Proteome plasticity during Physcomitrium patens spore germination - from the desiccated phase to heterotrophic growth and reconstitution of photoautotrophy.

The establishment of moss spores is considered a milestone in plant evolution. They harbor protein networks underpinning desiccation tolerance and accumulation of storage compounds that can be found already in algae and that are also utilized in seeds and pollen. Furthermore, germinating spores must produce proteins that drive the transition through heterotrophic growth to the autotrophic plant. To get insight into the plasticity of this proteome, we investigated it at five timepoints of moss (Physcomitrium patens) spore germination and in protonemata and gametophores. The comparison to previously published Arabidopsis proteome data of seedling establishment showed that not only the proteomes of spores and seeds are functionally related, but also the proteomes of germinating spores and young seedlings. We observed similarities with regard to desiccation tolerance, lipid droplet proteome composition, control of dormancy, and ß-oxidation and the glyoxylate cycle. However, there were also striking differences. For example, spores lacked any obvious storage proteins. Furthermore, we did not detect homologs to the main triacylglycerol lipase in Arabidopsis seeds, SUGAR DEPENDENT1. Instead, we discovered a triacylglycerol lipase of the oil body lipase family and a lipoxygenase as being the overall most abundant proteins in spores. This finding indicates an alternative pathway for triacylglycerol degradation via oxylipin intermediates in the moss. The comparison of spores to Nicotiana tabacum pollen indicated similarities for example in regards to resistance to desiccation and hypoxia, but the overall developmental pattern did not align as in the case of seedling establishment and spore germination.

Plasticity of the Arabidopsis leaf lipidome and proteome in response to pathogen infection and heat stress.

Plants must cope with a variety of stressors during their life cycle, and the adaptive responses to these environmental cues involve all cellular organelles. Among them, comparatively little is known about the contribution of cytosolic lipid droplets (LDs) and their core set of neutral lipids and associated surface proteins to the rewiring of cellular processes in response to stress. Here, we analyzed the changes that occur in the lipidome and proteome of Arabidopsis (Arabidopsis thaliana) leaves after pathogen infection with Botrytis cinerea or Pseudomonas syringae, or after heat stress. Analyses were carried out in wild-type plants and the oil-rich double mutant trigalactosyldiacylglycerol1-1 sugar dependent 1-4 (tgd1-1 sdp1-4) that allowed for an allied study of the LD proteome in stressed leaves. Using liquid chromatography-tandem mass spectrometry-based methods, we showed that a hyperaccumulation of the primary LD core lipid triacylglycerol is a general response to stress and that acyl chain and sterol composition are remodeled during cellular adaptation. Likewise, comparative analysis of the LD protein composition in stress-treated leaves highlighted the plasticity of the LD proteome as part of the general stress response. We further identified at least two additional LD-associated proteins, whose localization to LDs in leaves was confirmed by confocal microscopy of fluorescent protein fusions. Taken together, these results highlight LDs as dynamic contributors to the cellular adaptation processes that underlie how plants respond to environmental stress.

SEED LIPID DROPLET PROTEIN1, SEED LIPID DROPLET PROTEIN2, and LIPID DROPLET PLASMA MEMBRANE ADAPTOR mediate lipid droplet-plasma membrane tethering.

Membrane contact sites (MCSs) are interorganellar connections that allow for the direct exchange of molecules, such as lipids or Ca2+ between organelles, but can also serve to tether organelles at specific locations within cells. Here, we identified and characterized three proteins of Arabidopsis thaliana that form a lipid droplet (LD)-plasma membrane (PM) tethering complex in plant cells, namely LD-localized SEED LD PROTEIN (SLDP) 1 and SLDP2 and PM-localized LD-PLASMA MEMBRANE ADAPTOR (LIPA). Using proteomics and different protein-protein interaction assays, we show that both SLDPs associate with LIPA. Disruption of either SLDP1 and SLDP2 expression, or that of LIPA, leads to an aberrant clustering of LDs in Arabidopsis seedlings. Ectopic co-expression of one of the SLDPs with LIPA is sufficient to reconstitute LD-PM tethering in Nicotiana tabacum pollen tubes, a cell type characterized by dynamically moving LDs in the cytosolic streaming. Furthermore, confocal laser scanning microscopy revealed both SLDP2.1 and LIPA to be enriched at LD-PM contact sites in seedlings. These and other results suggest that SLDP and LIPA interact to form a tethering complex that anchors a subset of LDs to the PM during post-germinative seedling growth in Arabidopsis.

Hydrogel-based and spheroid-based autologous chondrocyte implantation of the knee show similar 2-year functional outcomes: An analysis based on the German Cartilage Registry (KnorpelRegister DGOU).

PURPOSE: To compare short-term patient-reported outcomes (PRO) of two contemporary matrix-associated autologous chondrocyte implantation (M-ACI) products for the treatment of large articular cartilage defects of the knee. METHODS: A retrospective, registry-based, matched-pair analysis was performed, comparing PRO of patients undergoing isolated M-ACI with either Spherox™, a spheroid-based ACI (Sb-ACI), or NOVOCART™ Inject, a hydrogel-based ACI product (Hb-ACI), for a focal full-thickness cartilage defect of the knee ≥4 cm2. Matching parameters included age, sex, body mass index, defect size, defect localization, symptom duration and previous surgeries. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the International Knee Documentation Committee (IKDC) score were obtained up to the 24-month follow-up. The total KOOS response rate and percentage of patients attaining a substantial clinical benefit (SCB) in KOOS subscores were calculated. RESULTS: A total of 45 patients per group were matched. The response rate after 24 months was not significantly different between the groups (Sb-ACI 64.4% vs. Hb-ACI 82.2%, p = 0.057). The number of patients with a SCB at 24 months was not significantly different in any KOOS subscore, despite significantly higher improvement of the total KOOS (14.8 ± 16.2 vs. 21.5 ± 15.4, p = 0.047) and KOOS pain in the Hb-ACI group (12.2 ± 18.6 vs. 20.6 ± 19.1, p = 0.037). The IKDC score in the Hb-ACI group was significantly higher at the 12- and 24-month follow-up (60.7 ± 20.2 vs. 70.9 ± 18.0, p = 0.013). CONCLUSION: The response rate and number of patients achieving an SCB were not significantly different between patients treated with Sb-ACI or Hb-ACI. Both procedures can achieve favourable 2-year PRO. Hb-ACI was associated with better PRO between 1 and 2 years postoperatively; however, the clinical relevance of this benefit is yet to be proven. LEVEL OF EVIDENCE: III, Retrospective comparative study.

The role of autologous bone grafting in matrix-associated autologous chondrocyte implantation at the knee: Results from the German Cartilage Registry (KnorpelRegister DGOU).

PURPOSE: To investigate whether concomitant autologous bone grafting adversely affects clinical outcome and graft survival after matrix-associated autologous chondrocyte implantation (M-ACI). METHODS: The present study examines registry data of patients who underwent M-ACI with or without autologous bone grafting for large-sized chondral or osteochondral defects. Propensity score matching was performed to exclude potential confounders. A total of 215 patients with similar baseline characteristics were identified. Clinical outcome was assessed at the time of surgery and at 6, 12, 24, 36 and 60 months using the Knee Injury and Osteoarthritis Outcome Score (KOOS). KOOS change, clinical response rate, KOOS subcomponents and failure rate were determined. RESULTS: Patients treated with M-ACI and autologous bone grafting achieved comparable clinical outcomes compared with M-ACI alone. At 24 months postoperatively, the patient-reported outcome (PRO) of patients treated with M-ACI and autologous bone grafting was even significantly better as measured by KOOS (74.9 ± 18.8 vs. 79.2 ± 15.4; p = 0.043). However, the difference did not exceed the minimal clinically important difference (MCID). In patients with M-ACI and autologous bone grafting, a greater change in KOOS relative to baseline was observed at 6 (9.3 ± 14.7 vs. 15.0 ± 14.7; p = 0.004) and 12 months (12.6 ± 17.2 vs. 17.7 ± 14.6; p = 0.035). Overall, a high clinical response rate was observed in both groups at 24 months (75.8% vs. 82.0%; p = n.s.). The estimated survival at the endpoint of reoperation for any reason was 82.1% (SD 2.8) at 8.4 years for isolated M-ACI and 88.7% (SD 2.4) at 8.2 years for M-ACI with autologous bone grafting (p = 0.039). CONCLUSIONS: Even in the challenging cohort of large osteochondral defects, the additional treatment with autologous bone grafting leads to remarkably good clinical outcomes in patients treated with M-ACI. In fact, they tend to benefit more from surgery, have lower revision rates and achieve clinical response rates earlier. Subchondral bone management is critical to the success of M-ACI and should be addressed in the treatment of borderline defects. LEVEL OF EVIDENCE: Level III.

Platelet-rich plasma injections for the management of knee osteoarthritis: The ESSKA-ICRS consensus. Recommendations using the RAND/UCLA appropriateness method for different clinical scenarios.

PURPOSE: The aim of this consensus was to develop evidence- and expert-based patient-focused recommendations on the appropriateness of intra-articular platelet-rich plasma (PRP) injections in different clinical scenarios of patients with knee osteoarthritis (OA). METHODS: The RAND/UCLA Appropriateness Method was used by the European Society of Sports Traumatology, Knee Surgery, and Arthroscopy (ESSKA), as well as the International Cartilage Regeneration and Joint Preservation Society (ICRS) to reach a consensus and produce recommendations for specific patient categories combining best available scientific evidence with the collective judgement of a panel of experts. RESULTS: Scenarios were defined based on first treatment vs first injective treatment vs second injective treatment, age (<50/50-65/66-80/>80), tibiofemoral vs patellofemoral involvement, OA level (Kellgren-Lawrence/KL 0-I/II-III/IV), and joint effusion (dry knee, minor-mild or major effusion). Out of 216 scenarios, in 84 (38.9%) the indication was considered appropriate, in 9 (4.2%) inappropriate and in 123 (56.9%) uncertain. The parameters associated with the highest consensus were PRP use after failed injective treatments (62.5%), followed by PRP after failed conservative treatments and KL 0-III scenarios (58.3%), while the highest uncertainty was found for PRP use as first treatment and KL IV OA (91.7% and 87.5% of uncertain scenarios, respectively). CONCLUSION: This ESSKA-ICRS consensus established recommendations on the appropriateness or inappropriateness of PRP injections for the treatment of knee OA, providing a useful reference for clinical practice. PRP injections are considered appropriate in patients aged ≤80 years with knee KL 0-III OA grade after failed conservative non-injective or injective treatments, while they are not considered appropriate as first treatment nor in KL IV OA grade. LEVEL OF EVIDENCE: Level I.

A seed-like proteome in oil-rich tubers.

There are numerous examples of plant organs or developmental stages that are desiccation-tolerant and can withstand extended periods of severe water loss. One prime example are seeds and pollen of many spermatophytes. However, in some plants, also vegetative organs can be desiccation-tolerant. One example are the tubers of yellow nutsedge (Cyperus esculentus), which also store large amounts of lipids similar to seeds. Interestingly, the closest known relative, purple nutsedge (Cyperus rotundus), generates tubers that do not accumulate oil and are not desiccation-tolerant. We generated nanoLC-MS/MS-based proteomes of yellow nutsedge in five replicates of four stages of tuber development and compared them to the proteomes of roots and leaves, yielding 2257 distinct protein groups. Our data reveal a striking upregulation of hallmark proteins of seeds in the tubers. A deeper comparison to the tuber proteome of the close relative purple nutsedge (C. rotundus) and a previously published proteome of Arabidopsis seeds and seedlings indicates that indeed a seed-like proteome was found in yellow but not purple nutsedge. This was further supported by an analysis of the proteome of a lipid droplet-enriched fraction of yellow nutsedge, which also displayed seed-like characteristics. One reason for the differences between the two nutsedge species might be the expression of certain transcription factors homologous to ABSCISIC ACID INSENSITIVE3, WRINKLED1, and LEAFY COTYLEDON1 that drive gene expression in Arabidopsis seed embryos.

Bipolar Lesions of the Knee Are Associated With Inferior Clinical Outcome Following Articular Cartilage Regeneration. A Propensity Score-Matched Analysis Including 238 Patients of the German Cartilage Registry (KnorpelRegister DGOU).

PURPOSE: To determine whether bipolar lesions (BL) are associated with inferior clinical outcome following articular cartilage regeneration (CR) compared to unipolar lesions (UL). METHODS: A registry-based study, including patients undergoing isolated CR for focal knee cartilage lesions was performed. Lesions were considered UL or BL depending on the opposing cartilage. Propensity score matching was applied to eliminate potential confounders. Two groups comprising 119 patients with similar baseline characteristics were matched. The Knee Injury and Osteoarthritis Outcome Score (KOOS) at baseline, 6, 12, 24, and 36 months following CR served as primary outcome measure. KOOS improvement, reaching the minimal clinically important difference (MCID), KOOS subcomponents, and failure rates were calculated. RESULTS: Autologous chondrocyte implantation (ACI) was the most frequently performed procedure in both groups with 63.0% (BL) and 46.6% (UL). There was a significant difference regarding KOOS at 24 months between UL (76.39 ± 14.96) and BL (69.83 ± 18.83; P = .028), which did not exceed the threshold of MCID. No significant difference was detected at any other follow-up. KOOS improvement from baseline was lower in the BL group at all follow-ups and peaked at 36 months in both groups (UL [26.00 ± 16.12] vs. BL [16.63 ± 17.29]; P = .024). The failure rate in the BL group was higher at 8.2% (9/110) compared to the UL group at 3.9% (4/98) (P = .256). CONCLUSIONS: BL were associated with worse clinical outcome 2 years following CR compared to UL. However, both groups showed an ongoing clinical improvement up to 3 years postoperatively and a low failure rate. While inferior clinical improvement and a lower clinical response rate may be expected in BL patients, the observed differences do not justify excluding these patients from CR. LEVEL OF EVIDENCE: Level III, retrospective comparative prognostic trial.

The German Arthroscopy Registry DART: what has happened after 5 years?

PURPOSE: The German Arthroscopy Registry (DART) has been initiated in 2017 with the aim to collect real-life data of patients undergoing knee, shoulder, hip or ankle surgery. The purpose of this study was to present an overview of the current status and the collected data thus far. METHODS: Data entered between 11/2017 and 01/2022 were analyzed. The number of cases (each case is defined as a single operation with or without concomitant procedures) entered for each joint, follow-up rates and trends between different age groups (18-29 years, 30-44 years, 45-64 years, ≥ 65 years) and across genders, and quality of life improvement (pre- vs. 1 year postoperative EQ visual analogue scale [EQ-VAS]) for frequently performed procedures (medial meniscus repair [MMR] vs. rotator cuff repair [RCR] vs. microfracturing of the talus [MFX-T]) were investigated. RESULTS: Overall, 6651 cases were entered into DART, forming three distinct modules classified by joint (5370 knee, 1053 shoulder and 228 ankle cases). The most commonly entered procedures were: knee: partial medial meniscectomy (n = 2089), chondroplasty (n = 1389), anterior cruicate ligament reconstruction with hamstring autograft (n = 880); shoulder: sub acromial decompression (n = 631), bursectomy (n = 385), RCR (n = 359); ankle: partial synovectomy (n = 117), tibial osteophyte resection (n = 72), loose body removal (n = 48). In the knee and shoulder modules, middle-aged patients were the predominant age group, whereas in the ankle module, the youngest age group was the most frequent one. The two oldest age groups had the highest 1-year follow-up rates across all modules. In the knee and shoulder module, 1-year follow-up rates were higher in female patients, whereas follow-up rates were higher in male patients in the ankle module. From pre- to 1-year postoperative, MFX-T (EQ-VAS: 50.0 [25-75% interquartile range: 31.8-71.5] to 75.0 [54.3-84.3]; ∆ + 25.0) led to a comparably larger improvement in quality of life than did MMR (EQ-VAS: 70.0 [50.0-80.0] to 85.0 [70.0-94.0]; ∆ + 15.0) or RCR (EQ-VAS: 67.0 [50.0-80.0] to 85.0 [70.0-95.0]; ∆ + 18.0). CONCLUSION: DART has been sufficiently established and collects high-quality patient-related data with satisfactory follow-up allowing for a comprehensive analysis of the collected data. The current focus lies on improving patient enrolment and follow-up rates as well as initiating the hip module.

Increased risk of reoperation and failure to attain clinically relevant improvement following autologous chondrocyte implantation of the knee in female patients and individuals with previous surgeries: a time-to-event analysis based on the German cartilage registry (KnorpelRegister DGOU).

PURPOSE: This study aimed to analyze the risk of reoperation following autologous chondrocyte implantation (ACI) of the knee utilizing third-generation ACI products in a time-to-event analysis and report on the associated patient-reported outcome measures (PROM) in case of reoperation. METHODS: Patients undergoing ACI were included from a longitudinal database. Patient age, sex, body mass index (BMI), number of previous surgeries, lesion localization, lesion size, symptom duration, as well as time and type of reoperation was extracted. A cox proportional-hazards model was applied to investigate the influence of baseline variables on risk of reoperation. Reoperation was defined as any type of subsequent ipsilateral knee surgery, excluding hardware removal. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was utilized to compare PROM between patients with and without reoperation. RESULTS: A total of 2039 patients were included with 1359 (66.7%) having a minimum follow-up of 24 months. There were overall 243 reoperations (prevalence 17.9%). Minor arthroscopic procedures (n = 96, 39.5%) and revision cartilage repair procedures (n = 78, 32.1%) were the most common reoperations. Nineteen patients (0.9%) reported conversion arthroplasty at 17.7 (10.4) months after ACI. Female sex (HR 1.5, 95% CI [1.2, 2.0], p = 0.002) and the presence of 1-2 previous surgeries (HR 1.5, 95% CI [1.1, 2.0], p = 0.010), or more than 2 previous surgeries (HR 1.9, 95% CI [1.2, 2.9], p = 0.004) were significantly associated with increased risk of reoperation following ACI. Significantly less patients surpassed the minimal clinically important difference (MCID) in the reoperation group at 24 months regarding the KOOS subscores pain (OR 1.6, 95% CI [1.1, 2.2]), quality of life (OR 2.2, 95% CI [1.6, 3.2]), symptoms (OR 2.0 [1.4, 2.9]), and sports (OR 2.0 [1.4, 2.8]). CONCLUSION: Female patients and individuals with a history of previous surgeries face an elevated risk of requiring reoperation after undergoing ACI, which is associated with failure to attain clinically relevant improvements. A thorough evaluation of the indications for ACI is paramount, particularly when patients have a history of previous surgeries. LEVEL OF EVIDENCE: Level III.

Sustained superiority in KOOS subscores after matrix-associated chondrocyte implantation using spheroids compared to microfracture.

PURPOSE: To evaluate the safety and efficacy of matrix-associated autologous chondrocyte implantation (ACI) using spheroids in comparison to arthroscopic microfracture for the treatment of symptomatic cartilage defects of the knee. METHODS: In a prospective multicenter-controlled trial, patients aged between 18 and 50 years, with single symptomatic focal cartilage defects between 1 and 4 cm2 (mean 2.6 ± 0.8, median 2.75, range 1.44-5.00) in the knee were randomized to treatment with ACI with spheroids (n = 52) or microfracture (n = 50). Primary clinical outcome was assessed by the Knee Injury and Osteoarthritis Outcome Score (KOOS). Analyses were performed in a defined hierarchical manner where outcomes of ACI were first compared to baseline values followed by a comparison to the microfracture group with repeated-measures ANCOVA with a non-inferiority approach. Subgroup analyses were performed to investigate the influence of age and defect size on the overall KOOS. Secondary clinical outcomes were the magnetic resonance observation of cartilage repair tissue (MOCART), modified Lysholm score and International Knee Documentation Committee (IKDC) examination form. Safety data focused on adverse events. Here the 5 years results are presented at which there were 33 observed cases in the ACI group and 30 in the microfracture group. RESULTS: The overall KOOS and its five subscores were significantly improved compared to baseline for both the ACI and microfracture group. Non-inferiority of ACI to microfracture was confirmed for the overall KOOS and the subscores, while for the subscores activities of daily living, quality of life and sports and recreation of the threshold for superiority was passed. In the ACI group, a notably more rapid initial improvement of the KOOS was found at three months for the older age group compared to the younger age group and the microfracture group. No other differences were found based on age or defect size. In addition, clinical improvement was found for the MOCART, modified Lysholm and IKDC examination form both the ACI and microfracture group. No safety concern related to either treatment was observed. CONCLUSION: This study confirms the safety and efficacy of matrix-associated ACI with spheroids at a mid to long-term follow-up. Non-inferiority of ACI to microfracture was confirmed for the overall KOOS and all subscores, while superiority was reached for the subscores activities of daily living, quality of life and sports and recreation in the ACI group. This underlines the importance of ACI for the young and active patients. LEVEL OF EVIDENCE: I.

Current practice of concomitant surgeries in cartilage repair of the femorotibial compartment of the knee: baseline data of 4968 consecutive patients from the German cartilage registry (KnorpelRegister DGOU).

INTRODUCTION: The treatment of underlying comorbidities is a field of rising interest in cartilage repair surgery. The aim of this study was to analyze the current practice of concomitant surgeries in cartilage repair of the knee especially in the medial or lateral femorotibial compartment. Type, frequency and distribution of additional surgeries for correction of malalignment, knee instability and meniscus deficiency should be evaluated. METHODS: Baseline data of 4968 patients of the German Cartilage Registry (KnorpelRegister DGOU) were analyzed regarding the distribution of concomitant surgeries in addition to regenerative cartilage treatment. RESULTS: Beyond 4968 patients 2445 patients with cartilage defects in the femorotibial compartment of the knee could be identified. Of these patients 1230 (50.3%) received additional surgeries for correction of malalignment, instability and meniscus deficiency. Predominant procedures were leg axis corrections (31.3%), partial meniscectomy (20.9%) and ACL reconstruction (13.4%). The distribution of the concomitant surgeries varied between cartilage defects according to the different defect genesis. Patients with traumatic defects were younger (36y) and received predominantly ACL reconstructions (29.2%) (degenerative: 6.7%), whereas patients with degenerative defects were older (43y) and underwent predominantly leg axis corrections (38.0%; traumatic: 11.0%). CONCLUSIONS: This study shows the high frequency and distinct distribution of the concomitant surgeries in addition to regenerative cartilage treatment procedures. Understanding of the underlying cause of the cartilage defect and addressing the comorbidities as a whole joint therapy are of utmost importance for a successful regenerative cartilage treatment. These data provide a baseline for further follow up evaluations and long-term outcome analysis. LEVEL OF EVIDENCE: II.

Patellofemoral cartilage defects are acceptable in patients undergoing high tibial osteotomy for medial osteoarthritis of the knee.

BACKGROUND: Patients suffering cartilage defects of the medial compartment with underlying varus deformity do benefit from high tibial osteotomy (HTO) even in the long term. Nonetheless, kinematic and geometric changes especially in the patellofemoral joint have been described. Purpose of the present study was to evaluate the influence of patellofemoral cartilage defects detected during the diagnostic arthroscopy and their influence on HTO's postoperative outcome. METHODS: Ninety patients with a mean follow-up of 10.08 ± 2.33 years after surgery were included. Patients were divided into four groups according to their cartilage status in the patellofemoral joint (A = no defects, B = isolated lesions of the patella, C = isolated lesions of the trochlea, D = kissing lesions). Functional outcome was evaluated before surgery and about ten years thereafter by relying on the IKDC, Lysholm, and KOOS scores. Radiological parameters were assessed pre- and six weeks postoperatively. RESULTS: In groups A to D, the HTO led to significant patellar distalisation in the sagittal view, with the mean indices remaining at or above the limit to a patella baja. All patients in all groups profited significantly from HTO (higher Lysholm score, lower VAS p < 0.001), patients in group D had the lowest outcome scores. Patella height negatively influenced outcome scores in group C (Blackburne-Peel-Index-VAS p = 0.033) and D (Caton-Deschamps-Index-Tegner p = 0.018), a larger valgus correction was associated with lower outcome scores in group D (Lysholm p = 0.044, KOOSpain 0.028, KOOSQOL p = 0.004). CONCLUSION: Long-term results of HTO for varus medial compartment osteoarthritis remain good to excellent even in the presence of patellofemoral defects. Overcorrection should be avoided. Distal biplanar HTO should be considered for patients presenting trochlear or kissing lesions of the patellofemoral joint. TRIAL REGISTRATION: DRKS00015733 in the German Registry of Clinical Studies.

Autologous chondrocyte implantation combined with anterior cruciate ligament reconstruction: similar short-term results in comparison with isolated cartilage repair in ligament intact joints.

PURPOSE: Both acute ruptures of the anterior cruciate ligament (ACL) as well as chronic ACL insufficiency show a high association with focal cartilage defects of the knee. However, the results after combined ACL reconstruction and cartilage repair are not well investigated. The aim of the present study was to investigate the short-term outcomes after autologous chondrocyte implantation (ACI) in combination with ACL reconstruction and to compare the results with patients who underwent isolated ACI in ligament intact knees. METHODS: All patients who were registered in the German Cartilage Registry with ACI for focal cartilage defects in the knee joint in combination with ACL reconstruction and who completed the 24 month follow-up were included in the study group. A matched-pair procedure according to gender, defect location, defect size, and age was used to create a control group of patients with isolated ACI in ACL intact joints. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the numeric analog scale for pain (NAS) were used to assess the preoperative state as well as the clinical outcomes 12 and 24 months after surgery. RESULTS: A total of 34 patients were included in both the study group (age mean 33.3 ± SD 8.8 years) and the control group (33.6 ± 8.4 years) with a median defect size of 466 (25%-75% IQR 375-600) mm2 and 425 (IQR 375-600) mm2, respectively. In comparison with the preoperative state (median 67, IQR 52-75), the study group showed a significant increase of the total KOOS after 12 months (78, IQR 70-86; p = 0.014) and after 24 months (81, IQR 70-84; p = 0.001). The NAS for pain did not change significantly in the postoperative course. In comparison with the control group there was no significant difference for the total KOOS neither preoperative (control group median 67, IQR 52-73) nor at any postoperative time point (12 months: 82, IQR 67-93; 24 months: 81, IQR 71-91). CONCLUSION: The clinical short-term outcomes after ACI at the knee joint in combination with ACL reconstruction are good and similar to the results after isolated ACI in ligament intact knees. LEVEL OF EVIDENCE: III.

The lack of retropatellar resurfacing at index surgery is significantly associated with failure in patients following patellofemoral inlay arthroplasty: a multi-center study of more than 260 patients.

PURPOSE: To evaluate the clinical outcomes of patients with a minimum 2-year follow-up following contemporary patellofemoral inlay arthroplasty (PFIA) and to identify potential risk factors for failure in a multi-center study. METHODS: All patients who underwent implantation of PFIA between 09/2009 and 11/2016 at 11 specialized orthopedic referral centers were enrolled in the study and were evaluated retrospectively at a minimum 2-year follow-up. Clinical outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Tegner Scale, the visual analogue scale (VAS) for pain, and subjective patient satisfaction. Pre- and perioperative risk factors were compared among failures and non-failures to determine potential risk factors. RESULTS: A total of 263 patients (85% follow-up rate) could be enrolled. The mean age at the time of index surgery was 49 ± 12 years with a mean postoperative follow-up of 45 ± 18 months. The overall failure rate was 11% (28 patients), of which 18% (5 patients) were patients with patella resurfacing at index surgery and 82% (23 patients) were patients without initial patella resurfacing. At final follow-up, 93% of the patients who did not fail were satisfied with the procedure with a mean transformed WOMAC Score of 84.5 ± 14.5 points, a mean KOOS Score of 73.3 ± 17.1 points, a mean Tegner Score of 3.4 ± 1.4 points and a mean VAS pain of 2.4 ± 2.0 points. An increased BMI was significantly correlated with a worse postoperative outcome. Concomitant procedures addressing patellofemoral instability or malalignment, the lack of patellofemoral resurfacing at the index surgery and a high BMI were significantly correlated with failure in our patient cohort. CONCLUSION: Patellofemoral inlay arthroplasty shows high patient satisfaction with good functional outcomes at short-term follow-up and thus can be considered a viable treatment option in young patients suffering from isolated patellofemoral arthritis. Patellar resurfacing at index surgery is recommended to decrease the risk of failure. LEVEL OF EVIDENCE: Retrospective case series, Level IV.

Factors correlating with patients' satisfaction after undergoing cartilage repair surgery-data from the German Cartilage Registry (KnorpelRegister DGOU).

Subjective patient satisfaction is the most relevant parameter for assessing the success of treatment after orthopaedic surgery. The aim of the present study was to correlate patient-reported outcome parameters (i.e., absolute KOOS, KOOS increase) and revision-free survival with patient's satisfaction. Furthermore, the study aimed on the identification of pre-operative factors that are associated with patient's satisfaction after the surgery.For the present study, 6305 consecutive patients from the German Cartilage Registry (KnorpelRegister DGOU) were analyzed. Patient characteristics and outcome were correlated with patients' satisfaction after a follow-up of three years by Spearman correlation. P values < 0.05 were considered statistically significant.Mean age was 37 ± 12.5 years, 59.7% patients were male, and 40.3% female. Most patients (46.7%) were treated with an autologous chondrocyte implantation (ACI). The strongest correlation of subjective satisfaction and the subscore quality of life (r = 0.682; p < 0.001) was found, whereas the post-operative increase in KOOS from the pre-operative value showed only a moderate correlation (r = 0.520; p < 0.001). There was also a significant correlation with the absolute KOOS value (r = 0.678; p < 0.001), the subscores pain (r = 0.652; p < 0.001), quality of life (r = 0.682; p < 0.001), and sports (r = 0.633; p < 0.001), whereas symptoms (r = 0.504, p < 0.001) and activities of daily life (r = 0.601; p < 0.001) showed a weaker correlation. Pain also correlated highly significant with the patient satisfaction 24 months after surgery (r = - 0.651, p < 0.001). The correlation between satisfaction after the 2nd and 3rd year (r = 0.727; p < 0.001) is stronger than correlation after six months and three years (r = 0.422, p < 0.001). All pre-operative parameters show a very weak correlation (r < 0.1).The use of standardized measuring instruments (KOOS and Pain) is a relevant outcome parameter in science and clinical practice, whereas absolute values represent satisfaction better than the individual increase. The subscores "pain," "quality of life," and "sports" represent satisfaction better than the subscores "symptoms" and "activity of daily life." Early satisfaction has only a moderate predictive value for satisfaction after 3 years, which is of great practical relevance in particular for the assessment of potential treatment failures. It is remarkable to note that a revision surgery is only very mildly associated with increased dissatisfaction. Pre-operative factors are not reliable prediction factors for post-operative patient satisfaction.

Parameters affecting baseline hip function in patients with cam-derived femoroacetabular impingement syndrome: data analysis from the German Cartilage Registry.

BACKGROUND: Using the database of the German Cartilage Registry (KnorpelRegister DGOU), this study aims to present patient- and joint-related baseline data in a large cohort of patients with cam-derived femoroacetabular impingement syndrome (FAI) and to detect symptom-determining factors. MATERIALS AND METHODS: Requiring cam morphology as the primary pathology, 362 patients were found to be eligible for inclusion in the study. The assessment of preoperative baseline data was performed using the patient-reported outcome measure-International Hip Outcome Tool (iHOT-33). Descriptive statistics were performed to present baseline data. Univariate and multiple regression with post hoc testing were used to identify patient- and joint-related factors that might affect the preoperative iHOT-33 and its subscores, respectively. RESULTS: The study collective's mean age was 36.71 ± 10.89 years, with 246 (68%) of them being male. The preoperative mean iHOT-33 total was 46.31 ± 20.33 with the subsection "sports and recreational activities" presenting the strongest decline (26.49 ± 20.68). The parameters "age," "sex," "body mass index" (BMI), and the confirmation of "previous surgery on the affected hip" were identified to statistically affect the preoperative iHOT-33. In fact, a significantly lower mean baseline score was found in patients aged > 40 years (p < 0.001), female sex (p < 0.001), BMI ≥ 25 kg/m2 (p = 0.002) and in patients with previous surgery on the affected hip (p = 0.022). In contrast, the parameters defect grade and size, labral tears, and symptom duration delivered no significant results. CONCLUSIONS: A distinct reduction in the baseline iHOT-33, with mean total scores being more than halved, was revealed. The parameters "age > 40 years," "female sex," "BMI ≥ 25," and confirmation of "previous surgery on the affected hip" were detected as significantly associated with decreased preoperative iHOT-33 scores. These results help to identify symptom-defining baseline characteristics of cam-derived FAI syndrome. TRIAL REGISTRATION: The German Cartilage Registry is conducted in accordance with the Declaration of Helsinki and registered at germanctr.de (DRKS00005617). Registered 3 January 2014-retrospectively registered. The registration of data was approved by the local ethics committees of every participating institution. Primary approval was given by the ethics committee at the University of Freiburg (No. 105/13). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00005617.

Safety and efficacy of matrix-associated autologous chondrocyte implantation with spheroid technology is independent of spheroid dose after 4 years.

PURPOSE: The aim of this study was to investigate the effect of product dose in autologous chondrocyte implantation (ACI) for the treatment of full-thickness cartilage defects of the knee and to assess its influence on clinical and morphological mid-term outcome. METHODS: Seventy-five patients were included in this single-blind, randomised, prospective, controlled clinical trial. Patients were assigned randomly to three different dose groups [low (3-7 spheroids/cm2), medium (10-30 spheroids/cm2), or high (40-70 spheroids/cm2)] and assessed using standardised clinical and morphological scoring systems (KOOS, IKDC, MOCART) for 4 years following the intervention. RESULTS: The analysis population comprised 75 patients (22 women, 53 men) aged 34 ± 9 years. Defect sizes ranged from 2 to 10 cm2 following intraoperative debridement. The assessment of the primary variable 'overall KOOS' showed a statistically significant improvement, compared with baseline, for each dose group, i.e., at baseline the mean 'overall KOOS' scores were 60.4 ± 13.6, 59.6 ± 15.4, and 51.1 ± 15.4 for the low-, medium-, and high-dose groups, respectively, and 57.0 ± 15.2 for 'all patients'. After 48 months those values improved to 80.0 ± 14.7, 84.0 ± 14.9, and 66.9 ± 21.5 in the respective dose groups and 77.1 ± 18.6 for 'all patients'. Pairwise comparisons of these dose groups did not reveal any statistically significant differences. Likewise, assessment of the subjective IKDC score revealed no statistically significant differences between the three dose groups up to the 48-month visit. However, between 12 and 48 months there was a low, but steady, improvement in the low-dose group and a substantial amelioration in the medium-dose group. The mean MOCART total scores 3 months after treatment were 59.8 ± 10.9, 64.5 ± 10.3, and 64.7 ± 9.4 for the low-, medium-, and high-dose groups, and 62.9 ± 10.3 for 'all patients'; 48 months after treatment these were 73.9 ± 13.1, 78.0 ± 12.4, and 74.3 ± 14.0 for the respective dose groups and 75.5 ± 13.1 for 'all patients'. CONCLUSIONS: Results of this study confirm the efficacy and safety of the applied "advanced therapy medicinal product"; no dose dependence was found either for the incidence or for the severity of any adverse reactions. All doses applied in the present study led to significant clinical improvement over time and can therefore be regarded as effective doses. The influence of product doses in the range investigated seems to be low and can be neglected. Thus, the authorised dose range of 10-70 spheroids/cm2 confirmed by this clinical trial offers a broad therapeutic window for the surgeon applying the product, thereby reducing the risk of over- or underdosing. LEVEL OF EVIDENCE: I.

Decision making for concomitant high tibial osteotomy (HTO) in cartilage repair patients based on a nationwide cohort study of 4968 patients.

BACKGROUND: High tibial osteotomy (HTO) for varus deformities is a common concomitant treatment in cartilage surgery. Aim of the present study was to analyze factors influencing the decision towards accompanying HTO in patients with cartilage defects of the medial femoral condyle, such as the amount of varus deformity. METHODS: Data from 4986 patients treated for cartilage defects of the knee from the German Cartilage Registry (KnorpelRegister DGOU) were used for the current analysis. Seven hundred and thirty-six patients fulfilled the inclusion criteria. Their data were analyzed for factors influencing the decision towards performing a concomitant HTO using t test, univariate and multivariate binary logistic regression models. RESULTS: The break point at which the majority of patients receive a concomitant HTO is 3° of varus deformity. Several factors apart from the amount of varus deformity (5.61 ± 2.73° vs. 1.72 ± 2.38°, p < 0.00) differed significantly between the group of patients with HTO and those without. These included defect size (441.6 ± 225.3 mm2 vs. 386.5 ± 204.2 mm2, p = 0.001), symptom duration (29.53 ± 44.58 months vs. 21.85 ± 34.17 months, p = 0.021), defect grade (62.5% IVa/IVb vs. 57.3% IVa/IVb, p = 0.014), integrity of corresponding joint surface (10.8% grade III-IV vs. 0.2% grade III-IV, p < 0.001), meniscus status (15.5% > 1/3 resected vs. 4.4% > 1/3 resected, p < 0.001) and number of previous surgeries (1.01 ± 1.06 vs. 0.75 ± 1.00, p = 0.001). In the stepwise multivariate binary logistic regression test, only the amount of varus deformity, symptom duration and quality of the corresponding joint surface remained significant predictors associated with performing a concomitant HTO. CONCLUSION: Based upon data from a nationwide cohort, additional HTO in context with cartilage repair procedures of the medial femoral condyle is frequently performed even in mild varus deformities less than 5°. Other factors also seem to influence decision for HTO.

Is debridement beneficial for focal cartilage defects of the knee: data from the German Cartilage Registry (KnorpelRegister DGOU).

INTRODUCTION: Focal cartilage defects of the knee are often treated with arthroscopic debridement. Existing literature discussing the benefit of debridement for small articular cartilage lesions is scarce, especially if the debridement was not part of a combined operative cartilage procedure including meniscal and ligament repair. The purpose of this study was to examine the patients´ benefit after arthroscopic debridement for the treatment of isolated focal chondral defects with or without partial meniscus resection. MATERIALS AND METHODS: Baseline (preoperative data) and 12-month follow-up of the five Knee Osteoarthritis Outcome Score (KOOS) subscores and the Numeric Rating Scale (NRS) for pain were analyzed in 126 patients undergoing debridement for focal chondral defects of the knee from the German Cartilage Registry. Sub-analysis for patients receiving isolated debridement and debridement with concomitant partial resection of meniscal pathologies was performed. Thus, four subgroups were created according to the treated defect size and presence of meniscal pathologies: "debridement-only < 2 cm2", "debridement-only > 2 cm2", "debridement and partial meniscus resection < 2 cm2" and "debridement and partial meniscus resection > 2 cm2". RESULTS: KOOS-subscores showed a significant increase from baseline to follow-up evaluation (p = 0.017-0.037) within the 126 patients. Sub-analysis showed significant improvement of all five KOOS-subscores in all three subgroups, except for the "debridement and partial meniscus resection > 2 cm2"-group: in this group the KOOS subscores symptoms and sports showed no significant improvement. The NRS scores revealed no significant changes from baseline to 12-month follow-up within the four subgroups. CONCLUSION: An overall benefit of arthroscopic debridement for focal cartilage lesions of the knee could be conducted. Isolated cartilage defects seem to benefit from debridement irrespectively of size. In patients with large cartilage defects (> 2 cm2) and concurrent meniscal pathology expectation to improvement should be humbled. Effective reduction of pain by arthroscopic debridement remains unclear.