Healthy Tendon Stem Cell-Derived Exosomes Promote Tendon-To-Bone Healing of Aged Chronic Rotator Cuff Tears by Breaking the Positive-Feedback Cross-Talk between Senescent Tendon Stem Cells and Macrophages through the Modulation of Macrophage Polarization.

The re-tear rate of rotator cuff tears (RCT) after surgical repair is high, especially in aged patients with chronic tears. Senescent tendon stem cells (s-TSCs) generally exist in aged and chronically torn rotator cuff tendons and are closely associated with impaired tendon-to-bone healing results. The present study found a positive feedback cross-talk between s-TSCs and macrophages. The conditioned medium (CM) from s-STCs can promote macrophage polarization mainly toward the M1 phenotype, whose CM reciprocally accelerated further s-TSC senescence. Additional healthy tendon stem-cells derived exosomes (h-TSC-Exos) can break this positive feedback cross-talk by skewing macrophage polarization from the M1 phenotype to the M2 phenotype, attenuating s-TSCs senescence. S-TSC senescence acceleration or attenuation effects induced by M1 or M2 macrophages are associated with the inhibition or activation of the bone morphogenetic protein 4 signaling pathway following RNA sequencing analysis. Using an aged-chronic rotator cuff tear rat model, it is found that h-TSC-Exos can shift the microenvironment in the tendon-to-bone interface from a pro-inflammatory to an anti-inflammatory type at the acute postoperative stage and improve the tendon-to-bone healing results, which are associated with the rejuvenated s-TSCs. Therefore, this study proposed a potential strategy to improve the healing of aged chronic RCT.

Comparation and evaluation of the accuracy of the sulcus localization method to establish the medial patellofemoral ligament femoral tunnel: a cadaveric and clinical study.

BACKGROUND: In anatomic medial patellofemoral ligament (MPFL) reconstruction, malpositioning of the MPFL femoral tunnel is common. A palpable sulcus reportedly exists at the anatomic femoral attachment of the MPFL. The present study aimed to investigate the accuracy of the sulcus localization method to establish the MPFL femoral tunnel. METHODS: A cadaveric study was first done on 12 knees to evaluate the accuracy of the sulcus localization method to establish the entry points of the MPFL femoral tunnel in comparison with the midpoint and fluoroscopic localization methods. The center of the native MPFL femoral attachment was served as the reference in the cadaveric study. A clinical study was then performed to further evaluate the accuracy of the sulcus localization method in 53 patients (60 knees). Schöttle's point was served as the reference in the clinical study. Femoral tunnel placement was defined as accurate when it was less than 5 mm from Schöttle's point. In both the cadaveric and clinical studies, MPFL femoral tunnel placement was assessed on postoperative reconstructed three-dimensional computed tomography images. In the cadaveric study, the accuracy of different localization methods was compared using analysis of variance. RESULTS: In the cadaveric study, the mean distances from the native MPFL attachment to the femoral tunnel entry point were 4.2 ± 1.0 mm (range 2.4-5.6 mm), 4.4 ± 1.4 mm (range 1.8-6.6 mm) and 2.9 ± 0.8 mm (range 1.9-4.4 mm) using the midpoint, fluoroscopic, and sulcus localization methods, respectively; this distance significantly differed between the midpoint and sulcus localization methods, and between the fluoroscopic and sulcus localization methods (p ≤ .05). While there were no significant differences between the midpoint and fluoroscopic localization methods (n.s.). In the clinical study, the mean distance between the femoral tunnel and Schöttle's point was 3.5 ± 1.5 mm (range 0.4-6.1 mm), with accurate tunnel placement achieved in 49 of 60 cases (82%). CONCLUSION: The sulcus localization method can accurately guide MPFL femoral tunnel placement. This method might be useful for orthopedic surgeons. LEVEL OF EVIDENCE: IV.

Assessment of relationship between three dimensional femoral notch volume and anterior cruciate ligament injury in Chinese Han adults: a retrospective MRI study.

PURPOSE: The studies of the relationship between anterior cruciate ligament (ACL) injury and notch size were in 2-D parameters in Han Chinese, the largest nation in the world, while few studies referred to the 3-D notch volume. The purpose of this study was to determine the differences in notch volume between individuals with and without ACL injuries and the optimal criterion value for abnormal notch volume and its sensitivity in predicting the risk of ACL injuries. METHODS: Two hundred eighty individuals were included in this study, including 140 patients with non-contact sports ACL injuries only and 140 age- and gender-matched individuals without ACL injuries. Both groups underwent pre-operative knee MRI examinations and femoral notches were traced manually on 2-D MRI images, then 3-D notch volume was calculated. RESULTS: The notch volume was extremely smaller in the ACL-injured group than that in the control group (5.94 ± 1.35 versus 6.86 ± 1.61 cm3, P < 0.001). The notch volume below 6.99 cm3 in males and 5.63 cm3 in females meant being prone to ACL injuries. Females tend to have smaller notch volume than males (5.53 ± 0.93 versus 7.28 ± 1.55 cm3, P < 0.001). The notch volume was in moderate correlation with the body height and weight and in weak correlation with the BMI but in no correlation with the age. CONCLUSIONS: In Chinese Han adults, the notch volume was significantly smaller in the ACL-injured individuals than in the ACL-intact ones, it was smaller in females than the males and it was correlated with the body height, weight and the BMI. Level of evidence Level III, case-control study.

Time-Dependent Effects of Arthroscopic Conditions on Human Articular Cartilage: An In Vivo Study.

PURPOSE: To assess time-dependent effects of arthroscopic conditions on human articular cartilage in vivo. METHODS: From each of 10 patients undergoing multiligament reconstruction of the knee under our routine arthroscopic conditions (gravity irrigation of 0.9% normal saline solution at room temperature with 150 cm H2O [110 mm Hg] pressure and pneumatic tourniquet under 270 mm Hg pressure), cartilage specimens were harvested from the lateral edge of the femoral notch at the beginning of the operation (baseline) and at 15-, 30-, 45-, and 60-minute time points during the operation. H&E staining and safranin O staining were used to evaluate the tissue structure, chondrocytes, and extracellular matrix (ECM) of the articular cartilage. Chondrocyte viability was evaluated, and a biochemical examination of the ECM was performed to detect changes in glycosaminoglycan and collagen content. The expression levels of genes associated with proinflammatory cytokines, ECM metabolism, and chondrocyte apoptosis of the articular cartilage were evaluated. RESULTS: At the 45- and 60-minute time points, an obvious impairment of tissue structure, a significant decrease in glycosaminoglycan content, and a significantly lower percentage chondrocyte viability were observed, as compared with baseline (P < .05). Regarding the tissue collagen content, no significant change was detected at any time point (P > .05). The gene expression examination at the 45- and 60-minute time points detected significant upregulation of interleukin 1ß and tumor necrosis factor α (P < .05), indicating an inflammatory response by the chondrocytes, and significant upregulation of aggrecanase 1 (P < .05), which indicates catabolism or the disturbance of aggrecan metabolism. CONCLUSIONS: Under current arthroscopic conditions, an operative duration of 45 minutes or longer can cause detrimental structural, biochemical, and metabolic effects on human articular cartilage. CLINICAL RELEVANCE: Arthroscopic skills should always be improved to reduce operation time and thus minimize the potential detrimental effects of arthroscopic conditions on articular cartilage.

Prevalence of bilateral Discoid Lateral Menisci (DLM) in patients operated for symptomatic DLM with a follow-up study on their asymptomatic contralateral knees: a Magnetic Resonance Imaging (MRI) assessment.

BACKGROUND: The purpose was to investigate prevalence of bilateral discoid lateral menisci (DLM) in Han Chinese patients who received surgery for symptomatic DLM, as well as a follow-up study of their asymptomatic contralateral knees using magnetic resonance imaging (MRI). METHODS: A total of 110 patients [50 males and 60 females; average age: 21.95 ± 12.77 years (range: 6 to 67 years)] admitted to our hospital with symptomatic DLM were treated with arthroscopic surgery. The contralateral asymptomatic knees were evaluated for DLM by MRI. Postoperative clinical evaluation was performed using the Lysholm knee scoring scale and International Knee Documentation Committee subjective knee evaluation. RESULTS: Eighty (72.73%) of 110 symptomatic DLM patients had bilateral DLM, of which 68 (85%) were of homotype (same type). Fourteen of 80 bilateral DLM patients were symptomatic and received operations in both knees. Twelve of remaining 66 bilateral DLM patients with asymptomatic one knee underwent a second arthroscopic surgery as their asymptomatic knees became symptomatic over the five-year interim. Of these 12 cases, seven exhibited no shift and five showed posterocentral meniscal shift. Furthermore, at least two cases showed progression from asymptomatic grade II to symptomatic grade III over the interim. All patients showed significant improvement after surgery. CONCLUSIONS: The bilateral DLM rate of Han Chinese patients with symptomatic DLM was relatively high at 72.7 %, and 85 % of those were of homotype.

Arthroscopic treatment of acute acromioclavicular joint dislocation by coracoclavicular ligament augmentation.

PURPOSE: Coracoclavicular (CC) ligament augmentation has been a method to treat acromioclavicular (AC) joint dislocation in recent years. The purpose of this paper is to describe our arthroscopic CC ligament augmentation technique in treating type III and V acute AC joint dislocations and to report the early clinical and radiological results. METHODS: From 2010 to 2011, twelve patients suffering from acute type III or V AC joint dislocations were arthroscopically treated in our department, by CC ligament augmentation after AC joint reduction. The post-operative outcomes were assessed through physical examination, radiographic examination and the Constant-Murley Shoulder Score. RESULTS: All patients post-operatively experienced anatomical reduction in their AC joint dislocation. No intraoperative complications occurred. At a mean follow-up at 24 months (ranging from 18 to 32 months), the mean Constant-Murley Shoulder Score significantly improved from 24.3 pre-operatively to 91.1 post-operatively. No neurovascular complications or secondary degenerative changes of the AC joint were detected in any of the patients. In one case, a second dislocation occurred 1 month post-operation because the patient had had another traumatic injury. This patient accepted a revision operation, but his AC joint eventually fixated into a subluxated position after his second injury. CONCLUSION: Based on the resultant successful repair in all cases, the arthroscopic CC ligament augmentation method has thus far proven to be a safe and reliable technique for treatment of acute type III or V AC joint dislocation. CLINICAL RELEVANCE: The arthroscopic CC ligament augmentation with a flip button/polyethylene belt repair is an efficient method to treat acute type III and V AC joint dislocations which should be popularized. LEVEL OF EVIDENCE: IV.

3-Dimensional Bioprinting of a Tendon Stem Cell-Derived Exosomes Loaded Scaffold to Bridge the Unrepairable Massive Rotator Cuff Tear.

BACKGROUND: Unrepairable massive rotator cuff tears (UMRCTs) are challenging to surgeons owing to the severely retracted rotator cuff musculotendinous tissues and extreme defects in the rotator cuff tendinous tissues. PURPOSE: To fabricate a tendon stem cell-derived exosomes loaded scaffold (TSC-Exos-S) and investigate its effects on cellular bioactivity in vitro and repair in a rabbit UMRCT model in vivo. STUDY DESIGN: Controlled laboratory study. METHODS: TSC-Exos-S was fabricated by loading TSC-Exos and type 1 collagen (COL-I) into a 3-dimensional bioprinted and polycaprolactone (PCL)-based scaffold. The proliferation, migration, and tenogenic differentiation activities of rabbit bone marrow stem cells (BMSCs) were evaluated in vitro by culturing them in saline, PCL-based scaffold (S), COL-I loaded scaffold (COL-I-S), and TSC-Exos-S. In vivo studies were conducted on a rabbit UMRCT model, where bridging was repaired with S, COL-I-S, TSC-Exos-S, and autologous fascia lata (FL). Histological and biomechanical analyses were performed at 8 and 16 weeks postoperatively. RESULTS: TSC-Exos-S exhibited reliable mechanical strength and subcutaneous degradation, which did not occur before tissue regeneration. TSC-Exos-S significantly promoted the proliferation, migration, and tenogenic differentiation of rabbit BMSCs in vitro. In vivo studies showed that UMRCT repaired with TSC-Exos-S exhibited significant signs of tendinous tissue regeneration at the bridging site with regard to specific collagen staining. Moreover, no significant differences were observed in the histological and biomechanical properties compared with those repaired with autologous FL. CONCLUSION: TSC-Exos-S achieved tendinous tissue regeneration in UMRCT by providing mechanical support and promoting the trend toward tenogenic differentiation. CLINICAL RELEVANCE: The present study proposes a potential strategy for repairing UMRCT with severely retracted musculotendinous tissues and large tendinous tissue defects.

Independent Risk Factors Associated With Venous Thromboembolism After Knee Arthroscopy: A Retrospective Study of 222 Patients.

Background: A serious complication after knee arthroscopy is venous thromboembolism (VTE), which includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). However, asymptomatic VTE is frequently undetected. Purpose: To (1) report the incidence of VTE after knee arthroscopy using ultrasound examination and computed tomography pulmonary angiography (CTPA) and (2) discover the independent risk factors of VTE after knee arthroscopy and determine the corresponding cutoff values of these indicators. Study Design: Case-control study; Level of evidence, 3. Methods: Included were 222 patients (115 male) who underwent arthroscopic knee procedures between October 2022 and January 2023. Baseline characteristics, blood test results, and VTE assessments were collected. During the 2-week follow-up, routine lower extremity vascular ultrasound was applied for DVT measurement, with CTPA evaluation for suspected PE. Patients were allocated into VTE and no-VTE groups, and descriptive statistics were used to analyze baseline data. Logistic regression analysis was used to determine the correlation between binary variables and the presence of postoperative VTE. Multivariate logistic regression analysis was further performed to determine the independent risk factors of VTE. Results: Of the 222 patients, 37 (16.7%) had DVT and 1 (0.5%) had both DVT and PE. Compared to the no-VTE group, the VTE group was significantly older, with more female patients; higher body mass index (BMI) and postoperative D-dimer level; and higher rates of hypertension, hyperlipidemia, varicose veins of the lower extremity, and abnormal postoperative fibrin degradation product level (P≤ .043 for all). Notably, operative time >20 minutes was not significantly associated with postoperative VTE (P = .513). The independent risk factors for VTE included age >32 years (odds ratio [OR], 20.71 [95% CI, 4.40-97.47]; P < .001), BMI >23 kg/m2 (OR, 3.52 [95% CI, 1.11-11.14]; P = .032), hyperlipidemia (OR, 6.81 [95% CI, 1.86-24.88]; P = .004), and postoperative D-dimer level >0.63 mg/L (OR, 34.01 [95% CI, 7.36-157.07]; P < .001). Conclusion: The incidence of VTE after knee arthroscopy was 16.7% at the 2-week follow-up. Age >32 years, BMI >23 kg/m2, hyperlipidemia, and postoperative D-dimer >0.63 mg/L were independent risk factors of postoperative VTE within 2 weeks after knee arthroscopy. For patients with knee arthroscopy, the cutoff value of postoperative D-dimer for VTE was found to be 0.63 mg/L for timely intervention.

The effect of platelet-rich plasma on patterns of gene expression in a dog model of anterior cruciate ligament reconstruction.

BACKGROUND: Autologous platelet-rich plasma (PRP) has been investigated as a potential promoter of tendon healing and has an enhancing effect on the anterior cruciate ligament (ACL) graft maturation process. However, the influence of PRP on the synthesis and degradation of the extracellular matrix during the ACL graft remodeling process has never been investigated. MATERIALS AND METHODS: Healthy and mature beagle dogs were randomly assigned to one of four groups: in group I (PRP group), ACL grafts were treated with PRP; in group II (control group), ACL grafts were treated with saline; in group III (sham group), only the knee joints were exposed; in group IV (normal control group), no surgery was performed to the knees. Ligament tissue was dissected at 2, 6, and 12 wk after surgery, and real-time PCR was performed using primers for growth factor-ß1 (TGF-ß1), collagen type1A1 (COL1Al), collagen type3A1 (COL3A1), decorin, biglycan, matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-13 (MMP-13), and tissue inhibitor of metalloproteinase-1 (TIMP-1). RESULT: In group I, the messenger RNA (mRNA) levels of collagen type 1A1, biglycan, and MMP-1 all increased 2, 6, and 12 wk after surgery, compared with group II (P < 0.05). At 2 and 6 wk after surgery, increased levels of COL3A1, MMP-1, and MMP-13 mRNA were also detected in group I (P < 0.05). Increased levels of TGF-ß1 mRNA was observed at 6 and 12 wk in group I after surgery (P < 0.05). CONCLUSIONS: During the graft remodeling process, we observed a time-dependent change of gene expression following ACL reconstruction surgery. Furthermore, our results demonstrate that PRP alters the expression of some target genes at certain time points, especially during the early stages of graft remodeling, which might explain the enhancing effect of PRP on the ACL graft maturation process.

Platelet-rich plasma enhances autograft revascularization and reinnervation in a dog model of anterior cruciate ligament reconstruction.

BACKGROUND: Autologous platelet-rich plasma (PRP) has been investigated as a potential promoter of tendon healing that affects the anterior cruciate ligament (ACL) graft maturation process. However, the influence of PRP on revascularization and reinnervation during the ACL graft remodeling has never been investigated. MATERIALS AND METHODS: We randomly assigned healthy and mature beagles to one of four groups. In group 1 (PRP group), we treated the ACL grafts with PRP. In group 2 (control group), we treated the ACL grafts with saline. In group 3 (sham group), we exposed only the knee joints. In group 4 (normal control group), no surgery was performed on the knees. We dissected the ligament tissue at 2, 6, and 12 wk after surgery and performed real-time polymerase chain reaction using primers for cluster of differentiation molecule 31, vascular endothelial growth factor, thrombospondin-1 (TSP-1), neurotrophin-3, growth-associated protein-43 (GAP-43), and nerve growth factor. RESULTS: We observed the increased expression of vascular endothelial growth factor, TSP-1, neurotrophin-3, GAP-43, and nerve growth factor mRNA in group 1 at 2, 6, and 12 wk after surgery, compared with that in group 2 (P < 0.05). We also detected increased levels of cluster of differentiation molecule 31 expression in group 1 (P < 0.05) at 2 and 6 wk after surgery. The levels of TSP-1 and GAP-43 mRNA were significantly increased in group 3 compared with those in group 4 at 2 wk after surgery (P < 0.05). CONCLUSIONS: During graft remodeling, we observed a time-dependent change in gene expression after ACL reconstruction surgery. In addition, these results demonstrate that PRP alters the expression of some target genes at certain times, particularly during the early stages of graft remodeling. Platelet-rich plasma could promote revascularization and reinnervation, which might explain the enhancing effect of PRP on ACL graft maturation.

Enhancement of Tendon-to-Bone Healing: Choose a Monophasic or Hierarchical Scaffold?

BACKGROUND: To enhance the healing of tendon to bone, various biomimetically hierarchical scaffolds have been proposed. However, the fabrication of such scaffolds is complicated. Furthermore, the most significant result after a routine repair is loss of the transition zone between the tendon and bone, whose main components are similar to fibrocartilage. PURPOSE: To compare tendon-to-bone healing results in a rabbit model using a monophasic graft (decellularized fibrocartilage graft; DFCG) and hierarchical graft (decellularized tendon-to-bone complex; DTBC) that contain the native hierarchical enthesis. STUDY DESIGN: Controlled laboratory study. METHODS: DFCG and DTBC were harvested from allogenic rabbits. A rabbit model of a chronic rotator cuff tear was established, and 3 groups were assessed: direct repair or repair with DFCG or DTBC fixed between the tendon and bone. Hierarchical evaluations of the repaired tendon-to-bone interface were performed with regard to the tendon zone, transition zone, and bone zone using histological staining and micro-computed tomography scanning. Biomechanical analysis was performed to evaluate the general healing strength. RESULTS: The healing results in the tendon zone exhibited no significant difference among the 3 groups at any time point. In the transition zone, the grade in the direct repair group was significantly lower than that in the DFCG and DTBC groups at 4 weeks, and the grade in the DFCG group was significantly lower than that in the DTBC group at this time point. However, any significant difference between the DFCG group and DTBC group could no longer be detected at 8 and 16 weeks, which was inconsistent with the results of the biomechanical analysis. Micro-computed tomography analysis showed no significant difference among the 3 groups with regard to bone mineral density at 16 weeks. CONCLUSION: A monophasic DFCG was able to achieve enhanced tendon-to-bone healing similar to that with hierarchical DTBC over the long term, with regard to both histological and biomechanical properties. CLINICAL RELEVANCE: Fabrication of a monophasic scaffold instead of a hierarchical scaffold to promote regeneration and remodeling of a transition zone, which was mainly composed of fibrocartilaginous matrix between the tendon and bone, may be sufficient to enhance tendon-to-bone healing.

Three-Dimensional Bioprinting of a Structure-, Composition-, and Mechanics-Graded Biomimetic Scaffold Coated with Specific Decellularized Extracellular Matrix to Improve the Tendon-to-Bone Healing.

Healing of a damaged tendon-to-bone enthesis occurs through the formation of fibrovascular scar tissue with greatly compromised histological and biomechanical properties instead of the regeneration of a new enthesis due to the lack of graded tissue-engineering zones in the interface during the healing process. In the present study, a structure-, composition-, and mechanics-graded biomimetic scaffold (GBS) coated with specific decellularized extracellular matrix (dECM) (GBS-E) aimed to enhance its cellular differentiation inducibilities was fabricated using a three-dimensional (3-D) bioprinting technique. In vitro cellular differentiation studies showed that from the tendon-engineering zone to the bone-engineering zone in the GBS, the tenogenic differentiation inducibility decreased in correspondence with an increase in the osteogenic differentiation inducibility. The chondrogenic differentiation inducibility peaked in the middle, which was in consistent with the graded cellular phenotypes observed in a native tendon-to-bone enthesis, while specific dECM coating from the tendon-engineering zone to the bone-engineering zone (tendon-, cartilage-, and bone-derived dECM, respectively) further enhanced its cellular differentiation inducibilities (GBS-E). In a rabbit rotator cuff tear model, histological analysis showed that the GBS-E group exhibited well-graded tendon-to-bone differentiated properties in the repaired interface that was similar to a native tendon-to-bone enthesis at 16 weeks. Moreover, the biomechanical properties in the GBS-E group were also significantly higher than those in other groups at 16 weeks. Therefore, our findings suggested a promising tissue-engineering strategy for the regeneration of a complex enthesis using a three-dimensional bioprinting technique.

Loading Mesenchymal Stem Cell-Derived Exosomes Into a Traditionally Designed Rotator Cuff Patch: A Potential Strategy to Enhance the Repair of Chronic Rotator Cuff Tear Associated With Degenerative Changes.

BACKGROUND: Retraction and degenerative changes of chronic rotator cuff tears limit the healing capacity after routine surgical repair. PURPOSE: To fabricate a mesenchymal stem cell-derived exosome (MSC-Exos) loaded patch and evaluate the effect of this patch on the activity of rabbit tenocytes in vitro and on the repair of chronic rotator cuff tears associated with degenerative changes in vivo. STUDY DESIGN: Controlled laboratory study. METHODS: The MSC-Exos loaded patch was fabricated using a dynamic wet-spinning system. In the in vitro studies, the proliferation and migration activities of tenocytes were evaluated by culturing tenocytes with saline, a fiber-aligned patch, or an MSC-Exos loaded patch. In the in vivo studies, a rabbit model of chronic rotator cuff tear was established and directly repaired, repaired with fiber-aligned patch augmentation (RFPA group), and repaired with MSC-Exos loaded patch augmentation (REPA group). Histological and biomechanical analyses were performed at 4, 8, and 12 weeks after surgery. RESULTS: An MSC-Exos loaded patch with inner aligned fibers, a loose microstructure, and reliable initial strength was fabricated using a dynamic wet-spinning system. The MSC-Exos loaded patch significantly promoted tenocyte proliferation and migration activities in vitro. In vivo, the REPA group exhibited significantly higher tendon maturing scores at 8 and 12 weeks after surgery compared with both the control and the RFPA groups. Fatty infiltration was significantly reduced in the REPA group at 4, 8, and 12 weeks compared with both the control and the RFPA groups. Biomechanical properties, including load to failure and stress, were also significantly improved at 12 weeks in the REPA group compared with both the control and the RFPA groups. CONCLUSION: Results in the present study suggested that an MSC-Exos loaded patch was able to enhance the repair of a chronic rotator cuff tear by providing mechanical support and minimizing degeneration. CLINICAL RELEVANCE: This work supported the idea that loading bioactive MSC-Exos into a traditionally designed rotator cuff patch might exert a better effect on the repair of chronic rotator cuff tears than augmented patch repair alone.

Anti-inflammatory and Tendon-Protective Effects of Adipose Stem Cell-Derived Exosomes with Concomitant Use of Glucocorticoids.

Glucocorticoid (GC) injections are commonly used in clinical practice to relieve pain and improve function in patients with multiple shoulder disabilities but cause detrimental effects on rotator cuff tendons. Adipose stem cell-derived exosomes (ASC-Exos) reportedly recover impaired tendon matrix metabolism by maintaining tissue homeostasis. However, it is unclear whether additional treatment with ASC-Exos overrides the detrimental effects of GCs without interfering with their anti-inflammatory effects. Thus, we aimed to investigate the anti-inflammatory effect of ASC-Exos with GCs and protective effect of ASC-Exos against GC-induced detriments. The present study comprised in vitro and in vivo studies. In vitro inflammatory analysis revealed that ASC-Exos exerted a synergic anti-inflammatory effect with GCs by significantly decreasing secretion of proinflammatory cytokines by RAW cells and increasing secretion of anti-inflammatory cytokines. In vitro cytoprotective analysis showed that ASC-Exos overrode GC-induced detrimental effects on tenocytes by significantly improving GC-suppressed cellular proliferation, migration, and transcription of tenocytic matrix molecules and degradative enzyme inhibitors and significantly decreasing GC-induced cell senescence, apoptosis, and transcription of ROS and tenocytic degradative enzymes. In vivo studies revealed that additional ASC-Exo injection restored impairments in histological and biomechanical properties owing to GC administration. Collectively, these results suggest that ASC-Exos exert a stronger anti-inflammatory effect in combination with GCs, overriding their detrimental effects on rotator cuff tendons.

Reconstruction for Chronic ACL Tears with or without Anterolateral Structure Augmentation in Patients at High Risk for Clinical Failure: A Randomized Clinical Trial.

BACKGROUND: The purpose of this trial was to determine whether anterior cruciate ligament reconstruction (ACLR) with anterolateral structure augmentation (ALSA) would result in better clinical outcomes in patients with a high risk of clinical failure. METHODS: From February 2017 to June 2018, 120 young, active adults with chronic anterior cruciate ligament injury and high risk of clinical failure were randomized. The patients were followed for >2 years, with 5 being lost to follow-up and 1 being withdrawn from the study. Clinical characteristics, operative findings, and postoperative clinical outcomes were analyzed. RESULTS: The analysis included data from 114 patients, including 95 men and 19 women with a mean age (and standard deviation) of 30.1 ± 6.7 years in the ACLR group and 30.1 ± 6.4 years in the ALSA group. The rate of clinical failure was 20.4% (11 of 54 patients) and 3.3% (2 of 60 patients) in the ACLR and ALSA groups, respectively (difference, 17.1%; 95% confidence interval [CI], 5.3% to 29.8%; p = 0.007). Significantly higher rates of return to the preinjury level of sports (48.3% versus 27.8%; difference, 20.5%; 95% CI, 2.7% to 36.6%; p = 0.024) and to a competitive level of play (63.3% versus 42.6%; difference, 22.3%; 95% CI, 4.1% to 38.8%; p = 0.027) was found in the ALSA group. CONCLUSIONS: Compared with isolated ACLR, combined ACLR and ALSA resulted in a reduction in persistent rotatory laxity and higher rates of return to preinjury and competitive levels of play at 2 years of follow-up in the population studied. Our study suggests that patients with high risk of clinical failure appear to be candidates for the ALSA approach. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Adipose Stem Cell-Derived Exosomes Recover Impaired Matrix Metabolism of Torn Human Rotator Cuff Tendons by Maintaining Tissue Homeostasis.

BACKGROUND: Adipose stem cell-derived exosomes (ASC-Exos) are reported to effectively prevent muscle atrophy and degeneration of torn rat rotator cuff, but their influence on human samples and their potential mechanism are still unclear. PURPOSE: We aimed to investigate the effects of ASC-Exos on the metabolic activities of torn human rotator cuff tendons and explore the potential mechanism behind it. STUDY DESIGN: Controlled laboratory study. METHODS: Diseased supraspinatus tendons were harvested from 15 patients with a mean ± SD age of 65.8 ± 3.2 years who underwent reverse shoulder arthroplasty for chronic rotator cuff tears associated with glenohumeral pathological changes. Each tendon was dissected into 3 × 4 × 4-mm explants: the ones derived from the same tendon were placed into 12-well plates and cultured in complete culture media (control) or in complete culture media supplemented with ASC-Exos for 72 hours. Afterward, the concentrations of cytokines secreted into the culture media-including interleukin 1ß (IL-1ß), IL-6, IL-8, and matrix metalloproteinase 9 (MMP-9)-were measured using enzyme-linked immunosorbent assay (ELISA). Tendons were stained with hematoxylin and eosin and immunohistochemistry (type I and III collagens) for histological analyses. Moreover, the expression of anabolic genes (TIMP-1 and TIMP-3; type I and III collagen encoding) and catabolic genes (MMP-9 and MMP-13) in tendons were measured using real-time quantitative polymerase chain reaction. Phosphorylated AMPKα and Wnt/ß-catenin pathways were assayed by western blotting to explore the potential mechanism of action of ASC-Exos. RESULTS: Secretion of proinflammatory cytokines, including IL-1ß, IL-6, and MMP-9, was significantly reduced in the ASC-Exos group as compared with the control group. Supraspinatus tendons in the ASC-Exos group exhibited superior histological properties, as demonstrated by higher tendon maturing scores and more type I collagen content, but there was no significant difference in type III collagen content between groups. Expression of MMP-9 and MMP-13 genes was decreased in the ASC-Exos group versus the control group. Increased expression of type I and III collagens and an elevated type I/III ratio were found in the ASC-Exos group when compared with the control group. There was no significant difference in the secretion of IL-8 and expression of TIMP-1 and TIMP-3 genes between the ASC-Exos and control groups. Western blotting revealed that ASC-Exos enhanced phosphorylated AMPKα and decreased ß-catenin levels to prevent tendon degeneration. CONCLUSION: ASC-Exos maintained metabolic homeostasis of torn human rotator cuff tendons to improve their histological properties, which might be achieved by enhancing AMPK signaling to suppress Wnt/ß-catenin activity. CLINICAL RELEVANCE: ASC-Exos could be used as an effective biological tool to promote healing in torn human rotator cuff tendons.

Radiographic Reference Points Do Not Ensure Anatomic Femoral Fixation Sites in Medial Patellofemoral Ligament Reconstruction: A Quantified Anatomic Localization Method Based on the Saddle Sulcus.

BACKGROUND: Medial patellofemoral ligament (MPFL) reconstruction is one of the main treatments for lateral patellar translation. Based on intraoperative true lateral radiographs, the accepted methods for femoral MPFL tunnel location are potentially inaccurate. Direct assessment of anatomic characteristics during surgery through palpation of the anatomic landmarks involving the saddle sulcus might help eliminate tunnel malposition. HYPOTHESIS: The saddle sulcus is a reliable osseous landmark where the MPFL attaches for tunnel placement. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 9 fresh-frozen unpaired human cadaveric knees were dissected; MPFL insertion point and relative osseous structures were marked. Three-dimensional images and transformed true lateral radiographs were obtained for analysis; 3 previously reported radiographic reference points for MPFL femoral tunnel placement were determined on all images and compared with the anatomic insertion. RESULTS: A saddle sulcus consistently existed where the MPFL was attached, located at 11.7 ± 5.9 mm from the apex of the adductor tubercle (AT) to the medial epicondyle (ME), 62.8% of the average distance between the apexes of the AT and ME, and 5.6 ± 2.8 mm perpendicular-posterior to the border connecting the AT and ME. The reported radiographic reference points were located at average distances of 6.2 ± 3.2 mm (Schöttle method), 5.9 ± 2.3 mm (Redfern method), and 7.3 ± 6.6 mm (Fujino method) from the saddle sulcus center on the true lateral radiographs. CONCLUSION: The saddle sulcus was a reliable landmark where the MPFL was anatomically attached, located approximately 12 mm from the AT to the ME (approximately 60% along a line from the AT to the ME) and 6 mm perpendicular-posterior to the border connecting the apexes of the AT and ME. Additionally, the saddle sulcus position presented variability on the femoral aspect of different knees. All of the average direct distances from the sulcus to the reference radiographic points exceeded 5 mm, and tunnel localizations on a true lateral radiograph were inaccurate. CLINICAL RELEVANCE: This study demonstrates the potential precise position of the saddle sulcus, according to the ME and AT, as a reliable anatomic landmark for MPFL femoral tunnel location. Radiographic reference points were not accurate during MPFL reconstruction. Direct palpation of the landmarks might be effective for femoral MPFL tunnel placement.

Arbitrary starting point of separation affects morphology of the 2 bundles of anterior cruciate ligament at insertion sites.

PURPOSE: To explore whether changes in the starting point of separation affect the morphology of the 2 bundles of the anterior cruciate ligament (ACL) at insertion. METHODS: Ten cadaveric knees were used to separate the ACL fibers into 2 bundles from 3 different starting points that were located at the proximal one fifth, two fifths, and three fifths of the inter-bundle mark line. The dividing lines between the 2 bundles at insertion and the area of the anteromedial (AM) bundle resulting from these different separations were compared, with data collected in groups I, II, and III, respectively. RESULTS: The angle of the dividing line and the long axis of the femoral footprint was 67.24 degrees +/- 11.94 degrees, 91.01 degrees +/- 11.16 degrees, and 116.03 degrees +/- 9.01 degrees in groups I, II, and III, respectively, and the percentage of the AM bundle area in the whole femoral footprint was 38.64% +/- 5.55%, 52.22% +/- 6.76%, and 65.09% +/- 4.53%, respectively. At the tibial insertion sites, the angle between the dividing line and the sagittal plane was 110.17 degrees +/- 13.26 degrees, 127.72 degrees +/- 8.94 degrees, and 149.28 degrees +/- 18.80 degrees in groups I, II, and III, respectively, and the percentage of the AM bundle area in the whole footprint was 25.72% +/- 3.82%, 40.41% +/- 3.73%, and 60.56% +/- 6.59%, respectively. There were statistical differences between the angle and the area data of each of the 2 groups at either the tibial or femoral insertion site. CONCLUSIONS: In an anatomic study of the ACL, changes in the point from which separation started resulted in noticeably different bundle morphology at the insertion. CLINICAL RELEVANCE: Proper separation will lead to a more accurate bundle description and, thus, a more accurate location of the tunnels in ACL reconstruction.

[Arthroscopic treatment of acute greater tuberosity fractures of the humerus].

OBJECTIVE: To study the outcome in the arthroscopic treatment of acute greater tuberosity fractures. METHODS: Twelve cases with acute great tuberosity fractures received reduction with arthroscopic treatment from August 2006 to December 2007. There were 7 males and 5 females. Eight cases were on left side and 4 on right side. The patients were operated at a mean age of 38 years old (range: 2745). The fractured fragments in displacements were greater than 5 mm. X-ray film and Constant score were used to evaluate the post-operative outcome. RESULTS: Three hollowed threaded screws with a washer were used to fix the big fractured fragments. The post-operative follow-up was a mean of 18 months (range: 14-33). The fracture fixations were excellent and bone union occurred. The patients received a mean Constant score of 92 (86-100) at the last follow-up. CONCLUSION: Arthroscopic treatment of acute greater tuberosity fractures is quite efficacious.

Tissue-Engineered Decellularized Allografts for Anterior Cruciate Ligament Reconstruction.

Anterior cruciate ligament (ACL) reconstruction with allografts is limited by high immunogenicity, poor cellularization, and delayed tendon-bone healing. Decellularized tendons (DAs) have been used as bioscaffolds to reconstruct ligaments with variable success. In the study, four kinds of decellularized allogeneic hamstring tendons were prepared and their microstructure and cytocompatibility were examined in vitro. The results showed that decellularized allografts neutralized by 5% calcium bicarbonate had typical reticular and porous microstructures with optical cytocompatibility. Tissue-engineering decellularized allografts (TEDAs) were prepared with the selected decellularized allografts and tendon stem/progenitor cells and used for ACL reconstruction in a rabbit model. Histological staining showed that the TEDAs promoted cellular infiltration and new vessel formation significantly and improved tendon-bone healing moderately compared to decellularized allografts. Better macroscopic scores and biomechanical results were observed in TEDA groups, but there were no significant differences between DA and TEDA groups at months 1, 2, and 3 postoperatively. Immunohistochemical data showed that the tissue-engineering decellularized allografts enhanced the expression of collagen I at each timepoint and collagen III at months 1 and 2. ELISA analysis showed that the tissue-engineering decellularized allografts reduced the secretion of IgE and IL-1ß within 1 month and promoted the secretion of IL-2, IL-4, IL-10, and IL-17 after 1 month. The results showed that tissue-engineering decellularized allografts strengthened intra-articular graft remodeling significantly and provided moderate improvements in tendon-bone healing by creating more suitable immune responses than decellularized allografts. The study revealed that tissue-engineering decellularized allografts as a promising option for ACL reconstruction could achieve more favorable outcomes.