, it is clear that additional studies, preclinical and clinical, are required to dissect the regulatory role of inflammatory response in osteoporotic fracture healing.

Cite this article: Bone Joint Res 2020;9(7):368–385.

Aims

Cigarette smoking has a negative impact on the skeletal system, causes a decrease in bone mass in both young and old patients, and is considered a risk factor for the development of osteoporosis. In addition, it disturbs the bone healing process and prolongs the healing time after fractures. The mechanisms by which cigarette smoking impairs fracture healing are not fully understood. There are few studies reporting the effects of cigarette smoking on new blood vessel formation during the early stage of fracture healing. We tested the hypothesis that cigarette smoke inhalation may suppress angiogenesis and delay fracture healing.

Aims

To assess the effect of physical exercise (PE) on the histological and transcriptional characteristics of proteoglycan-induced arthritis (PGIA) in BALB/c mice.

Objectives. MicroRNAs (miRNAs) have been reported as key regulators of bone formation, signalling, and repair. Fracture healing is a proliferative physiological process where the body facilitates the repair of a bone fracture. The aim of our study was to explore the effects of microRNA-186 (miR-186) on fracture healing through the bone morphogenetic protein (BMP) signalling pathway by binding to Smad family member 6 (SMAD6) in a mouse model of femoral fracture. Methods. Microarray analysis was adopted to identify the regulatory miR of SMAD6. 3D micro-CT was performed to assess the bone volume (BV), bone volume fraction (BVF, BV/TV), and bone mineral density (BMD), followed by a biomechanical test for maximum load, maximum radial degrees, elastic radial degrees, and rigidity of the femur. The positive expression of SMAD6 in fracture tissues was measured. Moreover, the miR-186 level, messenger RNA (mRNA) level, and protein levels of SMAD6, BMP-2, and BMP-7 were examined. Results. MicroRNA-186 was predicted to regulate SMAD6. Furthermore, SMAD6 was verified as a target gene of miR-186. Overexpressed miR-186 and SMAD6 silencing resulted in increased callus formation, BMD and BV/TV, as well as maximum load, maximum radial degrees, elastic radial degrees, and rigidity of the femur. In addition, the mRNA and protein levels of SMAD6 were decreased, while BMP-2 and BMP-7 levels were elevated in response to upregulated miR-186 and SMAD6 silencing. Conclusion. In conclusion, the study indicated that miR-186 could activate the BMP signalling pathway to promote fracture healing by inhibiting SMAD6 in a mouse model of femoral fracture. Cite this article: Bone Joint Res 2019;8:550–562

Objectives

The aim of this study was to provide a comprehensive understanding of alterations in messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in cartilage affected by osteoarthritis (OA).

Objectives

Adult mice lacking the transcription factor NFAT1 exhibit osteoarthritis (OA). The precise molecular mechanism for NFAT1 deficiency-induced osteoarthritic cartilage degradation remains to be clarified. This study aimed to investigate if NFAT1 protects articular cartilage (AC) against OA by directly regulating the transcription of specific catabolic and anabolic genes in articular chondrocytes.

Aims

Despite declining frequency of blood transfusion and electrolyte supplementation following total joint arthroplasty, postoperative blood analyses are still routinely ordered for these patients. This study aimed to determine the rate of blood transfusion and electrolyte restoration in arthroplasty patients treated with a perioperative blood conservation protocol and to identify risk factors that would predict the need for transfusion and electrolyte supplementation.

Objectives

Many in vitro studies have investigated the mechanism by which mechanical signals are transduced into biological signals that regulate bone homeostasis via periodontal ligament fibroblasts during orthodontic treatment, but the results have not been systematically reviewed. This review aims to do this, considering the parameters of various in vitro mechanical loading approaches and their effects on osteogenic and osteoclastogenic properties of periodontal ligament fibroblasts.

During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions.

Cite this article: I. Qayoom, D. B. Raina, A. Širka, Š. Tarasevičius, M. Tägil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548–560. DOI: 10.1302/2046-3758.710.BJR-2018-0015.R2.

Aims

This study reviews the use of a titanium mesh cage (TMC) as an adjunct to intramedullary nail or plate reconstruction of an extra-articular segmental long bone defect.

Aims

The success of anterior cruciate ligament reconstruction (ACLR) depends on osseointegration at the graft-tunnel interface and intra-articular ligamentization. Our aim was to conduct a systematic review of clinical and preclinical studies that evaluated biological augmentation of graft healing in ACLR.

Despite its intrinsic ability to regenerate form and function after injury, bone tissue can be challenged by a multitude of pathological conditions. While innovative approaches have helped to unravel the cascades of bone healing, this knowledge has so far not improved the clinical outcomes of bone defect treatment. Recent findings have allowed us to gain in-depth knowledge about the physiological conditions and biological principles of bone regeneration. Now it is time to transfer the lessons learned from bone healing to the challenging scenarios in defects and employ innovative technologies to enable biomaterial-based strategies for bone defect healing. This review aims to provide an overview on endogenous cascades of bone material formation and how these are transferred to new perspectives in biomaterial-driven approaches in bone regeneration.

Cite this article: T. Winkler, F. A. Sass, G. N. Duda, K. Schmidt-Bleek. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. Bone Joint Res 2018;7:232–243. DOI: 10.1302/2046-3758.73.BJR-2017-0270.R1.

Objectives

Diabetes mellitus (DM) is known to impair fracture healing. Increasing evidence suggests that some microRNA (miRNA) is involved in the pathophysiology of diabetes and its complications. We hypothesized that the functions of miRNA and changes to their patterns of expression may be implicated in the pathogenesis of impaired fracture healing in DM.

Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass and deterioration of bone microarchitecture, which results in increased bone fragility and fracture risk. Casein kinase 2-interacting protein-1 (CKIP-1) is a protein that plays an important role in regulation of bone formation. The effect of CKIP-1 on bone formation is mainly mediated through negative regulation of the bone morphogenetic protein pathway. In addition, CKIP-1 has an important role in the progression of osteoporosis. This review provides a summary of the recent studies on the role of CKIP-1 in osteoporosis development and treatment.

Cite this article: X. Peng, X. Wu, J. Zhang, G. Zhang, G. Li, X. Pan. The role of CKIP-1 in osteoporosis development and treatment. Bone Joint Res 2018;7:173–178. DOI: 10.1302/2046-3758.72.BJR-2017-0172.R1.

Objectives

The aim of this systematic literature review was to assess the clinical level of evidence of commercially available demineralised bone matrix (DBM) products for their use in trauma and orthopaedic related surgery.

Objectives

In order to screen the altered gene expression profile in peripheral blood mononuclear cells of patients with osteoporosis, we performed an integrated analysis of the online microarray studies of osteoporosis.

Aims

We aimed to assess the influence of ethnicity on the incidence of heterotopic ossification (HO) after total hip arthroplasty (THA).

Objectives

We performed a systematic review of the literature to determine the safety and efficacy of bone morphogenetic protein (BMP) compared with bone graft when used specifically for revision spinal fusion surgery secondary to pseudarthrosis.

Objectives

The biomembrane (induced membrane) formed around polymethylmethacrylate (PMMA) spacers has value in clinical applications for bone defect reconstruction. Few studies have evaluated its cellular, molecular or stem cell features. Our objective was to characterise induced membrane morphology, molecular features and osteogenic stem cell characteristics.

The continual cycle of bone formation and resorption is carried out by osteoblasts, osteocytes, and osteoclasts under the direction of the bone-signaling pathway. In certain situations the host cycle of bone repair is insufficient and requires the assistance of bone grafts and their substitutes. The fundamental properties of a bone graft are osteoconduction, osteoinduction, osteogenesis, and structural support. Options for bone grafting include autogenous and allograft bone and the various isolated or combined substitutes of calcium sulphate, calcium phosphate, tricalcium phosphate, and coralline hydroxyapatite. Not all bone grafts will have the same properties. As a result, understanding the requirements of the clinical situation and specific properties of the various types of bone grafts is necessary to identify the ideal graft. We present a review of the bone repair process and properties of bone grafts and their substitutes to help guide the clinician in the decision making process.

Cite this article: Bone Joint J 2016;98-B(1 Suppl A):6–9.

The aim of this study was to assess the effect of injecting genetically engineered chondrocytes expressing transforming growth factor beta 1 (TGF-β1) into the knees of patients with osteoarthritis. We assessed the resultant function, pain and quality of life.

A total of 54 patients (20 men, 34 women) who had a mean age of 58 years (50 to 66) were blinded and randomised (1:1) to receive a single injection of the active treatment or a placebo. We assessed post-treatment function, pain severity, physical function, quality of life and the incidence of treatment-associated adverse events. Patients were followed at four, 12 and 24 weeks after injection.

At final follow-up the treatment group had a significantly greater improvement in the mean International Knee Documentation Committee score than the placebo group (16 points; -18 to 49, vs 8 points; -4 to 37, respectively; p = 0.03). The treatment group also had a significantly improved mean visual analogue score at final follow-up (-25; -85 to 34, vs -11 points; -51 to 25, respectively; p = 0.032). Both cohorts showed an improvement in Western Ontario and McMaster Osteoarthritis Index and Knee Injury and Osteoarthritis Outcome Scores, but these differences were not statistically significant. One patient had an anaphylactic reaction to the preservation medium, but recovered within 24 hours. All other adverse events were localised and resolved without further action.

This technique may result in improved clinical outcomes, with the aim of slowing the degenerative process, leading to improvements in pain and function. However, imaging and direct observational studies are needed to verify cartilage regeneration. Nevertheless, this study provided a sufficient basis to proceed to further clinical testing.

Cite this article: Bone Joint J 2015;97-B:924–32.

Construction of a functional skeleton is accomplished through co-ordination of the developmental processes of chondrogenesis, osteogenesis, and synovial joint formation. Infants whose movement in utero is reduced or restricted and who subsequently suffer from joint dysplasia (including joint contractures) and thin hypo-mineralised bones, demonstrate that embryonic movement is crucial for appropriate skeletogenesis. This has been confirmed in mouse, chick, and zebrafish animal models, where reduced or eliminated movement consistently yields similar malformations and which provide the possibility of experimentation to uncover the precise disturbances and the mechanisms by which movement impacts molecular regulation. Molecular genetic studies have shown the important roles played by cell communication signalling pathways, namely Wnt, Hedgehog, and transforming growth factor-beta/bone morphogenetic protein. These pathways regulate cell behaviours such as proliferation and differentiation to control maturation of the skeletal elements, and are affected when movement is altered. Cell contacts to the extra-cellular matrix as well as the cytoskeleton offer a means of mechanotransduction which could integrate mechanical cues with genetic regulation. Indeed, expression of cytoskeletal genes has been shown to be affected by immobilisation. In addition to furthering our understanding of a fundamental aspect of cell control and differentiation during development, research in this area is applicable to the engineering of stable skeletal tissues from stem cells, which relies on an understanding of developmental mechanisms including genetic and physical criteria. A deeper understanding of how movement affects skeletogenesis therefore has broader implications for regenerative therapeutics for injury or disease, as well as for optimisation of physical therapy regimes for individuals affected by skeletal abnormalities.

Cite this article: Bone Joint Res 2015;4:105–116

Currently, there is no animal model in which to evaluate the underlying physiological processes leading to the heterotopic ossification (HO) which forms in most combat-related and blast wounds. We sought to reproduce the ossification that forms under these circumstances in a rat by emulating patterns of injury seen in patients with severe injuries resulting from blasts. We investigated whether exposure to blast overpressure increased the prevalence of HO after transfemoral amputation performed within the zone of injury. We exposed rats to a blast overpressure alone (BOP-CTL), crush injury and femoral fracture followed by amputation through the zone of injury (AMP-CTL) or a combination of these (BOP-AMP). The presence of HO was evaluated using radiographs, micro-CT and histology. HO developed in none of nine BOP-CTL, six of nine AMP-CTL, and in all 20 BOP-AMP rats. Exposure to blast overpressure increased the prevalence of HO.

This model may thus be used to elucidate cellular and molecular pathways of HO, the effect of varying intensities of blast overpressure, and to evaluate new means of prophylaxis and treatment of heterotopic ossification.

Cite this article: Bone Joint J 2015;97-B:572–6

The December 2014 Research Roundup³⁶⁰ looks at: demineralised bone matrix not as good as we thought?; trunk control following ACL reconstruction; subclinical thyroid dysfunction: not quite subclinical?; establishing musculoskeletal function in mucopolysaccharidosis; starting out: a first year in consultant practice under the spotlight; stroke and elective surgery; sepsis and clots; hip geometry and arthritis incidence; and theatre discipline and infection.

A common situation presenting to the orthopaedic surgeon today is a worn acetabular liner with substantial acetabular and pelvic osteolysis. The surgeon has many options for dealing with osteolytic defects. These include allograft, calcium based substitutes, demineralised bone matrix, or combinations of these options with or without addition of platelet rich plasma. To date there are no clinical studies to determine the efficacy of using bone-stimulating materials in osteolytic defects at the time of revision surgery and there are surprisingly few studies demonstrating the clinical efficacy of these treatment options. Even when radiographs appear to demonstrate incorporation of graft material CT studies have shown that incorporation is incomplete. The surgeon, in choosing a graft material for a surgical procedure must take into account the efficacy, safety, cost and convenience of that material.

Cite this article: Bone Joint J 2014;96-B (11 Suppl A):70–2.

The treatment of infected nonunions is difficult. Antibiotic cement-coated (ACC) rods provide stability as well as delivering antibiotics. We conducted a review of 110 infected nonunions treated with ACC rods. Patients were divided into two groups: group A (67 patients) with an infected arthrodesis, and group B (43 patients) with an infected nonunion in a long bone. In group A, infected arthrodesis, the success rate after the first procedure was 38/67 (57%), 29/67 (43%) required further surgery for either control of infection or non-union. At last follow-up, five patients required amputation, representing a limb salvage rate of 62/67 (93%) overall. In all, 29/67 (43%) presented with a bone defect with a mean size of 6.78 cm (2 to 25). Of those with a bone defect, 13/29 (45%) required further surgery and had a mean size of defect of 7.2 cm (3.5 to 25). The cultures were negative in 17/67 (26%) and the most common organism cultured was methicillin-resistant staphylococcus aureus (MRSA) (23/67, (35%)). In group B, long bones nonunion, the success rate after the first procedure was 26/43 (60%), 17/43 (40%) required further surgery for either control of infection or nonunion. The limb salvage rate at last follow-up was 43/43 (100%). A total of 22/43 (51%) had bone defect with a mean size of 4.7 cm (1.5 to 11.5). Of those patients with a bone defect, 93% required further surgery with a mean size of defect of 5.4 cm (3 to 8.5). The cultures were negative in 10/43 (24%) and the most common organism cultured was MRSA, 15/43 (35%). ACC rods are an effective form of treatment for an infected nonunion, with an acceptable rate of complications.

Cite this article: Bone Joint J 2014; 96-B:1349–54

The August 2014 Spine Roundup³⁶⁰ looks at: rhBMP complicates cervical spine surgery; posterior longitudinal ligament revisited; thoracolumbar posterior instrumentation without fusion in burst fractures; risk modelling for VTE events in spinal surgery; the consequences of dural tears in microdiscectomy; trends in revision spinal surgery; radiofrequency denervation likely effective in facet joint pain and hooks optimally biomechanically transition posterior instrumentation.

Objectives

Effects of insulin-like growth factor 1 (IGF1), fibroblast growth factor 2 (FGF2) and bone morphogenetic protein 2 (BMP2) on the expression of genes involved in the proliferation and differentiation of osteoblasts in culture were analysed. The best sequence of growth factor addition that induces expansion of cells before their differentiation was sought.

Using the United States Nationwide Inpatient Sample, we identified national trends in revision spinal fusion along with a comprehensive comparison of comorbidities, inpatient complications and surgical factors of revision spinal fusion compared to primary spinal fusion.

In 2009, there were 410 158 primary spinal fusion discharges and 22 128 revision spinal fusion discharges. Between 2002 and 2009, primary fusion increased at a higher rate compared with revision fusion (56.4% vs 51.0%; p < 0.001). In 2009, the mean length of stay and hospital charges were higher for revision fusion discharges than for primary fusion discharges (4.2 days vs 3.8 days, p < 0.001; USD $91 909 vs. $87 161, p < 0.001). In 2009, recombinant human bone morphogenetic protein (BMP) was used more in revision fusion than in primary fusion (39.6% vs 27.6%, p < 0.001), whereas interbody devices were used less in revision fusion (41.8% vs 56.6%, p < 0.001).

In the multivariable logistic regression model for all spinal fusions, depression (odds ratio (OR) 1.53, p < 0.001), psychotic disorders (OR 1.49, p < 0.001), deficiency anaemias (OR 1.35, p < 0.001) and smoking (OR 1.10, p = 0.006) had a greater chance of occurrence in revision spinal fusion discharges than in primary fusion discharges, adjusting for other variables. In terms of complications, after adjusting for all significant comorbidities, this study found that dural tears (OR 1.41; p < 0.001) and surgical site infections (OR 3.40; p < 0.001) had a greater chance of occurrence in revision spinal fusion discharges than in primary fusion discharges (p < 0.001). A p-value < 0.01 was considered significant in all final analyses.

Cite this article: Bone Joint J 2014;96-B:807–16.

The June 2014 Trauma Roundup. 360 . looks at: BMP use increasing wound complication rates in trauma surgery; can we predict re-admission in trauma?; humeral bundle nailing; how best to treat high-angle femoral neck fractures?; hyperglycaemia and infection; simultaneous soft-tissue and bony repair in terrible triad injuries; metaphyseal malunion in the forearm leading to function restrictions; delayed fixation of the distal radius: not a bad option; and fasciotomies better with shoelaces

The April 2014 Spine Roundup. 360 . looks at: medical treatment for ankylosing spondylitis; unilateral TLIF effective; peg fractures akin to neck of femur fractures; sleep apnoea and spinal surgery; scoliosis in osteogenesis imperfect; paediatric atlanto-occipital dislocation; back pain and obesity: chicken or egg?; BMP associated with lumbar plexus deficit; and just how common is back pain?

The April 2014 Trauma Roundup³⁶⁰ looks at: is it safe to primarily close dog bite wounds?; conservative transfusion evidence based in hip fracture surgery; tibial nonunion is devastating to quality of life; sexual dysfunction after traumatic pelvic fracture; hemiarthroplasty versus fixation in displaced femoral neck fractures; silver VAC dressings “Gold Standard” in massive wounds; dual plating for talar neck fracture; syndesmosis and fibular length easiest errors in ankle fracture surgery; and dual mobility: stable as a rock in fracture.

The February 2014 Trauma Roundup³⁶⁰ looks at: predicting nonunion; compartment Syndrome; octogenarian RTCs; does HIV status affect decision making in open tibial fractures?; flap timing and related complications; proximal humeral fractures under the spotlight; restoration of hip architecture with bipolar hemiarthroplasty in the elderly; and short versus long cephalomedullary nails for the treatment of intertrochanteric hip fractures in patients over 65 years.

We carried out a systematic review of the literature to evaluate the evidence regarding the clinical results of the Ilizarov method in the treatment of long bone defects of the lower limbs.

Only 37 reports (three non-randomised comparative studies, one prospective study and 33 case-series) met our inclusion criteria. Although several studies were unsatisfactory in terms of statistical heterogeneity, our analysis appears to show that the Ilizarov method of distraction osteogenesis significantly reduced the risk of deep infection in infected osseous lesions (risk ratio 0.14 (95% confidence interval (CI) 0.10 to 0.20), p < 0.001). However, there was a rate of re-fracture of 5% (95% CI 3 to 7), with a rate of neurovascular complications of 2.2% (95% CI 0.3 to 4) and an amputation rate of 2.9% (95% CI 1.4 to 4.4).The data was generally not statistically heterogeneous. Where tibial defects were > 8 cm, the risk of re-fracture increased (odds ratio 3.7 (95% CI 1.1 to 12.5), p = 0.036).

The technique is demanding for patients, illustrated by the voluntary amputation rate of 1.6% (95% CI 0 to 3.1), which underlines the need for careful patient selection.

Cite this article: Bone Joint J 2013;95-B:1673–80.

Congenital pseudarthrosis of the tibia (CPT) is a rare but well recognised condition. Obtaining union of the pseudarthrosis in these children is often difficult and may require several surgical procedures. The treatment has changed significantly since the review by Hardinge in 1972, but controversies continue as to the best form of surgical treatment. This paper reviews these controversies.

Cite this article: Bone Joint J 2013;95-B:1027–34.

We reviewed 59 bone graft substitutes marketed by 17 companies currently available for implantation in the United Kingdom, with the aim of assessing the peer-reviewed literature to facilitate informed decision-making regarding their use in clinical practice. After critical analysis of the literature, only 22 products (37%) had any clinical data. Norian SRS (Synthes), Vitoss (Orthovita), Cortoss (Orthovita) and Alpha-BSM (Etex) had Level I evidence. We question the need for so many different products, especially with limited published clinical evidence for their efficacy, and conclude that there is a considerable need for further prospective randomised trials to facilitate informed decision-making with regard to the use of current and future bone graft substitutes in clinical practice.

Cite this article: Bone Joint J 2013;95-B:583–97.

The April 2013 Spine Roundup. 360 . looks at: smuggling spinal implants; local bone graft and PLIF; predicting disability with slipped discs; mortality and spinal surgery; spondyloarthropathy; brachytherapy; and fibrin mesh and BMP

We evaluated the efficacy of Escherichia coli-derived recombinant human bone morphogenetic protein-2 (E-BMP-2) in a mini-pig model of spinal anterior interbody fusion. A total of 14 male mini-pigs underwent three-level anterior lumbar interbody fusion using polyether etherketone (PEEK) cages containing porous hydroxyapatite (HA). Four groups of cages were prepared: 1) control (n = 10 segments); 2) 50 μg E-BMP-2 (n = 9); 3) 200 μg E-BMP-2 (n = 10); and 4) 800 μg E-BMP-2 (n = 9). At eight weeks after surgery the mini-pigs were killed and the specimens were evaluated by gross inspection and manual palpation, radiological evaluation including plain radiographs and micro-CT scans, and histological analysis. Rates of fusion within PEEK cages and overall union rates were calculated, and bone formation outside vertebrae was evaluated. One animal died post-operatively and was excluded, and one section was lost and also excluded, leaving 38 sites for assessment. This rate of fusion within cages was 30.0% (three of ten) in the control group, 44.4% (four of nine) in the 50 μg E-BMP-2 group, 60.0% (six of ten) in the 200 μg E-BMP-2 group, and 77.8% (seven of nine) in the 800 μg E-BMP-2 group. Fusion rate was significantly increased by the addition of E-BMP-2 and with increasing E-BMP-2 dose (p = 0.046). In a mini-pig spinal anterior interbody fusion model using porous HA as a carrier, the implantation of E-BMP-2-loaded PEEK cages improved the fusion rate compared with PEEK cages alone, an effect that was significantly increased with increasing E-BMP-2 dosage.

Cite this article: Bone Joint J 2013;95-B:217–23.

Periosteum is important for bone homoeostasis through the release of bone morphogenetic proteins (BMPs) and their effect on osteoprogenitor cells. Smoking has an adverse effect on fracture healing and bone regeneration. The aim of this study was to evaluate the effect of smoking on the expression of the BMPs of human periosteum. Real-time polymerase chain reaction was performed for BMP-2,-4,-6,-7 gene expression in periosteal samples obtained from 45 fractured bones (19 smokers, 26 non-smokers) and 60 non-fractured bones (21 smokers, 39 non-smokers). A hierarchical model of BMP gene expression (BMP-2 > BMP-6 > BMP-4 > BMP-7) was demonstrated in all samples. When smokers and non-smokers were compared, a remarkable reduction in the gene expression of BMP-2, -4 and -6 was noticed in smokers. The comparison of fracture and non-fracture groups demonstrated a higher gene expression of BMP-2, -4 and -7 in the non-fracture samples. Within the subgroups (fracture and non-fracture), BMP gene expression in smokers was either lower but without statistical significance in the majority of BMPs, or similar to that in non-smokers with regard to BMP-4 in fracture and BMP-7 in non-fracture samples. In smokers, BMP gene expression of human periosteum was reduced, demonstrating the effect of smoking at the molecular level by reduction of mRNA transcription of periosteal BMPs. Among the BMPs studied, BMP-2 gene expression was significantly higher, highlighting its role in bone homoeostasis

We systematically reviewed the published literature on the complications of closing wedge high tibial osteotomy for the treatment of unicompartmental osteoarthritis of the knee. Publications were identified using the Cochrane Library, MEDLINE, EMBASE and CINAHL databases up to February 2012. We assessed randomised (RCTs), controlled group clinical (CCTs) trials, case series in publications associated with closing wedge osteotomy of the tibia in patients with osteoarthritis of the knee and finally a Cochrane review. Many of these trials included comparative studies (opening wedge versus closing wedge) and there was heterogeneity in the studies that prevented pooling of the results.

The August 2012 Research Roundup³⁶⁰ looks at: PRP and chondrogenic differentiation; basic fibroblast growth factor; whether glucosamine works; randomised trials; ossification of the ligamentum flavum; treadmill running; inhibiting BMP antagonists; and whether NSAIDs delay union after all.

Introduction

The pathogenesis of rotator cuff disease (RCD) is complex and not fully understood. This systematic review set out to summarise the histological and molecular changes that occur throughout the spectrum of RCD.

Objectives

There is increasing application of bone morphogenetic proteins (BMPs) owing to their role in promoting fracture healing and bone fusion. However, an optimal delivery system has yet to be identified. The aims of this study were to synthesise bioactive BMP-2, combine it with a novel α-tricalcium phosphate/poly(D,L-lactide-co-glycolide) (α-TCP/PLGA) nanocomposite and study its release from the composite.

Congenital pseudarthrosis of the tibia is an uncommon manifestation of neurofibromatosis type 1 (NF1), but one that remains difficult to treat due to anabolic deficiency and catabolic excess. Bone grafting and more recently recombinant human bone morphogenetic proteins (rhBMPs) have been identified as pro-anabolic stimuli with the potential to improve the outcome after surgery. As an additional pharmaceutical intervention, we describe the combined use of rhBMP-2 and the bisphosphonate zoledronic acid in a mouse model of NF1-deficient fracture repair.

Fractures were generated in the distal tibiae of neurofibromatosis type 1-deficient (Nf1^+/−) mice and control mice. Fractures were open and featured periosteal stripping. All mice received 10 μg rhBMP-2 delivered in a carboxymethylcellulose carrier around the fracture as an anabolic stimulus. Bisphosphonate-treated mice also received five doses of 0.02 mg/kg zoledronic acid given by intraperitoneal injection.

When only rhBMP but no zoledronic acid was used to promote repair, 75% of fractures in Nf1^+/− mice remained ununited at three weeks compared with 7% of controls (p < 0.001). Systemic post-operative administration of zoledronic acid halved the rate of ununited fractures to 37.5% (p < 0.07).

These data support the concept that preventing bone loss in combination with anabolic stimulation may improve the outcome following surgical treatment for children with congenital pseudarthoris of the tibia and NF1.

The presacral retroperitoneal approach for axial lumbar interbody fusion (presacral ALIF) is not widely reported, particularly with regard to the mid-term outcome. This prospective study describes the clinical outcomes, complications and rates of fusion at a follow-up of two years for 26 patients who underwent this minimally invasive technique along with further stabilisation using pedicle screws. The fusion was single-level at the L5-S1 spinal segment in 17 patients and two-level at L4–5 and L5-S1 in the other nine. The visual analogue scale for pain and Oswestry Disability Index scores were recorded pre-operatively and during the 24-month study period. The evaluation of fusion was by thin-cut CT scans at six and 12 months, and flexion-extension plain radiographs at six, 12 and 24 months. Significant reductions in pain and disability occurred as early as three weeks postoperatively and were maintained. Fusion was achieved in 22 of 24 patients (92%) at 12 months and in 23 patients (96%) at 24 months. One patient (4%) with a pseudarthrosis underwent successful revision by augmentation of the posterolateral fusion mass through a standard open midline approach.

There were no severe adverse events associated with presacral ALIF, which in this series demonstrated clinical outcomes and fusion rates comparable with those of reports of other methods of interbody fusion.

The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for the treatment of congenital pseudarthrosis of the tibia has been investigated in only one previous study, with promising results. The aim of this study was to determine whether rhBMP-2 might improve the outcome of this disorder. We reviewed the medical records of five patients with a mean age of 7.4 years (2.3 to 21) with congenital pseudarthrosis of the tibia who had been treated with rhBMP-2 and intramedullary rodding. Ilizarov external fixation was also used in four of these patients. Radiological union of the pseudarthrosis was evident in all of them at a mean of 3.5 months (3.2 to 4) post-operatively. The Ilizarov device was removed after a mean of 4.2 months (3.0 to 5.3). These results indicate that treatment of congenital pseudarthrosis of the tibia using rhBMP-2 in combination with intramedullary stabilisation and Ilizarov external fixation may improve the initial rate of union and reduce the time to union.

Further studies with more patients and longer follow-up are necessary to determine whether this surgial procedure may significantly enhance the outcome of congenital pseudarthrosis of the tibia, considering the refracture rate (two of five patients) in this small case series.

Orthopaedic surgery is in an exciting transitional period as modern surgical interventions, implants and scientific developments are providing new therapeutic options. As advances in basic science and technology improve our understanding of the pathology and repair of musculoskeletal tissue, traditional operations may be replaced by newer, less invasive procedures which are more appropriately targeted at the underlying pathophysiology. However, evidence-based practice will remain a basic requirement of care. Orthopaedic surgeons can and should remain at the forefront of the development of novel therapeutic interventions and their application. Progression of the potential of bench research into an improved array of orthopaedic treatments in an effective yet safe manner will require the development of a subgroup of specialists with extended training in research to play an important role in bridging the gap between laboratory science and clinical practice. International regulations regarding the introduction of new biological treatments will place an additional burden on the mechanisms of this translational process, and orthopaedic surgeons who are trained in science, surgery and the regulatory environment will be essential. Training and supporting individuals with these skills requires special consideration and discussion by the orthopaedic community.

In this paper we review some traditional approaches to the integration of orthopaedic science and surgery, the therapeutic potential of current regenerative biomedical science for cartilage repair and ways in which we may develop surgeons with the skills required to translate scientific discovery into effective and properly assessed orthopaedic treatments.

This paper outlines the recent development of an exchange Travelling Fellowship scheme between the British and American Orthopaedic Research Societies.

We used demineralised bone matrix (DBM) to augment re-attachment of tendon to a metal prosthesis in an in vivo ovine model of reconstruction of the extensor mechanism at the knee. We hypothesised that augmentation of the tendon-implant interface with DBM would enhance the functional and histological outcomes as compared with previously reported control reconstructions without DBM. Function was assessed at six and 12 weeks postoperatively, and histological examination was undertaken at 12 weeks.

A significant increase of 23.5% was observed in functional weight-bearing at six weeks in the DBM-augmented group compared with non-augmented controls (p = 0.004). By 12 weeks augmentation with DBM resulted in regeneration of a more direct-type enthesis, with regions of fibrocartilage, mineralised fibrocartilage and bone. In the controls the interface was predominantly indirect, with the tendon attached to the bone graft-hydroxyapatite base plate by perforating collagen fibres.

Chondral damage to the knee is common and, if left untreated, can proceed to degenerative osteoarthritis. In symptomatic patients established methods of management rely on the formation of fibrocartilage which has poor resistance to shear forces. The formation of hyaline or hyaline-like cartilage may be induced by implanting autologous, cultured chondrocytes into the chondral or osteochondral defect.

Autologous chondrocyte implantation may be used for full-thickness chondral or osteochondral injuries which are painful and debilitating with the aim of replacing damaged cartilage with hyaline or hyaline-like cartilage, leading to improved function. The intermediate and long-term functional and clinical results are promising.

We provide a review of autologous chondrocyte implantation and describe our experience with the technique at our institution with a mean follow-up of 32 months (1 to 9 years).

The procedure is shown to offer statistically significant improvement with advantages over other methods of management of chondral defects.

Articular cartilage repair remains a challenge to surgeons and basic scientists. The field of tissue engineering allows the simultaneous use of material scaffolds, cells and signalling molecules to attempt to modulate the regenerative tissue. This review summarises the research that has been undertaken to date using this approach, with a particular emphasis on those techniques that have been introduced into clinical practice, via in vitro and preclinical studies.

Heterotopic ossification occurring after the use of commercially available bone morphogenetic proteins has not been widely reported. We describe four cases of heterotopic ossification in patients treated with either recombinant bone morphogenetic protein 2 or recombinant bone morphogenetic protein 7. We found that while some patients were asymptomatic, heterotopic ossification which had occurred around a joint often required operative excision with good results.

In order to investigate the osteoinductive properties of allograft used in impaction grafting and the effect of strain during impaction on these properties, we designed an in vitro experiment to measure strain-related release of bone morphogenetic protein-7 (BMP-7) from fresh-frozen femoral head allograft. A total of 40 10 mm cubes of cancellous bone were cut from ten samples of fresh-frozen femoral head. The marrow was removed from the cubes and the baseline concentrations of BMP-7 were measured. Specimens from each femoral head were allocated to four groups and subjected to different compressive strains with a material testing machine, after which BMP-7 activity was reassessed. It was present in all groups. There was a linear increase of 102.1 pg/g (95% confidence interval 68.6 to 135.6) BMP-7 for each 10% increase in strain. At 80% strain the mean concentration of BMP-7 released (830.3 pg/g bone) was approximately four times that released at 20% strain. Activity of BMP-7 in fresh-frozen allograft has not previously been demonstrated. This study shows that the freezing and storage of femoral heads allows some maintenance of biological activity, and that impaction grafting provides a source of osteoinductive bone for remodelling.

We have shown that BMP-7 is released from fresh-frozen femoral head cancellous bone in proportion to the strain applied to the bone. This suggests that the impaction process itself may contribute to the biological process of remodelling and bony incorporation.

We describe a patient with insufficient bone regeneration of the tibia after bone transport over an intramedullary nail, in whom union was ultimately achieved after exchange nailing and intramedullary application of rh-bone morphogenetic protein-7 at the site of distraction.

The feasibility of bone transport with bone substitute and the factors which are essential for a successful bone transport are unknown. We studied six groups of 12 Japanese white rabbits. Groups A to D received cylindrical autologous bone segments and groups E and F hydroxyapatite prostheses. The periosteum was preserved in group A so that its segments had a blood supply, cells, proteins and scaffold. Group B had no blood supply. Group C had proteins and scaffold and group D had only scaffold. Group E received hydroxyapatite loaded with recombinant human bone morphogenetic protein-2 and group F had hydroxyapatite alone.

Distraction osteogenesis occurred in groups A to C and E which had osteo-conductive transport segments loaded with osteo-inductive proteins. We conclude that scaffold and proteins are essential for successful bone transport, and that bone substitute can be used to regenerate bone.

Bone allografts can be used in any kind of surgery involving bone from minor defects to major bone loss after tumour resection. This review describes the various types of bone grafts and the current knowledge on bone allografts, from procurement and preparation to implantation. The surgical conditions for optimising the incorporation of bone are outlined, and surgeon expectations from a bone allograft discussed.

The literature on fracture repair has been reviewed. The traditional concepts of delayed and nonunion have been examined in terms of the phased and balanced anabolic and catabolic responses in bone repair. The role of medical manipulation of these inter-related responses in the fracture healing have been considered.

Heterotopic ossification following joint replacement in the lower limb occurs in 3% to 90% of cases. Higher grades of heterotopic ossification can result in significant limitation of function and can negate the benefits of joint replacement. The understanding of the pathophysiology of this condition has improved in recent years. It would appear to be related to a combination of systemic and local factors, including over-expression of bone morphogenetic protein-4. There is currently little evidence to support the routine use of prophylaxis for heterotopic ossification in arthroplasty patients, but prophylaxis is recommended by some for high-risk patients. Radiotherapy given as one dose of 7 Gy to 8 Gy, either pre-operatively (< four hours before) or post-operatively (within 72 hours of surgery), appears to be more effective than indometacin therapy (75 mg daily for six weeks). In cases of prophylaxis against recurrent heterotopic ossification following excision, recent work has suggested that a combination of radiotherapy and indometacin is effective. Advances in our understanding of this condition may permit the development of newer, safer treatment modalities.

External fixation of distal tibial fractures is often associated with delayed union. We have investigated whether union can be enhanced by using recombinant bone morphogenetic protein-7 (rhBMP-7). Osteoinduction with rhBMP-7 and bovine collagen was used in 20 patients with distal tibial fractures which had been treated by external fixation (BMP group). Healing of the fracture was compared with that of 20 matched patients in whom treatment was similar except that rhBMP-7 was not used. Significantly more fractures had healed by 16 (p = 0.039) and 20 weeks (p = 0.022) in the BMP group compared with the matched group. The mean time to union (p = 0.002), the duration of absence from work (p = 0.018) and the time for which external fixation was required (p = 0.037) were significantly shorter in the BMP group than in the matched group. Secondary intervention due to delayed healing was required in two patients in the BMP group and seven in the matched group. RhBMP-7 can enhance the union of distal tibial fractures treated by external fixation

The efficacy of β-tricalcium phosphate (β-TCP) loaded with bone morphogenetic protein-2 (BMP-2)-gene-modified bone-marrow mesenchymal stem cells (BMSCs) was evaluated for the repair of experimentally-induced osteonecrosis of the femoral head in goats.

Bilateral early-stage osteonecrosis was induced in adult goats three weeks after ligation of the lateral and medial circumflex arteries and delivery of liquid nitrogen into the femoral head. After core decompression, porous β-TCP loaded with BMP-2 gene- or β-galactosidase (gal)-gene-transduced BMSCs was implanted into the left and right femoral heads, respectively. At 16 weeks after implantation, there was collapse of the femoral head in the untreated group but not in the BMP-2 or β-gal groups. The femoral heads in the BMP-2 group had a normal density and surface, while those in the β-gal group presented with a low density and an irregular surface. Histologically, new bone and fibrous tissue were formed in the macropores of the β-TCP. Sixteen weeks after implantation, lamellar bone had formed in the BMP-2 group, but there were some empty cavities and residual fibrous tissue in the β-gal group. The new bone volume in the BMP-2 group was significantly higher than that in the β-gal group. The maximum compressive strength and Young’s modulus of the repaired tissue in the BMP-2 group were similar to those of normal bone and significantly higher than those in the β-gal group.

Our findings indicate that porous β-TCP loaded with BMP-2-gene-transduced BMSCs are capable of repairing early-stage, experimentally-induced osteonecrosis of the femoral head and of restoring its mechanical function.

Iontophoresis is a novel technique which may be used to facilitate the movement of antibiotics into the substance of bone using an electrical potential applied externally. We have examined the rate of early infection in allografts following application of this technique in clinical practice. A total of 31 patients undergoing revision arthroplasty or surgery for limb salvage received 34 iontophoresed sequential allografts, of which 26 survived for a minimum of two years. The mean serum antibiotic levels after operation were low (gentamicin 0.37 mg/l (0.2 to 0.5); flucloxacillin 1 mg/l (0 to 1) and the levels in the drains were high (gentamicin 40 mg/l (2.5 to 131); flucloxacillin 17 mg/l (1 to 43). There were no early deep infections. Two late infections were presumed to be haemotogenous; 28 of the 34 allografts were retained. In 12 patients with pre-existing proven infection further infection has not occurred at a mean follow-up of 51 months (24 to 82).

Since bone morphogenetic proteins (BMPs) are highly homologous, we investigated the hypothesis that recombinant BMP-4 of the genome of Xenopus laevis (rxBMP-4) may influence the proliferation or differentiation of human primary osteoblast-like cells (HPOC), as occurs with recombinant human BMP (rhBMP-2). HPOC were incubated in the presence of either rxBMP-4, rhBMP-2 or basic fibroblast growth factor (rh-bFGF). The last two were used as positive controls and are known to induce differentiation or proliferation of HPOC, respectively. rxBMP-4 (50 ng/ml and 100 ng/ml) induced a differentiation of HPOC to almost the same extent as rhBMP-2, whereas the addition of rh-bFGF, applied in the same concentration, failed to have any influence on cell differentiation. rh-bFGF however, provoked an increase in cell proliferation of up to 150% when compared with non-stimulated HPOC, while rhBMP-2 and rxBMP-4 had no such effect. Our results indicate an equipotent effect of rhBMP-2 and rxBMP-4 obtained from Xenopus laevis on the differentiation and proliferation of human primary osteoblast-like cells

Ossification of the ligamentum flavum and secondary spinal-cord compression were produced experimentally in mice by implanting bone morphogenetic protein (BMP) in the lumbar extradural space. The ligamentum flavum became hypertrophied and ossified, and protruded into the spinal canal. The thickness of the ossified ligament increased gradually with time, leading to compression and deformation of the spinal cord which showed various degrees of degeneration. Demyelination occurred in the posterior and lateral white columns and neuronal loss or chromatolysis in the grey matter. The pathological findings in the experimental animals closely resemble those found in the human disease and suggest that BMP may be a causative factor of ossification of the ligamentum flavum in man. This experimental model may be useful for the study of myelopathy caused by gradual spinal-cord compression

In dogs, resection of a length of the ulna equal to twice the diameter of the mid-shaft leaves a defect which consistently fails to unite. In response to an implant of 100 mg of bovine bone morphogenetic protein (BMP), the defect becomes filled by callus consisting of fibrocartilage, cartilage and woven bone within four weeks. The cartilage is resorbed and replaced by new bone in four to eight weeks. Woven bone is then resorbed, colonised by bone marrow cells and remodelled into lamellar bone. Union of the defect is produced by 12 weeks. Control defects filled with autogeneic cortical bone chips unite after the same period. In regeneration induced by bone morphogenetic protein (BMP) and in repair enhanced by bone graft, union depends upon the proliferation of cells within and around the bone ends. Our working hypothesis is that BMP induces the differentiation of perivascular connective tissue cells into chondroblasts and osteoprogenitor cells and thereby augments the process of bone regeneration from the cells already present in the endosteum and periosteum