Analysis of differentially expressed genes in torn rotator cuff tendon tissues in diabetic patients through RNA-sequencing.

BACKGROUND: Rotator cuff tears (RCT) is a common musculoskeletal disorder in the shoulder which cause pain and functional disability. Diabetes mellitus (DM) is characterized by impaired ability of producing or responding to insulin and has been reported to act as a risk factor of the progression of rotator cuff tendinopathy and tear. Long non-coding RNAs (lncRNAs) are involved in the development of various diseases, but little is known about their potential roles involved in RCT of diabetic patients. METHODS: RNA-Sequencing (RNA-Seq) was used in this study to profile differentially expressed lncRNAs and mRNAs in RCT samples between 3 diabetic and 3 nondiabetic patients. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed to annotate the function of the differentially expressed genes (DEGs). LncRNA-mRNA co-expression network and competing endogenous RNA (ceRNA) network were constructed to elucidate the potential molecular mechanisms of DM affecting RCT. RESULTS: In total, 505 lncRNAs and 388 mRNAs were detected to be differentially expressed in RCT samples between diabetic and nondiabetic patients. GO functional analysis indicated that related lncRNAs and mRNAs were involved in metabolic process, immune system process and others. KEGG pathway analysis indicated that related mRNAs were involved in ferroptosis, PI3K-Akt signaling pathway, Wnt signaling pathway, JAK-STAT signaling pathway and IL-17 signaling pathway and others. LncRNA-mRNA co-expression network was constructed, and ceRNA network showed the interaction of differentially expressed RNAs, comprising 5 lncRNAs, 2 mRNAs, and 142 miRNAs. TF regulation analysis revealed that STAT affected the progression of RCT by regulating the apoptosis pathway in diabetic patients. CONCLUSIONS: We preliminarily dissected the differential expression profile of lncRNAs and mRNAs in torn rotator cuff tendon between diabetic and nondiabetic patients. And the bioinformatic analysis suggested some important RNAs and signaling pathways regarding inflammation and apoptosis were involved in diabetic RCT. Our findings offer a new perspective on the association between DM and progression of RCT.

Associations between obesity, diabetes mellitus, and cardiovascular disease with progression states of knee osteoarthritis (KOA).

BACKGROUND: Data on common comorbidities targeting at different progression states of knee osteoarthritis (KOA) in continuous time are limited. AIMS: To examine the associations between obesity, diabetes mellitus (DM), and cardiovascular disease (CVD) with the progression of KOA. METHODS: Data were obtained from the Osteoarthritis Initiative for up to 48 months. Progression states of KOA were defined as (1) normal; (2) asymptomatic radiographic KOA (RKOA, Kellgren-Lawrence grade ≥ 2 in at least one knee); (3) only knee symptoms; (4) symptomatic KOA (SxKOA, a combination of RKOA and knee symptoms in the same knee). A multi-state Markov model was used to investigate the associations while accounting for potential confounders. RESULTS: Participants with obesity had an increased risk of developing RKOA [normal to asymptomatic RKOA, adjusted hazard ratio (aHR) 1.55, 95% confidence interval (95% CI) (1.07, 2.24); only knee symptoms to SxKOA, aHR 2.25, 95% CI (1.60, 3.18)], and an increased risk of developing knee symptoms [normal to only knee symptoms, aHR 1.45, 95% CI (1.15, 1.83); asymptomatic RKOA to SxKOA, aHR 1.33, 95% CI (1.16, 1.52)]. DM was also significantly associated with development of RKOA or knee symptoms [normal to asymptomatic RKOA, aHR 1.92, 95% CI (1.12, 3.30); normal to only knee symptoms, aHR 1.78, 95% CI (1.12, 2.84)]. Knee symptoms were less likely to be relieved among participants with CVD, compared with those without [only knee symptoms to normal, aHR 0.60, 95% CI (0.38, 0.94)]. CONCLUSIONS: Obesity, DM and CVD are associated with an increased risk for SxKOA progression. Common comorbidities should be considered to prevent KOA development.

Association between changes in hip-knee-ankle angle and hindfoot alignment after total knee arthroplasty for varus knee osteoarthritis.

BACKGROUND: The change in hip-knee-ankle (HKA) angle after total knee arthroplasty (TKA) may cause an adjustment in hindfoot alignment (HFA). However, the relationship between the changes in HKA angle and HFA is still not well studied. This study aimed to investigate the association between HKA angle and hindfoot alignment changes after TKA for varus knee osteoarthritis. METHODS: A prospective study was carried out in which 108 patients with varus knee deformities were radiographically and clinically evaluated before and 3 months after TKA. The relationship of change in HFA with correction in HKA angle was investigated. RESULTS: The results showed that the HFA was adjusted significantly by 3 months after TKA (p < 0.001), along with improved American Orthopaedic Foot and Ankle Society (AOFAS) ankle hindfoot score (p < 0.001). Next, a univariate correlation and linear regression analysis showed that the change in HFA was weakly correlated with the change in HKA angle (r=-0.262, ß=-0.14, 95 % CI: -0.23 to -0.04, P = 0.006). Further stratified analysis and interaction tests revealed that age has a distinct effect on the correlation between the changes in HFA and HKA angle. The correlation was dramatically greater in the group under 65 years (r=-0.474, ß=-0.26, 95 % CI: -0.41 to -0.12, P = 0.001), whilst, no correlation was observed in those above 65 years old (r=-0.036, ß=-0.02, 95 % CI: -0.14 to 0.11, P = 0.779). CONCLUSIONS: Our findings indicated that correction of HKA after TKA tend to promote adjustment in the hindfoot alignment toward re-balance of the whole lower limb weight-bearing axis. However, this mechanism obviously weakens in elderly patients. Therefore, if apparent hindfoot deformity exists in these patients before TKA, more perioperative intervention is required for hindfoot adjustment, and even HKA undercorrection may be considered.

Tenomodulin regulates matrix remodeling of mouse tendon stem/progenitor cells in an ex vivo collagen I gel model.

Tenomodulin (Tnmd) is predominantly expressed in tendon and ligament tissues. Loss of Tnmd in mice leads to a profound phenotype in vitro, characterized by reduced self-renewal but increased senescence of mouse tendon stem/progenitor cells (mTSPCs), as well as in vivo, by significantly impaired early tendon healing. Interestingly, injuried Achilles tendons from Tnmd-deficient mice showed inferior tendon repair, which was characterized by less contracted fibrovascular scars with disorganized matrix composition in comparison to wild type (WT) mice at day 8 after injury. To better understand Tnmd role in tendon repair, here we implemented an ex vivo three-dimensional (3D) collagen gel model and investigated whether Tnmd knockout affects the collagen contraction of mTSPCs. TSPCs were isolated from WT and Tnmd knockout (KO) tendons at 6, 9, 12, and 18 months of age. Adhesion assay demonstrated that loss of Tnmd in mTSPCs resulted in reduced adhesion to collagen type I. Quantitative time-dependent analysis revealed that Tnmd-deficient mTSPCs of all ages have significantly reduced capacity to contract collagen matrix in comparison to WT cells. Furthermore, 18 months old mTSPCs of both genotypes showed lower collagen contractility than cells obtained from 6, 9, and 12 months old animals, demonstrating an overall effect of organismal aging on matrix remodeling. Nevertheless, both cell types had a similar survival rate for the 5 days of cultivation within the gels. Lastly, quantitative PCR for 48 different genes revealed that the knockout of Tnmd majorly affected the gene expression profile of mTSPCs, as several transcription factors, tendon matrix, collagen cross-linking, and lineage maker genes were down-regulated. Taken together, our results clearly demonstrated that loss of Tnmd in mTSPCs led to profoundly altered gene expression profile, insufficient adhesion to collagen type I, and impaired ability to contract the extracellular matrix.

Tuberoplasty reduces resistance force in dynamic shoulder abduction for irreparable rotator cuff tears: a cadaveric biomechanical study.

BACKGROUND: Arthroscopic tuberoplasty is an optional technique for managing irreparable rotator cuff tears. However, there is a lack of studies investigating the resistance force during shoulder abduction in cases of irreparable rotator cuff tears and tuberoplasty. HYPOTHESES: In shoulders with irreparable rotator cuff tears, impingement between the greater tuberosity (GT) and acromion increases the resistance force during dynamic shoulder abduction. Tuberoplasty is hypothesized to reduce this resistance force by mitigating impingement. STUDY DESIGN: Controlled laboratory study. METHODS: Eight cadaveric shoulders, with a mean age of 67.75 years (range, 63-72 years), were utilized. The testing sequence included intact rotator cuff condition, irreparable rotator cuff tears (IRCTs), burnishing tuberoplasty, and prosthesis tuberoplasty. Burnishing tuberoplasty refers to the process wherein osteophytes on the GT are removed using a bur, and the GT is subsequently trimmed to create a rounded surface that maintains continuity with the humeral head. Deltoid forces and actuator distances were recorded. The relationship between deltoid forces and actuator distance was graphically represented in an ascending curve. Data were collected at five points within each motion cycle, corresponding to actuator distances of 20 mm, 30 mm, 40 mm, 50 mm, and 60 mm. RESULTS: In the intact rotator cuff condition, resistance forces at the five points were 34.25 ± 7.73 N, 53.75 ± 7.44 N, 82.50 ± 14.88 N, 136.25 ± 30.21 N, and 203.75 ± 30.68 N. In the IRCT testing cycle, resistance forces were 46.13 ± 7.72 N, 63.75 ± 10.61 N, 101.25 ± 9.91 N, 152.5 ± 21.21 N, and 231.25 ± 40.16 N. Burnishing tuberoplasty resulted in resistance forces of 32.25 ± 3.54 N, 51.25 ± 3.54 N, 75.00 ± 10.69 N, 115.00 ± 10.69 N, and 183.75 ± 25.04 N. Prosthesis tuberoplasty showed resistance forces of 29.88 ± 1.55 N, 49.88 ± 1.36 N, 73.75 ± 7.44 N, 112.50 ± 7.07 N, and 182.50 ± 19.09 N. Both forms of tuberoplasty significantly reduced resistance force compared to IRCTs. Prosthesis tuberoplasty further decreased resistance force due to a smooth surface, although the difference was not significant compared to burnishing tuberoplasty. CONCLUSION: Tuberoplasty effectively reduces resistance force during dynamic shoulder abduction in irreparable rotator cuff tears. Prosthesis tuberoplasty does not offer a significant advantage over burnishing tuberoplasty in reducing resistance force. CLINICAL RELEVANCE: Tuberoplasty has the potential to decrease impingement, subsequently reducing resistance force during dynamic shoulder abduction, which may be beneficial in addressing conditions like pseudoparalysis.

Arthroscopic Resection for Extra-articular Ganglion Cysts of Gastrocnemius Near Vessels.

Extra-articular ganglion cysts arising from the gastrocnemius tendon near popliteal vessels can cause pain and claudication. Open resection of this kind of cyst has been described frequently because the vessels can be well protected with a retractor. However, it's a challenge to remove cysts that are near vessels under arthroscopy, because a retractor cannot be used in arthroscopic surgery. This article will report a method of arthroscopic resection for extra-articular ganglion cysts near popliteal vessels.

A Hybrid Scaffold Induces Chondrogenic Differentiation and Enhances In Vivo Cartilage Regeneration.

Extensively researched tissue engineering strategies involve incorporating cells into suitable biomaterials, offering promising alternatives to boost tissue repair. In this study, a hybrid scaffold, Gel-DCM, which integrates a photoreactive gelatin-hyaluronic acid hydrogel (Gel) with an oriented porous decellularized cartilage matrix (DCM), was designed to facilitate chondrogenic differentiation and cartilage repair. The Gel-DCM exhibited excellent biocompatibility in vitro, promoting favorable survival and growth of human adipose-derived stem cells (hADSCs) and articular chondrocytes (hACs). Gene expression analysis indicated that the hACs expanded within the Gel-DCM exhibited enhanced chondrogenic phenotype. In addition, Gel-DCM promoted chondrogenesis of hADSCs without the supplementation of exogenous growth factors. Following this, in vivo experiments were conducted where empty Gel-DCM or Gel-DCM loaded with hACs/hADSCs were used and implanted to repair osteochondral defects in a rat model. In the control group, no implants were delivered to the injury site. Interestingly, macroscopic, histological, and microcomputed tomography scanning results revealed superior cartilage restoration and subchondral bone reconstruction in the empty Gel-DCM group compared with the control group. Moreover, both hACs-loaded and hADSCs-loaded Gel-DCM implants exhibited superior repair of hyaline cartilage and successful reconstruction of subchondral bone, whereas defects in the control groups were predominantly filled with fibrous tissue. These observations suggest that the Gel-DCM can provide an appropriate three-dimensional chondrogenic microenvironment, and its combination with reparative cell sources, ACs or ADSCs, holds great potential for facilitating cartilage regeneration.

Tendon stem/progenitor cells are promising reparative cell sources for multiple musculoskeletal injuries of concomitant articular cartilage lesions associated with ligament injuries.

BACKGROUND: Trauma-related articular cartilage lesions usually occur in conjunction with ligament injuries. Torn ligaments are frequently reconstructed with tendon autograft and has been proven to achieve satisfactory clinical outcomes. However, treatments for the concomitant articular cartilage lesions are still very insufficient. The current study was aimed to evaluate whether stem cells derived from tendon tissue can be considered as an alternative reparative cell source for cartilage repair. METHODS: Primary human tendon stem/progenitor cells (hTSPCs) were isolated from 4 male patients (32 ± 8 years) who underwent ACL reconstruction surgery with autologous semitendinosus and gracilis tendons. The excessive tendon tissue after graft preparation was processed for primary cell isolation with an enzyme digestion protocol. Decellularization cartilage matrix (DCM) was used to provide a chondrogenic microenvironment for hTSPCs. Cell viability, cell morphology on the DCM, as well as their chondrogenic differentiation were evaluated. RESULTS: DAPI staining and DNA quantitative analysis (61.47 µg per mg dry weight before and 2.64 µg/mg after decellularization) showed that most of the cells in the cartilage lacuna were removed after decellularization process. Whilst, the basic structure of the cartilage tissue was preserved and the main ECM components, collagen type II and sGAG were retained after decellularization, which were revealed by DMMB assay and histology. Live/dead staining and proliferative assay demonstrated that DCM supported attachment, survival and proliferation of hTSPCs with an excellent biocompatibility. Furthermore, gene expression analysis indicated that chondrogenic differentiation of hTSPC was induced by the DCM microenvironment, with upregulation of chondrogenesis-related marker genes, COL 2 and SOX9, without the use of exogenous growth factors. CONCLUSION: DCM supported hTSPCs attachment and proliferation with high biocompatibility. Moreover, TSPCs underwent a distinct chondrogenesis after the induction of a chondrogenic microenvironment provided by DCM. These results indicated that TSPCs are promising reparative cell sources for promoting cartilage repair. Particularly, in the cohort that articular cartilage lesions occur in conjunction with ligament injuries, autologous TSPCs can be isolated from a portion of the tendon autograph harvested for ligaments reconstruction. In future clinical practice, combined ligament reconstruction with TSPCs- based therapy for articular cartilage repair can to be considered to achieve superior repair of these associated injuries, in which autologous TSPCs can be isolated from a portion of the tendon autograph harvested for ligaments reconstruction.

DHA attenuates cartilage degeneration by mediating apoptosis and autophagy in human chondrocytes and rat models of osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease that usually occurs in the elderly, and docosahexaenoic acid (DHA) plays a therapeutic role in cardiovascular disease, diabetes, and rheumatoid arthritis (RA) with its anti-inflammatory and antioxidant effects. The objective of this study is to investigate the effect and mechanism of DHA on hypertrophic differentiation and senescence of OA chondrocytes to provide a theoretical basis for the effect of OA clinical treatment. A human OA chondrocyte model was established by IL-1ß, and a rat model of OA was established by anterior cruciate ligament (ACL) transection and medial meniscectomy. The result showed DHA promoted chondrocyte proliferation and reduced apoptosis. Transmission electron microscopy (TEM) analysis showed that there were more autophagosomes in the cytoplasm under the treatment of DHA. Compared to the OA group, samples from the OA + DHA group showed thickened cartilage, reduced degeneration, and an increased rate of collagen II-positive cells, while the Mankin score was significantly lower. In addition, DHA decreased the expression of phosphorylated mammalian target of rapamycin (p-mTOR) and the ratio of light chain 3-I/II (LC3-I/II) and increased the expression of Beclin-1 and Bcl-2 measured by western blot analysis. Therefore, DHA promotes chondrocyte proliferation, reduces apoptosis, and increases autophagy in OA chondrocytes, a process that is accomplished by inhibiting the expression of mTOR, c-Jun N-terminal kinase (JNK), and p38 signaling pathways, providing new perspectives and bootstrap points for the prevention and treatment of OA.

Tendon Stem/Progenitor Cell-Laden Nanofiber Hydrogel Enhanced Functional Repair of Patellar Tendon.

Functional repair of tendons remains a challenge to be overcome for both clinicians and scientists. We have previously reported a three-dimensional RADA peptide hydrogel that provides a suitable microenvironment for human tendon stem/progenitor cells (TSPCs) survival and tenogenesis. In this study, we explore the potential of in vivo patellar tendon repair by human TSPC-laden RADA hydrogel in rats, which were sacrificed at 4 and 8 weeks after operation. Hind limb function test, macroscopical and histological examination, tendon cell amount and alignment analysis, and radiographic assessments were performed at several time points. Our results demonstrated that human TSPC-laden RADA hydrogel (RADA+TSPC group) boosted in vivo patellar tendon repair with better ambulatory function recovery compared with the control groups, in which tendon defects were untreated (Defect group) or treated with RADA hydrogel alone (RADA group). In addition, better macroscopic appearance and improved matrix organization in the repaired tendon with less cell amount and reduced adipocyte accumulation and blood vessel formation were observed in the RADA+TSPC group. Moreover, tendon defect treated with TSPC-laden RADA hydrogel resulted in diminished heterotopic ossification (HO) at 8 weeks postoperation, which was indicated by both X-ray examination and micro-computed tomography scan. Taken together, the combination of TSPC and nanofiber hydrogel provide an optimistic alternative method to accelerate functional tendon repair with reduced HO. Impact statement Our study clearly demonstrates the combination of tendon stem/progenitor cell and nanofiber hydrogel provide a new and optimistic tissue engineering strategy to treat tendon injury by accelerating functional tendon repair with reduced heterotopic ossification. The clinical translation is also very promising, which can provide a minimally invasive, nonsurgical, or complementary treatment methods to treat human tendon injury.

Stem Cell Applications and Tenogenic Differentiation Strategies for Tendon Repair.

Tendons are associated with a high injury risk because of their overuse and age-related tissue degeneration. Thus, tendon injuries pose great clinical and economic challenges to the society. Unfortunately, the natural healing capacity of tendons is far from perfect, and they respond poorly to conventional treatments when injured. Consequently, tendons require a long period of healing and recovery, and the initial strength and function of a repaired tendon cannot be completely restored as it is prone to a high rate of rerupture. Nowadays, the application of various stem cell sources, including mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs), for tendon repair has shown great potential, because these cells can differentiate into a tendon lineage and promote functional tendon repair. However, the mechanism underlying tenogenic differentiation remains unclear. Moreover, no widely adopted protocol has been established for effective and reproducible tenogenic differentiation because of the lack of definitive biomarkers for identifying the tendon differentiation cascades. This work is aimed at reviewing the literature over the past decade and providing an overview of background information on the clinical relevance of tendons and the urgent need to improve tendon repair; the advantages and disadvantages of different stem cell types used for boosting tendon repair; and the unique advantages of reported strategies for tenogenic differentiation, including growth factors, gene modification, biomaterials, and mechanical stimulation.

Global Research Trends in Tendon Stem Cells from 1991 to 2020: A Bibliometric and Visualized Study.

Background: Tendinopathy is a disabling musculoskeletal disorder affecting the athletics and general populations. There have been increased studies using stem cells in treating tendon diseases. The aim of this bibliometric and visualized study is to comprehensively investigate the current status and global trends of research in tendon stem cells. Methods: Publications related to tendon stem cells from 1991 to 2020 were retrieved from Web of Science and then indexed using a bibliometric methodology. VOSviewer software was used to conduct the visualized study, including coauthorship, cocitation, and cooccurrence analysis and to analyze the publication trends of research in tendon stem cells. Results: In total, 2492 articles were included and the number of publications increased annually worldwide. The United States made the largest contribution to this field, with the most publications (938 papers, 37.64%), citation frequency (68,195 times), and the highest H-index (103). The most contributive institutions were University of Pittsburgh (96 papers), Zhejiang University (70 papers), Shanghai Jiao Tong University, and Chinese University of Hong Kong (both 64 papers). The Journal of Orthopaedic Research published the most relative articles. Studies could be classified into five clusters: "Animal study," "Tissue engineering," "Clinical study," "Mechanism research," and "Stem cells research", which show a balanced development trend. Conclusion: Publications on tendon stem cells may reached a platform based on current global trends. According to the inherent changes of hotspots in each cluster and the possibilities of cross-research, the research in tendon stem cells may exist a balanced development trend.

Prevalence Trends of Site-Specific Osteoarthritis From 1990 to 2019: Findings From the Global Burden of Disease Study 2019.

OBJECTIVE: To estimate systematic and anatomic site-specific age-standardized prevalence rates (ASRs) and analyze the secular trends of osteoarthritis (OA) at global, regional, and national levels. METHODS: Data were derived from the Global Burden of Disease Study 2019. ASRs and their estimated annual percentage changes (EAPCs) were used to describe the secular trends of OA according to age group, sex, region, country, and territory, as well as the joints involved. RESULTS: Globally, prevalent cases of OA increased by 113.25%, from 247.51 million in 1990 to 527.81 million in 2019. ASRs were 6,173.38 per 100,000 in 1990 and 6,348.25 per 100,000 in 2019, with an average annual increase of 0.12% (95% confidence interval [95% CI] 0.11%, 0.14%). The ASR of OA increased for the knee, hip, and other joints, but decreased for the hand, with EAPCs of 0.32 (95% CI 0.29, 0.34), 0.28 (95% CI 0.26, 0.31), 0.18 (95% CI 0.18, 0.19), and -0.36 (95% CI -0.38, -0.33), respectively. OA prevalence increased with age and revealed female preponderance, geographic diversity, and disparity with regard to anatomic site. OA of the knee contributed the most to the overall burden, while OA of the hip had the highest EAPC in most regions. CONCLUSION: OA has remained a major public health concern worldwide over the past decades. The prevalence of OA has increased and diversified by geographic location and affected joint. Prevention and early treatment are pivotal to mitigating the growing burden of OA.

Incidence of hip fracture among middle-aged and older Chinese from 2013 to 2015: results from a nationally representative study.

China is experiencing remarkable changes in people aging and migration. Therefore, the incidence and associated factors for hip fracture might differ from previous results. A nationally representative study of hip fracture enables policymakers to formulate preventive strategies and provide information on resource allocation. PURPOSE: To estimate the incidence of hip fracture, between 2013 and 2015, among the middle-aged and older Chinese population. METHODS: Individuals with hip fractures between 2013 and 2015 were identified from the China Health and Retirement Longitudinal Study. The sex-specific incidence and the associated factors of hip fracture were assessed. RESULTS: Among 19,112 individuals (51.4% women; mean age 60.5 years) included in the analysis, 408 (2.13%) had a hip fracture between 2013 and 2015. Moreover, the annual incidence of hip fracture for men and women were 1065 and 1069 per 100,000, respectively. The incidence of hip fracture increased with age (p < 0.001). A history of chronic disease, being unmarried, and individuals without insurance were associated with a higher incidence of hip fracture. Interestingly, the incidence of hip fracture was higher among individuals with fewer years of education (p = 0.002). The North-East regions of China had the lowest incidence of hip fracture (1022 per 100,000) between 2013 and 2015, followed by the North (1602 per 100,000), South-Central (2055 per 100,000), East (2173 per 100,000), and South-West (2537 per 100,000) regions. Finally, the incidence was highest among participants living in the North-West region (3244 per 100,000). CONCLUSION: Between 2013 and 2015, the incidence of hip fracture is high among the middle-aged and older Chinese population. Furthermore, it varied significantly according to sociodemographic and geographic factors. Therefore, the support of targeted health policies and cost-effective preventive strategies are warranted in China.

Association of patellofemoral morphology and alignment with the radiographic severity of patellofemoral osteoarthritis.

BACKGROUND: Risk factors for the severity of patellofemoral osteoarthritis (PFOA) are poorly understood. This research aims to evaluate the association between patellofemoral joint (PFJ) morphology and alignment with the radiographic severity of PFOA. METHODS: A retrospective analysis of CT scan and lateral radiograph data were acquired in patients with PFOA. The radiographic grade of PFOA and tibiofemoral osteoarthritis (TFOA), lateral and medial trochlear inclination angle, sulcus angle, and the Wiberg classification of patella morphology, the congruence angle, patellar tilt angle, and lateral patellar angles, and tibial tubercle trochlear groove distance (TT-TG) and patella height (i.e., Caton-Deschamps index) were assessed using CT scans and sagittal radiographs of the knee. All the PFJ morphology and alignment data were divided into quarters, and the relationships between each of these measures and the severity of PFOA were investigated. RESULTS: By studying 150 patients with PFOA, we found a U-shaped relationship between the Caton-Deschamps index and the severity of PFOA (P < 0.001). A lower value of sulcus angle and lateral patellar angle, a higher value of congruence angle, and type III patella were associated with more severity of lateral PFOA. Compared with the highest quarter of each measure, the adjusted odds ratios (OR) of the severity of PFOA in the lowest quarter of sulcus angle, lateral patellar angle, and congruence angle; and type I patella was 8.80 (p = 0.043), 16.51 (P < 0.001), 0.04 (P < 0.001), and 0.18 (p = 0.048) respectively. CONCLUSIONS: Extreme value of patella height, a higher value of lateral patellar displacement and lateral patellar tilt, lower value of sulcus angle, and type III patella were associated with more severity of PFOA.

An anisotropic nanocomposite hydrogel guides aligned orientation and enhances tenogenesis of human tendon stem/progenitor cells.

The uniform and aligned arrangement of tendon cells is a marker of tendon tissue morphology and the embodiment of its biological anisotropy. However, most of the hydrogels used for tendon tissue engineering do not present anisotropic structures. In this work, a magnetically-responsive nanocomposite hydrogel composed of collagen type I (COL I) and aligned iron oxide nanoparticles (IOPs) was investigated for potential application in tendon tissue engineering. COL I with a mixture of remotely aligned IOPs (A/IOPs) and human tendon stem/progenitor cells (COL I-A/IOPs-hTSPCs) was prepared and the alignment of IOPs was induced under a remote magnetic field. Following the gelation of COL I, a stable and anisotropic nanocomposite COL I-A/IOPs hydrogel was formed. In addition, hTSPCs embedded in COL I with random IOPs (COL I-R/IOPs-hTSPCs) and in pure COL I (COL I-hTSPCs) were used as control groups. Cell viability, proliferation, morphology, cell row formation, and alignment of IOPs and hTSPCs were evaluated over time. In addition, a comprehensive gene expression profile of 48 different genes, including tendon-related genes and lineage/cross-linking genes, was obtained by implementing designer quantitative RT-PCR plates. The hTSPCs morphology followed the orientation of the anisotropic COL I-A/IOPs hydrogel with increased row formation in comparison to pristine COL I and COL-R/IOPs. Moreover, higher proliferation rate and significant upregulation of tendon gene markers were measured in comparison to hTSPCs cultivated in the COL I-R/IOPs and COL I. Thus, we suggest that providing the cells with aligned focal contact points, namely the aligned IOPs, is sufficient to provoke an immense effect on the formation of aligned cell rows. Taken together, we report a novel strategy for directing stem cell behavior without the use of exogenous growth factors or pre-aligned COL I fibers, and propose that anisotropic nanocomposite hydrogels hold great potential for tendon tissue engineering applications.

Corrigendum: Stem Cells in Rotator Cuff Injuries and Reconstructions: A Systematic Review and Meta-Analysis.

Current Stem Cell Research & Therapy, 2019, 14(8): 683-697 Heyong Yin's affiliation should be: Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University, Beijing China; Zexing Yan's affiliation should be: Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong University, No.324, Road Jing Wu Wei Qi, Jinan 250021, Shandong, China. The Original Paragraph Provided is Mentioned Below: Fanxiao Liu1, Qingqi Meng2, Heyong Yin3,* and Zexing Yan3,* 1Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong University, No.324, Road Jing Wu Wei Qi, Jinan 250021, Shandong, China; 3Department of Trauma Surgery, University of Regensburg, Am biopark 9, 93049 Regensburg, Germany.

Aged Tendon Stem/Progenitor Cells Are Less Competent to Form 3D Tendon Organoids Due to Cell Autonomous and Matrix Production Deficits.

Tendons are dense connective tissues, which are critical for the integrity and function of our musculoskeletal system. During tendon aging and degeneration, tendon stem/progenitor cells (TSPCs) experience profound phenotypic changes with declined cellular functions that can be linked to the known increase in complications during tendon healing process in elderly patients. Tissue engineering is a promising approach for achieving a complete recovery of injured tendons. However, use of autologous cells from aged individuals would require restoring the cellular fitness prior to implantation. In this study, we applied an established cell sheet model for in vitro tenogenesis and compared the sheet formation of TSPC derived from young/healthy (Y-TSPCs) versus aged/degenerative (A-TSPCs) human Achilles tendon biopsies with the purpose to unravel differences in their potential to form self-assembled three-dimensional (3D) tendon organoids. Using our three-step protocol, 4 donors of Y-TSPCs and 9 donors of A-TSPCs were subjected to cell sheet formation and maturation in a period of 5 weeks. The sheets were then cross evaluated by weight and diameter measurements; quantification of cell density, proliferation, senescence and apoptosis; histomorphometry; gene expression of 48 target genes; and collagen type I protein production. The results revealed very obvious and significant phenotype in A-TSPC sheets characterized by being fragile and thin with poor tissue morphology, and significantly lower cell density and proliferation, but significantly higher levels of the senescence-related gene markers and apoptotic cells. Quantitative gene expression analyses at the mRNA and protein levels, also demonstrated abnormal molecular circuits in the A-TSPC sheets. Taken together, we report for the first time that A-TSPCs exhibit profound deficits in forming 3D tendon tissue organoids, thus making the cell sheet model suitable to investigate the molecular mechanisms involved in tendon aging and degeneration, as well as examining novel pharmacologic strategies for rejuvenation of aged cells.

Three-dimensional self-assembling nanofiber matrix rejuvenates aged/degenerative human tendon stem/progenitor cells.

The poor healing capacity of tendons is known to worsen in the elderly. During tendon aging and degeneration, endogenous human tendon stem/progenitor cells (hTSPCs) experience profound pathological changes. Here, we explored a rejuvenation strategy for hTSPCs derived from aged/degenerated Achilles tendons (A-TSPCs) by providing three-dimensional (3D) nanofiber hydrogels and comparing them to young/healthy TSPCs (Y-TSPCs). RADA peptide hydrogel has a self-assembling ability, forms a nanofibrous 3D niche and can be further functionalized by adding RGD motifs. Cell survival, apoptosis, and proliferation assays demonstrated that RADA and RADA/RGD hydrogels support A-TSPCs in a comparable manner to Y-TSPCs. Moreover, they rejuvenated A-TSPCs to a phenotype similar to that of Y-TSPCs, as evidenced by restored cell morphology and cytoskeletal architecture. Transmission electron, confocal laser scanning and atomic force microscopies demonstrated comparable ultrastructure, surface roughness and elastic modulus of A- and Y-TSPC-loaded hydrogels. Lastly, quantitative PCR revealed similar expression profiles, as well a significant upregulation of genes related to tenogenesis and multipotency. Taken together, the RADA-based hydrogels exert a rejuvenating effect by recapitulating in vitro specific features of the natural microenvironment of human TSPCs, which strongly indicates their potential to direct cell behaviour and overcome the challenge of cell aging and degeneration in tendon repair.

Stem Cells in Rotator Cuff Injuries and Reconstructions: A Systematic Review and Meta-Analysis.

BACKGROUND: Multiple studies have focused on stem cell-based treatments for rotator cuff disorders; however, the outcomes are not consistent. OBJECTIVES: This systematic review and meta-analysis were performed to evaluate the effects of stem cells on rotator cuff healing. METHODS: A detailed search of relevant studies was conducted in three databases including Pubmed/ Medline, Cochrane library, and Embase databases, using the following keywords: "rotator cuff" or "Tissue Engineering" AND "stem cell" from inception to January 01, 2019. The standard mean difference (SMD) and 95% confidence interval (CI) for each individual study were extracted from the original studies or calculated based on relevant data and pooled to obtain integrated estimates using random effects modeling. RESULTS: A total of 22 studies were identified. The results demonstrated that the ultimate strain in the stem cell group was significantly higher than that in the control group at 4 and 8 weeks. Muscle weight in the stem cell group was higher than the control group at 8 weeks, while no significant differences were detected at 16 weeks. The stem cell group had lower visual analog scale scores (VAS) at 1, 3, and 6 months, and higher American shoulder and elbow surgeons score (ASES) at 3 months. In addition, the walking distance, time, and speed in the stem cell group were significantly superior to those in the control group. CONCLUSIONS: This meta-analysis confirms that stem cells improved the rehabilitation of rotator cuff disorders. However, larger-scale studies are needed to further support these findings.