Aims. The aim of this study was to prepare a scoping review to investigate the use of biologic therapies in the treatment of musculoskeletal injuries in professional and Olympic athletes. Methods. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews and Arksey and O’Malley frameworks were followed. A three-step search strategy identified relevant published primary and secondary studies, as well as grey literature. The identified studies were screened with criteria for inclusion comprising clinical studies evaluating the use of biologic therapies in professional and Olympic athletes, systematic reviews, consensus statements, and conference proceedings. Data were extracted using a standardized tool to form a descriptive analysis and a thematic summary. Results. A total of 202 studies were initially identified, and 35 met criteria for the scoping review; 33 (94.3%) were published within the last eight years, and 18 (51.4%) originated from the USA. Platelet rich plasma was the most studied biologic therapy, being evaluated in 33 (94.3%) studies. Ulnar collateral ligament and hamstring injuries were the conditions most studied (nine (25.7%) studies and seven (20.0%) studies, respectively). Athletes most frequently participated in baseball, soccer, and American football. Only two (5.7%) studies were level 1 evidence, with interpretation and comparison between studies limited by the variations in the injury profile, biologic preparations, and rehabilitation protocols. Conclusion. There is diverse use of biologic therapies in the management of musculoskeletal injuries in professional and Olympic athletes. There is currently insufficient high-level evidence to support the widespread use of biologic therapies in athletes. Further research priorities include the development of condition/pathology-specific preparations of biologic therapies, and of outcome measures and imaging modalities sufficiently sensitive to detect differences in outcomes, should they exist. Cite this article: Bone Joint J 2021;103-B(7):1189–1196

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

There is good scientific rationale to support the use of growth factors to promote musculoskeletal tissue regeneration. However, the clinical effectiveness of platelet-rich plasma (PRP) and other blood-derived products has yet to be proven. Characterization and reporting of PRP preparation protocols utilized in clinical trials for the treatment of musculoskeletal disease is highly inconsistent, and the majority of studies do not provide sufficient information to allow the protocols to be reproduced. Furthermore, the reporting of blood-derived products in orthopaedics is limited by the multiple PRP classification systems available, which makes comparison of results between studies challenging. Several attempts have been made to characterize and classify PRP; however, no consensus has been reached, and there is lack of a comprehensive and validated classification. In this annotation, we outline existing systems used to classify preparations of PRP, highlighting their advantages and limitations. There remains a need for standardized universal nomenclature to describe biological therapies, as well as a comprehensive and reproducible classification system for autologous blood-derived products. Cite this article: Bone Joint J 2019;101-B:891–896

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. . Materials and Methods. In all, 1879 studies were identified across three databases. Following assessment against strict criteria, 112 studies were included (20 clinical studies; 92 animal studies). . Results. Seven categories of biological interventions were identified: growth factors, biomaterials, stem cells, gene therapy, autologous tissue, biophysical/environmental, and pharmaceuticals. The methodological quality of animal studies was moderate in 97%, but only 10% used clinically relevant outcome measures. The most interventions in clinical trials target the graft-tunnel interface and are applied intraoperatively. Platelet-rich plasma is the most studied intervention, but the clinical outcomes are mixed, and the methodological quality of studies was suboptimal. Other biological therapies investigated in clinical trials include: remnant-augmented ACLR; bone substitutes; calcium phosphate-hybridized grafts; extracorporeal shockwave therapy; and adult autologus non-cultivated stem cells. Conclusion. There is extensive preclinical research supporting the use of biological therapies to augment ACLR. Further clinical studies that meet the minimum standards of reporting are required to determine whether emerging biological strategies will provide tangible benefits in patients undergoing ACLR. Cite this article: Bone Joint J 2018;100-B:271–84

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

This article reviews the current knowledge of the intervertebral disc (IVD) and its association with low back pain (LBP). The normal IVD is a largely avascular and aneural structure with a high water content, its nutrients mainly diffusing through the end plates. IVD degeneration occurs when its cells die or become dysfunctional, notably in an acidic environment. In the process of degeneration, the IVD becomes dehydrated and vascularised, and there is an ingrowth of nerves. Although not universally the case, the altered physiology of the IVD is believed to precede or be associated with many clinical symptoms or conditions including low back and/or lower limb pain, paraesthesia, spinal stenosis and disc herniation. New treatment options have been developed in recent years. These include biological therapies and novel surgical techniques (such as total disc replacement), although many of these are still in their experimental phase. Central to developing further methods of treatment is the need for effective ways in which to assess patients and measure their outcomes. However, significant difficulties remain and it is therefore an appropriate time to be further investigating the scientific basis of and treatment of LBP

Aims

Knee osteoarthritis (OA) is characterized by a chronic inflammatory process involving multiple cytokine pathways, leading to articular cartilage degeneration. Intra-articular therapies using pharmaceutical or autologous anti-inflammatory factors offer potential non-surgical treatment options. Autologous protein solution (APS) is one such product that uses the patient’s blood to produce a concentrate of cells and anti-inflammatory cytokines. This study evaluated the effect of a specific APS intra-articular injection (nSTRIDE) on patient-reported outcome measures compared to saline in moderate knee OA.

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.

There has been a marked increase in the number of hip arthroscopies performed over the past 16 years, primarily in the management of femoroacetabular impingement (FAI). Insights into the pathoanatomy of FAI, and high-level evidence supporting the clinical effectiveness of arthroscopy in the management of FAI, have fuelled this trend. Arthroscopic management of labral tears with repair may have superior results compared with debridement, and there is now emerging evidence to support reconstructive options where repair is not possible. In situations where an interportal capsulotomy is performed to facilitate access, data now support closure of the capsule in selective cases where there is an increased risk of postoperative instability. Preoperative planning is an integral component of bony corrective surgery in FAI, and this has evolved to include computer-planned resection. However, the benefit of this remains controversial. Hip instability is now widely accepted, and diagnostic criteria and treatment are becoming increasingly refined. Instability can also be present with FAI or develop as a result of FAI treatment. In this annotation, we outline major current controversies relating to decision-making in hip arthroscopy for FAI.

Cite this article: Bone Joint J 2022;104-B(5):532–540.