Controversies in regenerative medicine: should knee joint osteoarthritis be treated with mesenchymal stromal cells?

Knee joint osteoarthritis is a complex immunological and degenerative disease. Current treatment strategies fail to alter its progression. Mesenchymal stromal cell (MSC) therapy for osteoarthritis has been object of research for more than 30 years. The aim of MSC therapy is intended to be holistic, with regeneration of all affected knee joint structures. The paracrine effect of the MSC secretome has been shown to be central for the regenerative capacity of MSCs. Activation of local knee-joint-specific MSCs leads to an immunomodulatory, anti-catabolic, anti-apoptotic and chondrogenic stimulus. Preclinical models have demonstrated the symptom- and disease-modifying effects of MSC therapy. At the bedside, there is evidence that autologous and allogeneic MSC therapy shows significant improvement in symptom-modifying and functional outcome. Despite this, a variety of contradictory clinical outcomes are available in the literature. The effectiveness of MSC therapy is still unclear, although there have been promising results. Regarding the diversity of cell sources, isolation, culture protocols and other factors, a comparison of different studies is difficult. Clinical translation of disease-modifying effects has not yet been shown. This narrative review presents a controversial overview of the current preclinical and clinical studies on MSC therapy in knee joint osteoarthritis.

Correlation of the Histological ICRS II Score and the 3D MOCART Score for the Analysis of Aged Osteochondral Regenerates in a Large Animal Model.

OBJECTIVE: Reliable outcome measures are essential to predict the success of cartilage repair techniques. Histology is probably the gold standard, but magnetic resonance imaging (MRI) has the potential to decrease the need for invasive histological biopsies. The 3D magnetic resonance observation of cartilage repair tissue (MOCART) score is a reliable yet elaborate tool. Moreover, literature is controversial concerning the correlation of histology and MRI. DESIGN: To test the applicability of the International Cartilage Regeneration and Joint Preservation Society (ICRS) II and MOCART 3D score for the evaluation of aged osteochondral regenerates in a large animal model, and to identify correlating histological and MRI parameters. Osteochondral defects in medial femoral condyles of n = 12 adult sheep were reconstructed with biodegradable bilayer implants. About 19.5 months postoperation, n = 10 joints were analyzed with MRI (3D MOCART score). Histological samples were analyzed using the ICRS II score; both pre- and post-training. The intraclass correlation coefficient, the inter-rater reliability, and the 95% confidence interval were calculated. Matching histological and MRI parameters were tested for correlation. RESULTS: We found a statistically significant correlation of all histological parameters. MRI parameters reflecting "overall" assessments had very strong inter-rater correlations. Statistically significant strong correlations were found for the MRI parameters defect filling, cartilage interface, bone interface, and surface. For defect overall (MRI) and overall assessment (ICRS II), we found a significant yet mild correlation. CONCLUSIONS: The ICRS II and the 3D MOCART score are applicable to aged osteochondral regenerates. Prior training on the scoring systems is essential. Select MRI and histological parameters correlate; however, the only statistically significant correlation was found for overall assessment.

Evaluation of the influence of platelet-rich plasma (PRP), platelet lysate (PL) and mechanical loading on chondrogenesis in vitro.

The aim of this work is to investigate the capability of PRP as an adjuvant therapy to autologous chondrocyte implantation (ACI) in combination with multi-axial load with respect to cartilage regeneration. Articular cartilage shows poor repair capacity and therapies for cartilage defects are still lacking. Well-established operative treatments include ACI, and growing evidence shows the beneficial effects of PRP. Platelets contain numerous growth factors, among them transforming growth factor beta (TGF-ß). Dynamic mechanical loading is known to be essential for tissue formation, improving extracellular matrix (ECM) production. For our ACI model monolayer expanded human chondrocytes were seeded into polyurethane scaffolds and embedded in fibrin (hChondro), in PRP-Gel (PRP), or in fibrin with platelet lysate (PL), which was added to the media once a week with a concentration of 50 vol%. The groups were either exposed to static conditions or multi-axial forces in a ball-joint bioreactor for 1 h per day over 2 weeks, mimicking ACI under physiological load. The culture medium was collected and analyzed for glycosaminoglycan (GAG), nitrite and transforming growth factor beta 1 (TGF-ß1) content. The cell-scaffold constructs were collected for DNA and GAG quantification; the expression of chondrogenic genes, TGF-ß and related receptors, as well as inflammatory genes, were analyzed using qPCR. Loading conditions showed superior chondrogenic differentiation (upregulation of COL2A1, ACAN, COMP and PRG4 expression) than static conditions. PRP and PL groups combined with mechanical loading showed upregulation of COL2A1, ACAN and COMP. The highest amount of total TGF-ß1 was quantified in the PL group. Latent TGF-ß1 was activated in all loaded groups, while the highest amount was found in the PL group. Load increased TGFBR1/TGFBR2 mRNA ratio, with further increases in response to supplements. In general, loading increased nitrite release into the media. However, over time, the media nitrite content was lower in the PL group compared to the control group. Based on these experiments, we conclude that chondrogenic differentiation is strongest when simulated ACI is performed in combination with dynamic mechanical loading and PRP-gel or PL supplementation. An inflammatory reaction was reduced by PRP and PL, which could be one of the major therapeutic effects. Loading presumably can enhance the action of TGF-ß1, which was predominantly activated in loaded PL groups. The combination of load and PRP represents an effective and promising synergy concerning chondrocyte-based cartilage repair.

Microfracture combined with anterior cruciate ligament reconstruction compared to isolated microfractures for osteochondral lesions.

There is limited evidence whether increased growth-factor and stem-cell influx during bone tunnel drilling for ACL-reconstruction enhances clinical results of microfracture treatment of small cartilage defects. The goal of this study was to compare clinical and radiological results in patients treated with microfracture alone and patients treated with microfracture plus ACL-reconstruction. A total of 67 patients that were either treated with microfracture alone (primary stable knees, n= 40) or microfracture plus ACL-reconstruction (ACL deficient knees, n= 27) were included and prospectively evaluated. Subjects were preoperatively assessed radiologically using the MR-based AMADEUS-score (Area Measurement and Depth & Underlying Structures) and clinically using the Lysholm-score before the intervention. At minimum 24-month follow-up, the regenerate tissue was assessed by the MR-based MOCART-score (Magnetic resonance observation of cartilage repair tissue) and by use of the Lysholm-Tegner-score for clinical evaluation. Preoperatively both groups had similar AMADEUS-scores. The Lysholm-score was significantly higher in the microfracture group (p < 0.001). In the postoperative assessment there was a significant difference (p = 0.04) in the MOCART-score in favor of the microfracture plus ACL-reconstruction group. The Lysholm-score significantly improved (p <0.001) in the microfracture plus ACL-reconstruction group and was significantly higher than in the microfracture group (p = 0.004). Conclusion: A combination of microfracture and ACL-reconstruction leads to comparable functional results, yet superior MOCART-scores as compared to microfracture alone. ACL reconstruction enhances biological healing responses in microfracture treated cartilage and thus improves clinical outcomes by additional bone marrow influx from bone tunnels.

Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization.

OBJECTIVE: Lumican (LUM) is a major extracellular matrix glycoprotein in adult articular cartilage and its expression is known to be upregulated upon cartilage degeneration. LUM is associated with the pathogen-associated molecular pattern (PAMP) activation of the TLR4 signalling cascade, with TLR4 being highly associated with inflammation in rheumatic diseases. However, the main role of the LUM structural molecule in osteoarthritis (OA) remains elusive. The aim of this study was, therefore, to understand the role of LUM during TLR4-mediated activation in OA. METHODS: After measuring LUM levels in synovial fluid (SF) of OA patients and lipopolysaccharide (LPS)-induced TLR4 activation, the role of LUM in the expression of pro-inflammatory molecules and cartilage degradation was assessed in vitro and ex vivo in a cartilage explant model. Primary macrophage activation and polarization were studied upon LUM co-stimulation with LPS. RESULTS: We demonstrate that LUM is not only significantly upregulated in SF from OA patients compared to healthy controls, but also that LUM increases lipopolysaccharide (LPS)-induced TLR4 activation. Furthermore, we show that a pathophysiological level of LUM augments the LPS-induced TLR4 activation and expression of downstream pro-inflammatory molecules, resulting in extensive cartilage degradation. LUM co-stimulation with LPS also provided a pro-inflammatory stimulus, upregulating primary macrophage activation and polarization towards the M1-like phenotype. CONCLUSIONS: These findings strongly support the role of LUM as a mediator of PAMP-induced TLR4 activation of inflammation, cartilage degradation, and macrophage polarization in the OA joint and potentially other rheumatic diseases.

What are the factors to affect outcome and healing of meniscus bucket handle tears?

INTRODUCTION: The purpose of this study is to identify patient, meniscus rupture and surgical characteristics that influence the outcome and clinical healing following operative repair of bucket handle tears. METHODS: Between 02/2006 and 10/2012, a total of 38 patients (14 women, 24 men) with bucket handle tears underwent surgical meniscus repair. There were 27 isolated repairs and 11 with concomitant anterior cruciate ligament (ACL) replacement. Patients were analyzed on an average of 44.4 months (range 15-96 months) after surgery by the use of standardized subjective scoring instruments [Lysholm, International Knee Documentation Committee (IKDC), Knee Injury and Osteoarthritis Outcome Score (KOOS) and Tegner Activity Scale (TAS)]. To identify factors affecting the outcome and suture survival, patient-specific, trauma-specific as well as meniscus- and surgery-specific factors were collected. Patients were divided in two groups with healed menisci (group 1) and re-rupture subjects (group 2). Meniscus re-rupture was defined as a clinical failure. RESULTS: There were 25 patients with healed menisci and 13 (34.2%) that sustained re-rupture and underwent either partial meniscectomy (n = 8) or re-suture (n = 5). Group 1 achieved slightly higher outcome compared to group 2 [Lysholm: 87.8 vs. 84.3 (p = 0.35), IKDC: 86.9 vs. 85.7 (p = 0.67), KOOS: 91.3 vs. 90.5 (p = 0.74)]. TAS was better for group 2 [5.9 vs. 6.8 (p = 0.36)]. Strong impact to result in a significantly increased outcome was identified for higher age, subjective knee joint stability, high preoperative Lysholm Score, short trauma-to-repair time, previous ACL reconstruction and a smaller number of sutures to fulfill meniscus repair. Lower patient age, male gender and higher activity level had the strongest impact to provoke re-rupture. CONCLUSION: Clinical outcome after meniscus bucket handle suture is satisfying. Re-rupture rate among this collective was 34.2%. Clear risk factors were identified for diminished clinical healing and outcome.

Spontaneous Minced Cartilage Procedure for Unexpectedly Large Femoral Condyle Surface Defect.

Articular cartilage defects at the knee joint are being identified and treated with increasing frequency. Chondrocytes may have strongest potential to generate high-quality repair tissue within the defective region, in particular when large diameter defects are present. Autologous chondrocyte implantation is not available in every country. We present a case where we spontaneously covered an acute cartilage defect, which was significantly larger than expected and loose during initial arthroscopic inspection after reading preoperative MRI, by mincing the separated fragment and directly implanting the autologous cartilage chips into the defective region.

Current status of anti-inflammatory therapy for posttraumatic osteoarthritis.

Although there is ample evidence that intra-articular injuries are associated with the up-regulation of pro-inflammatory cytokines, the success of anti-inflammatory, disease-modifying treatments to prevent posttraumatic osteoarthritis (PTOA) remain uncertain. To summarize the current status of anti-inflammatory therapy for PTOA, we conducted a systematic review. 9 clinical studies in humans were identified applying anti-inflammatory agents to prevent or treat PTOA. A total of 347 patients aged an average 41 ±â€ˆ14 years were included in this review. 5 studies had comparable designs with randomized allocation. Those studies of course had a statistically significant higher Coleman Methodology Score (65 ±â€ˆ6) than the case-control studies (39 ±â€ˆ13, p = 0.013). The most frequently reported main outcome parameter was pain assessed by different scales (n = 7), the most examined joint the knee (n = 7). The majority of the analyses (n = 6) focused on the intra-articular (IA) application of hyaluronic acid (HA) reporting mainly positive effects. One study stated positive results following IA administration of Interleukin 1 receptor antagonist in -patients presenting rupture of the anterior cruciate ligament. Platelet-rich plasma was also used to relieve symptoms following acute injury, but the study quality was too low to conclude any effects. Although the initial data, especially regarding IA HA injection, are encouraging, study designs differ substantially. Therefore, current data does not allow us to conclude that anti-inflammatory therapy following acute injuries has beneficial effects on short- or long-term outcomes.

Risk factors for heterotopic ossification and spur formation after total knee arthroplasty.

INTRODUCTION: The present study investigated the incidence and risk factors of heterotopic ossification (HO) after implantation of knee prosthesis. MATERIALS AND METHODS: We undertook a retrospective cohort study in 434 cases (363 patients) treated with a total knee replant using a Press-Fit-Condylar (P.F.C.(®)Sigma(®)) prosthesis. The occurrence of HO in radiograph after a follow-up period of 11.2 ± 2.4 months was correlated in a regression model with a variety of influencing factors. RESULTS: 21 patients (4.8 %) developed heterotopic ossifications, all located in the area of the distal femur. The only risk factor found concerning the development of HO was osteoarthritis when compared to rheumatoid arthritis (OR = 4.07, 95 % CI 1.18-14.05; p = 0.0201) and postoperative wound healing problems (OR = 11.32, 95 % CI 3.26-39.33; p = 0.0001). Notching (OR = 2.22, 95 % CI 0.92-5.36; p = 0.0765) and osteophyte forming (hypertrophic) arthrosis (OR = 2.40, 95 % CI 0.97-5.95; p = 0.0596), however, were associated with the development of a bony spur in the contact area of the femoral component of the prosthesis. CONCLUSIONS: Our study has revealed that patients with rheumatoid arthritis are at lower risk of HO than patients with osteoarthritis. An impairment of wound healing would appear to promote the development of a HO. Notching and hypertrophic arthrosis are highly likely to be associated with the development of a bony spur in the ventral contact area of the prosthesis.

Alignment does not influence cartilage T2 in asymptomatic knee joints.

PURPOSE: To investigate whether the static knee alignment affects articular cartilage ultrastructures when measured using T2 relaxation among asymptomatic subjects. METHODS: Both knee joints (n = 96) of 48 asymptomatic volunteers (26 females, 22 males; 25.4 ± 1.7 years; no history of major knee trauma or surgery) were evaluated clinically (Lysholm, Tegner) and by MRI (hip-knee-ankle angle, standard knee protocol, T2 mapping). Group (n = 4) division was as follows: neutral (<1° varus/valgus), mild varus (2°-4° varus), severe varus (>4° varus) and valgus (2°-4° valgus) deformity with n = 12 subjects/group; n = 24 knees/group. Regions of interest (ROI) for T2 assessment were placed within full-thickness cartilage across the whole joint surface and were divided respecting compartmental as well as functional joint anatomy. RESULTS: Leg alignment was 0.7° ± 0.5° varus among neutral, 3.0° ± 0.6° varus among mild varus, 5.0° ± 1.1° varus among severe varus and 2.5° ± 0.7° valgus among valgus group subjects and thus significantly different. No differences between the groups emerged from clinical measures. No morphological pathology was detected in any knee joint. Global T2 values (42.3 ± 2.3; 37.7-47.9 ms) of ROIs placed within every knee joint per subject were not different between alignment groups or between genders, respectively. CONCLUSION: Static frontal plane leg malalignment does not affect cartilage ultrastructure among young, asymptomatic individuals as measured by T2 quantitative imaging. LEVEL OF EVIDENCE: Cross-sectional study, Level II-III.

[Cartilage biopsy for autologous chondrocyte implantation (ACI)]. / Die Knorpelbiopsie im Rahmen der autologen Knorpelzelltransplantation (ACT).

Autologous chondrocyte implantation (ACI) is an established two-step procedure for the treatment of full-thickness cartilage defects of the knee. Cartilage harvest from the affected knee joint represents the first step of this procedure and is essential for further in vitro expansion of autologous chondrocytes. Nevertheless, the cartilage biopsy process itself is underrepresented in the scientific literature and currently there is only a limited amount of data available addressing this process. Biopsy location as well as the technique itself and instruments used for cartilage collection are not well defined and only little standardisation can be found. The article describes the relevant aspects of the biopsy in the context of ACI with regard to the literature available. Follow-up studies to better define and standardise the cartilage biopsy process are thus required.

Microporous calcium phosphate ceramics as tissue engineering scaffolds for the repair of osteochondral defects: Histological results.

Treatment of defects in joint cartilage aims to re-establish normal joint function. In vitro experiments have shown that the application of synthetic scaffolds is a promising alternative to existing therapeutic options. A sheep study was conducted to test the suitability of microporous pure ß-tricalcium phosphate (TCP) ceramics as tissue engineering scaffolds for the repair of osteochondral defects. Cylindrical plugs of microporous ß-TCP (diameter: 7mm; length: 25mm; porosity: 43.5±2.4%; pore diameter: ~5µm) with interconnecting pores were used. Scaffolds were seeded with autologous chondrocytes in vitro and cultured for 4weeks. A drill hole (diameter 7mm) was placed in both medial femoral condyles of sheep. For the left knee the defect was filled with a TCP plug and for the right knee the defect was left empty. After 6, 12, 26 and 52weeks, seven animals from each group were killed and studied. The samples were examined employing histological, histomorphometric and immunohistological methods as well as various imaging techniques (X-ray, microcomputer tomography and scanning electron microscopy). After explantation the cartilage defects were first assessed macroscopically. There were no signs of infection or inflammation. Histological grading scales were used for assessment of bony integration and cartilage repair. An increasing degradation (81% after 52weeks) of the ceramic with concomitant bone formation was observed. The original structure of cancellous bone was almost completely restored. After 26 and 52weeks, collagen II-positive hyaline cartilage was detected in several samples. New subchondral bone had formed. The formation of cartilage began at the outer edge and proceeded to the middle. According to the O'Driscoll score, values corresponding to healthy cartilage were not reached after 1year. Integration of the newly formed cartilage tissue into the surrounding native cartilage was found. The formation of biomechanical stable cartilage began at the edge and progressed towards the centre of the defect. After 1year this process was still not completed. Microporous ß-TCP scaffolds seeded with chondrocytes are suitable for the treatment of osteochondral defects.

Autologous chondrocyte implantation in children and adolescents.

PURPOSE: Autologous chondrocyte implantation (ACI) is a well-established treatment method for cartilage defects in knees. Age-related grouping was based on expression data of cartilage-specific markers. Specificities of ACI in the different populations were analysed. METHODS: Two hundred and sixty-seven patients undergoing ACI in the knee between 2006 and 2010 were included in this analysis. Cell characteristics and expression data of cartilage-specific surface markers as CD44, aggrecan and collagen type II were statistically analysed for age association. Epidemiological data of the defined groups were compared. Course of treatment was evaluated using MRI. RESULTS: A correlation analysis showed statistically significant associations between age and aggrecan or collagen type II expression in all patients <30 years. A cluster analysis could predict age-dependent expression of these markers separating groups with an average age of 18.1 ± 2.3 and 23.6 ± 4.2 years, respectively (p < 0.02). Discriminance analysis suggested the age border between adults and juveniles at about 20 years. There was no influence of age on cell characteristics or CD44 expression. In the 19 of 267 patients with an age ≤18 years, gender distribution was not different compared to adults, but patella was significantly more affected. Cartilage lesions were mainly caused by osteochondritis dissecans (OCD) and trauma. The Knee Osteoarthritis Scoring System in MRI reached 4.8 ± 2.3 points before, declining to 3.3 ± 2.3 points 6 and 12 months after the operation. CONCLUSIONS: Age-related expression of cartilage-specific markers allows definition of adolescents in cartilage regenerating surgery. Chondromalacia in these patients is mainly caused by OCD or trauma. LEVEL OF EVIDENCE: Case series, Level IV.

Microporous calcium phosphate ceramics as tissue engineering scaffolds for the repair of osteochondral defects: biomechanical results.

This work investigated the suitability of microporous ß-tricalcium phosphate (TCP) scaffolds pre-seeded with autologous chondrocytes for treatment of osteochondral defects in a large animal model. Microporous ß-TCP cylinders (Ø 7 mm; length 25 mm) were seeded with autologous chondrocytes and cultured for 4 weeks in vitro. Only the upper end of the cylinder was seeded with chondrocytes. Chondrocytes formed a multilayer on the top. The implants were then implanted in defects (diameter 7 mm) created in the left medial femoral condyle of ovine knees. The implants were covered with synovial membrane from the superior recess of the same joint. For the right knees, an empty defect with the same dimensions served as control. Twenty-eight sheep were split into 6-, 12-, 26- and 52 week groups of seven animals. Indentation tests with a spherical (Ø 3mm) indenter were used to determine the biomechanical properties of regenerated tissue. A software-based limit switch was implemented to ensure a maximal penetration depth of 200 µm and maximal load of 1.5 N. The achieved load, the absorbed energy and the contact stiffness were measured. Newly formed cartilage was assessed with the International Cartilage Repair Society Visual Assessment Scale (ICRS score) and histomorphometric analysis. Results were analysed statistically using the t-test, Mann-Whitney U-test and Wilcoxon test. Statistical significance was set at p<0.05. After 6 weeks of implantation, the transplanted area tolerated an indentation load of 0.05±0.20 N. This value increased to 0.10±0.06 N after 12 weeks, to 0.27±0.18 N after 26 weeks, and 0.27±0.11 N after 52 weeks. The increase in the tolerated load was highly significant (p<0.0001), but the final value was not significantly different from that of intact cartilage (0.30±0.12 N). Similarly, the increase in contact stiffness from 0.87±0.29 N mm-(1) after 6 weeks to 3.14±0.86 N mm(-1) after 52 weeks was highly significant (p<0.0001). The absorbed energy increased significantly (p=0.02) from 0.74×10(-6)±0.38×10(-6) Nm after 6 weeks to 2.83×10(-6)±1.35×10(-6) Nm after 52 weeks. At 52 weeks, the International Cartilage Repair Society (ICRS) scores for the central area of the transplanted area and untreated defects were comparable. In contrast, the score for the area from the edge to the centre of the transplanted area was significantly higher (p=0.001) than the score for the unfilled defects. A biomechanically stable cartilage was built outside the centre of defect. After 52 weeks, all but one empty control defect were covered by bone and a very thin layer of cartilage (ICRS 7 points). The empty hole could still be demonstrated beneath the bone. The histomorphometric evaluation revealed that 81.0±10.6% of TCP was resorbed after 52 weeks. The increase in TCP resorption and replacement by spongy bone during the observation period was highly significant (p<0.0001). In this sheep trial, the mechanical properties of microporous TCP scaffolds seeded with transplanted autologous chondrocytes were similar to those of natural cartilage after 52 weeks of implantation. However, the central area of the implants had a lower ICRS score than healthy cartilage. Microporous TCP was almost fully resorbed at 52 weeks and replaced by bone.

Clinical outcome following the first-line, single lesion microfracture at the knee joint.

CASE SERIES: Level of evidence, 4. BACKGROUND: Arthroscopic microfracture of chondral defects across the knee joint is a frequent treatment modality. There is only limited information on the clinical outcome in patients without previous surgery and single lesions. PURPOSE: Evaluation of clinical outcome following microfracture in patients without previous surgery and single lesions and identification of prognostic factors. METHODS: Inclusion criteria were patients with single-lesion knee joint first-line microfracturing at minimum 2 years postoperatively. Charts were reviewed to identify patient and defect characteristics. Clinical outcome was evaluated by IKDC and Lysholm knee scores, Tegner activity scale and a numeric analogue scale (NAS) for function and pain (10 = highest possible function, no pain). RESULTS: Totally, 145 patients (age at operation 47.92 ± 15.7) met inclusion criteria. Average defect size was 2.7 ± 1.9 cm(2). Postoperatively, IKDC was 73.1 ± 18.5, Lysholm 77.6 ± 19.1, Tegner 4.5 ± 1.7, NAS pain 6.5 ± 2.6 and NAS function 6.4 ± 2.3. Significantly better clinical outcome was observed in male patients than in female patients. Regression analysis including all patient and defect characteristics highlighted that singly the parameter shorter symptom duration (P = 0.018) significantly predicted an improved postoperative clinical outcome. CONCLUSION: Microfracturing results in a satisfying clinical outcome, but no full recovery in patients without previous surgery and single lesions. Specific parameters facilitate outcome prognosis and therefore may aid in indicating surgery.

Reoperative characteristics after microfracture of knee cartilage lesions in 454 patients.

PURPOSE: There is only limited information on those patients who fail following microfracture treatment at the knee joint. Evaluation was made of factors associated with treatment failure and clinical outcome assessment among this collective. METHODS: The study included a total of 560 patients who had previously undergone microfracture for the treatment of symptomatic knee joint cartilage lesions. For the remainder of this study, inclusion criteria were patients that underwent reoperation at the initially operated knee joint (index knee) due to symptoms related to the primary site of microfracture intervention (failure patients) with a minimum postoperative follow-up of 2 years. The remaining cohort of patients served as internal control (non-failure patients). Chart reviews were performed to identify patient and defect characteristics. Patients were evaluated for postoperative Lysholm knee scores, Tegner activity scale, as well as preoperative and postoperative numeric analogue scales (NAS) for function and pain (10 = highest possible function, no pain). RESULTS: A total of 454/560 (81.1 %) subjects were completely evaluated. Overall, 123/454 patients (26.9 %) (age at operation 43.9 ± 14.1 years, 56 female, BMI 25.8 ± 3.6, 30 smokers, 61.1 ± 68.3 month symptom duration, postoperative follow-up 5.0 ± 2.1) met the inclusion criteria. The postoperative Lysholm score was 63.0 ± 24.6 and the Tegner score was 4.0; NAS function improved from 2.8 ± 1.8 to 4.8 ± 2.2 (P < 0.001), and NAS pain improved from 3.2 ± 2.1 to 5.0 ± 2.4 (P < 0.001). Exclusively, the overall defect size/knee joint was smaller (P = 0.006), postoperative follow-up was longer (P = 0.002), and existense of previous surgery (77.2 vs. 51.6 %, P < 0.001) was more frequent in failure subjects when comparing to non-failure patients (n = 331). The overall clinical outcome among failure subjects was significantly worse when comparing to non-failure subjects. Regression analysis identified that lower preoperative NAS values, being a smoker, and patello-femoral lesions were associated with a higher probability of reoperation. CONCLUSION: Within the collective presented here, microfracturing was associated with a high frequency of reoperation. Clinical outcome is worse when compared with that of patients without reoperation. Specific parameters can be identified that increase the eventuality of failure following microfracture treatment. LEVEL OF EVIDENCE: IV.

[Factors that influence clinical outcome following autologous chondrocyte implantation for cartilage defects of the knee]. / Einflussfaktoren auf das Behandlungsergebnis nach autologer Knorpelzelltransplantation (ACT) am Kniegelenk.

AIM: Since its introduction in 1994, autologous chondrocyte implantation (ACI) has become an established surgical treatment for symptomatic isolated cartilage defects of the knee. Success rates vary between 80 and 95% and the clinical outcome seems to depend on various individual factors. The aim of the present review article is to summarise factors that affect clinical outcome following ACI for treatment of symptomatic cartilage defects of the knee based upon the scientific literature available on this topic. METHODS: The present publication represents a non-systematic review including publications which were considered relevant describing factors that influence clinical outcome following ACI for treatment of symptomatic full thickness cartilage defects of the knee. In order to identify relevant literature concerning complications following cartilage repair, medical databases including "medline", "ovid" and "web of science" were searched for the terms "autologous chondrocyte implantation", "autologous chondrocyte transplantation", "prognostic factor", "clinical outcome", "cartilage repair", "cartilage defect" and "cartilage regeneration". The literature search was performed in April 2010. RESULTS: Factors that influence clinical outcome following ACI for treatment of cartilage defects of the knee include patient-specific parameters on the one hand, such as body mass index, nicotine abusus, patients age, prior surgical treatment, duration of symptoms and more, and defect characteristics such as containment, defect location, defect size, number of defects treated, on the other hand. Furthermore, surgical technique, cell quality and rehabilitation seem to significantly influence the clinical outcome following autologous chondrocyte implantation. Among all factors identified as relevant for clinical outcome, some of these parameters are fixed and cannot be changed by either the surgeon nor the patient, while others can be influenced and even changed during the treatment and rehabilitation of a patient who underwent ACI. CONCLUSION: Knowledge of all relevant parameters that influence clinical outcome following ACI is essential in order to achieve an optimal clinical outcome in patients with cartilage defects of the knee. This paper presents a review of the scientific literature available which focuses on the questions as to what parameters influence the outcome of a patient following ACI for treatment of cartilage defects of the knee. No isolated factors could be identified that influence the outcome following ACI alone, but it seems that clinical outcome is influenced by many different parameters. These parameters should be considered carefully, at the time of decision about what kind of treatment is applied. Furthermore, the patient should be informed especially about those parameters which can be influenced by him-/herself in order to create good prerequisites for the surgical treatment.

A combination of shear and dynamic compression leads to mechanically induced chondrogenesis of human mesenchymal stem cells.

There is great interest in how bone marrow derived stem cells make fate decisions. Numerous studies have investigated the role of individual growth factors on mesenchymal stem cell differentiation, leading to protocols for cartilage, bone and adipose tissue. However, these protocols overlook the role of biomechanics on stem cell differentiation. There have been various studies that have applied mechanical stimulation to constructs containing mesenchymal stem cells, with varying degrees of success. One critical fate decision is that between cartilage and bone. Articular motion is a combination of compressive, tensile and shear deformations; therefore, one can presume that compression alone is unlikely to be a sufficient mechanical signal to generate a cartilage-like tissue in vitro. Within this study, we aimed to determine the role of shear on the fate of stem cell differentiation. Specifically, we investigated the potential enhancing effect of surface shear, superimposed on cyclic axial compression, on chondrogenic differentiation of human bone marrow-derived stem cells. Using a custom built loading device we applied compression, shear or a combination of both stimuli onto fibrin/polyurethane composites in which human mesenchymal stem cells were embedded, while no exogenous growth-factors were added to the culture medium. Both compression or shear alone was insufficient for the chondrogenic induction of human mesenchymal stem cells. However, the application of shear superimposed upon dynamic compression led to significant increases in chondrogenic gene expression. Histological analysis detected sulphated glycosaminoglycan and collagen II only in the compression and shear group. The results obtained may provide insight into post-operative care after cell therapy involving mesenchymal stromal cells.

[Chondrocytes - one cell type, different subpopulations : characteristics and behavior of different types of chondrocytes and implications for tissue engineering applications]. / Chondrozyten - ein Zelltyp, verschiedene Subpopulationen : Merkmale und Verhalten verschiedener Chondrozyten und Implikationen für deren Einsatz zum "Tissue Engineering"

Chondrocytes represent the most important cell source for engineering of cartilaginous tissues. Depending on the tissue type and the localization within the tissue, these cells may behave differently. Numerous studies have been done to compare articular, nasal, auricular, and costal chondrocytes in order to evaluate differences between knee and ankle joint cartilage and to investigate topographical variations within an articular joint. Moreover, the zonal structure of articular cartilage needs to be considered because it leads to phenotypical differences between chondrocytes of the superficial and the deeper zones. Several studies indicate, however, that even differentiated chondrocytes demonstrate a certain plasticity and strive to adapt their phenotypes to a new mechanical and biochemical environment. The aim of this review is to report on similarities and differences of chondrocytes from different tissues, zones, and topographical locations. In particular, an overview of recent results from comparative studies is presented, and possible consequences for the design of tissue engineering models are discussed.

T2 assessment and clinical outcome following autologous matrix-assisted chondrocyte and osteochondral autograft transplantation.

OBJECTIVE: Both, matrix-assisted chondrocyte transplantation (MACT) and osteochondral autograft transplantation (OCT), are applied for treatment of articular cartilage defects. While previous clinical studies have compared the respective outcome, there is no such information investigating the ultrastructural composition using T2 mapping comparing cartilage T2 values of the repair tissue (RT). METHODS: Eighteen patients that underwent MACT or OCT for treatment of cartilage defects at the knee joint (nine MACT, nine OCT) were matched for gender (one female, eight male pairs), age (33.8), body mass index (BMI) (28.3), defect localization, and postoperative interval (41.6 months). T2 assessment was accomplished by T2 maps, while the clinical evaluation included the Lysholm and Cincinnati knee scores, a visual analogue scale (VAS) for pain, the Tegner activity scale, and the Short Form-36. RESULTS: Global T2 values of healthy femoral cartilage (HC) were similar among groups, while T2 values of the RT following MACT (46.8ms, SD 8.6) were significantly lower when compared to RT T2 values after OCT (55.5ms, SD 6.7) (P=0.048). MACT values were also significantly lower in comparison to HC (52.5ms, SD 7.9) within MACT patients (P=0.046), while OCT values were significantly higher compared to HC (49.9ms, SD 5.1) within OCT patients (P=0.041). The clinical outcome following MACT was consistently superior to that after OCT while only the Lysholm score reached the level of significance (MACT 77.0, OCT 66.8; P=0.04). CONCLUSION: These findings indicate that MACT and OCT result in a different ultrastructural outcome, which is only partially represented by the clinical picture.