Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis.

Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but is still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development (referred to as the RAPID-E protocol). Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II, but additionally expressed Collagen X, indicative of hypertrophy. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans.

Gait kinematics and knee stability 10-years following posterior-stabilised total knee arthroplasty comparable to healthy adults >55.

PURPOSE: The purpose of this study was to compare the long-term objective biomechanical and functional parameters of a high-flexion total knee arthroplasty (TKA) design against healthy older adults to determine whether knee biomechanics are comparable in both populations. METHODS: One cohort of patients with a primary TKA, and a cohort of healthy adults over 55 years old with no musculoskeletal deficits or arthritis participated. Bilateral knee range of motion (RoM) was assessed with a goniometer, and gait patterns were analysed with a three-dimensional-motion capture system. An arthrometer quantified the anterior-posterior laxity of each knee. Statistical analyses were performed in SPSS software (α = 0.05). RESULTS: Twenty-three knees were replaced in 20 patients. At 9.8 ± 3.1 years postoperatively, patients' knees had a statistically significantly poorer RoM than healthy controls' knees (n = 23) due to limited flexion; p < 0.0001. Patients also failed to achieve the same degree of knee flexion as controls during downhill gait. No kinematic differences were observed during mid-flexion in level nor downhill gait; a state that has been associated with instability (p = 0.614; not significant [n.s]). There were no differences between groups in knee laxity (n.s). CONCLUSION: Patients in this study had similar gait patterns to healthy older adults during mid-flexion and were no more likely than the healthy controls to exhibit anterior-posterior translation of the knee > 7 mm; a known risk factor of instability. However, the knee flexion range was poorer. This likely led to bilateral pathological knee flexion patterns during downhill gait. LEVEL OF EVIDENCE: Level III.

The biomechanical and functional outcomes of autologous chondrocyte implantation for articular cartilage defects of the knee: A systematic review.

PURPOSE: Autologous chondrocyte implantation (ACI) is primarily performed in active, young patients to treat knee pain and functional limitations resulting from articular cartilage injury. Nevertheless, the functional outcomes of ACI remain poorly understood. This systematic review aimed to evaluate the biomechanical and functional outcomes of ACI. METHODS: Ovid MEDLINE, Embase, and Web of Science were systematically searched using the terms 'Knee OR Knee joint AND Autologous chondrocyte implantation OR ACI'. Inclusion and exclusion criteria were used to screen publications by title, abstract, and full text. Study quality and bias were assessed by two reviewers. Means and standard deviations of all collected variables were calculated and presented in the review. PROSPERO ID: CRD42021238768. RESULTS: Nineteen articles including 20 ACI cohorts were included. In general, the average range of motion (ROM) improved with clinical (>5°) and statistical significance (p < 0.05) postoperatively: 130.5 ± 14.8° to 136.1 ± 10.2°. Knee strength significantly improved within the first two postoperative years but remained poorer than control groups at final follow-up. No statistical differences were found between ACI and control groups in their ability to perform functional activities like the 6-minute walk test. CONCLUSION: Knee range of motion generally improved following ACI. Although, some studies reported that knee strengths remained significantly poorer than healthy controls, particularly >2-years postoperatively, implying that longer-term strength training may benefit patients.However, the volume of research and current level of evidence remain low, thus further research is required to better understand the impact of ACI on knee function and guide future rehabilitative protocols.

The recombinant Link module of human TSG-6 suppresses cartilage damage in models of osteoarthritis: A potential disease-modifying OA drug.

OBJECTIVE: To investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA. DESIGN: Knee articular cartilages from OA patients were analyzed for TSG-6 protein and mRNA expression using immunohistochemistry and RNAscope, respectively. The inhibitory activities of TSG-6 and its isolated Link module (Link_TSG6) on cytokine-induced degradation of OA cartilage explants were compared. Human mesenchymal stem/stromal cell-derived chondrocyte pellet cultures were used to determine the effects of Link_TSG6 and full-length TSG-6 on IL-1α-, IL-1ß-, or TNF-stimulated ADAMTS4, ADAMTS5, and MMP13 mRNA expression. Link_TSG6 was administered i.a. to the rat ACLTpMMx model; cartilage damage and tactile allodynia were assessed. RESULTS: TSG-6 is predominantly associated with chondrocytes in regions of cartilage damage where high TSG-6 expression aligns with low MMP13, the major collagenase implicated in OA progression. Link_TSG6 is more potent than full-length TSG-6 at inhibiting cytokine-mediated matrix breakdown in human OA cartilage explants;>50% of donor cartilages, from 59 tested, were responsive to Link_TSG6 treatment. Link_TSG6 also displayed more potent effects in 3D pellet cultures, suppressing ADAMTS4, ADAMTS5, and MMP13 gene expression, which was consistent with reduced aggrecanase and collagenase activities in explant cultures. Link_TSG6 treatment reduced touch-evoked pain behavior and dose-dependently inhibited cartilage damage in a rodent model of surgically-induced OA. CONCLUSIONS: Link_TSG6 has enhanced chondroprotective activity compared to the full-length TSG-6 protein and shows potential as a disease modifying OA drug via its inhibition of aggrecanase and collagenase activity.

A systematic review of outcomes of high tibial osteotomy for the valgus knee.

PURPOSE: Osteoarthritis is a prolific condition in an increasingly ageing and obese population. Research into treatments of this condition and their efficacy are vital. Outcomes of high tibial osteotomy (HTO) for the varus knee is widely reported. There is less evidence for HTO in the valgus knee. This systematic review aimed to compile all literature reporting the outcomes of HTO to correct the valgus knee, focusing on post-operative clinical outcomes. METHODS: Ovid MEDLINE, Embase and Web of Science were searched using key terms: Osteoarthritis [All Fields] AND High tibial osteotomy [All Fields] AND Lateral OR Valgus [All Fields]. Papers were screened for eligibility based on an inclusion and exclusion criteria. Full text screening was completed by two reviewers and data was extracted from the agreed included papers by one reviewer. Quality assessments of the papers were also conducted. PROSPERO ID: CRD42021239045. RESULTS: Across 17 papers reporting 517 knees, the average pre-operative femorotibial and hip-knee-ankle angles were corrected from 13.6 ± 7.0° and 4.9 ± 1.9° valgus to 2.8 ± 2.9° and 1.2 ± 1.7° varus. Studies show that the procedure is successful at offloading the lateral knee compartment and some evidence it can delay the need for a total knee replacement. However, its impact on overall quality of life remains poorly understood. CONCLUSIONS: High tibial osteotomy may be a viable treatment option for valgus knee deformities caused by lateral compartment osteoarthritis. Nevertheless, research into the procedure remains limited. Importantly, our understanding of the relationship between the achieved alignment and outcome remains largely unknown. LEVEL OF EVIDENCE: IV.

The Relationships between Coronal Plane Alignments and Patient-Reported Outcomes Following High Tibial Osteotomy: A Systematic Review.

OBJECTIVE: This systematic review aimed to determine whether coronal angular corrections correlate with patient reported outcomes following valgus-producing high tibial osteotomy (HTO). DESIGN: Ovid MEDLINE, Embase, and Web of Science were systematically searched. Studies that reported hip-knee-ankle angles (HKA) or femorotibial angles (FTA), and the Oxford Knee Score (OKS), visual analogue scale (VAS) score, Knee Injury and Osteoarthritis Outcome Score (KOOS), or EQ-5D before and after valgus-producing HTO were eligible. Correlation analyses were performed where appropriate to investigate the relationships between variables. PROSPERO ID: CRD42019135467. RESULTS: This study included 39 articles including 50 cohorts. VAS was reported in 22 studies, OKS in 9, KOOS in 12 and EQ-5D in 2. The HKA angle was corrected from 7.1° ± 1.7° varus to 2.3° ± 1.7° valgus at final follow-up. The FTA changed from 3.0° ± 2.0° varus to 7.7° ± 1.3° valgus. Outcome scores improved with clinical and statistical significance postoperatively. Spearman correlations for nonparametric data revealed greater changes in knee alignment were moderately associated with larger improvements in VAS scores (r = 0.50). Furthermore, those who experienced greater changes in alignment showed larger improvements in the KOOS Activity and Quality of Life domains (r = 0.72 and r = 0.51, respectively). CONCLUSION: On average, patients did not achieve the "ideal correction" of 3° to 6° valgus postoperatively. Nevertheless, statistical and clinical improvements in patient-reported outcome measure scores were consistently reported. This suggests that the "ideal correction" may be more flexible than 3° to 6°.

Custom Implants in TKA Provide No Substantial Benefit in Terms of Outcome Scores, Reoperation Risk, or Mean Alignment: A Systematic Review.

BACKGROUND: Failure to accurately replicate the native anatomy and biomechanics of the knee has been suggested to contribute to dissatisfaction after TKA. Custom implants promise a personalized surgical approach, with the aim of improving patient satisfaction and pain as well as lowering revision rates. However, some published research on custom TKA implants has found no clinically important improvements in postoperative validated outcomes scores, risks of revision or reoperation, and implant alignment. In the interest of helping to settle this controversy, a systematic review seems warranted. QUESTION/PURPOSE: In this systematic review, we asked whether custom implants result in clinically important improvements over conventional off-the-shelf implants for anatomically uncomplicated primary TKA in terms of (1) validated outcomes scores, (2) the risk of revision or reoperation, and (3) implant alignment. METHODS: The US National Library of Medicine (PubMed/Medline), Embase, Web of Science, and Cochrane Database of Systematic Reviews were systematically searched to identify publications from the past 10 years relevant to this review. Publications that compared the clinical outcome measures, number of revisions and reoperations, and radiological assessment of implant alignment of custom and standard implants with validated endpoints were eligible for inclusion. In the interest of capturing as much potentially relevant information as possible, we applied no requirement for minimum follow-up duration. Clinical outcomes were assessed using patient-reported outcome (PROM) scores including the Knee Society Score (KSS), Forgotten Joint Score, and Knee Injury and Osteoarthritis Outcome Score. The risk for revision or reoperation were evaluated by the number of early and late manipulations, debridement procedures, and replacement of one or more components. Implant alignment was compared using postoperative deviation from the neutral (0°) mechanical axis of the limb and each component and the posterior tibial slope. All qualified studies were retrospective, and all compared custom implants with standard implants. Data on 1510 patients were reviewed (749 with custom implants and 761 with off-the-shelf implants). The mean follow-up time ranged from 12 to 33 months. RESULTS: There was no apparent advantage to custom implants in terms of PROM scores. Of the five studies evaluating clinical outcomes, only one reported better KSS-Function scores at 3 months; two reported no difference, and two found inferior KSS scores. In several studies, custom implants were associated with more frequent reoperations than standard implants. Although in general there were no differences between custom and standard implants in terms of mean coronal plane limb alignment, one of seven studies found that the proportion of patients whose alignment was outside ± 3° from the neutral axis in the coronal plane was lower in the custom group than in the standard group. CONCLUSION: With generally poorer outcomes scores for pain and function, generally higher risks of reoperation and reintervention, and no overall benefit to alignment, custom implants for primary TKA for the general population currently appear to be inferior to standard implants. Whether the slight reduction in the proportion of patients with alignment outliers observed in a minority of studies will result in a substantial reduction in revision risk over time must be addressed by future studies. However, until or unless such a reduction is proven, we recommend against the routine use of custom implants in practice because of increased costs and the risks associated with their novelty. LEVEL OF EVIDENCE: Level III, therapeutic study.

The First Report of the International Cartilage Regeneration and Joint Preservation Society's Global Registry.

OBJECTIVE: The International Cartilage Regeneration and Joint Preservation Society's (ICRS's) global registry, aims to be the best source of information for patients and an unbiased resource of evidence-based medicine for scientists and clinicians working to help those unfortunate enough to suffer the pain and disability associated with articular cartilage lesions. This article constitutes the scientific summary of the reports' main findings. DESIGN: The article outlines the historical precedents in the development of orthopedic registries from the earliest tumor registries, then local arthroplasty databases that led ultimately to international collaborations between national arthroplasty and soft tissue registries. The ICRS global cartilage registry was designed from the outset as a GDPR (General Data Protection Regulation) compliant, multilingual, multinational cooperative system. It is a web-based user-friendly, live in 11 languages by end 2019, which can be accessed via https://cartilage.org/society/icrs-patient-registry/. Patients and clinicians enter data by smartphone, tablet, or computer on any knee cartilage regeneration and joint preservation treatment, including the use of focal arthroplasty. Knee Injury and Osteoarthritis Outcome Score and Kujala patient-reported outcome measures are collected preoperatively, 6 months, 12 months, and annually for ten years thereafter. EQ-5D data collection will allow cost-effectiveness analysis. Strengths, weaknesses, and future plans are discussed. RESULTS: Since inception the registry has 264 users across 50 countries. Major findings are presented and discussed, while the entire first ICRS global registry report is available at https://cartilage.org/society/icrs-patient-registry/registry-annual-reports/. Conclusion. A measure of the maturity of any registry is the publication of its findings in the peer reviewed literature. With the publication of its first report, the ICRS global registry has achieved that milestone.

Clinically Relevant Molecular Biomarkers for Use in Human Knee Osteoarthritis: A Systematic Review.

OBJECTIVE: Biomarkers in osteoarthritis (OA) could serve as objective clinical indicators for various disease parameters, and act as surrogate endpoints in clinical trials for disease-modifying drugs. The aim of this systematic review was to produce a comprehensive list of candidate molecular biomarkers for knee OA after the 2013 ESCEO review and discern whether any have been studied in sufficient detail for use in clinical settings. DESIGN: MEDLINE and Embase databases were searched between August 2013 and May 2018 using the keywords "knee osteoarthritis," "osteoarthritis," and "biomarker." Studies were screened by title, abstract, and full text. Human studies on knee OA that were published in the English language were included. Excluded were studies on genetic/imaging/cellular markers, studies on participants with secondary OA, and publications that were review/abstract-only. Study quality and bias were assessed. Statistically significant data regarding the relationship between a biomarker and a disease parameter were extracted. RESULTS: A total of 80 studies were included in the final review and 89 statistically significant individual molecular biomarkers were identified. C-telopeptide of type II collagen (CTXII) was shown to predict progression of knee OA in urine and serum in multiple studies. Synovial fluid vascular endothelial growth factor concentration was reported by 2 studies to be predictive of knee OA progression. CONCLUSION: Despite the clear need for biomarkers of OA, the lack of coordination in current research has led to incompatible results. As such, there is yet to be a suitable biomarker to be used in a clinical setting.

A Randomized Controlled Trial Comparing Traditional Plaster Cast Rehabilitation With Functional Walking Boot Rehabilitation for Acute Achilles Tendon Ruptures.

BACKGROUND: There has been a shift toward functional nonoperative rehabilitation in the treatment of Achilles tendon rupture (ATR) despite a shortage of studies directly comparing nonoperative functional rehabilitation with traditional nonoperative immobilization. PURPOSE: To compare patient-reported outcome measures and functional outcomes for nonoperatively treated ATR with traditional cast immobilization or functional rehabilitation in a walking boot. STUDY DESIGN: Randomized controlled clinical trial; Level of evidence, 2. METHODS: In a single-center nonblinded study, 140 patients were randomized to compare treatment for acute ATR in (1) an immobilizing cast in reducing degrees of equinus over a 10-week period with 8 weeks of nonweightbearing mobilization or (2) a walking boot for 8 weeks with reducing equinus and immediate full weightbearing. Exclusion criteria were delayed presentation >2 weeks after injury, tendon reruptures, and latex allergy. Analysis was undertaken on an intention-to-treat basis. RESULTS: A total of 69 patients (median age, 41 years [interquartile range, 33-50.5 years]) were randomized to walking boot treatment and 71 patients (41 [32-49]) to cast treatment. At 6 months, patients treated in a walking boot reported better Short Musculoskeletal Function Assessment (SMFA) dysfunction index (6.62 [2.21-12.50] vs 10.66 [4.96-13.42]; P = .050), SMFA bother index (7.29 [2.08-14.58] vs 10.42 [5.73-19.27]; P = .04), Achilles Tendon Total Rupture Score (71.5 [53.50-84.25] vs 54.0 [37-76]; P = .01), and Foot and Ankle Questionnaire core score (91 [81.89-97.55] vs 85 [78.25-92.09]; P = .04). At 1 year, there was no difference in SMFA dysfunction index (2.21 [0.74-5.88] vs 2.94 [1.47-6.62]; P = .25), SMFA bother index (2.08 [0-9.38] vs 5.21 [0.52-11.98]; P = .25), Achilles Tendon Total Rupture Score (92 [72.50-96] vs 87.5 [66.0-94.75]; P = .21), or Foot and Ankle Questionnaire core score (97.75 [89.46-99.00] vs 95.50 [90.88-97.50]; P = .18). Rerupture occurred in 5 and 11 patients (P = .075) and venous thromboembolism in 2 and 3 patients (P = .67) in the boot and cast groups, respectively. Fifteen patients in the boot group but none in the cast group had skin problems (P < .001). Patients treated in a boot returned to driving at a median 12 weeks (vs 13 weeks for cast; P = .045), but there was no difference in time to return to work (P = .48). CONCLUSION: Functional rehabilitation with early weightbearing is a safe alternative to traditional immobilizing treatment for ATR, giving better early functional outcomes, albeit with a higher incidence of transient minor skin complications. REGISTRATION: NCT02598843 (ClinicalTrials.gov identifier).

Undertriage of the elderly major trauma patient continues in major trauma centre care: a retrospective cohort review.

BACKGROUND: Major trauma (Injury Severity Score (ISS) ≥16) in older people is increasing, but concerns persist that major trauma is not always recognised in older patients on triage. This study compared undertriage of older and younger adult major trauma patients in the major trauma centre (MTC) setting to investigate this concern. METHODS: A retrospective review of Trauma Audit and Research Network data was conducted for three MTCs in the UK for 3 months in 2014. Age, ISS, injury mechanism and injured areas were examined for all severely injured patients (ISS ≥16) and appropriate major trauma triage rates measured via the surrogate markers of trauma team activation and the presence of a consultant first attender, as per standards for major trauma care set by National Confidential Enquiry into Patient Outcomes and Deaths, Royal College of Surgeons of England and the British Orthopaedic Association. Trends in older (age ≥65) and younger (ages 18-64) adult major trauma presentation, triage and reception were reviewed. RESULTS: Of 153 severely injured patients, 46 were aged ≥65. Older patients were significantly less likely to receive the attention of a consultant first attender or trauma team. Similar trends were also seen on subgroup analysis by mechanism of injury or number of injured body areas. Older major trauma patients exhibit a higher mortality, despite a lower median ISS (older patient ISS=20 (IQR 16-25), younger patient ISS=25 (IQR 18-29)). CONCLUSION: Older major trauma patients are at greater risk of undertriage, even in the MTC environment. Existing hospital trauma triage practices should be further investigated to explain and reduce undertriage of elderly trauma patients.

Advanced functional biomechanical analysis of medial rotation knee arthroplasty.

BACKGROUND: The Medacta GMK-Sphere total knee arthroplasty (TKA) is designed to mimic the movements and stabilimidty of a natural knee for optimal post-operative function and mobility. This study aimed to quantify the early functional outcome of patients with this implant. METHODS: Patients due to undergo TKA to treat end-stage osteoarthritis were recruited into this study. Functional tests of knee range of motion (ROM), strength, and gait kinematics were carried out pre-operatively and one year post-operatively at routine clinics. Motion capture technology and a force transducer were used to collect all data. Normality tests were completed on all data sets to confirm normal distribution of the data, then paired t-tests were used to statistically compare the results. The level of significance was set as α = 0.05. RESULTS: Sixty-three patients underwent pre-operative assessments; of which 30 returned one year post-operatively and consented to have follow-up testing. The operative knee was found to have poorer function than the contralateral knee pre-operatively (p < 0.05). Post-operatively, knee ROM significantly improved on the operative side to a mean of 116.1 ± 19.0. Gait kinematics also improved, especially in the frontal plane, but some abnormal traits remained in the sagittal plane. Knee strength decreased post-operatively. CONCLUSIONS: The Medacta GMK-Sphere TKA improves knee range of motion sufficiently within the first postoperative year to allow patients to carry out most activities of daily living (>110° knee flexion), but continued poor knee strength may limit their abilities to complete tasks which are more biomechanically demanding than walking.

Health costs and efficiencies of patient-specific and single-use instrumentation in total knee arthroplasty: a randomised controlled trial.

Aim: To investigate whether patient-specific instrumentation (PSI) and single-use instrumentation (SUI) improve operating room efficiency in terms of time and cost to the healthcare provider over conventional/reusable instrumentation (CVR) when performing total knee arthroplasty (TKA). Patients and methods: Patients requiring TKA were randomised into one of four surgical groups: CVR, CVS (conventional/SUI), PSR (PSI/reusable) and PSS (PSI/SUI). All surgical procedures were video recorded to determine specific surgical time intervals. Other variables reported included the number of instrument trays used, missing equipment, direct instrument costs and the weight of the instruments the staff had to handle. Oxford Knee Score (OKS), estimated blood loss and lengths of hospital stay were also recorded as markers of patient experience. Results: PSR was significantly quicker in all the recorded time intervals, used less trays, experienced less missing equipment and resulted in lower blood loss and shorter hospital stays. SUI reported significantly slower operating room times and resulted in higher blood loss, but SUI was 88% lighter and 20% cheaper on average when compared with their reusable counterparts. Despite the economic advantages of PSI and SUI, the patients who reported greatest improvements in OKS were those allocated to the CVR group, but no clinically meaningful difference in OKS was found at any time point. Conclusions: PSI and SUI for TKA have the potential of reducing operating room times over conventional, reusable sets. This reduction will benefit theatre personnel ergonomically, while presenting the healthcare provider with potential cost-saving benefits in terms of reduced sterilisation costs and surgical times.

Effect of Alendronic Acid on Fracture Healing: A Multicenter Randomized Placebo-Controlled Trial.

There is a concern that bisphosphonates may impair fracture healing because of their inhibitory effects on bone turnover. Here we evaluated the effects of early bisphosphonate therapy on fracture healing and functional outcome following a fracture of the distal radius. The fracture and bisphosphonates (FAB) trial was a double-blind, randomized, placebo-controlled trial involving 15 trauma centers in the United Kingdom. We enrolled 421 bisphosphonate-naive patients aged ≥50 years with a radiographically confirmed fracture of the distal radius and randomized them in a 1:1 ratio to receive alendronic acid 70 mg once weekly (n = 215) or placebo (n = 206) within 14 days of the fracture. The primary outcome measure was the proportion of fractures that had radiologically united at 4 weeks as assessed by an observer, blinded to treatment allocation. Secondary outcomes included the Disabilities of the Arm Shoulder and Hand (DASH) questionnaire, range of wrist movement and grip strength, pain and analgesia requirements, and the rate of malunion. The mean ± SD age of participants was 63 ± 8.5 years and 362 (86%) were female. At 4 weeks, 48 of 202 (23.8%) fractures had united in the alendronic acid group compared with 52 of 187 (27.8%) in the placebo group (observed absolute proportion difference 4.0%; 95% CI, -4.7% to 12.8%; p = 0.36). The absolute proportion difference between groups based on imputed data was 4.5% (95% CI, -4.7% to 13.8%; p = 0.30). There was no significant difference in the proportion of fractures that had united at any other time point and no differences in the DASH score, pain at the fracture site, grip strength, or any other clinical outcome. We conclude that among patients aged 50 years and above with a distal radius fracture, early administration of alendronic acid does not adversely affect fracture union or clinical outcome. These findings suggest bisphosphonate therapy can be safely commenced early after fracture if clinically indicated. © 2019 American Society for Bone and Mineral Research.

Gait variability and motor control in patients with knee osteoarthritis as measured by the uncontrolled manifold technique.

Knee osteoarthritis (OA) causes pain, reduced muscular strength and stiffness of the affected joint. In response, the motor control mechanism is altered, potentially compromising stability during acts of daily living. Reduced walking stability can be quantified in terms of gait variability. This study therefore aimed to identify and quantify the effects of knee arthritis on gait variability. Fifty adults (25 males/25 females) with end-stage OA of the knee sufficiently symptomatic to require joint replacement, walked on a self-paced treadmill for 2min. A motion capture system was used to record 50 consecutive gait cycles from each patient. Kinematic variability of gait was analysed using the uncontrolled manifold technique (UCM). The position of the centre of mass (COM) was chosen as the task variable for the analysis. Results showed that our patient cohort were able to maintain a stable COM whilst walking, through adopting variable combinations of hip, knee and ankle kinematics. The greatest magnitudes of instability (based on the UCM ratios) occurred during initial contact and terminal stance. Active extension of the knee joint to approximately 5° is required during these gait cycle events, meaning that these gait events are highly quadriceps dependent. This study identified and quantified components of the gait cycle where patients with knee OA are most unstable. Employment of this technique could therefore allow specific personalised prescription for prehabilitation and rehabilitation.

Autologous chondrocyte implantation in the knee: systematic review and economic evaluation.

BACKGROUND: The surfaces of the bones in the knee are covered with articular cartilage, a rubber-like substance that is very smooth, allowing frictionless movement in the joint and acting as a shock absorber. The cells that form the cartilage are called chondrocytes. Natural cartilage is called hyaline cartilage. Articular cartilage has very little capacity for self-repair, so damage may be permanent. Various methods have been used to try to repair cartilage. Autologous chondrocyte implantation (ACI) involves laboratory culture of cartilage-producing cells from the knee and then implanting them into the chondral defect. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of ACI in chondral defects in the knee, compared with microfracture (MF). DATA SOURCES: A broad search was done in MEDLINE, EMBASE, The Cochrane Library, NHS Economic Evaluation Database and Web of Science, for studies published since the last Health Technology Assessment review. REVIEW METHODS: Systematic review of recent reviews, trials, long-term observational studies and economic evaluations of the use of ACI and MF for repairing symptomatic articular cartilage defects of the knee. A new economic model was constructed. Submissions from two manufacturers and the ACTIVE (Autologous Chondrocyte Transplantation/Implantation Versus Existing Treatment) trial group were reviewed. Survival analysis was based on long-term observational studies. RESULTS: Four randomised controlled trials (RCTs) published since the last appraisal provided evidence on the efficacy of ACI. The SUMMIT (Superiority of Matrix-induced autologous chondrocyte implant versus Microfracture for Treatment of symptomatic articular cartilage defects) trial compared matrix-applied chondrocyte implantation (MACI®) against MF. The TIG/ACT/01/2000 (TIG/ACT) trial compared ACI with characterised chondrocytes against MF. The ACTIVE trial compared several forms of ACI against standard treatments, mainly MF. In the SUMMIT trial, improvements in knee injury and osteoarthritis outcome scores (KOOSs), and the proportion of responders, were greater in the MACI group than in the MF group. In the TIG/ACT trial there was improvement in the KOOS at 60 months, but no difference between ACI and MF overall. Patients with onset of symptoms < 3 years' duration did better with ACI. Results from ACTIVE have not yet been published. Survival analysis suggests that long-term results are better with ACI than with MF. Economic modelling suggested that ACI was cost-effective compared with MF across a range of scenarios. LIMITATIONS: The main limitation is the lack of RCT data beyond 5 years of follow-up. A second is that the techniques of ACI are evolving, so long-term data come from trials using forms of ACI that are now superseded. In the modelling, we therefore assumed that durability of cartilage repair as seen in studies of older forms of ACI could be applied in modelling of newer forms. A third is that the high list prices of chondrocytes are reduced by confidential discounting. The main research needs are for longer-term follow-up and for trials of the next generation of ACI. CONCLUSIONS: The evidence base for ACI has improved since the last appraisal by the National Institute for Health and Care Excellence. In most analyses, the incremental cost-effectiveness ratios for ACI compared with MF appear to be within a range usually considered acceptable. Research is needed into long-term results of new forms of ACI. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013083. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The Infrapatellar Fat Pad as a Source of Perivascular Stem Cells with Increased Chondrogenic Potential for Regenerative Medicine.

Perivascular stem cells (PSCs) are the natural ancestors of mesenchymal stem cells (MSCs) and are the stem cells responsible for homeostasis and repair in vivo. Prospectively identified and isolated PSCs have demonstrated increased plasticity and osteogenic potential. Cells from the infrapatellar fat pad (IFP) have demonstrated increased chondrogenic potential compared with those from subcutaneous fat. This research assessed the chondrogenic potential of IFP PSCs compared with MSCs from the IFP and bone marrow. Immunohistochemistry demonstrated the location of perivascular markers (CD146, CD34, neural/glial antigen 2 [NG2], platelet-derived growth factor receptor-ß [PDGFRß], and α-smooth muscle actin [α-SMA]) in relation to endothelial markers (CD31, CD144, von Willebrand factor [vWF]). Pericytes and adventitial cells were isolated from the stromal vascular fraction (3.8% and 21.2%, respectively) using flow cytometry with a viability of 88%. The mean numbers of pericytes and adventitial cells isolated were 4.6 ± 2.2 × 104 and 16.2 ± 3.2 × 104 , respectively, equating to 7.9 ± 4.4 × 103 and 20.8 ± 4.3 × 103 cells per gram of harvested tissue. Fluorescence-activated cell sorting demonstrated that cultured PSCs were CD44+CD90+CD105+; polymerase chain reaction and immunocytochemistry demonstrated that pericytes retained their CD146+ phenotype and expressed the pericyte markers PDGFRß and NG2. Differentiation was confirmed using histochemical stains and genetic expression. Using a pellet model, the IFP PSCs and the MSCs generated significantly more extracellular matrix than bone marrow MSCs (p < .001 and p = .011, respectively). The IFP PSCs generated significantly more extracellular matrix than IFP MSCs (p = .002). Micromass culture demonstrated that differentiated PSCs were upregulated compared with MSCs for COL2A1, ACAN, and SOX9 expression by factors of 4.8 ± 1.3, 4.3 ± 0.9, and 7.0 ± 1.7, respectively. The IFP was a significantly better source of chondrogenic stem cells compared with bone marrow. PSCs generated significantly more extracellular matrix than culture-derived MSCs. Stem Cells Translational Medicine 2017;6:77-87.

Cell Viability in Arthroscopic Versus Open Autologous Chondrocyte Implantation.

BACKGROUND: Autologous chondrocyte implantation (ACI) is an effective method of repair of articular cartilage defects. It is a 2-stage operation, with the second stage most commonly performed via mini-arthrotomy. Arthroscopic ACI is gaining popularity, as it is less invasive and may accelerate early rehabilitation. However, handling and manipulation of the implant have been shown to cause chondrocyte cell death. PURPOSE: To assess the number and viability of cells delivered via an open versus arthroscopic approach in ACI surgery. STUDY DESIGN: Controlled laboratory study. METHODS: Sixteen ACI surgeries were performed on young cadaveric knees by 2 experienced surgeons: 8 via mini-arthrotomy and 8 arthroscopically. Live and dead cells were stained and counted on implants after surgery. The cell number and viability were assessed using confocal laser scanning microscopy. Surgery was timed from knife to skin until the end of cycling the knee 10 times after implantation of the cell-membrane construct. RESULTS: On receipt of cell membranes after transportation from the laboratory, ≥92% of the cells were viable. There were significantly more remaining cells (8.47E+07 arthroscopic vs 1.41E+08 open; P < .001) and 16 times more viable cells (3.62% arthroscopic vs 37.34% open; P < .001) on the implants when they were inserted via mini-open surgery compared with the arthroscopic technique. Open surgery was of a significantly shorter duration (6 vs 32 minutes; P < .001). CONCLUSION: In this study, there were significantly more viable cells on the implant when ACI was performed via mini-arthrotomy compared with an arthroscopic technique. CLINICAL RELEVANCE: The viability of cells delivered for ACI via an arthroscopic approach was 16 times less than via an open approach. The mini-arthrotomy approach is recommended until long-term clinical comparative data are available.