Intermediate-Term Clinical Outcomes of High-Density Autologous Chondrocyte Implantation in Patients with Concomitant Anterior Cruciate Ligament Reconstruction and Focal Chondral Lesions.

OBJECTIVE: To investigate intermediate-term clinical results in patients with concomitant anterior cruciate ligament (ACL) reconstruction and chondral defect treated with high-density autologous chondrocyte implantation (HD-ACI) compared to patients without ACL tear but with a chondral lesion and HD-ACI treatment. DESIGN: Forty-eight patients with focal chondral lesions underwent HD-ACI (24 with ACL reconstruction after an ACL injury and 24 with an intact ACL). Follow-up assessments occurred at 6, 12, and 24 months. Patient-reported knee function and symptoms were assessed using the International Knee Documentation Committee (IKDC) questionnaire, pain was measured using the Visual Analog Scale (VAS), and adverse events were monitored. Physical activity was assessed using the Tegner Activity Level Scale, and cartilage healing was evaluated with the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. RESULTS: No significant adverse events occurred during follow-up. Both groups showed significant improvements at 2 years compared to baseline (VAS: 8.0 ± 1.3 to 1.4 ± 2.0 [normal ACL]; 7.4 ± 2.3 to 2.1 ± 2.3 [ACL reconstruction]; IKDC: 39.2 ± 10.6 to 76.1 ± 22.0 [intact ACL]; 35.6 ± 12.1 to 74.6 ± 20.9 [ACL reconstruction]). Patients in both groups exceeded the minimal clinically important difference (MCID) for IKDC scores. The Tegner Activity Level Scale decreased immediately after surgery and increased after 2 years, with 70.6% (normal ACL) and 89.5% (ACL reconstruction) returning to their preinjury activity levels. No significant differences in the MOCART score were observed between the groups. CONCLUSIONS: ACL reconstruction does not appear to reduce the outcomes (at 2 years) of HD-ACI.

Cartilage Defect Treatment Using High-Density Autologous Chondrocyte Implantation (HD-ACI).

Hyaline cartilage's inability to self-repair can lead to osteoarthritis and joint replacement. Various treatments, including cell therapy, have been developed for cartilage damage. Autologous chondrocyte implantation (ACI) is considered the best option for focal chondral lesions. In this article, we aimed to create a narrative review that highlights the evolution and enhancement of our chondrocyte implantation technique: High-Density-ACI (HD-ACI) Membrane-assisted Autologous Chondrocyte Implantation (MACI) improved ACI using a collagen membrane as a carrier. However, low cell density in MACI resulted in softer regenerated tissue. HD-ACI was developed to improve MACI, implanting 5 million chondrocytes per cm2, providing higher cell density. In animal models, HD-ACI formed hyaline-like cartilage, while other treatments led to fibrocartilage. HD-ACI was further evaluated in patients with knee or ankle defects and expanded to treat hip lesions and bilateral defects. HD-ACI offers a potential solution for cartilage defects, improving outcomes in regenerative medicine and cell therapy. HD-ACI, with its higher cell density, shows promise for treating chondral defects and advancing cartilage repair in regenerative medicine and cell therapy.

Genome-wide CRISPR activation screening in senescent cells reveals SOX5 as a driver and therapeutic target of rejuvenation.

Our understanding of the molecular basis for cellular senescence remains incomplete, limiting the development of strategies to ameliorate age-related pathologies by preventing stem cell senescence. Here, we performed a genome-wide CRISPR activation (CRISPRa) screening using a human mesenchymal precursor cell (hMPC) model of the progeroid syndrome. We evaluated targets whose activation antagonizes cellular senescence, among which SOX5 outperformed as a top hit. Through decoding the epigenomic landscapes remodeled by overexpressing SOX5, we uncovered its role in resetting the transcription network for geroprotective genes, including HMGB2. Mechanistically, SOX5 binding elevated the enhancer activity of HMGB2 with increased levels of H3K27ac and H3K4me1, raising HMGB2 expression so as to promote rejuvenation. Furthermore, gene therapy with lentiviruses carrying SOX5 or HMGB2 rejuvenated cartilage and alleviated osteoarthritis in aged mice. Our study generated a comprehensive list of rejuvenators, pinpointing SOX5 as a potent driver for rejuvenation both in vitro and in vivo.

Consensus Delphi study on guidelines for the assessment of anterior cruciate ligament injuries in children.

BACKGROUND: Knee examination guidelines in minors are intended to aid decision-making in the management of knee instability. CLINICAL QUESTION: A Delphi study was conducted with a formal consensus process using a validated methodology with sufficient scientific evidence. A group consensus meeting was held to develop recommendations and practical guidelines for use in the assessment of instability injuries in children. KEY FINDINGS: there is a lack of evidence to analyse anterior cruciate ligament injuries in children and their subsequent surgical management if necessary. Diagnostic guidelines and clinical assessment of the patient based on a thorough examination of the knee are performed and a guide to anterior cruciate ligament exploration in children is developed. CLINICAL APPLICATION: In the absence of a strong evidence base, these established guidelines are intended to assist in that decision-making process to help the clinician decide on the most optimal treatment with the aim of benefiting the patient as much as possible. Following this expert consensus, surgical treatment is advised when the patient has a subjective sensation of instability accompanied by a pivot shift test ++, and may include an anterior drawer test + and a Lachman test +. If these conditions are not present, the conservative approach should be chosen, as the anatomical and functional development of children, together with a physiotherapy programme, may improve the evolution of the injury.

High-Density Autologous Chondrocyte Implantation as Treatment for Ankle Osteochondral Defects.

PURPOSE: Two-year follow-up to assess efficacy and safety of high-density autologous chondrocyte implantation (HD-ACI) in patients with cartilage lesions in the ankle. DESIGN: Twenty-four consecutive patients with International Cartilage repair Society (ICRS) grade 3-4 cartilage lesions of the ankle were included. Five million chondrocytes per cm2 of lesion were implanted using a type I/III collagen membrane as a carrier and treatment effectiveness was assessed by evaluating pain with the visual analogue scale (VAS) and American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score at baseline, 12-month, and 24-month follow-up, together with dorsal and plantar flexion. Magnetic resonance observation for cartilage repair tissue (MOCART) score was used to evaluate cartilage healing. Histological study was possible in 5 cases. RESULTS: Patients' median age was 31 years (range 18-55 years). Median VAS score was 8 (range 5-10) at baseline, 1.5 (range 0-8) at 12-month follow-up, and 2 (rang e0-5) at 24-month follow-up (P < 0.001). Median AOFAS score was 39.5 (range 29-48) at baseline, 90 (range 38-100) at 12-month follow-up, and 90 (range 40-100) at 24-month follow-up (P < 0.001). Complete dorsal flexion significantly increased at 12 months (16/24, 66.7%) and 24 months (17/24, 70.8%) with regard to baseline (13/24, 54.2%) (P = 0.002). MOCART at 12- and 24-month follow-ups were 73.71 ± 15.99 and 72.33 ± 16.21. Histological study confirmed that neosynthetized tissue was cartilage with hyaline extracellular matrix and numerous viable chondrocytes. CONCLUSION: HD-ACI is a safe and effective technique to treat osteochondral lesions in the talus, providing good clinical and histological results at short- and mid-term follow-ups.

In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche.

Short-term, systemic expression of the Yamanaka reprogramming factors (Oct-3/4, Sox2, Klf4 and c-Myc [OSKM]) has been shown to rejuvenate aging cells and promote tissue regeneration in vivo. However, the mechanisms by which OSKM promotes tissue regeneration are unknown. In this work, we focus on a specific tissue and demonstrate that local expression of OSKM, specifically in myofibers, induces the activation of muscle stem cells or satellite cells (SCs), which accelerates muscle regeneration in young mice. In contrast, expressing OSKM directly in SCs does not improve muscle regeneration. Mechanistically, expressing OSKM in myofibers regulates the expression of genes important for the SC microenvironment, including upregulation of p21, which in turn downregulates Wnt4. This is critical because Wnt4 is secreted by myofibers to maintain SC quiescence. Thus, short-term induction of the Yamanaka factors in myofibers may promote tissue regeneration by modifying the stem cell niche.

[Cell and molecular medicine in musculoskeletal system lession (sports) (healing cells)]. / Medicina celular y molecular en las lesiones del sistema músculo esquelético (deporte). (Células para curar).

In the last years a number of different tools which will be commonly used in the future have merged. Among them, the use of therapeutical cells (Cell Therapy) or the use of bio-active molecules after the identification of the molecular basis of a given pathology (Molecular Medicine), are two approaches. Currently, the autologous chondrocyte implantation to treat the articular cartilage lesions is considered as a consolidated therapy.

Proposal for a Clinical Analysis of Patellar Tendon Pathologies: In Search of Efficient Therapeutic Indications.

Development and advances in our understanding of basic sciences such as anatomy, biochemistry, histology, and biomechanics have led to a better knowledge of tendon injuries. Likewise, technological advances in available therapies have conditioned the rise of new therapeutic techniques, turning both diagnosis and therapeutic indications into the foundation of treatment for patellar tendon disorders. Furthermore, we often find no correlation between patellar tendon function and structure, as studied and diagnosed from images taken and referred symptoms. This statement proposes an analytic procedure that ensures a specific therapeutic goal instead of applying a specific drug or therapeutic technique, with the aim of establishing parameters that define the kind of tendinopathy clinicians see, taking into account all conditioning factors that may affect a patellar tendinopathy. These include etiological factors, systemic illnesses affecting tendons, local mechanical causes and clinical presentation, range of clinical presentations, symptom persistence, and pain location, as well as those factors described by echography, with or without the presence of neoangiogenesis and location of the pathology, and magnetic resonance imaging. Diagnosing patellar tendinopathies requires deployment of a complex and thorough assessment process for each individual case and should include all variables that basic sciences have provided. Once a diagnosis has been made, a therapeutic strategy that includes all existing variables should be established. The more precise a diagnosis is, the more selective the treatment options become.

Study of Telomere Length in Preimplanted Cultured Chondrocytes.

DESIGN: In the process of cell division, the extremes of the eukaryotic chromosomes are progressively shortening, and this phenomenon is related to cell degeneration and senescence. The treatment of cartilage lesions with autologous chondrocytes implies that cells proliferate in an artificial environment. We have studied the viability of cultured chondrocytes after measurement of their telomere length before implantation. METHODS: Articular cartilage biopsies (B1, B2, and B3) were obtained from 3 patients (2 males and 1 female) with knee cartilage defects, who were going to be treated with chondrocyte implantation. Chondrocytes were cultured in DMEM with autologous serum. After the third passage, an aliquot of 1 million cells was removed to estimate the telomere length and the remaining cells were implanted. Telomere length was measured by quantitative fluorescent in situ hybridization (Q-FISH). Patients' clinical outcome was determined preoperatively, and 12 and 24 months postimplantation with the International Knee Documentation Committee (IKDC) questionnaire. RESULTS: After chondrocyte implantation, IKDC score doubled at 12 and 24 months with regard to the basal value. After 3 passages, chondrocytes were cultured for a mean of 45.67 days, the mean duplication time being 4.53 days and the mean number of cell divisions being 10.04 during the culture period. The 20th percentile of telomere lengths were 6.84, 6.96, and 7.06 kbp and the median telomere lengths 10.30, 10.47, and 10.73 kbp, respectively. No significant correlation was found between IKDC score and telomere length. CONCLUSION: Culturing autologous chondrocytes for implantation is not related to cell senescence in terms of telomere length.

Mutations in foregut SOX2+ cells induce efficient proliferation via CXCR2 pathway.

Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2+ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as KrasG12D and p53 deletion. GFP-based lineage-tracing experiments indicate that SOX2+ cells are the cells-of-origin of esophagus and stomach hyperplasia. Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion. p53 homozygous deletion is required for the acquisition of an invasive potential, and KrasG12D expression, but not p53 deletion, suffices for tumor formation. Global gene expression analysis reveals secreting factors upregulated in the hyperplasia induced by oncogenic KRAS and highlights a crucial role for the CXCR2 pathway in driving hyperplasia. Collectively, the array of genetic models presented here demonstrate that stratified epithelial cells are susceptible to oncogenic insults, which may lead to a better understanding of tumor initiation and aid in the design of new cancer therapeutics.

Cartilage Defect Treatment Using High-Density Autologous Chondrocyte Implantation: Two-Year Follow-up.

OBJECTIVE: The aim of this work was to study the short- and mid-term effectiveness and safety of high-density autologous chondrocyte implantation (HD-ACI) in the first 50 patients with knee cartilage damage treated in our unit. DESIGN: Fifty consecutive patients with cartilage lesions (Outerbridge grade III-IV) in the knee treated with HD-ACI were included in this study. Chondrocytes were isolated from a nonbearing cartilage area biopsy and were cultured until 40 to 50 million cells were obtained. Five million chondrocytes per cm2 of a porcine collagen type I/III membrane were implanted covering the defect. Procedure effectiveness was assessed by evaluating pain, swelling, and range of mobility (flexion and extension) at 6-, 12-, and 24-month follow-up. The International Knee Documentation Committee (IKDC) subjective evaluation form was used to evaluate symptoms and functions of the knee. RESULTS: The percentage of patients with pain and swelling decreased progressively in the following visits, with differences being statistically significant ( P < 0.001 and P = 0.040, respectively). IKDC scores improved progressively throughout the 24-month follow-up ( P < 0.001). Thus, the mean IKDC score improvement was 26.3 points (95% confidence interval [CI] = 18.2-34.4 points) at 12 months and 31.0 points (95% CI = 22.9-39 points) at 24 months. No significant differences were found when performing extension ( P = 0.112). Flexion significantly improved by 25.1° at 24-month follow-up ( P = 0.013). CONCLUSIONS: HD-ACI is a safe and effective technique for the treatment of cartilage defects, improving clinical and subjective perception of knee functionality. These preliminary results encourage future studies comparing this technique with traditional ACI.

Epidemiology of injuries in the Spanish national futsal male team: a five-season retrospective study.

BACKGROUND: Futsal started being played in 1930 and the number of futsal players has increased all over the world ever since. Nonetheless, despite the fact that Spain is one of the most relevant national teams worldwide, information on the incidence of injuries and their anthropometric characteristics is sparse in this country. AIM: To analyse medical assistance provided to players in their prematch concentration camps with the Spanish national team over five seasons, from 2010-2011 to 2014-2015, and also to collect data regarding anthropometric characteristics. MATERIALS AND METHODS: This is a retrospective and detailed study of injuries players suffered over these five seasons. All variables were registered on an Excel spreadsheet and later analysed statistically. RESULTS: 411 injuries were studied in total. The dominant somatotype was mesomorph and the injured pivots were both the most endomorphic and the most mesomorphic. The most injured body structure was the hamstring muscles, occurring due to training and intrinsic mechanisms, where fatigue was the most frequent diagnosis. Only a few complementary examinations were carried out and prematch withdrawal was rare. DISCUSSION: The skinfold test total sum was lower than that of the Spanish 11-a-side players or than that in the lower category futsal Spanish players. In various research studies analysing exclusively injuries occurring in matches, the most frequent injury is ligament injury by extrinsic mechanism. The body mass index was not a useful parameter when assessing players' appropriate weight. Most injuries occurred in training sessions, mostly by intrinsic mechanism; the highest percentage of traumatic injuries occurred in official matches.

Viability of Pathologic Cartilage Fragments as a Source for Autologous Chondrocyte Cultures.

OBJECTIVE: To study if a culture of chondrocytes can be obtained from pathologic hyaline cartilage (PHC) fragments. DESIGN: Twenty-five men and 9 women with osteochondritis dissecans (OCD) in 11 cases, arthrosis in 13 patients, and trauma in the remaining 10 cases were included. The PHC fragments and a small sample of the next healthy cartilage were extracted by arthroscopy. According to the appearance, the PHC samples were divided into fixed (3 cases), flapped (6 patients), or loose bodies (25 cases), depending on the attachment degree of the cartilage to the subchondral bone. Approximately half of each pathologic sample and the whole healthy one were digested to isolate the cells trying to establish the cell culture. RESULTS: We were able to establish a cell culture in 7 out of 34 (20.6%) PHC samples (positive samples), whereas in the remaining 27 (79.4%) no cell growth was observed (negative samples). Most of the negative samples were loose bodies (P = 0.005) taken from patients with OCD or arthrosis (P = 0.001) with an evolution time of more than 1 year (P < 0.001). The best binary logistic regression model (P < 0.001) showed that the only factor affecting the establishment of cell culture was the evolution time (P = 0.044). CONCLUSION: It is possible to culture chondrocytes from osteochondral fragments if they are traumatic, within a year of injury and not from fragments due to arthrosis or OCD.

The Importance of the Intercondylar Notch in Anterior Cruciate Ligament Tears.

BACKGROUND: The factors associated with anterior cruciate ligament (ACL) tears are not completely clear. Some studies have shown that patients with a narrow intercondylar notch have a predisposition for ACL tears. PURPOSE: To determine the relationship between the α angle and intercondylar notch width measurements and ACL tears. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 530 patients (308 with ACL rupture, 222 with healthy ACLs) were included in this study. The α angle and intercondylar width were measured from magnetic resonance images (MRIs). Binary logistic regression analysis was performed to determine the influence of the variables on ACL status (normal or torn). Odds ratios (ORs) and their respective 95% CIs were also calculated. RESULTS: No significant differences in patient age and the affected knee were found between patients with normal or torn ACLs. The mean α angle was higher in patients with a torn ACL than in those with an intact one (57.5° ± 5.5° vs 56.2° ± 4.5°; P = .009). Intercondylar width was significantly lower in patients with a torn ACL than in those with an intact one (18.2 ± 3.1 vs 19.5 ± 3.6 mm; P < .001). A highly significant difference between men and women was found for mean intercondylar notch width (19.3 ± 3.3 vs 17.4 ± 3.1 mm; P < .001). In a logistic regression model, sex, intercondylar width, and α angle were statistically significant when adjusted for age. CONCLUSION: Study results suggest that the ACL tears are associated with a narrow intercondylar notch and a high α angle, and that tears occur more frequently in men than in women. CLINICAL RELEVANCE: The model proposed in this study could be used by the physician in the medical office as a tool to identify the risk factors that may predispose a patient for a potential ACL tear.

Increasing the Dose of Autologous Chondrocytes Improves Articular Cartilage Repair: Histological and Molecular Study in the Sheep Animal Model.

BACKGROUND: We hypothesized that implanting cells in a chondral defect at a density more similar to that of the intact cartilage could induce them to synthesize matrix with the features more similar to that of the uninjured one. METHODS: We compared the implantation of different doses of chondrocytes: 1 million (n = 5), 5 million (n = 5), or 5 million mesenchymal cells (n = 5) in the femoral condyle of 15 sheep. Tissue generated by microfracture at the trochlea, and normal cartilage from a nearby region, processed as the tissues resulting from the implantation, were used as references. Histological and molecular (expression of type I and II collagens and aggrecan) studies were performed. RESULTS: The features of the cartilage generated by implantation of mesenchymal cells and elicited by microfractures were similar and typical of a poor repair of the articular cartilage (presence of fibrocartilage, high expression of type I collagen and a low mRNA levels of type II collagen and aggrecan). Nevertheless, in the samples obtained from tissues generated by implantation of chondrocytes, hyaline-like cartilage, cell organization, low expression rates of type I collagen and high levels of mRNA corresponding to type II collagen and aggrecan were observed. These histological features, show less variability and are more similar to those of the normal cartilage used as control in the case of 5 million cells implantation than when 1 million cells were used. CONCLUSIONS: The implantation of autologous chondrocytes in type I/III collagen membranes at high density could be a promising tool to repair articular cartilage.

Epiphyseal femoral tumour resection under intraosseous endoscopic control.

We have resected 4 benign cystic femoral head tumours under intraosseous endoscopic control. The resections were completely extraarticular through a tunnel made in the femoral neck from the lateral cortex. The procedures were assessed endoscopically with the help of a standard arthroscope. With a minimum follow-up of 1 year (range 1-16 years), there were no recurrences. Mean age at time of surgery was 23 years (range 19-26 years). Only 1 (fibrous defect) needed prophylactic osteosynthesis with a dynamic hip screw. The lateral approach through a bone tunnel allows preservation of the joint. The creation of a wider tunnel (10-15 mm) avoids the need for an irrigation system, without debilitating the bone structure, and simplifies the surgical procedure.