Introduction. Non-union is agonising for patients, complex for surgeons and a costly burden to our healthcare service; as such, its management must be well defined. There is debate as to the requirements for the successful treatment of such patients, in particular, the need for additional biological therapies to ensure union. This study's primary aim was to determine if operative treatment alone was an effective treatment for the non-union of long bones in the upper and lower limbs compared to the pre-existing literature using biological therapies. Materials and Methods. A single-centre retrospective cohort study using prospectively collected data was performed. Inclusion was defined as patients 16 years or older with a radiologically confirmed non-union of the upper or lower limb long bones managed with surgical treatment alone between 2014–2019, with at least a 12 month follow up. Patients with bone defects or whose non-unions were treated with biological therapies were excluded from this study. The primary aim was assessed via the outcomes of union, time to union and RUST score. Results. 82 patients were included, 43 receiving percutaneous interventions and 39 receiving open interventions. Overall, a union rate of 97.56% was achieved with a mean time to union of 6.43 months. The mean RUST score increased from 6.09 at diagnosis to a final RUST score of 11.36 (p < 0.0001). Surgical factors showed that percutaneous interventions were most successful with a union rate of 100.00% with a mean time to union of 6.29 months. Augmentation surgery was associated with the shortest time to union of 4.47 months. Binary regression showed no statistically significant influence of patient factors. In 16 patients, complications were observed, including limb length discrepancy, ongoing pain and subsequent ankle problems. Conclusions. These results show non-inferior outcomes using operative treatment alone in non-union management as compared to the pre-existing literature on using biological therapies. Percutaneous interventions showed the most successful results and patient factors seemed to have little influence on this method's success. The continued use of biological therapies as a first line treatment should be questioned

Stem cells represent an exciting biological therapy for the management of many musculoskeletal tissues that suffer degenerative disease and/or where the reparative process results in non-functional tissue (‘failed healing’). The original hypothesis was that implanted cells would differentiate into the target tissue cell type and synthesise new matrix. However, this has been little evidence that this happens in live animals compared to the laboratory, and more recent theories have focussed on the immunomodulatory effects via the release of paracrine factors that can still improve the outcome, especially since inflammation is now considered one of the central processes that drive poor tendon healing. Because of the initial ‘soft’ regulatory environment for the use of stem cells in domestic mammals, bone and fat-derived stem cells quickly established themselves as a useful treatment for naturally occurring musculoskeletal diseases in the horse more than 20 years ago (Smith, Korda et al. 2003). Since the tendinopathy in the horse has many similarities to human tendinopathy, we propose that the following challenges and, the lessons learnt, in this journey are highly relevant to the development of stem cells therapies for human tendinopathy:. Source – while MSCs can be recovered from many tissues, the predominant sources for autologous MSCs have been bone and fat. Other sources, including blood, amnion, synovium, and dental pulp have also been commercialised for allogenic treatments. Preparation – ex vivo culture requires transport from a licensed laboratory while ‘minimally manipulated’ preparations can be prepared patient-side. Cells also need a vehicle for transport and implantation. Delivery – transport of cells from the laboratory to the clinic for autologous ex vivo culture techniques; implantation technique (usually by ultrasound-guided injection to minimise damage to the cells (or, more rarely, incorporated into a scaffold). They can also be delivered by regional perfusion via venous or arterial routes. Retention – relatively poor although small numbers of cells do survive for at least 5 months. Immediate loss to the lungs if the cells are administered via vascular routes. Synovially administered cells do not engraft into tendon. Adverse effects – very safe although needle tracts often visible (but do not seen to adversely affect the outcome). Allogenic cells require careful characterisation for MHC Class II antigens to avoid anaphylaxis or reduced efficacy. Appropriate injuries to treat – requires a contained lesion when administered via intra-lesional injection. Intrasynovial tendon lesions are more often associated with surface defects and are therefore less appropriate for treatment. Earlier treatment appears to be more effective than delayed, when implantation by injection is more challenging. Efficacy - beneficial effects shown at both tissue and whole animal (clinical outcome) level in naturally-occurring equine tendinopathy using bone marrow-derived autologous MSCs Recent (licenced) allogenic MSC treatment has shown equivalent efficacy while intra-synovial administration of MSCs is ineffective for open intra-synovial tendon lesions. Regulatory hurdles – these have been lighter for veterinary treatments which has facilitated their development. There has been greater regulation of commercial allogenic MSC preparations which have required EMA marketing authorisation

Osteoarthritis (OA) is a painful and disabling chronic condition that constitutes a major challenge to health care worldwide. There is currently no cure for OA and the analgesic pharmaceuticals available do not offer adequate and sustained pain relief, often being associated with significant undesirable side effects. Another disease associated with degenerating joints is Intervertebral disc degeneration (IVDD) which is a leading cause of chronic back pain and loss of function. It is characterized by the loss of extracellular matrix, specifically proteoglycan and collagen, tissue dehydration, fissure development and loss of disc height, inflammation, endplate sclerosis, cell death and hyperinnervation of nociceptive nerve fibers. The adult human IVD seems incapable of intrinsic repair and there are currently no proven treatments to prevent, stop or even retard disc degeneration. Fusion is currently the most common surgical treatment of symptomatic disc disease. However, radiographic follow-up studies have revealed that many patients develop adjacent segment disc degeneration due to altered spine biomechanics. The development of safe and efficacious disease modifying OA drugs (DMOADs) that treat pain and inflammation in joints will improve our ability to control the disease. I addition, a biologic treatment of IVDD is desirable. This presentation will provide an overview of recent advances and future prospects of a multimodal biologic treatment of OA, and IVDD. We will focus on Link N, a naturally occurring peptide representing the N terminal region of link protein and the first 1–8 residues of Link N (short Link N, sLN) responsible for the biologic therapy in question

The treatment of rheumatoid arthritis (RA) has recently seen a paradigm shift with the introduction of biologic therapy, but there is concern that this will result in an increased incidence of infection. The occurrence of infection in RA patients who have undergone biologic therapy has recently been documented in a few reports, but this is the first report of Salmonella infection after total knee arthroplasty (TKA) in a RA patient receiving etanercept therapy. Here we report the successful treatment of a rare case of Salmonella septic arthritis. A 61-year-old man with a 4-year history of RA was treated with methylprednisolone and methotrexate, and he consulted us because of right gonalgia. Treatment with infliximab was started, but as this was not effective, his medication was changed sequentially to etanercept 6 months later. Finally, TKA was performed on the right knee with antibiotic-loaded acryl cement (ALAC). The postoperative course was uneventful, etanercept was administered routinely from the 2nd postoperative week. The patient was discharged after 4 weeks. Five weeks after TKA, however, the patient visited us because of acute swelling and tenderness around the right knee. His laboratory values included a white blood cell count of 9300/mm3, an erythrocyte sedimentation rate of 81.0 mm/h and a C-reactive protein level of 11.3 mg/dl. Fluid obtained by joint aspiration was cloudy and dark-yellow, and prosthetic joint infection was diagnosed. The patient underwent emergency debridement by arthroscopic surgery, followed immediately by injection of 0.5 g carbapenem every 12 hours and continuous closed irrigation-suction of the joint for 2 weeks. Culture of the joint fluid revealed Salmonella enteritidis infection, which was not sensitive to aminoglycoside which we used as ALAC. The patient was treated with intravenous carbapenem for 3 weeks, oral levofloxacin at a daily dose of 300 mg for 2 weeks successively, and oral minocycline at 200 mg daily for 3 months. At follow-up 12 months after surgery, physical and blood examinations and plain radiographs demonstrated no recurrence of the infection, and the patient has resumed taking etanercept. The range of flexion in the treated knee is 0 to 145 degrees. Salmonella arthritis is classified as septic arthritis and reactive arthritis, and septic arthritis is more likely if Salmonella is identified by culture of joint fluid. Salmonella septic arthritis has not been considered an intraoperative contaminant during joint replacement. Recently, it has become apparent that biologic therapies can play major roles in the pathogenesis of RA, and also that immuno-suppressive drugs may become risk factors for Salmonella septic arthritis. In conclusion, our patient had a successful outcome after prompt debridement and treatment with appropriate antibiotics, without the need for implant removal. It is important to be mindful of the possibility of infection and to carry out surgery immediately if a patient presents with symptoms after biologic therapy

Objectives. Biologic agents (BIO) drastically changed the rheumatoid arthritis (RA) therapy from starting to use biologics at 2003 in Japan. The rate of orthopaedic surgery, especially total joint arthroplasty (TJA) may reflect trends in disease severity, management and health outcomes. Methods. We surveyed the number and rate of orthopaedic surgeries and TJA in RA treatment with BIO in the last decade, so called BIO-era. Results. We had 18,701 cases of orthopaedic surgeries, including 491 rheumatoid surgeries from 2004 to 2013. They contained 382 cases of total joint arthroplasties (78%), including 258 total knee arthroplasty (TKA), 80 total hip arthroplasty (THA), 18 total elbow arthroplasty (TEA), 14 total ankle arthroplasty (TAA), 4 swanson arthroplasty for fingers. The numbers of orthopaedic surgery increased year by year. The rate of rheumatoid surgeries not changed in the last decade (r=0.8, p<0.05, Fig. 1). The numbers of TSA and TEA in 2009–2013 increased twice compared to them in 2004–2008, but TKA and THA not changed. We had 241 RA patients treated by biologics agents from 2003, including 60 rheumatoid surgeries with the biologic therapy. Over half of rheumatoid surgeries were TJA (37 cases; 61%), including 26 cases for lower joint; 11 cases for upper joint. The rate of upper TJA more increased than that of lower joint in the RA patients with BIO in this decade. Conclusion. TJA for upper joint that improve the quality of life may increase in the RA patients with biologic therapy, because their disease activity and attitudes have changed year by year in this BIO-era

In recent years, novel therapies for intervertebral disc (IVD) regeneration have been developed that are based on the delivery of cells, biomaterials or bioactive molecules. The efficacy of these biological therapies depends on the type and degree of IVD degeneration. Whole organ culture bioreactors provide an attractive platform for pre-clinical testing of IVD therapeutics, since the cells are maintained within their native extracellular matrix, and the endplate remains intact to fulfil its function. Moreover, defined regimes of mechanical stress are applied to the IVD, representing either physiological or degenerative, detrimental loading. Different degrees of degeneration can be induced by high load, low nutrition, enzyme injection, and/or mechanical damage; while recent organ culture models also implement an inflammatory component. Using whole organ culture models, we found that mesenchymal stem cell injection into nucleotomized IVDs had an anabolic effect on the IVD cells. Furthermore, hyaluronan hydrogels were beneficial for cell delivery and mechanical support. We also found that anti-inflammatory treatment could partially prevent the induction of cytokines in an inflammatory model. However, chemokine delivery did not induce a significant repair response in an annulus fibrosus defect. In line with 3R principles, relevant ex-vivo models are essential to reliably test biological IVD treatments

Modern athletes are constantly susceptible to performance-threatening injury as they push their bodies to greater limits and endure higher physical stresses. Loss of performance and training time can adversely and permanently affect a sportsperson’s career. Now more than ever with advancing medical technology the answer may lie in biologic therapy. We have been using peripheral blood stem cells (PBSC) clinically and have been able to demonstrate that stem cells differentiate into target cells to enable regenerative repair. The potential of this technique as a regenerative agent can be seen in three broad applications: 1) articular cartilage, 2) bone and 3) soft tissue. This article highlights the successful cases, among many, in all three of these applications

Osteoarthritis (OA) of the spine and diarthrodial joints is by far the most common cause of chronic disability in people over 50 years of age. The disease has a striking impact on quality of life and represents an enormous societal and economic cost, a burden that will increase greatly as populations age. OA is a complex condition with broad pathology. Damage to the articular cartilage is a consistent feature, accompanied by changes to the subchondral bone and synovium. Progression of the disease involves further degeneration of the articular cartilage, damage to the underlying bone and morphological changes that include subchondral bone thickening, development of cysts, osteophytes and inflammation of the synovium. Enhanced production of proinflammatory cytokines and matrix metalloproteinases accelerates degradation of the articular cartilage. It is striking that no approved pharmacological intervention, biological therapy or procedure prevents the progressive destruction of the OA joint. All current treatments, without exception, produce symptomatic rather than regenerative results. While there have been some exciting developments in the search for OA treatments in the last decade, including matrix metalloproteinase inhibitors, anti-TNF and anti-IL1 drugs for example, none of these has to date emerged as an effective medicinal product. There is thus an urgent and compelling need to identify, validate and test new biological therapeutics. Stromal cell therapy represents one such compelling approach. The results from several early clinical studies have indicated that this approach holds a great deal of promise for the treatment of OA. Most studies have involved direct intraarticular injection of a suspension of mesenchymal stromal cells (MSCs) for treatment of knee OA. Results from a number of controlled patient studies have suggested that this treatment results in an effective repair response. Although data regarding mechanism of action are limited, it appears that the cells have an anti-inflammatory effect, possibly targeting cells within the synovium, rather than a direct cartilage repair effect. Several recent reports have highlighted a dramatic and sustained response in patients receiving MSC treatment. For example, allogeneic expanded adipose-derived MSCs have been shown to be safe and effective in the treatment of complex perianal fistulas in Crohn's disease. Also, allogeneic bone marrow-derived MSCs has a been shown to have a positive effect in pediatric acute graft versus host disease. These observations point to a mechanism of action that involves host immunomodulation, but this needs further examination. Within the field of musculoskeletal disease effective translation of MSC technology has been hindered by a lack of randomized controlled patient studies, severe inconsistencies regarding the preparation and characterization of the cell product, and an incomplete understanding of the therapeutic mechanism. Direct to consumer clinics have flourished in some countries, providing cell treatments to OA patients. Most or all of these utilize unexpanded cell fractions from marrow or fat without even rudimentary product characterization and may report an exaggerated clinical outcome. Data from these clinics is not likely to yield information that will be useful. In fact, a recent systemic review of clinical trials involving MSC treatment in OA indicated that only a limited number of studies provided high quality evidence and long term follow up. Many suffered from a lack of consistency, including a diversity of methods for MSC preparation, and thus did not contribute to a supporting evidence base. There is a compelling need to provide clear and unambiguous clinical proof of concept relating to MSC treatment for OA. The ADIPOA2 study, currently active in Europe, will go some way towards achieving this. This is a 150 patient, phase 2b study designed to to assess the efficacy of a single injection of autologous adipose-derived MSCs in the treatment of mild to moderate OA of the knee, active and unresponsive to conservative therapy for at least 12 months

Juvenile idiopathic arthritis(JIA) is chronic inflammation commonly occurs in early childhood. Recently, biological therapies are used in JIA at the early stage as same as rheumatoid arthritis, due to retain joint cartilage. However, some of young patients have painful knee problems requiring knee replacement. We experienced 4 cases of JIA treated by knee arthroplasty. The average age at surgery was 33.5 years (range, 26–38 years) with a mean follow-up of 9.5 years (range, 5–18 years). We evaluated the knee range of motion and functional outcomes by the Knee Society Score (KSS), implant selection, postoperative complication, surgery of another joint. Mean range of motion improved from 76.3° (0°–120°) at pre-operation to 110.6° (80°–130°) at post-operation (P<0.05). Mean KSS increased from 47.3 ±20.1 preoperatively to 86.9 ±11.1 (P<0.01) at last follow-up and the mean KSS function from 27.5 ±25.9 to 62.5±20.2 at last follow-up (P<0.05). All of the TKAs were cemented, 5 were cruciate-retaining implant designs, whereas 2 TKAs had constrained posterior stabilized implant designs. Patellar resurfacing was undergone in all knees. Bone graft required in 1 knee within severe knee deformity. Complication were occurred in 5 knees. Medial instability in 2 knees. Skin necrosis, MCL avulsion, recurrence of the synovitis are one in each. All cases had polyarticular type. Previous THA had undergone in 5 hips, synovectomy in 3 knees, foot surgery in 2 feet. At latest follow-up, 1 of 8 TKAs (12.5%) had been revised, and had revision of its polyethylene exchange only. Patients with JIA often have valgus alignment with a flexion contracture and poor bone quality is also frequently compromised. Prescribed immunosuppressive medication or biological agents may cause to infection. In our series there were no infection, but some of these need much more soft tissue release because of severe deformity and flexion contracture. TKA survivorship for JIA is inferior to that typically seen in younger patients with osteoarthritis or rheumatoid arthritis. The knee of conservative therapy were often caused to severe functional limitations. Timimg of TKA may be indicated no matter how young the patient is. Extending timing of TKA may leads to worse outcome and postoperative function. But it may be caution that the surgical exposure can be difficult, because of stiffness, flexion contracture, bony deformity, osteopenia

Aims

Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease.

Rheumatoid arthritis is the most common inflammatory disease of the joints affecting about 0.5% of adults, women more often than men with a peak age of onset of 35–45 years. It is usually progressive affecting further joints and the destructive disease process causes irreversible bony erosions and the joints become structurally deformed, with long-term pain and disability. It has an early and significant impact on the person’s ability to work and socio-economic status with work capacity restricted in a third within a year and within 3 years almost half 40 may be registered work disabled. The aims of management of rheumatoid arthritis are to reduce pain an inflammation; reduce disability; prevent joint damage and progression; and to reduce the comorbidities that are associated with the disease. As joint damage is irreversible it is important to diagnose the disease and institute disease modifying anti-rheumatic therapy as soon as possible. There is as yet no way of preventing the disease. Lifestyle interventions of avoiding obesity, maintaining physical activity and avoiding smoking may improve outcome. Symptoms can be effectively controlled with analgesics and NSAIDs and joint damage can be reduced with disease modifying antirheumatic therapy with consequent benefits to quality of life. Biological therapies, such as anti TNF, are the latest advance that is dramatically improving the outlook for those developing RA. Rehabilitation interventions can improve and maintain function, including dynamic training. Surgery also has an important role, predominantly arthroplasty when pharmacological therapies have not adequately prevented joint damage. Effective management of rheumatoid arthritis requires early diagnosis and treatment by recognising those with early inflammatory arthritis and for expert assessment within 6 weeks to decide about disease modifying anti-rheumatic therapy. This should be in addition to symptomatic therapy, rehabilitation and education to improve understanding of their chronic disease and to encourage self management. Such management should be provided through a multiprofessional and multidisciplinary group. People with RA need regular monitoring to ensure optimal disease management. This will reduce the risk of longterm joint damage and disability and will lessen indirect costs of RA. This approach requires systems for early diagnosis and for referral to experts, which includes education of primary care physicians to enable them to recognise synovitis. Public education is also needed to ensure early presentation to the primary care physician at the onset of symptoms

Background. While the human embryonic, foetal and juvenile intervertebral disc (IVD) is composed of large vacuolated notochordal cells, these morphologically distinct cells are lost with skeletal maturity being replaced by smaller nucleus pulpous cells. Notochordal cells are thought to be fundamental in maintaining IVD homeostasis and, hence, their loss in humans may be a key initiator of degeneration, leading ultimately to back pain. Therefore, it is essential to understand the human notochordal cell phenotype to enable the development of novel biological/regenerative therapies. Methods. CD24+ notochordal cells and CD24- sclerotomal cells were sorted from enzymatically-digested human foetal spines (7.5–14 WPC, n=5) using FACS. Sorting accuracy was validated using qPCR for known notochordal markers and Affymetrix cDNA microarrays performed. Differential gene expression was confirmed (qPCR) and Interactive Pathway Analysis (IPA) performed. Results. CD24+ve notochordal cells (mean 10.4%) and CD24-ve sclerotomal cells (mean 60.9% CD24-) were successfully sorted. Higher expression of notochordal markers CD24 and brachyury was identified in CD24+ve cells. Hierarchical clustering and PCA mapping revealed distinct differences in the gene expression profile of CD24+ and CD24- cells. Top notochordal markers were CD24, STMN2. RTN1, PRPH and CXCL12. IPA identified IL-1 receptor antagonist (IL-1RN) and noggin as master regulators of notochordal cell phenotype. Conclusions. This study has, for the first time, defined human foetal notochordal cell phenotype and identified important pathways and upstream regulators. In particular, IL-1RN and noggin are of interest as master regulators of notochordal cell function, suggesting vital roles for these molecules in IVD development and homeostasis. Conflicts of interest. No conflicts of interest. Sources of funding. We would like to acknowledge UKRMP Acellular Hub, MRC, NIHR Musculoskeletal BRU and The Rosetrees Trust for funding this research

Osteoarthritis (OA) is the most common degenerative joint disease causing joint immobility and chronic pain. Treatment is mainly based on alleviating pain and reducing disease progression. During OA progression the chondrocyte undergoes a hypertrophic switch in which extracellular matrix (ECM) -degrading enzymes are released, actively degrading the ECM. However, cell biological based therapies to slow down or reverse this katabolic phenotype are still to be developed. Bone morphogenetic protein 7 (BMP-7) has been shown to have OA disease-modifying properties. BMP-7 suppresses the chondrocyte hypertrophic and katabolic phenotype and may be the first biological treatment to target the chondrocyte phenotype in OA. However, intra-articular use of BMP-7 is at risk in the proteolytic and hydrolytic joint-environment. Weekly intra-articular injections are necessary to maintain biological activity, a frequency unacceptable for clinical use. Additionally, production of GMP-grade BMP-7 is challenging and expensive. To enable its clinical use, we sought for BMP-7 mimicking peptides better compatible with the joint-environment while still biologically active and which potentially can be incorporated in a drug-delivery system. We hypothesized that human BMP-7 derived peptides are able to mimic the disease modifying properties of the full-length human BMP-7 protein on the OA chondrocyte phenotype. A BMP-7 peptide library was synthesized consisting of overlapping 20-mer peptides with 18 amino-acids overlap between sequential peptides. OA human articular chondrocytes (HACs) were isolated from OA cartilage from total knee arthroplasty (n=18 donors). HACs were exposed to BMP-7 (1 nM) or BMP-7 library peptides at different concentrations (1, 10, 100 or 1000 nM). Gene-expression levels of important chondrogenic-, hypertrophic-, cartilage degrading- and inflammatory mediators were determined by RT-qPCR. GAG and ALP activity were determined using a colorimetric assay and PGE levels were measured by EIA. During the BMP-7 peptide library screening human BMP-7 derived peptides were screened for their full-length human BMP-7 mimicking properties at different concentrations (1, 10, 100 or 1000nM) on a pool of human chondrocytes. Gene expression as well as GAG, ALP and PGE2 level analysis revealed two distinct peptide regions in the BMP-7 protein based on their pro-chondrogenic and anti-OA phenotype actions on human OA chondrocytes. The two most promising peptides were further analysed for their OA chondrocyte disease modifying properties in the presence of OA synovial fluid, showing similar OA phenotype suppressive activity. Conclusively, we successfully identified two peptide regions in the BMP-7 protein with in vitro OA suppressive actions. Further biochemical fine-tuning of the peptides, and in vivo evaluation, will potentially result in the first peptide-based experimental OA treatment, addressing the hypertrophic and katabolic chondrocyte phenotype in OA

Aims

The use of biologics in the treatment of musculoskeletal injuries in Olympic and professional athletes appears to be increasing. There are no studies which currently map the extent, range, and nature of existing literature concerning the use and efficacy of such therapies in this arena. The objective of this scoping review is to map the available evidence regarding the use of biologics in the treatment of musculoskeletal injuries in Olympic and professional sport.

Cell therapies hold significant promise for the treatment of injured or diseased musculoskeletal tissues. However, despite advances in research, there is growing concern about the increasing number of clinical centres around the world that are making unwarranted claims or are performing risky biological procedures. Such providers have been known to recommend, prescribe, or deliver so called ‘stem cell’ preparations without sufficient data to support their true content and efficacy. In this annotation, we outline the current environment of stem cell-based treatments and the strategies of marketing directly to consumers. We also outline the difficulties in the regulation of these clinics and make recommendations for best practice and the identification and reporting of illegitimate providers.

Cite this article: Bone Joint J 2020;102-B(2):148–154

Objectives

The incidence of acute Achilles tendon rupture appears to be increasing. The aim of this study was to summarize various therapies for acute Achilles tendon rupture and discuss their relative merits.

The August 2015 Research Roundup360 looks at: Lightbulbs, bleeding and procedure durations; Infection and rheumatoid agents; Infection rates and ‘bundles of care’ revisited; ACI: new application for a proven technology?; Hydrogel coating given the thumbs up; Hydroxyapatite as a smart coating?