Injection of Leukocyte-Poor Platelet-Rich Plasma for Moderate-to-Large Rotator Cuff Tears Does Not Improve Clinical Outcomes but Reduces Retear Rates and Fatty Infiltration: A Prospective, Single-Blinded Randomized Study.

OBJECTIVES: To determine whether leukocyte-poor platelet-rich plasma (Lp-PRP) reduced retear rates, reduced fatty infiltration, and improved functional outcomes in patients with degenerative moderate-to-large rotator cuff tears. METHODS: This was a randomized controlled study at a single center. A consecutive series of 104 patients with moderate-to-large rotator cuff tears was enrolled and randomly allocated to a control group (double-row suture-bridge arthroscopic rotator cuff repair alone, n = 52) and a study group (double-row suture-bridge repair followed by 3 Lp-PRP injections at the tendon repair site during surgery, at days 7 and 14 after surgery, n = 52). All patients were followed up for 27.2 months (range 24-36 months), with University of California at Los Angeles (UCLA) shoulder rating scale, the Constant score, and a visual analog scale (VAS) evaluated respectively. The integrity and fatty infiltration of repaired tissue were assessed by magnetic resonance imaging using the Sugaya classification and Goutallier grade classification at 24 months after surgery. Statistical analysis was performed based on the t test, χ2 test, and the Kendall tau-b correlation coefficient. RESULTS: Four patients refused follow-up, and 11 patients had incomplete data. Eventually, a total of 89 patients were available for 24 months follow-up. The mean UCLA score increased from 14.80 ± 2.53 to 29.37 ± 2.06 in control group and from 13.74 ± 3.30 to 30.14 ± 2.32 in study group (P = .103). The mean Constant score increased from 46.56 ± 5.90 to 86.83 ± 4.94 in control group and from 44.37 ± 7.92 to 88.80 ± 4.92 in study group (P = .063). The VAS score decreased from 3.22 ± 1.24 to 0.97 ± 1.12 in control group and in 3.49 ± 1.52 to 1.16 ± 0.99 in study group (P = .41). All differences in UCLA score, Constant score, and VAS between pre- and postoperation achieved minimal clinically important differences proposed for arthroscopic rotator cuff repair. Of the 89 patients, 76 had magnetic resonance imaging performed at 24 months after surgery. The retear rate was 17.6% in study group, which was lower than that in control group (38.1%, P = .049). In addition, the Goutallier grade was found to be significant difference between groups postoperatively (Kendall tau-b -0.24, P = .03) but no significant difference preoperatively (Kendall tau-b -0.18, P = .11). There were no complications in the patients. CONCLUSIONS: Our procedures involving repeated injections of Lp-PRP during surgery and at days 7 and 14, as described in this study, have positive effects on reducing retear rate and promoting Goutallier grade in patients following arthroscopic rotator cuff repair and could also provide substantial clinical outcomes that reach the minimal clinically important difference for surgical treatment. However, given the numbers available for analysis, it did not promote better clinical results when compared with the control group. LEVEL OF EVIDENCE: II, randomized controlled study.

Is Platelet-rich Plasma Injection Effective for Chronic Achilles Tendinopathy? A Meta-analysis.

BACKGROUND: Chronic Achilles tendinopathy is common in the general population, and platelet-rich plasma (PRP) is seeing increased use to treat this problem. However, studies disagree as to whether PRP confers a beneficial effect for chronic Achilles tendinopathy, and no one to our knowledge has pooled the available randomized trials in a formal meta-analysis to try to reconcile those differences. QUESTIONS/PURPOSES: In the setting of a systematic review and meta-analysis of randomized controlled trials (RCTs), we asked: Does PRP plus eccentric strength training result in (1) greater improvements in Victorian Institute of Sports Assessment-Achilles (VISA-A) scores; (2) differences in tendon thickness; or (3) differences in color Doppler activity compared with placebo (saline) injections plus eccentric strength training in patients with chronic Achilles tendinopathy? METHODS: A search of peer-reviewed articles was conducted to identify all RCTs using PRP injection with eccentric training for chronic Achilles tendinopathy in the electronic databases of PubMed, Web of Science (SCI-E/SSCI/A&HCI), and EMBASE from January 1981 to August 2017. Results were limited to human RCTs and published in all languages. Two reviewers assessed study quality using the Cochrane Collaboration risk-of-bias tool. All the included studies had low risk of bias. The primary endpoint was improvement in the VISA-A score, which ranges from 0 to 100 points, with higher scores representing increased activity and less pain; we considered the minimum clinically important difference on the VISA-A to be 12 points. Secondary outcomes were tendon thickness change (with a thicker tendon representing more severe disease), color Doppler activity (with more activity representing a poorer result), and other functional measures (such as pain and return to sports activity). Four RCTs involving 170 participants were eligible and included 85 participants treated with PRP injection and eccentric training and 85 treated with saline injection and eccentric training. The patients in both PRP and placebo (saline) groups seemed comparable at baseline. We assessed for publication bias using a funnel plot and saw no evidence of publication bias. Based on previous studies, we had 80% power to detect a 12-point difference on the VISA-A score with the available sample size in each group. RESULTS: With the numbers available, there was no difference between the PRP and saline groups regarding the primary outcome (VISA-A score: mean difference [MD], 5.3; 95% confidence interval [CI], -0.7 to 11.3; p = 0.085). Likewise, we found no difference between the PRP and saline groups in terms of our secondary outcomes of tendon thickness change (MD, 0.2 mm; 95% CI, 0.6-1.0 mm; p = 0.663) and color Doppler activity (MD, 0.1; 95% CI, -0.7 to 0.4; p = 0.695). CONCLUSIONS: PRP injection with eccentric training did not improve VISA-A scores, reduce tendon thickness, or reduce color Doppler activity in patients with chronic Achilles tendinopathy compared with saline injection. Larger randomized trials are needed to confirm these results, but until or unless a clear benefit has been demonstrated in favor of the new treatment, we cannot recommend it for general use. LEVEL OF EVIDENCE: Level I, therapeutic study.

Autograft or Allograft? Irradiated or Not? A Contrast Between Autograft and Allograft in Anterior Cruciate Ligament Reconstruction: A Meta-analysis.

PURPOSE: To compare the clinical outcomes and adverse events associated with irradiated and nonirradiated allografts in anterior cruciate ligament (ACL) reconstruction. METHODS: PubMed, Web of Science, and EMBASE were searched for randomized controlled trials from January 1990 to March 2018 to compare autograft with allograft in ACL reconstruction. Both objective and subjective outcomes of the function and adverse events were meta-analyzed. Two comparisons were summarized: (1) autograft and nonirradiated allograft and (2) autograft and irradiated allograft. The bias risk was based on the Cochrane Handbook for Systematic Reviews of Interventions. The overall risk ratio or weighted mean difference was calculated using a fixed- or random-effects model. Heterogeneity between studies was evaluated by the Q and the I2 statistics. RESULTS: Eleven trials were included in this review for meta-analysis. A total of 1,172 patients were involved (465 autograft and 461 nonirradiated allograft; 141 autograft and 138 irradiated allograft patients). The average follow-up varied from 2 to >10 years. The mean patient age varied from 22 to 32.8 years. The total failure rate was 2.5%. Our analyses demonstrated better clinical outcomes in autograft than irradiated allograft, which could be observed clearly through the International Knee Documentation Committee score (3.84; 95% confidence interval [CI], 1.93-5.76; P < .0001; I2 = 0%), Lysholm score (2.94; 95% CI, 0.66-5.22; P = .01; I2 = 0%), and Tegner score (0.14; 95% CI, -0.08 to 0.36; P = .22; I2 = 0%) with fewer adverse events 0.20 (95% CI, 0.11-0.39; P < .00001; I2 = 0%). There were no significant differences in autograft and nonirradiated allograft groups (P = .47, P = .27, P = .24, and P = .24, respectively). CONCLUSIONS: Autograft offered greater advantages in functional outcomes and adverse events than irradiated allograft in ACL reconstruction; however, there were no significant differences between autograft and nonirradiated allograft in ACL reconstruction. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and Level II studies.

The Effect of Cartilage Fragments on Femoral Tunnel Widening After Anterior Cruciate Ligament Reconstruction: A Prospective Randomized Controlled Study.

PURPOSE: To analyze the effect of cartilage fragments on tunnel widening and tendon-bone integration at 2 years' follow-up after anterior cruciate ligament reconstruction (ACLR). METHODS: A prospective randomized controlled study was performed in 116 patients who underwent ACLR with autologous hamstring tendons augmented with cartilage fragments (study group, n = 56) or without any augmentation (control group, n = 60). All patients were followed up for 25.6 months (range, 24-28 months), and the International Knee Documentation Committee score, Lysholm score, and visual analog scale score were determined. Computed tomography scans of all patients were obtained 2 years after surgery to evaluate the diameter of the femoral tunnel and thereby assess the amount of tunnel widening. Magnetic resonance imaging evaluation was performed 2 years postoperatively to evaluate the status of the graft in the femoral tunnel. In addition, 5 patients underwent biopsy of the tendon-bone interface at 24 months postoperatively with histologic assessment and transmission electron microscopy. RESULTS: A total of 107 patients completed the follow-up. There were no significant differences between the 2 groups in terms of International Knee Documentation Committee score (P = .07), Lysholm score (P = .10), and visual analog scale score (P = .57) at 24 months' follow-up. The femoral tunnel diameter and the tunnel widening percentage in the study group were significantly smaller than those in the control group (P < .001). The signal-noise quotient value of the graft in the femoral tunnel was 10.4 ± 7.0 in the study group, which was significantly lower than that in the control group (19.5 ± 9.2, P < .001). Histologic studies of the tendon-bone interface showed that there were more bone formations containing chondroid cells with aligned connective tissue in the study group compared with the control group; in addition, the diameter of the collagen fibrils in the study group was considerably thicker than that in the control group (P < .05). CONCLUSIONS: The use of cartilage fragments was effective in preventing femoral tunnel widening and seemed to promote the tendon-bone integration process after ACLR. LEVEL OF EVIDENCE: Level II, prospective randomized controlled study.

Pharmacological Regulation of In Situ Tissue Stem Cells Differentiation for Soft Tissue Calcification Treatment.

Calcification of soft tissues, such as heart valves and tendons, is a common clinical problem with limited therapeutics. Tissue specific stem/progenitor cells proliferate to repopulate injured tissues. But some of them become divergent to the direction of ossification in the local pathological microenvironment, thereby representing a cellular target for pharmacological approach. We observed that HIF-2alpha (encoded by EPAS1 inclined form) signaling is markedly activated within stem/progenitor cells recruited at calcified sites of diseased human tendons and heart valves. Proinflammatory microenvironment, rather than hypoxia, is correlated with HIF-2alpha activation and promoted osteochondrogenic differentiation of tendon stem/progenitor cells (TSPCs). Abnormal upregulation of HIF-2alpha served as a key switch to direct TSPCs differentiation into osteochondral-lineage rather than teno-lineage. Notably, Scleraxis (Scx), an essential tendon specific transcription factor, was suppressed on constitutive activation of HIF-2alpha and mediated the effect of HIF-2alpha on TSPCs fate decision. Moreover, pharmacological inhibition of HIF-2alpha with digoxin, which is a widely utilized drug, can efficiently inhibit calcification and enhance tenogenesis in vitro and in the Achilles's tendinopathy model. Taken together, these findings reveal the significant role of the tissue stem/progenitor cells fate decision and suggest that pharmacological regulation of HIF-2alpha function is a promising approach for soft tissue calcification treatment.

One-Step Cartilage Repair Technique as a Next Generation of Cell Therapy for Cartilage Defects: Biological Characteristics, Preclinical Application, Surgical Techniques, and Clinical Developments.

PURPOSE: To provide a comprehensive overview of the basic science rationale, surgical technique, and clinical outcomes of 1-step cartilage repair technique used as a treatment strategy for cartilage defects. METHODS: A systematic review was performed in the main medical databases to evaluate the several studies concerning 1-step procedures for cartilage repair. The characteristics of cell-seed scaffolds, behavior of cells seeded into scaffolds, and surgical techniques were also discussed. Clinical outcomes and quality of repaired tissue were assessed using several standardized outcome assessment tools, magnetic resonance imaging scans, and biopsy histology. RESULTS: One-step cartilage repair could be divided into 2 types: chondrocyte-matrix complex (CMC) and autologous matrix-induced chondrogenesis (AMIC), both of which allow a simplified surgical approach. Studies with Level IV evidence have shown that 1-step cartilage repair techniques could significantly relieve symptoms and improve functional assessment (P < .05, compared with preoperative evaluation) at short-term follow-up. Furthermore, magnetic resonance imaging showed that 76% cases in all included case series showed at least 75% defect coverage in each lesion, and 3 studies clearly showed hyaline-like cartilage tissue in biopsy tissues by second-look arthroscopy. CONCLUSIONS: The 1-step cartilage repair technique, with its potential for effective, homogeneous distribution of chondrocytes and multipotent stem cells on the surface of the cartilage defect, is able to regenerate hyaline-like cartilage tissue, and it could be applied to cartilage repair by arthroscopy. LEVEL OF EVIDENCE: Level IV, systematic review of Level II and IV studies.

Autologous chondrocyte implantation: Is it likely to become a saviour of large-sized and full-thickness cartilage defect in young adult knee?

PURPOSE: A literature review of the first-, second- and third-generation autologous chondrocyte implantation (ACI) technique for the treatment of large-sized (>4 cm(2)) and full-thickness knee cartilage defects in young adults was conducted, examining the current literature on features, clinical scores, complications, magnetic resonance image (MRI) and histological outcomes, rehabilitation and cost-effectiveness. METHODS: A literature review was carried out in the main medical databases to evaluate the several studies concerning ACI treatment of large-sized and full-thickness knee cartilage defects in young adults. RESULTS: ACI technique has been shown to relieve symptoms and improve functional assessment in large-sized (>4 cm(2)) and full-thickness knee articular cartilage defect of young adults in short- and medium-term follow-up. Besides, low level of evidence demonstrated its efficiency and durability at long-term follow-up after implantation. Furthermore, MRI and histological evaluations provided the evidence that graft can return back to the previous nearly normal cartilage via ACI techniques. Clinical outcomes tend to be similar in different ACI techniques, but with simplified procedure, low complication rate and better graft quality in the third-generation ACI technique. CONCLUSION: ACI based on the experience of cell-based therapy, with the high potential to regenerate hyaline-like tissue, represents clinical development in treatment of large-sized and full-thickness knee cartilage defects. LEVEL OF EVIDENCE: IV.

Efficacy of platelet-rich plasma in arthroscopic repair of full-thickness rotator cuff tears: a meta-analysis.

BACKGROUND: The use of platelet-rich plasma (PRP) is an innovative clinical therapy, especially in arthroscopic rotator cuff repair. The purpose of this study was to compare the clinical improvement and tendon-to-bone healing with and without PRP therapy in arthroscopic rotator cuff repair. METHODS: A systematic search was done in the major medical databases to evaluate the studies using PRP therapy (PRP+) or with no PRP (PRP-) for the treatment of patients with rotator cuff tears. We reviewed clinical scores such as the Constant score, the American Shoulder and Elbow Surgeons score, the University of California at Los Angeles (UCLA) Shoulder Rating Scale, the Simple Shoulder Test, and the failure-to-heal rate by magnetic resonance imaging between PRP+ and PRP- groups. RESULTS: Five studies included in this review were used for a meta-analysis based on data availability. There were no statistically significant differences between PRP+ and PRP- groups for overall outcome scores (P > .05). However, the PRP+ group exhibited better healing rates postoperatively than the PRP- group (P = .03) in small/moderate full-thickness tears. CONCLUSION: The use of PRP therapy in full-thickness rotator cuff repairs showed no statistically significant difference compared with no PRP therapy in clinical outcome scores, but the failure-to-heal rate was significantly decreased when PRP was used for treatment of small-to-moderately sized tears. PRP therapy may improve tendon-to-bone healing in patients with small or moderate rotator cuff tears.

Therapeutic effect of electroacupuncture, massage, and blocking therapy on external humeral epicondylitis.

OBJECTIVE: To compare two therapeutic methods: electroacupuncture + massage + blocking therapy, and blocking therapy alone in the treatment of external humeral epicondylitis. METHODS: Eighty-six patients were randomized into two groups with 43 in each. The treatment group received electroacupuncture + massage + blocking therapy, while the control group received blocking therapy only. A course of electroacupuncture treatment included therapy once a day for 10 days. There were 10 treatments in a massage course and massage was given once a day, with a 1-week interval given before the next course. A course of blocking treatment included therapy once a week, for two total treatments, and generally no more than three times. The therapeutic effects were evaluated with the visual analog scale (VAS), grip strength index (GSI) score, and Mayo elbow performance score (MEPS) before treatment and at 0, 6, 12, and 24 months after treatment to observe the total effective rate. RESULTS: In the treatment and control groups before treatment and at 0, 6, 12, and 24 months after treatment, the VAS scores were: 6.5 +/- 1.9 and 6.4 +/- 1.6; 4.6 +/- 1.3 and 4.6 +/- 1.7; 4.8 +/- 1.3 and 4.8 +/- 1.2; 4.6 +/- 1.2 and 6.6 +/- 1.6; and 6.5 +/- 1.6 and 6.5 +/- 1.3, respectively. The GSI scores were 63 +/- 8 and 63 +/- 8; 84 +/- 6 and 82 +/- 7; 82 +/- 7 and 82 +/- 6; 84 +/- 6 and 62 +/- 8; and 64 +/- 6 and 64 +/- 7, respectively. The MEPS of both groups were 65 +/- 7 and 66 +/- 8; 85 +/- 6 and 84 +/- 7; 84 +/- 5 and 84 +/- 7; 80 +/- 7 and 66 +/- 6; and 65 +/- 6 and 65 +/-7, respectively. The total effective rates of the treatment and control groups at 0, 6, 12, and 24 months after treatment were 87.5% and 85.0%; 85.0% and 82.5%; 80.0% and 12.5%; and 2.5% and 5.0%, respectively. Compared with the treatment group, the control group had greater joint function, better therapeutic effect, and lower pain intensity (P<0.01), indicating a high recurrence rate in the 12th month after treatment. There were no differences in VAS, GSI, or MEPS at 0, 6, and 24 months after treatment (P> 0.05) between the two groups. CONCLUSION: We found that both methods were effective for external humeral epicondylitis. After 6 months of treatment, the effects were good in both groups. However, in the 12th month, the control group had a relatively severe relapse. After 24 months, both groups relapsed. The effect of electroacupuncture, massage, and blocking therapy used in combination lasted longer, delaying the recurrence of the disease.

Magnetic Seeding of SPIO-BMSCs Into a Biphasic Scaffold Can Promote Tendon-Bone Healing After Rotator Cuff Repair.

BACKGROUND: The tendon-bone interface (TBI) in the rotator cuff has a poor intrinsic capacity for healing, which increases the risk of retear after rotator cuff repair (RCR). However, facilitating regeneration of the TBI still remains a great clinical challenge. Herein, the authors established a novel strategy based on magnetic seeding to enhance the TBI regeneration. HYPOTHESIS: Magnetic seeding bone marrow mesenchymal stem cells labeled with superparamagnetic iron oxide (SPIO-BMSCs) into a biphasic scaffold can promote tendon-bone healing after RCR. STUDY DESIGN: Controlled laboratory study. METHODS: BMSCs were labeled with SPIOs. Prussian blue staining, CCK-8 tests, Western blot, and quantitative reverse transcription polymerase chain reaction (PCR) were used to determine the optimal effect concentration of SPIOs on cell bioactivities and abilities. Then SPIO-BMSCs were magnetically seeded into a biphasic scaffold under a magnetic field. The seeding efficacy was assessed by a scanning electron microscope, and the potential mechanism in chondrogenic differentiation after seeding SPIO-BMSCs into the scaffold was evaluated by Western blot and PCR. Furthermore, the effect of SPIO-BMSC/biphasic scaffold on tendon-bone healing after RCR using a rat model was examined using histological analysis, enzyme-linked immunosorbent assay, and biomechanical evaluation. RESULTS: BMSCs labeled with 100 µg/mL SPIO had no effect on cell bioactivities and the ability of chondrogenic differentiation. SPIO-BMSCs were magnetically seeded into a biphasic scaffold, which offered a high seeding efficacy to enhance chondrogenic differentiation of SPIO-BMSCs via the CDR1as/miR-7/FGF2 pathway for TBI formation in vitro. Furthermore, in vivo application of the biphasic scaffold with magnetically seeded SPIO-BMSCs showed their regenerative potential, indicating that they could significantly accelerate and promote TBI healing with superior biomechanical properties after RCR in a rat rotator cuff tear model. CONCLUSION: Magnetically seeding SPIO-BMSCs into a biphasic scaffold enhanced seeding efficacy to promote cell distribution and condensation. This construct enhanced the chondrogenesis process via the CDR1as/miR-7/FGF2 pathway and further promoted tendon-bone healing after RCR in a rat rotator cuff tear model. CLINICAL RELEVANCE: This study provides an alternative strategy for improving TBI healing after RCR.

Silk fibroin hydrogel adhesive enables sealed-tight reconstruction of meniscus tears.

Despite orientationally variant tears of the meniscus, suture repair is the current clinical gold treatment. However, inaccessible tears in company with re-tears susceptibility remain unresolved. To extend meniscal repair tools from the perspective of adhesion and regeneration, we design a dual functional biologic-released bioadhesive (S-PIL10) comprised of methacrylated silk fibroin crosslinked with phenylboronic acid-ionic liquid loading with growth factor TGF-ß1, which integrates chemo-mechanical restoration with inner meniscal regeneration. Supramolecular interactions of ß-sheets and hydrogen bonds richened by phenylboronic acid-ionic liquid (PIL) result in enhanced wet adhesion, swelling resistance, and anti-fatigue capabilities, compared to neat silk fibroin gel. Besides, elimination of reactive oxygen species (ROS) by S-PIL10 further fortifies localized meniscus tear repair by affecting inflammatory microenvironment with dynamic borate ester bonds, and S-PIL10 continuously releases TGF-ß1 for cell recruitment and bridging of defect edge. In vivo rabbit models functionally evidence the seamless and dense reconstruction of torn meniscus, verifying that the concept of meniscus adhesive is feasible and providing a promising revolutionary strategy for preclinical research to repair meniscus tears.

A pathological joint-liver axis mediated by matrikine-activated CD4+ T cells.

The knee joint has long been considered a closed system. The pathological effects of joint diseases on distant organs have not been investigated. Herein, our clinical data showed that post-traumatic joint damage, combined with joint bleeding (hemarthrosis), exhibits a worse liver function compared with healthy control. With mouse model, hemarthrosis induces both cartilage degeneration and remote liver damage. Next, we found that hemarthrosis induces the upregulation in ratio and differentiation towards Th17 cells of CD4+ T cells in peripheral blood and spleen. Deletion of CD4+ T cells reverses hemarthrosis-induced liver damage. Degeneration of cartilage matrix induced by hemarthrosis upregulates serological type II collagen (COL II), which activates CD4+ T cells. Systemic application of a COL II antibody blocks the activation. Furthermore, bulk RNAseq and single-cell qPCR analysis revealed that the cartilage Akt pathway is inhibited by blood treatment. Intra-articular application of Akt activator blocks the cartilage degeneration and thus protects against the liver impairment in mouse and pig models. Taken together, our study revealed a pathological joint-liver axis mediated by matrikine-activated CD4+ T cells, which refreshes the organ-crosstalk axis and provides a new treatment target for hemarthrosis-related disease. Intra-articular bleeding induces cartilage degradation through down-reulation of cartilage Akt pathway. During this process, the soluble COL II released from the damaged cartilage can activate peripheral CD4+ T cells, differention into Th17 cells and secretion of IL-17, which consequently induces liver impairment. Intra-articular application of sc79 (inhibitor of Akt pathway) can prevent the cartilage damage as well as its peripheral influences.

Intra-articular delivery of geraniol encapsulated by pH/redox-responsive nanogel ameliorates osteoarthritis by regulating oxidative stress and inflammation.

Osteoarthritis (OA) remains a challenging condition due to limited drug bioavailability within the avascular and dense cartilage matrix. This study introduces a pH/redox-responsive nanogel for enhanced delivery of geraniol in OA therapy. We investigated geraniol's role in preventing chondrocyte matrix degradation and designed a pH/redox-responsive nanogel as a delivery platform. Our methods included Western blot, histological staining, and immunohistochemistry. Geraniol treatment reduced Keap1 expression while elevating Nrf2 and HO-1 levels, effectively inhibiting cartilage matrix degradation. The pH/redox-responsive nanogel further enhanced geraniol's therapeutic impact. Our study demonstrates that geraniol encapsulated within a pH/redox-responsive nanogel mitigates OA by regulating oxidative stress and inflammation. This innovative approach holds potential as an effective OA therapeutic strategy.

Cartilage fragments combined with BMSCs-Derived exosomes can promote tendon-bone healing after ACL reconstruction.

Anterior cruciate ligament reconstruction (ACLR) often fails due to the inability of tendon-bone integration to regenerate normal tissues and formation of fibrous scar tissues in the tendon-bone interface. Cartilage fragments and exosomes derived from bone mesenchymal stromal cells (BMSCs-Exos) can enhance enthesis healing. Nevertheless, the effects on the tendon-bone healing of ACLR remain unknown. This study found that BMSCs-Exos can promote the proliferation of chondrocytes in cartilage fragments, and activated the expression of chondro-related genes SOX9 and Aggrecan. The optimal effect concentration was 1012 events/uL. Besides, BMSCs-Exos could significantly upregulated the expression of BMP7 and Smad5 in cartilage fragments, and further enhanced the expression of chondrogenic genes. Moreover, this study established a rat model of ACLR and implanted the BMSCs-Exos/cartilage fragment complex into the femoral bone tunnel. Results demonstrated that the mean diameters of the femoral bone tunnels were significantly smaller in the BE-CF group than those in the CF group (p = 0.038) and control group (p = 0.007) at 8 weeks after surgery. Besides, more new bone formation was observed in the femoral tunnels in the BE-CF group, as demonstrated by a larger BV/TV ratio based on the reconstructed CT scans. Histological results also revealed the regeneration of tendon-bone structures, especially fibrocartilage. Thus, these findings provide a promising result that BMSCs-Exos/cartilage fragment complex can prevent the enlargement of bone tunnel and promote tendon-bone healing after ACLR, which may have resulted from the regulation of the BMP7/Smad5 signaling axis.

Stimulation by Exosomes from Hypoxia Preconditioned Human Umbilical Vein Endothelial Cells Facilitates Mesenchymal Stem Cells Angiogenic Function for Spinal Cord Repair.

Revascularization treatment is a critical measure for tissue engineering therapies like spinal cord repair. As multipotent stem cells, mesenchymal stem cells (MSCs) have proven to regulate the lesion microenvironment through feedback to the microenvironment signals. The angiogenic capacities of MSCs have been reported to be facilitated by vein endothelial cells in the niche. As emerging evidence demonstrated the roles of exosomes in cell-cell and cell-microenvironment communications, to cope with the ischemia complication for treatment of traumatic spinal cord injury, the study extracts the microenvironment factors to stimulate angiogenic MSCs through using exosomes (EX) derived from hypoxic preconditioned (HPC) human umbilical vein endothelial cells (HUVEC). The HPC treatment with a hypoxia time segment of only 15 min efficiently enhanced the function of EX in facilitating MSCs angiogenesis activity. MSCs stimulated by HPC-EX showed significant tube formation within 2 h, and the in vivo transplantation of the stimulated MSCs elicited effective nerve tissue repair after rat spinal cord transection, which could be attributed to the pro-angiogenic and anti-inflammatory impacts of the MSCs. Through the simulation of MSCs using HPC-tailored HUVEC exosomes, the results proposed an efficient angiogenic nerve tissue repair strategy for spinal cord injury treatment and could provide inspiration for therapies based on stem cells and exosomes.

Discovery of Muscle-Tendon Progenitor Subpopulation in Human Myotendinous Junction at Single-Cell Resolution.

The myotendinous junction (MTJ) is a complex and special anatomical area that connects muscles and tendons, and it is also the key to repairing tendons. Nevertheless, the anatomical structure and connection structure of MTJ, the cluster and distribution of cells, and which cells are involved in repairing the tissue are still unclear. Here, we analyzed the cell subtype distribution and function of human MTJ at single-cell level. We identified four main subtypes, including stem cell, muscle, tendon, and muscle-tendon progenitor cells (MTP). The MTP subpopulation, which remains the characteristics of stem cells and also expresses muscle and tendon marker genes simultaneously, may have the potential for bidirectional differentiation. We also found the muscle-tendon progenitor cells were distributed in the shape of a transparent goblet; muscle cells first connect to the MTP and then to the tendon. And after being transplanted in the MTJ injury model, MTP exhibited strong regenerative capability. Finally, we also demonstrated the importance of mTOR signaling for MTP maintenance by in vitro addition of rapamycin and in vivo validation using mTOR-ko mice. Our research conducted a comprehensive analysis of the heterogeneity of myotendinous junction, discovered a special cluster called MTP, provided new insights into the biological significance of myotendinous junction, and laid the foundation for future research on myotendinous junction regeneration and restoration.

[Intermediate outcomes of alumina-on-alumina bearing total hip arthroplasty].

OBJECTIVE: To explore the intermediate outcomes of third-generation alumina-on-alumina total hip arthroplasty (THA). METHODS: A consecutive series of 165 primary alumina-on-alumina total hip arthroplasties were performed in 135 patients. Three patients died and 13 patients lost follow-up so that a total of 119 patients (146 hips) were available for study. The mean patient age was 53.4 ± 11.0 years old (range: 26 - 79). Hydroxyapatite. (HA)-coated press-fit acetabular cups were used in all cases. At femoral side, 123 cases were implanted with HA-coated uncemented stems and 23 cases implanted with high polished double taped cemented stems. All patients were evaluated clinically and radiographically after a minimal follow-up duration of 60 months. RESULTS: The preoperative mean Harris hip score of 49.6 ± 7.9 points improved to 91.7 ± 3.0 points at the last follow-up (P < 0.05). The 5-year survival for any reason lead to revision was 96.6%. Five hips were under revision, 1 for acetabular shell loosening and migration, 1 for Vancouver B2 periprosthetic fracture, 1 for fracture of pure alumina liner and 2 for infections. All other prostheses demonstrated no radiographic evidence of loosening. No periprosthetic osteolysis was found. There were 2 cases of dislocations and 2 patients presented postoperatively with "squeaking-like" hips. CONCLUSION: The clinical and radiographic outcomes after primary THA with third-generation ceramic-on-ceramic bearing surfaces are favorable after a minimal follow-up duration of 5 years. The modified alumina-on-alumina bearing implants offer a better option for younger and active patients.

Effectiveness of Various Dosages and Administration Methods of Tanezumab for the Treatment of Pain in Knee and Hip Osteoarthritis: a Network Meta-Analysis.

BACKGROUND: Previous meta-analyses have reported the superiority of tanezumab versus placebo in the treatment of osteoarthritis (OA). However, they did not compare different injection methods (intravenous or subcutaneous), doses of injection. OBJECTIVE: The goal of this network meta-analysis (NMA) was to evaluate the therapeutic effects of different dosages and methods of injection of tanezumab on relieving pain in patients with OA. METHODS: An online systematic search was performed by using the PubMed, Cochrane Library, EMBASE, and ClinicalTrials.gov databases from inception to November 9, 2019. The goal was to identify randomized controlled trials (RCTs) that concentrated on the therapeutic effects of different dosages and methods of injection of tanezumab in patients with OA. The pairwise meta-analyses with the fixed effects model were undertaken with the "meta" package using R 3.6.0 programming language. In addition, an NMA with fixed effects was assessed using a gemtc software. The surface under the cumulative ranking curve value of each intervention was calculated to obtain a hierarchy of treatments. RESULTS: Of the 328 RCTs identified through the literature search, 12 RCTs were included in the current NMA. In terms of the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function subscales, the most effective treatment was intravenous injection of tanezumab (10 mg; surface under the cumulative ranking curve values of 90% and 88%, respectively), and the least effective therapy was subcutaneous injection of tanezumab (2.5 mg; 20% and 19%). CONCLUSIONS: To achieve high therapeutic efficacy and avoid treatment failure, an intravenous injection of tanezumab (10 mg) is recommended as an efficacious therapy, facilitating pain relief in patients with OA. However, this conclusion may also be affected by the limitations of this study owing to the small sample size and data heterogeneity, and further research should therefore be conducted to eliminate these limitations and to confirm the findings.

Exosomes in osteoarthritis and cartilage injury: advanced development and potential therapeutic strategies.

Articular cartilage injury is a common clinical problem, which can lead to joint dysfunction, significant pain, and secondary osteoarthritis (OA) in which major surgical procedures are mandatory for treatment. Exosomes, as endosome-derived membrane-bound vesicles, participating in intercellular communications in both physiological and pathophysiological conditions, have been attached great importance in many fields. Recently, the significance of exosomes in the development of OA has been gradually concerned, while the therapeutic value of exosomes in cartilage repair and OA treatment has also been gradually revealed. The functional difference of different types and derivations of exosomes are determined by their specific contents. Herein, we provide comprehensive understanding on exosome and OA, including how exosomes participating in OA, the therapeutic value of exosomes for cartilage injury/OA, and related bioengineering strategies for future therapeutic design.