Infrapatellar fat pad adipose-derived stem cells co-cultured with articular chondrocytes from osteoarthritis patients exhibit increased chondrogenic gene expression.

AIM: The variable results in clinical trials of adipose tissue-derived stem cells (ASCs) for chondral defects may be due to the different ex vivo culture conditions of the ASCs which are implanted to treat the lesions. We sought to determine the optimal in vitro chondrocyte co-culture condition that promotes infrapatellar fat pad-derived (IFPD) ASC chondrogenic gene expression in a novel co-culture combination. METHODS: In our study, we utilized an in vitro autologous co-culture of IFPD ASCs and articular chondrocytes derived from Kellgren-Lawrence Grade III/IV osteoarthritic human knee joints at ASC-to-chondrocyte seeding log ratios of 1:1, 10:1, and 100:1. Gene expression following in vitro co-culture was quantified by RT-qPCR with a panel comprising COL1A1, COL2A1, COL10A1, L-SOX5, SOX6, SOX9, ACAN, HSPG2, and COMP for chondrogenic gene expression. RESULTS: The chondrogenic gene expression profiles from co-cultures were greater than would be expected from an expression profile modeled from chondrocyte and ASC-only monocultures. Additionally, chondrogenic gene expression decreased with increasing ASC-to-chondrocyte seeding ratios. CONCLUSIONS: These findings provide insight into the mechanisms underlying clinical ASC therapies and signifies that IFPD ASCs pre-conditioned by chondrocyte co-culture may have improved chondrogenic potential for cartilage repair. This model can help further understand IFPD ASCs in chondral and osteochondral repair and the chondrogenic pathways involved. Video Abstract.

Evaluating the Effect of Hypoxia on Human Adult Mesenchymal Stromal Cell Chondrogenesis In Vitro: A Systematic Review.

Human adult mesenchymal stromal cells (MSCs) from a variety of sources may be used to repair defects in articular cartilage by inducing them into chondrogenic differentiation. The conditions in which optimal chondrogenic differentiation takes place are an area of interest in the field of tissue engineering. Chondrocytes exist in vivo in a normally hypoxic environment and thus it has been suggested that exposing MSCs to hypoxia may also contribute to a beneficial effect on their differentiation. There are two main stages in which MSCs can be exposed to hypoxia, the expansion phase when cells are cultured, and the differentiation phase when cells are induced with a chondrogenic medium. This systematic review sought to explore the effect of hypoxia at these two stages on human adult MSC chondrogenesis in vitro. A literature search was performed on PubMed, EMBASE, Medline via Ovid, and Cochrane, and 24 studies were ultimately included. The majority of these studies showed that hypoxia during the expansion phase or the differentiation phase enhances at least some markers of chondrogenic differentiation in adult MSCs. These results were not always demonstrated at the protein level and there were also conflicting reports. Studies evaluating continuous exposure to hypoxia during the expansion and differentiation phases also had mixed results. These inconsistent results can be explained by the heterogeneity of studies, including factors such as different sources of MSCs used, donor variability, level of hypoxia used in each study, time exposed to hypoxia, and differences in culture methodology.

Use of human induced pluripotent stem cells for cartilage regeneration in vitro and within chondral defect models of knee joint cartilage in vivo: a Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic literature review.

BACKGROUND AIMS: Articular cartilage has limited regenerative ability when damaged through trauma or disease. Failure to treat focal chondral lesions results in changes that inevitably progress to osteoarthritis. Osteoarthritis is a major contributor to disability globally, which results in significant medical costs and lost wages every year. Human induced pluripotent stem cells (hiPSCs) have long been considered a potential autologous therapeutic option for the treatment of focal chondral lesions. Although there are significant advantages to hiPSCs over other stem cell options, such as mesenchymal and embryonic stem cells, there are concerns regarding their ability to form bona fide cartilage and their tumorgenicity in vivo. METHODS: The authors carried out a systematic literature review on the use of hiPSCs to produce differentiated progeny capable of producing high-quality cartilage in vitro and regenerate cartilage in osteochondral defects in vivo in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight studies were included in the review that used hiPSCs or their derived progeny in xenogeneic transplants in animal models to regenerate cartilage in osteochondral defects of the knee joint. The in vitro-differentiated, hiPSC-derived and in vivo defect repair ability of the hiPSC-derived progeny transplants were assessed. RESULTS: Most studies reported the generation of high-quality cartilage-producing progeny that were able to successfully repair cartilage defects in vivo. No tumorigenicity was observed. CONCLUSIONS: The authors conclude that hiPSCs offer a valuable source of cartilage-producing progeny that show promise as an effective cell-based therapy in treating focal chondral lesions.

The Effectiveness of Anti-Nerve Growth Factor Monoclonal Antibodies in the Management of Pain in Osteoarthritis of the Hip and Knee: A PRISMA Systematic Review and Meta-Analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of the efficacy of anti-nerve growth factor (NGF) monoclonal antibodies in osteoarthritis pain (hip and knee). DESIGN: Grade the evidence for anti-NGF use. METHODS: An interdisciplinary work group conducted a literature search for anti-NGF use in osteoarthritis. The systematic review was performed in accordance with methods described by the Cochrane collaboration. General inclusion criteria included all osteoarthritis trials studying any monoclonal anti-NGF antibody at any dose/phase. Excluded studies were those where participants received NSAIDs or analgesics other than anti-NGF antibodies. The Jadad Scale score was used to assess the quality of the included studies. RESULTS: Thirteen studies were included in the analysis, involving 8145 participants with a diagnosis of hip and/or knee osteoarthritis. Anti-NGF antibody treatment was associated with a significant improvement in all Western Ontario and McMaster Universities Arthritis Index (WOMAC) indices when compared to placebo. These agents were not associated with a significantly increased incidence of serious adverse events but were associated with significant increases in therapy discontinuation due to adverse events or side effects (e.g., peripheral neuropathy). CONCLUSIONS: Future randomized clinical trials are needed to characterize the overall risk-to-benefit ratio of anti-NGF antibodies in managing pain associated with OA, particularly with long-term use, in order to verify their efficacy and safety in clinical practice.

The Use of Infrapatellar Fat Pad-Derived Mesenchymal Stem Cells in Articular Cartilage Regeneration: A Review.

Cartilage is frequently damaged with a limited capacity for repair. Current treatment strategies are insufficient as they form fibrocartilage as opposed to hyaline cartilage, and do not prevent the progression of degenerative changes. There is increasing interest in the use of autologous mesenchymal stem cells (MSC) for tissue regeneration. MSCs that are used to treat articular cartilage defects must not only present a robust cartilaginous production capacity, but they also must not cause morbidity at the harvest site. In addition, they should be easy to isolate from the tissue and expand in culture without terminal differentiation. The source of MSCs is one of the most important factors that may affect treatment. The infrapatellar fat pad (IPFP) acts as an important reservoir for MSC and is located in the anterior compartment of the knee joint in the extra-synovial area. The IPFP is a rich source of MSCs, and in this review, we discuss studies that demonstrate that these cells have shown many advantages over other tissues in terms of ease of isolation, expansion, and chondrogenic differentiation. Future studies in articular cartilage repair strategies and suitable extraction as well as cell culture methods will extend the therapeutical application of IPFP-derived MSCs into additional orthopedic fields, such as osteoarthritis. This review provides the latest research concerning the use of IPFP-derived MSCs in the treatment of articular cartilage damage, providing critical information for the field to grow.

The role of the immune system in tendon healing: a systematic review.

INTRODUCTION: The role of the immune system in tendon healing relies on polymorphonucleocytes, mast cells, macrophages and lymphocytes, the 'immune cells' and their cytokine production. This systematic review reports how the immune system affects tendon healing. SOURCES OF DATA: We registered our protocol (registration number: CRD42019141838). After searching PubMed, Embase and Cochrane Library databases, we included studies of any level of evidence published in peer-reviewed journals reporting clinical or preclinical results. The PRISMA guidelines were applied, and risk of bias and the methodological quality of the included studies were assessed. We excluded all the articles with high risk of bias and/or low quality after the assessment. We included 62 articles assessed as medium or high quality. AREAS OF AGREEMENT: Macrophages are major actors in the promotion of proper wound healing as well as the resolution of inflammation in response to pathogenic challenge or tissue damage. The immune cells secrete cytokines involving both pro-inflammatory and anti-inflammatory factors which could affect both healing and macrophage polarization. AREAS OF CONTROVERSY: The role of lymphocytes, mast cells and polymorphonucleocytes is still inconclusive. GROWING POINTS: The immune system is a major actor in the complex mechanism behind the healing response occurring in tendons after an injury. A dysregulation of the immune response can ultimately lead to a failed healing response. AREAS TIMELY FOR DEVELOPING RESEARCH: Further studies are needed to shed light on therapeutic targets to improve tendon healing and in managing new way to balance immune response.

Tendon healing in presence of chronic low-level inflammation: a systematic review.

BACKGROUND: Tendinopathy is a common musculoskeletal condition affecting subjects regardless of their activity level. Multiple inflammatory molecules found in ex vivo samples of human tendons are related to the initiation or progression of tendinopathy. Their role in tendon healing is the subject of this review. SOURCES OF DATA: An extensive review of current literature was conducted using PubMed, Embase and Cochrane Library using the term 'tendon', as well as some common terms of tendon conditions such as 'tendon injury OR (tendon damage) OR tendonitis OR tendinopathy OR (chronic tendonitis) OR tendinosis OR (chronic tendinopathy) OR enthesitis' AND 'healing' AND '(inflammation OR immune response)' as either key words or MeSH terms. AREAS OF AGREEMENT: An environment characterized by a low level of chronic inflammation, together with increased expression of inflammatory cytokines and growth factors, may influence the physiological tendon healing response after treatment. AREAS OF CONTROVERSY: Most studies on this topic exhibited limited scientific translational value because of their heterogeneity. The evidence associated with preclinical studies is limited. GROWING POINTS: The role of inflammation in tendon healing is still unclear, though it seems to affect the overall outcome. A thorough understanding of the biochemical mediators of healing and their pathway of pain could be used to target tendinopathy and possibly guide its management. AREAS TIMELY FOR DEVELOPING RESEARCH: We require further studies with improved designs to effectively evaluate the pathogenesis and progression of tendinopathy to identify cellular and molecular targets to improve outcomes.

Autologous adipose tissue grafting for the management of the painful scar.

BACKGROUND AIMS: There is currently no definitive treatment for the painful scar. Autologous adipose tissue grafting (AATG) as a treatment option for scars has become increasingly popular and there is now an abundance of evidence in the literature that supports its application. Some studies suggest that human adipose tissue is a rich source of multipotent mesenchymal stromal cells. To our knowledge, there is currently no systematic literature review to date that examines the effectiveness of AATG for reducing pain in scars. Our novel systematic review aims to examine clinical studies on the use of AATG in the treatment of the painful scar. METHODS: A literature search was performed using the following databases: PubMed, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Medline, Cochrane library and Embase. The following key words and search terms were used: adipose stem cells, scar, pain, autologous fat grafting, scar management and neuropathic pain. Human interventional studies using autologous adipose tissue grafting for the treatment of painful scars including case series, case-control, cohort studies and randomized controlled trials were reviewed. RESULTS: A total of 387 studies were found and 18 studies from January 1990 to January 2019 were identified as relevant for the purpose of this systematic review. Two studies were evidence level V, seven were evidence level IV, six were evidence level III, two were evidence level II and one was level I. A total of 337 scars were assessed in 288 patients for improvement in pain after scar treatment using adipose tissue grafting. An improvement in the analgesic effect was recorded in 12 of the 18 studies with adipose tissue grafting. A total of 233 of the 288 treated subjects responded with reduction in pain, whereas the rest did not. We carried out a pooled analysis of the studies and observed an odds ratio of 3.94 (P = 0.00001) when comparing pain reduction to no change in pain. CONCLUSIONS: We conclude that AATG is a promising and safe modality for the treatment of the painful scar. There is an abundance of low-level evidence to support its use as an alternative treatment but there is a lack of high-level evidence at present to support its standard use. Future long-term randomized controlled trials with analgesic scores as the primary outcome measures are required to assess long-term efficacy.

Are the Biological and Biomechanical Properties of Meniscal Scaffolds Reflected in Clinical Practice? A Systematic Review of the Literature.

The aim of this PRISMA review was to assess whether the CMI and Actifit scaffolds, when used in clinical practice, improve clinical outcomes and demonstrate the ideal biological and biomechanical properties of scaffolds: being chondroprotective, porous, resorbable, able to mature and promote regeneration of tissue. This was done by only including studies that assessed clinical outcome and used a scale to assess both integrity of the scaffold and its effects on articular cartilage via MRI. A search was performed on PubMed, EMBASE, Scopus and clinicaltrials.gov. 2457 articles were screened, from which eight studies were selected: four used Actifit, three used CMI and one compared the two. All studies reported significant improvement in at least one clinical outcome compared to baseline. Some studies suggested that the scaffolds appeared to show porosity, mature, resorb and/or have possible chondroprotective effects, as assessed by MRI. The evidence for clinical translation is limited by differences in study methodology and small sample sizes, but is promising in terms of improving clinical outcomes in the short to mid-term. Higher level evidence, with MRI and histological evaluation of the scaffold and articular cartilage, is now needed to further determine whether these scaffolds exhibit these useful properties.

Use of stem cells and growth factors in rotator cuff tendon repair.

The management of rotator cuff tears continues to prove challenging for orthopaedic surgeons. Such tears affect most age groups and can lead to significant morbidity in patients. The aetiology of these tears is likely to be multifactorial; however, an understanding of the mechanisms involved is still under review. Despite advancements in surgical operative techniques and the materials used, post-operative recurrence rates after surgical repair remain high. A growing area of research surrounds biological adjuncts used to improve the healing potential of the repaired tissues. This review of recent publications focuses on the strengths and limitations of using stem cells and growth factors in rotator cuff repair.

Evaluating the Current Literature on Treatments Containing Adipose-Derived Stem Cells for Osteoarthritis: a Progress Update.

PURPOSE OF REVIEW: Recent studies have investigated the effect of treatments containing adipose-derived mesenchymal stem cells (ADMSCs) on human osteoarthritis. These have mostly used biologic adjuvants which may influence results. Thus, the purpose of this systematic review is to evaluate the current literature on these treatments when used in isolation. RECENT FINDINGS: Five studies in this review used cultured ADMSCs, while four studies used stromal vascular fraction and three used micro-fragmented adipose tissue to deliver ADMSCs. No studies reported serious treatment-related adverse effects and all reported improvements in clinical measures for at least one dose. This was not necessarily reflected in imaging evaluations nor were improvements always maintained. Current low-level evidence is limited due to variability in study methodology but indicates that treatments containing ADMSCs, when used in isolation, are safe and have the potential to reduce pain and improve function. Randomized controlled trials are now needed.

Acetic Acid as Part of a Debridement Protocol During Revision Total Knee Arthroplasty.

BACKGROUND: Thorough debridement is mandatory in revision for infected total knee arthroplasties (TKA). We investigated a novel adjuvant chemical debridement strategy using acetic acid (AA) that seeks to create a hostile environment for microorganisms. We report the first orthopedic in vivo series using an AA soak in infected TKAs. We also investigated the in vitro efficacy of AA against bacteria isolated from these knees. METHODS: Twenty-three patients with infected TKA were treated with a standard debridement protocol and chemical debridement with a 20-minute AA soak. In parallel, bacteria from infected TKAs were cultured for in vitro susceptibility testing with AA solutions of different concentrations to understand its potential mechanism of action. RESULTS: Intraoperatively, there were no physiological responses during the AA soak or on release of the tourniquet. Postoperatively, there was no increase in analgesic requirements or wound or soft-tissue complications. Clinical follow-up continued for 24 months to monitor recurrent infection. In vitro, zones of inhibition were formed on less than 40% of the organisms, demonstrating that AA was not directly bactericidal against the majority of the isolates. However, when cultured in a bacterial suspension, AA completely inhibited the growth of the isolates at concentrations as low as 0.19% vol/vol. CONCLUSION: This study has shown that the use of 3% AA soak, as part of a debridement protocol is safe in patients. While the exact mechanism of action is yet to be determined, AA concentrations as low as 0.19% vol/vol in vitro are sufficient to completely inhibit bacterial growth.

Tibial Crest Osteotomy in Extensile Knee Exposure-A Modified, Low-Energy, Suture Technique.

BACKGROUND: Tibial crest osteotomy is an established extensile knee approach. Complications include mal-union, non-union, and fixation problems.We have designed a technique aimed at reducing complications through the principles of low-energy osteotomy and suture repair. METHODS: We reviewed our clinical and radiological results in 159 consecutive patients 181 osteotomies with a mean age of 66 years, and an average follow up of 22 months. RESULTS: Union occurred in all osteotomies (100%) at a mean period of 11 weeks. Proximal migration averaging 11.5 mm occurred in 6 osteotomies (3%). Crest fragmentation occurred in 11 osteotomies (6%), with all cases resulting in uncomplicated union. No extensor mechanism failure or complications related to the suture material occurred. CONCLUSION: We conclude that this technique results in satisfactory outcomes whilst avoiding hardware-related problems.

Adipose-derived regenerative therapies for the treatment of knee osteoarthritis.

Knee osteoarthritis is a degenerative condition with a significant disease burden and no disease-modifying therapy. Definitive treatment ultimately requires joint replacement. Therapies capable of regenerating cartilage could significantly reduce financial and clinical costs. The regenerative potential of mesenchymal stromal cells (MSCs) has been extensively studied in the context of knee osteoarthritis. This has yielded promising results in human studies, and is likely a product of immunomodulatory and chondroprotective biomolecules produced by MSCs in response to inflammation. Adipose-derived MSCs (ASCs) are becoming increasingly popular owing to their relative ease of isolation and high proliferative capacity. Stromal vascular fraction (SVF) and micro-fragmented adipose tissue (MFAT) are produced by the enzymatic and mechanical disruption of adipose tissue, respectively. This avoids expansion of isolated ASCs ex vivo and their composition of heterogeneous cell populations, including immune cells, may potentiate the reparative function of ASCs. In this editorial, we comment on a multicenter randomized trial regarding the efficacy of MFAT in treating knee osteoarthritis. We discuss the study's findings in the context of emerging evidence regarding adipose-derived regenerative therapies. An underlying mechanism of action of ASCs is proposed while drawing important distinctions between the properties of isolated ASCs, SVF, and MFAT.

Advances in the understanding of the aetiology of Dupuytren's disease.

Dupuytren's disease is a fibroproliferative disease of the palmar fascia which has been described for centuries, yet the aetiology and pathophysiology remain poorly understood. Surgery and collagenase injections comprise the main therapeutic options but disease recurrence is common. We explore the evidence underlying the current disease theories and outline other potential therapeutic options.

Important perioperative factors, guidelines and outcomes in the management of hip fracture.

Hip fractures are common injuries in the elderly and are associated with significant morbidity and mortality. There are multiple perioperative factors that must be considered when managing these patients. These include analgesia, timing of surgery, choice of operation, type of anaesthesia, postoperative complications and comorbidities. Guidelines from The National Institute for Health and Care Excellence and the National Hip Fracture Database have been updated to reflect many of the above, but the importance of psychosocial factors is still emerging. This article focuses on the evidence for the key perioperative factors in hip fracture management and the tools available to predict hip fracture outcome.

Tendon healing is adversely affected by low-grade inflammation.

BACKGROUND: Tendinopathy is common, presents with pain and activity limitation, and is associated with a high risk of recurrence of the injury. Tendinopathy usually occurs as a results of a disrupted healing response to a primary injury where cellular and molecular pathways lead to low grade chronic inflammation. MAIN FINDINGS: There has been a renewed interest in investigating the role of Inflammation in the pathogenesis of tendinopathy, in particular during the initial phases of the condition where it may not be clinically evident. Understanding the early and late stages of tendon injury pathogenesis would help develop new and effective treatments addressed at targeting the inflammatory pathways. CONCLUSION: This review outlines the role of low-grade Inflammation in the pathogenesis of tendinopathy, stressing the role of proinflammatory cytokines, proteolytic enzymes and growth factors, and explores how Inflammation exerts a negative influence on the process of tendon healing.

Bioactive Glass: Methods for Assessing Angiogenesis and Osteogenesis.

Biomaterials are playing an increased role in the regeneration of damaged or absent bone tissue in the context of trauma, non-union, infection or congenital abnormality. Restoration of not only the physical scaffold that bone provides, but also of its homeostatic functions as a calcium store and hematopoietic organ are the gold standards of any regenerative procedure. Bioactive glasses are of interest as they can bond with the host bone and induce further both bone and blood vessel growth. The composition of the bioactive glasses can be manipulated to maximize both osteogenesis and angiogenesis, producing a 3D scaffolds that induce bone growth whilst also providing a structure that resists physiological stresses. As the primary endpoints of studies looking at bioactive glasses are very often the ability to form substantial and healthy tissues, this review will focus on the methods used to study and quantify osteogenesis and angiogenesis in bioactive glass experiments. These methods are manifold, and their accuracy is of great importance in identifying plausible future bioactive glasses for clinical use.

An overview of the key principles and guidelines in the management of pelvic fractures.

Pelvic fractures are complex injuries with a range of different presentations depending on the mechanism of trauma. Due to the morbidity and mortality of pelvic fractures, patients require thorough investigation and timely management with multidisciplinary input. Various surgical and non-surgical techniques can be used to treat pelvic fractures, as well as any associated visceral injuries. Following repair, it is important to remain vigilant for postoperative complications such as infection, sexual and urinary dysfunction, chronic pain and adverse psychological health. This article summarises the relevant UK guidance and literature and presents them in a format that follows the patient's journey. In doing so, it highlights the key perioperative factors that need to be considered in cases of pelvic fracture.

Principles and guidelines in the management of ankle fractures in adults.

Ankle fractures are common injuries that have many physical and psychosocial complications. As a result, it is important to be aware of how these patients present and are managed perioperatively. Detailed guidelines from NICE and the British Orthopaedic Association have been produced on this topic, including recent developments such as the decision to weight-bear early after surgery and the use of virtual fracture clinics. This article provides an overview of the key perioperative factors that need to be considered in cases of ankle fracture and the relevant clinical guidelines.