Ethics in musculoskeletal regenerative medicine; guidance in choosing the appropriate comparator in clinical trials.

BACKGROUND: Regenerative Medicine (RM) techniques aimed at the musculoskeletal system are increasingly translated to clinical trials and patient care. This revolutionary era in science raises novel ethical challenges. One of these challenges concerns the appropriate choice of the comparator in (randomized controlled) trials, including the ethically contentious use of sham procedures. To date, only general guidelines regarding the choice of the comparator exist. OBJECTIVE: To provide specific guidelines for clinical trial comparator choice in musculoskeletal RM. METHODS: In this manuscript, we discuss the ethics of comparator selection in RM trials. First, we make a classification of RM interventions according to different health states from disease prevention, return to normal health, postponing RM treatment, supplementing RM treatment, substituting RM treatment, improving RM outcome, and slowing progression. Subsequently, per objective, the accompanying ethical points to consider are evaluated with support from the available literature. RESULTS: a sham procedure is demonstrated to be an ethically acceptable comparator in RM trials with certain objectives, but less appropriate for musculoskeletal RM interventions that aim at preventing disease or substituting a surgical treatment. The latter may be compared to 'standard of care'. CONCLUSION: From a scientific perspective, choosing the correct comparator based on ethical guidelines is a step forward in the success of musculoskeletal RM.

Meniscus regeneration combining meniscus and mesenchymal stromal cells in a degradable meniscus implant: an in vitro study.

Meniscus regeneration is an unmet clinical need as damage to the meniscus is common and causes early osteoarthritis. The aim of the present study was to investigate the feasibility of a one-stage cell-based treatment for meniscus regeneration by augmenting a resorbable collagen-based implant with a combination of recycled meniscus cells and mesenchymal stromal cells (MSCs). Cell communication and fate of the different cell types over time in co-culture were evaluated by connexin 43 staining for gap junctions and polymerase chain reaction (PCR) to discriminate between meniscus cells and MSCs, based on a Y-chromosome gene. To define optimal ratios, human meniscus cells and bone-marrow-derived MSCs were cultured in different ratios in cell pellets and type I collagen hydrogels. In addition, cells were seeded on the implant in fibrin glue by static seeding or injection. Cellular communication by gap junctions was shown in co-culture and a decrease in the amount of MSCs over time was demonstrated by PCR. 20 : 80 and 10 : 90 ratios showed significantly highest glycosaminoglycan and collagen content in collagen hydrogels. The same statistical trend was found in pellet cultures. Significantly more cells were present in the injected implant and cell distribution was more homogenous as compared to the statically seeded implant. The study demonstrated the feasibility of a new one-stage cell-based procedure for meniscus regeneration, using 20 % meniscus cells and 80 % MSCs seeded statically on the implant. In addition, the stimulatory effect of MSCs towards meniscus cells was demonstrated by communication through gap junctions.

Incidence of symptomatic osteochondritis dissecans lesions of the knee: a population-based study in Olmsted County.

OBJECTIVE: To (1) define population-based incidence of knee Osteochondritis dissecans (OCD) lesions using the population of Olmsted County, (2) examine trends over time, and (3) evaluate rate of surgical management over time. METHOD: Study population included 302 individuals who were diagnosed with knee OCD lesions between January 1, 1976 and December 31, 2014. Complete medical records were reviewed to extract injury and treatment details. Age- and gender-specific incidence rates were calculated and adjusted to the 2010 US population. Poisson regression analyses were performed to examine incidence and surgery trends by age, gender, and calendar period. RESULTS: Overall age- and gender-adjusted incidence annual incidence of knee OCD lesions was 6.09 per 100,000 person-years. The incidence was significantly higher (P < 0.001) in males (8.82, 95% CI 7.63 to 10.00 per 100,000) compared to females (3.32, 95% CI 2.61 to 4.04 per 100,000). Age- and gender-specific incidence was highest in both males and females in the 11-15 years old at 39.06 and 16.15 per 100,000, respectively. In males aged 11-15 years, OCD incidence increased significantly over the study period from 20.68 in 1976-1985 to 48.16 in 2006-2014 (per 100,000). CONCLUSIONS: Overall age- and gender-adjusted annual incidence of knee OCD lesions in the Olmsted Country Population was 6.09 per 100,000 person-years with a significantly higher incidence in males compared to females. The highest incidence for both males and females occurred between the ages 11-15 years. Trends indicate increasing OCD incidence in younger males and decreasing surgical management in females over the last decade.

Arthroscopic airbrush assisted cell implantation for cartilage repair in the knee: a controlled laboratory and human cadaveric study.

OBJECTIVE: The objective of this study was to investigate the feasibility of arthroscopic airbrush assisted cartilage repair. METHODS: An airbrush device (Baxter) was used to spray both human expanded osteoarthritic chondrocytes and choncrocytes with their pericellular matrix (chondrons) at 1 × 10(6) cells/ml fibrin glue (Tissucol, Baxter) in vitro. Depth-dependent cell viability was assessed for both methods with confocal microscopy. Constructs were cultured for 21 days to assess matrix production. A controlled human cadaveric study (n = 8) was performed to test the feasibility of the procedure in which defects were filled with either arthroscopic airbrushing or needle extrusion. All knees were subjected to 60 min of continuous passive motion and scored on outline attachment and defect filling. RESULTS: Spraying both chondrocytes and chondrons in fibrin glue resulted in a homogenous cell distribution throughout the scaffold. No difference in viability or matrix production between application methods was found nor between chondrons and chondrocytes. The cadaveric study revealed that airbrushing was highly feasible, and that defect filling through needle extrusion was more difficult to perform based on fibrin glue adhesion and gravity-induced seepage. Defect outline and coverage scores were consistently higher for extrusion, albeit not statistically significant. CONCLUSION: Both chondrons and chondrocytes can be evenly distributed in a sprayed fibrin glue scaffold without affecting viability while supporting matrix production. The airbrush technology is feasible, easier to perform than needle extrusion and allows for reproducible arthroscopic filling of cartilage defects.

Overexpression of hsa-miR-148a promotes cartilage production and inhibits cartilage degradation by osteoarthritic chondrocytes.

OBJECTIVE: Hsa-miR-148a expression is decreased in Osteoarthritis (OA) cartilage, but its functional role in cartilage has never been studied. Therefore, our aim was to investigate the effects of overexpressing hsa-miR-148a on cartilage metabolism of OA chondrocytes. DESIGN: OA chondrocytes were transfected with a miRNA precursor for hsa-miR-148a or a miRNA precursor negative control. After 3, 7, 14 and 21 days, real-time PCR was performed to examine gene expression levels of aggrecan (ACAN), type I, II, and X collagen (COL1A1, COL2A1, COl10A1), matrix metallopeptidase 13 (MMP13), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and the serpin peptidase inhibitor, clade H (heat shock protein 47), member 1 (SERPINH1). After 3 weeks, DNA content and proteoglycan and collagen content and release were determined. Type II collagen was analyzed at the protein level by Western blot. RESULTS: Overexpression of hsa-miR-148a had no effect on ACAN, COL1A1 and SERPINH1 gene expression, but increased COL2A1 and decreased COL10A1, MMP13 and ADAMTS5 gene expression. Luciferase reporter assay confirmed direct interaction of miR-148a and COL10A1, MMP13 and ADAMTS5. The matrix deposited by the miR-148a overexpressing cells contained more proteoglycans and collagen, in particular type II collagen. Proteoglycan and collagen release into the culture medium was inhibited, but total collagen production was increased. CONCLUSION: Overexpression of hsa-miR-148a inhibits hypertrophic differentiation and increases the production and deposition of type II collagen by OA chondrocytes, which is accompanied by an increased retention of proteoglycans. Hsa-miR-148a might be a potential disease-modifying compound in OA, as it promotes hyaline cartilage production.

Enhanced cell-induced articular cartilage regeneration by chondrons; the influence of joint damage and harvest site.

OBJECTIVE: Interactions between chondrocytes and their native pericellular matrix provide optimal circumstances for regeneration of cartilage. However, cartilage diseases such as osteoarthritis change the pericellular matrix, causing doubt to them as a cell source for autologous cell therapy. METHODS: Chondrons and chondrocytes were isolated from stifle joints of goats in which cartilage damage was surgically induced in the right knee. After 4 weeks of regeneration culture, DNA content and proteoglycan and collagen content and release were determined. RESULTS: The cartilage regenerated by chondrons isolated from the damaged joint contained less proteoglycans and collagen compared to chondrons from the same harvest site in the nonoperated knee (P < 0.01). Besides, chondrons still reflected whether they were isolated from a damaged joint, even if they where isolated from the opposing or adjacent condyle. Although chondrocytes did not reflect this diseased status of the joint, chondrons always outperformed chondrocytes, even when isolated from the damaged joints (P < 0.0001). Besides increased cartilage production, the chondrons showed less collagenase activity compared to the chondrocytes. CONCLUSION: Chondrons still outperform chondrocytes when they were isolated from a damaged joint and they might be a superior cell source for articular cartilage repair and cell-induced cartilage formation.

A vision on the future of articular cartilage repair.

An AO Foundation (Davos, Switzerland) sponsored workshop "Cell Therapy in Cartilage Repair" from the Symposium "Where Science meets Clinics" (September 5-7, 2013, Davos) gathered leaders from medicine, science, industry, and regulatory organisations to debate the vision of cell therapy in articular cartilage repair and the measures that could be taken to narrow the gap between vision and current practice. Cell-based therapy is already in clinical use to enhance the repair of cartilage lesions, with procedures such as microfracture and articular chondrocyte implantation. However, even though long term follow up is good from a clinical perspective and some of the most rigorous randomised controlled trials in the regenerative medicine/orthopaedics field show beneficial effect, none of these options have proved successful in restoring the original articular cartilage structure and functionality in patients so far. With the remarkable recent advances in experimental research in cell biology (new sources for chondrocytes, stem cells), molecular biology (growth factors, genes), biomaterials, biomechanics, and translational science, a combined effort between scientists and clinicians with broad expertise may allow development of an improved cell therapy for cartilage repair. This position paper describes the current state of the art in the field to help define a procedure adapted to the clinical situation for upcoming translation in the patient.

One-stage focal cartilage defect treatment with bone marrow mononuclear cells and chondrocytes leads to better macroscopic cartilage regeneration compared to microfracture in goats.

OBJECTIVE: The combination of chondrocytes and mononuclear fraction (MNF) cells might solve the expansion induced dedifferentiation problem of reimplanted cells in autologous chondrocytes implantation as sufficient cells would be available for direct, one-stage, implantation. Earlier in vitro work already showed a positive stimulation of cartilage specific matrix production when chondrocytes and MNF cells were combined. Therefore, this study aimed to evaluate cartilage regeneration using a one-stage procedure combining MNF cells and primary chondrocytes for the treatment of focal cartilage lesions in goats compared to microfracture treatment. DESIGN: Freshly created focal cartilage defects were treated with either a combination of chondrocytes and MNF cells embedded in fibrin glue or microfracture treatment. After 6 months follow-up local regeneration as well as the general joint cartilage health were evaluated using validated scores and biochemical assays. RESULTS: Macroscopic (P = 0.015) scores for the cartilage surface at the treated defect were, after 6 months, significantly higher for the chondrocyteMNF treatment compared to microfracture-treated defects, but microscopic scores were not (P = 0.067). The articulating cartilage showed more (P = 0.005) degeneration following microfracture treatment compared to chondrocyteMNF treatment. Biochemical glycosaminoglycans (GAG) evaluation did not reveal differences between the treatments. Both treatments had resulted in a slight to moderate cartilage degeneration at other locations in the joint. CONCLUSION: In conclusion, treatment of focal articular cartilage lesions in goats using a combination of MNF cells from bone marrow and unexpanded chondrocytes leads to better macroscopic regeneration compared to microfracture, however needs further fine-tuning to decrease the negative influence on other joint compartments.

Delayed gadolinium enhanced MRI of cartilage (dGEMRIC) can be effectively applied for longitudinal cohort evaluation of articular cartilage regeneration.

OBJECTIVE: Delayed gadolinium enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) facilitates non-invasive evaluation of the glycosaminoglycan content in articular cartilage. The primary aim of this study was to show that the dGEMRIC technique is able to monitor cartilage repair following regenerative cartilage treatment. DESIGN: Thirty-one patients with a focal cartilage lesion underwent a dGEMRIC scan prior to cartilage repair surgery and at 3 and 12 months follow-up. At similar time points clinical improvement was monitored using the Knee injury and Osteoarthritis Outcome Score (KOOS) and Lysholm questionnaires. Per MRI scan several regions-of-interest (ROIs) were defined for different locations in the joint. The dGEMRIC index (T1gd) was calculated for each ROI. Repeated-measures analysis of variance (RMANOVA) analysis was used to evaluate improvement in clinical scores and MRI T1gd over time. Also regression analysis was performed to show the influence of local repair on cartilage quality at distant locations in the knee. RESULTS: Clinical scores and the dGEMRIC T1gd per ROI showed a statistically significant improvement (P < 0.01), from baseline, at 12 months follow-up. Also, improvement from baseline in T1gd of the ROI defining the treated cartilage defect showed a direct relationship (P < 0.007) to the improvement of the T1gd of ROI at other locations in the joint. CONCLUSIONS: The dGEMRIC MRI protocol is a useful method to evaluate cartilage repair. In addition, local cartilage repair influenced the cartilage quality at other location in the joint. These findings validate the use of dGEMRIC for non-invasive evaluation of the effects of cartilage regeneration.

An explorative study comparing levels of soluble mediators in control and osteoarthritic synovial fluid.

OBJECTIVE: Soluble mediators in synovial fluid (SF) are acknowledged as key players in the pathophysiology of osteoarthritis (OA). However, a wide-spectrum screening of such mediators in SF is currently lacking. In this study, the levels of 47 mediators in the SF of control donors and osteoarthritic (OA) patients were compared. MATERIALS & METHODS: SF was collected from control donors (n = 16) and end-stage knee OA patients (n = 18) and analysed for 47 cytokines, chemokines and growth factors using several multiplex enzyme-linked immunosorbent assays (ELISAs). A Mann-Whitney U test was used to determine differences between OA and control controls. A principal component analysis (PCA) was performed to cluster the 47 mediators. RESULTS: The majority of the mediators could be detected in both control and OA SF. Interleukin (IL)-6, interferon inducible protein (IP)-10, macrophage derived chemokine (MDC), platelet derived growth factor (PDGF)-AA and regulated on activation normal T cell expressed and secreted (RANTES) levels were found to be higher in OA compared to control SF (P < 0.001). Leptin, IL-13, macrophage inflammatory protein (MIP)-1ß, soluble CD40 (sCD40L) levels were higher and eotaxin and granulocyte colony-stimulating factor (G-CSF) levels were lower in OA SF than in control SF, albeit borderline significant (P < 0.05). The PCA enabled identification of six clusters of mediators, which explained 76% of the variance. CONCLUSIONS: The current study provides the first extensive profile of cytokines, chemokines and growth factors present in control and OA SF. Increased levels of mediators such as MDC and IL-6 imply involvement of inflammatory processes and might be associated with the influx of inflammatory cells in OA synovial tissue. Moreover, the performed cluster analysis indicated multiple clusters, which could indicate different pathophysiological pathways in the joint.

Comparative study of depth-dependent characteristics of equine and human osteochondral tissue from the medial and lateral femoral condyles.

Articular cartilage defects are common after joint injuries. When left untreated, the biomechanical protective function of cartilage is gradually lost, making the joint more susceptible to further damage, causing progressive loss of joint function and eventually osteoarthritis (OA). In the process of translating promising tissue-engineering cartilage repair approaches from bench to bedside, pre-clinical animal models including mice, rabbits, goats, and horses, are widely used. The equine species is becoming an increasingly popular model for the in vivo evaluation of regenerative orthopaedic approaches. As there is also an increasing body of evidence suggesting that successful lasting tissue reconstruction requires an implant that mimics natural tissue organization, it is imperative that depth-dependent characteristics of equine osteochondral tissue are known, to assess to what extent they resemble those in humans. Therefore, osteochondral cores (4-8 mm) were obtained from the medial and lateral femoral condyles of equine and human donors. Cores were processed for histology and for biochemical quantification of DNA, glycosaminoglycan (GAG) and collagen content. Equine and human osteochondral tissues possess similar geometrical (thickness) and organizational (GAG, collagen and DNA distribution with depth) features. These comparable trends further underscore the validity of the equine model for the evaluation of regenerative approaches for articular cartilage.

dGEMRIC as a tool for measuring changes in cartilage quality following high tibial osteotomy: a feasibility study.

OBJECTIVE: The high tibial osteotomy (HTO) is an effective strategy for treatment of painful medial compartment knee osteoarthritis. Effects on cartilage quality are largely unknown. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) enables non-invasive assessment of cartilage glycosaminoglycan content. This study aimed to evaluate if dGEMRIC could detect relevant changes in cartilage glycosaminoglycan content following HTO. DESIGN: Ten patients with medial compartment osteoarthritis underwent a dGEMRIC scan prior to HTO, and after bone healing and subsequent hardware removal. A dGEMRIC index (T1Gd) was used for changes in cartilage glycosaminoglycan content, a high T1Gd indicating a high glycosaminoglycan content and vice versa. Radiographic analysis included mechanical axis and tibial slope measurement. clinical scores [knee osteoarthritis outcome scale (KOOS), visual analogue score (VAS) for pain, Knee Society clinical rating system (KSCRS)] before, 3 and 6 months after HTO and after hardware removal were correlated to T1Gd changes. RESULTS: Overall a trend towards a decreased T1Gd, despite HTO, was observed. Before and after HTO, lateral femoral condyle T1Gd was higher than medial femoral condyle (MFC) T1Gd and tibial cartilage T1Gd was higher than that of femoral cartilage (P < 0.001). The MFC had the lowest T1Gd before and after HTO. Clinical scores all improved significantly (P < 0.01), KOOS Symptoms and QOL were moderately related to changes in MFC T1Gd. CONCLUSIONS: dGEMRIC effectively detected differences in cartilage quality within knee compartments before and after HTO, but no changes due to HTO were detected. Hardware removal post-HTO seems essential for adequate T(1)Gd interpretation. T(1)Gd was correlated to improved clinical scores on a subscore level only. Longer follow-up after HTO may reveal lasting changes. ClinicalTrials.gov registration ID: NCT01269944.

The Value of SPECT/CT for Knee Osteoarthritis: A Systematic Review.

BACKGROUND: Single photon emission computed tomography (SPECT/CT) is a diagnostic option for knee osteoarthritis patients without osteoarthritic features on X-ray; however, the added value of SPECT/CT remains debatable in the diagnostic algorithm. OBJECTIVE: To review the added value of SPECT/CT in the diagnostic algorithm of knee osteoarthritis. STUDY DESIGN: Systematic review. METHODS: A systematic search was carried out in the databases EMBASE, MEDLINE, and the Cochrane collaboration. The retrieved articles were screened for relevance on title and abstract. This was followed by a full-text study quality appraisal of the remaining articles. Finally, a total of 9 trials were included. RESULTS: The use of SPECT/CT might objectify some clinical knee osteoarthritis symptoms. It could correlate with findings on plain radiography and magnetic resonance imaging. Furthermore, there is some evidence SPECT/CT gives additional information compared with these imaging modalities; however, superiority is not proven. The uptake on SPECT could predict the intraoperative macroscopic findings. Yet the clinical relevance remains unclear. CONCLUSION: There is no strong evidence SPECT/CT should play a role in the diagnosing and decision-making processes of knee osteoarthritis. Yet there is evidence suggesting SPECT/CT might give additional information in the diagnosing process. More research would be of added value to answer this research question.

Evaluation of histological scoring systems for tissue-engineered, repaired and osteoarthritic cartilage.

OBJECTIVE: Regeneration of hyaline cartilage has been the focus of an increasing number of research groups around the world. One of the most important outcome measures in evaluation of its success is the histological quality of cartilaginous tissue. Currently, a variety of histological scoring systems is used to describe the quality of osteoarthritic, in vivo repaired or in vitro engineered tissue. This review aims to provide an overview of past and currently used histological scoring systems, in an effort to aid cartilage researchers in choosing adequate and validated cartilage histological scoring systems. METHODS: Histological scoring systems for analysis of osteoarthritic, tissue engineered and in vivo repaired cartilage were reviewed. The chronological development as well as the validity and practical applicability of the scoring systems is evaluated. RESULTS: The Histological-Histochemical Grading System (HHGS) or a HHGS-related score is most often used for evaluation of osteoarthritic cartilage, however the Osteoarthritis Research Society International (OARSI) Osteoarthritis Cartilage Histopathology Assessment System seems a valid alternative. The O'Driscoll score and the International Cartilage Repair Society (ICRS) II score may be used for in vivo repaired cartilage. The 'Bern score' seems most adequate for evaluation of in vitro engineered cartilage. CONCLUSION: A great variety of histological scoring systems exists for analysis of osteoarthritic or normal, in vivo repaired or tissue-engineered cartilage, but only few have been validated. Use of these validated scores may considerably improve exchange of information necessary for advances in the field of cartilage regeneration.

Quality of scaffold fixation in a human cadaver knee model.

OBJECTIVE: Newly developed regenerative cartilage interventions based on the application of 3D-scaffolds require a further evaluation of the surgical techniques involved. The present study compared four different scaffold fixation techniques [fibrin glue (FG), transosseous (TS) fixation, biodegradable pin (BP) fixation and continuous cartilage sutures (CS)] to implant a custom-printed porous PEOT/PBT1000/70/30 scaffold in a human cadaver knee model. METHODS: After implantation, the knees were subjected to a vertically oriented loaded continuous passive motion (CPM) protocol. The fixation techniques were evaluated after 60 and a subsequent 150 motion cycles, focusing on area coverage, outline attachment and scaffold integrity. After the total of 210 cycles, also an endpoint fixation test was performed. RESULTS: The fixation techniques revealed marginal differences for area coverage and outline attachment after 60 and 150 cycles. The FG scored higher on scaffold integrity compared to TS (P<0.05) and CS (P=0.01). Endpoint fixation was highest for the CS, whereas FG showed a weak final fixation strength (P=0.01). CONCLUSIONS: This study showed that optimal fixation cannot be combined always with high scaffold integrity. Special attention devoted to scaffold properties in relation to the fixation technique may result in an improvement of scaffold fixation, and thus clinical cartilage regenerative approaches involving these scaffolds.

Cartilage degeneration in the goat knee caused by treating localized cartilage defects with metal implants.

OBJECTIVE: The purpose of the current study was to investigate the feasibility of applying defect-size femoral implants for the treatment of localized cartilage defects in a 1-year follow-up model. METHODS: In 13 goats, a medial femoral condyle defect was created in both knees. Defects were randomly treated by immediate placement of an oxidized zirconium (OxZr) (n=9) or cobalt-chromium (CoCr) implant (n=9) or left untreated (n=8). Six un-operated knee joints served as a control. Animals were sacrificed at 52 weeks. Joints were evaluated macroscopically. Cartilage quality was analyzed macroscopically and microscopically and cartilage repair of untreated defects was scored microscopically. Glycosaminoglycan (GAG) content, release and synthesis were measured in tissue and medium. Implant osseointegration was measured by automated histomorphometry. RESULTS: Cartilage repair score of the defects was 13.3+/-3.0 out of 24 points (0=no repair, 24=maximal repair). Articular evaluation scores decreased (indicative of degeneration) in untreated defects and in defects treated with either implant (P<0.05). Macroscopical, microscopical and biochemical analysis showed that the presence of untreated defects and the implants caused considerable degeneration of medial tibial plateau, and to a lesser extent of the lateral compartment. Mean bone-implant contact was extensive and not different between materials (39.5+/-28.1% for OxZr and 42.3+/-31.5% for CoCr) (P=0.873). CONCLUSIONS: Considerable cartilage degeneration was induced in the articulating cartilage of the medial tibial plateau 1 year after creating an osteochondral defect in the medial femoral condyle. Treating this defect with a small metal implant, made of either OxZr or CoCr, could not prevent this degeneration. Further optimization of defect-size implants and their placement is required to make this the therapy of choice for the treatment of local cartilage defects.

Formalin fixation affects equilibrium partitioning of an ionic contrast agent-microcomputed tomography (EPIC-µCT) imaging of osteochondral samples.

OBJECTIVE: Equilibrium Partitioning of an Ionic Contrast agent with microcomputed tomography (EPIC-µCT) is a non-invasive technique to quantify and visualize the three-dimensional distribution of glycosaminoglycans (GAGs) in fresh cartilage tissue. However, it is unclear whether this technique is applicable to already fixed tissues. Therefore, this study aimed at investigating whether formalin fixation of bovine cartilage affects X-ray attenuation, and thus the interpretation of EPIC-µCT data. DESIGN: Osteochondral samples (n=24) were incubated with ioxaglate, an ionic contrast agent, for 22h prior to µCT scanning. The samples were scanned in both formalin-fixed and fresh conditions. GAG content was measured using a biochemical assay and normalized to wet weight, dry weight, and water content to determine potential reasons for differences in X-ray attenuation. RESULTS: The expected zonal distribution of contrast agent/GAGs was observed for both fixed and fresh cartilage specimens. However, despite no significant differences in GAG concentrations or physical properties between fixed and fresh samples, the average attenuation levels of formalin-fixed cartilage were 14.3% lower than in fresh samples. CONCLUSIONS: EPIC-µCT is useful for three-dimensional visualization of GAGs in formalin-fixed cartilage. However, a significant reduction in X-ray attenuation for fixed (compared to fresh) cartilage must be taken into account and adjusted for accordingly when quantifying GAG concentrations using EPIC-µCT.

Efficacy of one-stage cartilage repair using allogeneic mesenchymal stromal cells and autologous chondron transplantation (IMPACT) compared to nonsurgical treatment for focal articular cartilage lesions of the knee: study protocol for a crossover randomized controlled trial.

BACKGROUND: Articular cartilage defects in the knee have poor intrinsic healing capacity and may lead to functional disability and osteoarthritis (OA). "Instant MSC Product accompanying Autologous Chondron Transplantation" (IMPACT) combines rapidly isolated recycled autologous chondrons with allogeneic MSCs in a one-stage surgery. IMPACT was successfully executed in a first-in-man investigator-driven phase I/II clinical trial in 35 patients. The purpose of this study is to compare the efficacy of IMPACT to nonsurgical treatment for the treatment of large (2-8 cm2) articular cartilage defects in the knee. METHODS: Sixty patients will be randomized to receive nonsurgical care or IMPACT. After 9 months of nonsurgical care, patients in the control group are allowed to receive IMPACT surgery. The Knee Injury and Osteoarthritis Outcome Score (KOOS), pain (numeric rating scale, NRS), and EuroQol five dimensions five levels (EQ5D-5 L) will be used to compare outcomes at baseline and 3, 6, 9, 12, and 18 months after inclusion. Cartilage formation will be assessed at baseline, and 6 and 18 months after inclusion using MRI. An independent rheumatologist will monitor the onset of a potential inflammatory response. (Severe) adverse events will be recorded. Lastly, the difference between IMPACT and nonsurgical care in terms of societal costs will be assessed by monitoring healthcare resource use and productivity losses during the study period. A health economic model will be developed to estimate the incremental cost-effectiveness ratio of IMPACT vs. nonsurgical treatment in terms of costs per quality adjusted life year over a 5-year time horizon. DISCUSSION: This study is designed to evaluate the efficacy of IMPACT compared to nonsurgical care. Additionally, safety of IMPACT will be assessed in 30 to 60 patients. Lastly, this study will evaluate the cost-effectiveness of IMPACT compared to nonsurgical care. TRIAL REGISTRATION: NL67161.000.18 [Registry ID: CCMO] 2018#003470#27 [EU-CTR; registered on 26 March 2019] NCT04236739 [ ClinicalTrials.gov ] [registered after start of inclusion; 22 January 2020].

Validation of the Knee Injury and Osteoarthritis Outcome Score (KOOS) for the treatment of focal cartilage lesions.

OBJECTIVE: To validate the Knee Injury and Osteoarthritis Outcome Score (KOOS) for the treatment of focal cartilage lesions. METHODS: A total of 40 patients (mean age 35+/-12 years), treated for a focal cartilage lesion in the knee were included in this study. Test-retest data were collected with an intermediate period of 2 days. Patients were asked to complete the Dutch KOOS and complementary questionnaires [short form-36 (SF-36), Lysholm, EuroQol-5D (EQ-5D)] to evaluate the clinimetric properties of the KOOS in terms of internal consistency (Cronbach's alpha), reliability [intra-class-correlation (ICC) and Bland and Altman plots], construct validity (Spearman's rank correlation), floor and ceiling effects and responsiveness. RESULTS: The Cronbach's alpha of the KOOS subdomains and total score ranged from 0.74 to 0.96. The overall ICC of the KOOS was 0.97 while the subscales ranged from 0.87 to 0.95. The Bland and Altman plots showed a small individual variance between the two assessments in time. Spearman's rank correlations between the subscales of the KOOS and representative subscales of the SF-36, Lysholm and EQ-5D were high to moderate ranging from 0.43 to 0.70. We observed no floor effect while the largest observed ceiling effect was 10.3%. The responsiveness was moderate to large with the effect size ranging from 0.70 to 1.32 and the standardized response mean 0.61 to 0.87. CONCLUSION: This study illustrates the validity and reliability of the KOOS in measuring the clinical condition of patients after treatment of focal cartilage lesions. This study provides a basis for the use of the KOOS for future clinical research in cartilage repair.

[Local treatment for persistent inflammatory arthritis of the knee: intra-articular injection of glucocorticoids and bed rest]. / Lokale behandeling van persisterende inflammatoire artritis van de knie: intra-articulaire injecties met glucocorticoïden en bedrust.

Two studies evaluating treatment options for persistent mono-arthritis are discussed. In one study arthroscopic lavage plus intra-articular glucocorticoids was compared with arthroscopic lavage without glucocorticoids, and with joint aspiration plus glucocorticoids. Both intra-articular glucocorticoids and lavage have their merits, but glucocorticoids appear to be slightly more effective. In the second study radioactive Yttrium plus intra-articular glucocorticoids was compared with glucocorticoids alone. Yttrium provided little additional value. There are some indications that a period of strict bed rest after treatment is beneficial. Intra-articular glucocorticoids should not be administered more frequently than three times per year in the same joint.