Synergistic effect of umbilical cord extracellular vesicles and rhBMP-2 to enhance the regeneration of a metaphyseal femoral defect in osteoporotic rats.

BACKGROUND: The aim of this study was to evaluate potential synergistic effects of a single, local application of human umbilical cord MSC-derived sEVs in combination with a low dose of recombinant human rhBMP-2 to promote the regeneration of a metaphyseal femoral defect in an osteoporotic rat model. METHODS: 6 weeks after induction of osteoporosis by bilateral ventral ovariectomy and administration of a special diet, a total of 64 rats underwent a distal femoral metaphyseal osteotomy using a manual Gigli wire saw. Defects were stabilized with an adapted Y-shaped mini-locking plate and were subsequently treated with alginate only, or alginate loaded with hUC-MSC-sEVs (2 × 109), rhBMP-2 (1.5 µg), or a combination of sEVs and rhBMP-2 (n = 16 for each group). 6 weeks post-surgery, femora were evaluated by µCT, descriptive histology, and biomechanical testing. RESULTS: Native radiographs and µCT analysis confirmed superior bony union with callus formation after treatment with hUC-MSC-sEVs in combination with a low dose of rhBMP-2. This finding was further substantiated by histology, showing robust defect consolidation 6 weeks after treatment. Torsion testing of the explanted femora revealed increased stiffness after application of both, rhBMP-2 alone, or in combination with sEVs, whereas torque was only significantly increased after treatment with rhBMP-2 together with sEVs. CONCLUSION: The present study demonstrates that the co-application of hUC-MSC-sEVs can improve the efficacy of rhBMP-2 to promote the regeneration of osteoporotic bone defects.

Enhancing Cranio-Maxillofacial Fracture Care in Low- and Middle-Income Countries: A Systematic Review.

Background: Cranio-maxillofacial (CMF) injuries represent a significant challenge in low- and middle-income countries (LMICs), exacerbated by inadequate infrastructure, resources, and training. This systematic review aims to evaluate the current strategies and solutions proposed in the literature to improve CMF fracture care in LMICs, focusing on education, patient transfer, and off-label solutions. Methods: A comprehensive literature search was conducted using PubMed/Medline from January 2000 to June 2023. Studies were selected based on the Preferred Reporting Items for Systematic Review and Meta-analysis Statement (PRISMA). Solutions were categorized into three main areas: education (digital and on-site teaching, fellowships abroad), patient transfer to specialized clinics, and off-label/non-operative solutions. Results: Twenty-three articles were included in the review, revealing a consensus on the necessity for enhanced education and training for local surgeons as the cornerstone for sustainable improvements in CMF care in LMICs. Digital platforms and on-site teaching were identified as key methods for delivering educational content. Furthermore, patient transfer to specialized national clinics and innovative off-label techniques were discussed as immediate solutions to provide quality care despite resource constraints. Conclusions: Effective CMF fracture care in LMICs requires a multifaceted approach, prioritizing the education and training of local healthcare professionals, facilitated patient transfer to specialized centers, and the adoption of off-label solutions to leverage available resources. Collaborative efforts between international organizations, local healthcare providers, and educational institutions are essential to implement these solutions effectively and improve patient outcomes in LMICs.

[Prehospital management in trauma patients and the increasing number of helicopter EMS transportations : An epidemiological study of the TraumaRegister DGU®]. / Präklinisches Management bei Traumapatienten und die zunehmende Zahl von Helikopter-Rettungstransporten : Eine epidemiologische Studie des TraumaRegister DGU®.

BACKGROUND/OBJECTIVE: To compare the prehospital treatment modalities and intervention regimens for major trauma patients with comparable injury patterns between Austria and Germany. PATIENTS AND METHODS: This analysis is based on data retrieved from the TraumaRegister DGU®. Data included severely injured trauma patients with an injury severity score (ISS) ≥ 16, an age ≥ 16 years, and who were primarily admitted to an Austrian (n = 4186) or German (n = 41,484) level I trauma center (TC) from 2008 to 2017. Investigated endpoints included prehospital times and interventions performed until final hospital admission. RESULTS: The cumulative time for transportation from the site of the accident to the hospital did not significantly differ between the countries (62 min in Austria, 65 min in Germany). Overall, 53% of all trauma patients in Austria were transported to the hospital with a helicopter compared to 37% in Germany (p < 0.001). The rate of intubation was 48% in both countries, the number of chest tubes placed (5.7% Germany, 4.9% Austria), and the frequency of administered catecholamines (13.4% Germany, 12.3% Austria) were comparable (Φ = 0.00). Hemodynamic instability (systolic blood pressure, BP ≤ 90 mmHg) upon arrival in the TC was higher in Austria (20.6% vs. 14.7% in Germany; p < 0.001). A median of 500 mL of fluid was administered in Austria, whereas in Germany 1000 mL was infused (p < 0.001). Patient demographics did not reveal a relationship (Φ = 0.00) between both countries, and the majority of patients sustained a blunt trauma (96%). The observed ASA score of 3-4 was 16.8% in Germany versus 11.9% in Austria. CONCLUSION: Significantly more helicopter EMS transportations (HEMS) were carried out in Austria. The authors suggest implementing international guidelines to explicitly use the HEMS system for trauma patients only a) for the rescue/care of people who have had an accident or are in life-threatening situations, b) for the transport of emergency patients with ISS > 16, c) for transportation of rescue or recovery personnel to hard to reach regions or, d) for the transport of medicinal products, especially blood products, organ transplants or medical devices.

Development of a Metaphyseal Non-Union Model in the Osteoporotic Rat Femur.

The aim of this current study was to establish a metaphyseal femoral non-union model in osteoporotic rats by comparing a power tool versus a manual tool for fracture creation. Twelve adult female Sprague Dawley rats were ovariectomized (OVX) and received a special diet for 6 weeks. Biweekly pQCT measurements confirmed a significant reduction in the cancellous and total bone mineral density in OVX rats compared to control (CTRL) animals. After 6 weeks, OVX rats underwent surgery creating a distal metaphyseal osteotomy, either using a piezoelectric- (n = 6) or a manual Gigli wire (n = 6) saw. Fractures were stabilized with a Y-shaped mini-locking plate. Within each group, three rats received Alginate directly into the fracture gap. OVX animals gained more weight over 8 weeks compared to CTRL animals. pQCT analysis showed a significant difference in the volumetric cancellous bone mineral density between OVX and CTRL rats. A histological examination of the osteoporotic phenotype was completed. Radiographic evaluation and Masson-Goldner trichrome staining with the piezoelectric saw failed to demonstrate bony bridging or a callus formation. New bone formation and complete healing were seen after 6 weeks in the Gigli group. For the creation of a metaphyseal atrophic non-union in the osteoporotic bone, a piezoelectric saw should be used.

Evaluation of the Potential of Umbilical Cord Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles to Improve Rotator Cuff Healing: A Pilot Ovine Study.

BACKGROUND: Despite significant advancements in surgical techniques to repair rotator cuff (RC) injuries, failure rates remain high and novel approaches to adequately overcome the natural biological limits of tendon and enthesis regeneration of the RC are required. Small extracellular vesicles (sEVs) derived from the secretome of human multipotent mesenchymal stromal cells (MSCs) have been demonstrated to modulate inflammation and reduce fibrotic adhesions, and therefore their local application could improve outcomes after RC repair. PURPOSE: In this pilot study, we evaluated the efficacy of clinical-grade human umbilical cord (hUC) MSC-derived sEVs (hUC-MSC-sEVs) loaded onto a type 1 collagen scaffold in an ovine model of acute infraspinatus tendon injury to improve RC healing. STUDY DESIGN: Controlled laboratory study. METHODS: sEVs were enriched from hUC-MSC culture media and were characterized by surface marker profiling. The immunomodulatory capacity was evaluated in vitro by T-cell proliferation assays, and particle count was determined by nanoparticle tracking analysis. Twelve skeletally mature sheep were subjected to partial infraspinatus tenotomy and enthesis debridement. The defects of 6 animals were treated with 2 × 1010 hUC-MSC-sEVs loaded onto a type 1 collagen sponge, whereas 6 animals received only a collagen sponge, serving as controls. Six weeks postoperatively, the healing of the infraspinatus tendon and the enthesis was evaluated by magnetic resonance imaging (MRI) and hard tissue histology. RESULTS: CD3/CD28-stimulated T-cell proliferation was significantly inhibited by hUC-MSC-sEVs (P = .015) that displayed the typical surface marker profile, including the presence of the MSC marker proteins CD44 and melanoma-associated chondroitin sulfate proteoglycan. The local application of hUC-MSC-sEVs did not result in any marked systemic adverse events. Histologically, significantly improved Watkins scores (P = .031) indicated improved tendon and tendon-to-bone insertion repair after sEV treatment and lower postcontrast signal of the tendon and adjacent structures on MRI suggested less residual inflammation at the defect area. Furthermore, the formation of osteophytes at the injury site was significantly attenuated (P = .037). CONCLUSION: A local, single-dose application of hUC-MSC-sEVs promoted tendon and enthesis healing in an ovine model of acute RC injury. CLINICAL RELEVANCE: Surgical repair of RC tears generally results in a clinical benefit for the patient; however, considerable rerupture rates have been reported. sEVs have potential as a cell-free biotherapeutic to improve healing outcomes after RC injury.

Reevaluation of a classification system: stable and unstable odontoid fractures in geriatric patients-a radiological outcome measurement.

OBJECTIVES: We carried out a retrospective cohort study to differentiate geriatric odontoid fractures into stable and unstable and correlated it with fracture fusion rates. Results are based on the literature and on our own experience. The authors propose that the simple Anderson and D'Alonzo classification may not be sufficient for geriatric patients. METHODS: There were 89 patients ≥ 65 years who presented at our institution with type II and III odontoid fractures from 2003 until 2017 and were included in this study. Each patient was categorized with CT scans to evaluate the type of fracture, fracture gap (mm), fracture angulation (°), fracture displacement (mm) and direction (ventral, dorsal). Fractures were categorized as stable [SF] or unstable [UF] distinguished by the parameters of its angulation (< / > 11°) and displacement (< / > 5 mm) with a follow-up time of 6 months. SFs were treated with a semi-rigid immobilization for 6 weeks, UFs surgically-preferably with a C1-C2 posterior fusion. RESULTS: The classification into SFs and UFs was significant for its angulation (P = 0.0006) and displacement (P < 0.0001). SF group (n = 57): A primary stable union was observed in 35, a stable non-union in 10, and an unstable non-union in 8 patients of which 4 were treated with a C1/2 fixation. The overall consolidation rate was 79%. UF group (n = 32): A posterior C1-C2 fusion was carried out in 23 patients, a C0 onto C4 stabilization in 7 and an anterior odontoid screw fixation in 2. The union rate was 100%. Twenty-one type II SFs (91%) consolidated with a nonoperative management (P < 0.001). A primary non-union occurred more often in type II than in type III fractures (P = 0.0023). There was no significant difference in the 30-day overall case fatality (P = 0.3786). CONCLUSION: To separate dens fractures into SFs and UFs is feasible. For SFs, semi-rigid immobilization provides a high consolidation rate. Stable non-unions are acceptable, and the authors suggest a posterior transarticular C1-C2 fixation as the preferred surgical treatment for UFs. LEVEL OF EVIDENCE: Level III.

VEGF-D-mediated signaling in tendon cells is involved in degenerative processes.

Vascular endothelial growth factor (VEGF) signaling is crucial for a large variety of cellular processes, not only related to angiogenesis but also in nonvascular cell types. We have previously shown that controlling angiogenesis by reducing VEGF-A signaling positively affects tendon healing. We now hypothesize that VEGF signaling in non-endothelial cells may contribute to tendon pathologies. By immunohistochemistry we show that VEGFR1, VEGFR2, and VEGFR3 are expressed in murine and human tendon cells in vivo. In a rat Achilles tendon defect model we show that VEGFR1, VEGFR3, and VEGF-D expression are increased after injury. On cultured rat tendon cells we show that VEGF-D stimulates cell proliferation in a dose-dependent manner; the specific VEGFR3 inhibitor SAR131675 reduces cell proliferation and cell migration. Furthermore, activation of VEGFR2 and -3 in tendon-derived cells affects the expression of mRNAs encoding extracellular matrix and matrix remodeling proteins. Using explant model systems, we provide evidence, that VEGFR3 inhibition prevents biomechanical deterioration in rat tail tendon fascicles cultured without load and attenuates matrix damage if exposed to dynamic overload in a bioreactor system. Together, these results suggest a strong role of tendon cell VEGF signaling in mediation of degenerative processes. These findings give novel insight into tendon cell biology and may pave the way for novel treatment options for degenerative tendon diseases.

Allergy-induced systemic inflammation impairs tendon quality.

BACKGROUND: Treatment of degenerating tendons still presents a major challenge, since the aetiology of tendinopathies remains poorly understood. Besides mechanical overuse, further known predisposing factors include rheumatoid arthritis, diabetes, obesity or smoking all of which combine with a systemic inflammation. METHODS: To determine whether the systemic inflammation accompanying these conditions contributes to the onset of tendinopathy, we studied the effect of a systemic inflammation induced by an allergic episode on tendon properties. To this end, we induced an allergic response in mice by exposing them to a timothy grass pollen allergen and subsequently analysed both their flexor and Achilles tendons. Additionally, we analysed data from a health survey comprising data from more than 10.000 persons for an association between the occurrence of an allergy and tendinopathy. FINDINGS: Biomechanical testing and histological analysis revealed that tendons from allergic mice not only showed a significant reduction of both elastic modulus and tensile stress, but also alterations of the tendon matrix. Moreover, treatment of 3D tendon-like constructs with sera from allergic mice resulted in a matrix-remodelling expression profile and the expression of macrophage-associated markers and matrix metalloproteinase 2 (MMP2) was increased in allergic Achilles tendons. Data from the human health study revealed that persons suffering from an allergy have an increased propensity to develop a tendinopathy. INTERPRETATION: Our study demonstrates that the presence of a systemic inflammation accompanying an allergic condition negatively impacts on tendon structure and function. FUNDING: This study was financially supported by the Fund for the Advancement of Scientific Research at Paracelsus Medical University (PMU-FFF E-15/22/115-LEK), by the Land Salzburg, the Salzburger Landeskliniken (SALK, the Health Care Provider of the University Hospitals Landeskrankenhaus and Christian Doppler Klinik), the Paracelsus Medical University, Salzburg and by unrestricted grants from Bayer, AstraZeneca, Sanofi-Aventis, Boehringer-Ingelheim.

Is the human sclera a tendon-like tissue? A structural and functional comparison.

Collagen rich connective tissues fulfill a variety of important functions throughout the human body, most of which having to resist mechanical challenges. This review aims to compare structural and functional aspects of tendons and sclera, two tissues with distinct location and function, but with striking similarities regarding their cellular content, their extracellular matrix and their low degree of vascularization. The description of these similarities meant to provide potential novel insight for both the fields of orthopedic research and ophthalmology.

In Vitro Evaluation of a Nanoparticle-Based mRNA Delivery System for Cells in the Joint.

Biodegradable and bioresponsive polymer-based nanoparticles (NPs) can be used for oligonucleotide delivery, making them a promising candidate for mRNA-based therapeutics. In this study, we evaluated and optimized the efficiency of a cationic, hyperbranched poly(amidoamine)s-based nanoparticle system to deliver tdTomato mRNA to primary human bone marrow stromal cells (hBMSC), human synovial derived stem cells (hSDSC), bovine chondrocytes (bCH), and rat tendon derived stem/progenitor cells (rTDSPC). Transfection efficiencies varied among the cell types tested (bCH 28.4% ± 22.87, rTDSPC 18.13% ± 12.07, hBMSC 18.23% ± 14.80, hSDSC 26.63% ± 8.81) and while an increase of NPs with a constant amount of mRNA generally improved the transfection efficiency, an increase of the mRNA loading ratio (2:50, 4:50, or 6:50 w/w mRNA:NPs) had no impact. However, metabolic activity of bCHs and rTDSPCs was significantly reduced when using higher amounts of NPs, indicating a dose-dependent cytotoxic response. Finally, we demonstrate the feasibility of transfecting extracellular matrix-rich 3D cell culture constructs using the nanoparticle system, making it a promising transfection strategy for musculoskeletal tissues that exhibit a complex, dense extracellular matrix.

Scleraxis expressing scleral cells respond to inflammatory stimulation.

The sclera is an ocular tissue rich of collagenous extracellular matrix, which is built up and maintained by relatively few, still poorly characterized fibroblast-like cells. The aims of this study are to add to the characterization of scleral fibroblasts and to examine the reaction of these fibroblasts to inflammatory stimulation in an ex vivo organotypic model. Scleras of scleraxis-GFP (SCX-GFP) mice were analyzed using immunohistochemistry and qRT-PCR for the expression of the tendon cell associated marker genes scleraxis (SCX), mohawk and tenomodulin. In organotypic tissue culture, explanted scleras of adult scleraxis GFP reporter mice were exposed to 10 ng/ml recombinant interleukin 1-ß (IL1-ß) and IL1-ß in combination with dexamethasone. The tissue was then analyzed by immunofluorescence staining of the inflammation- and fibrosis-associated proteins IL6, COX-2, iNOS, connective tissue growth factor, MMP2, MMP3, and MMP13 as well as for collagen fibre degradation using a Collagen Hybridizing Peptide (CHP) binding assay. The mouse sclera displayed a strong expression of scleraxis promoter-driven GFP, indicating a tendon cell-like phenotype, as well as expression of scleraxis, tenomodulin and mohawk mRNA. Upon IL1-ß stimulation, SCX-GFP+ cells significantly upregulated the expression of all proteins analysed. Moreover, IL1-ß stimulation resulted in significant collagen degradation. Adding the corticosteroid dexamethasone significantly reduced the response to IL1-ß stimulation. Collagen degradation was significantly enhanced in the IL1-ß group. Dexamethasone demonstrated a significant rescue effect. This work provides insights into the characteristics of scleral cells and establishes an ex vivo model of scleral inflammation.

Load-induced regulation of tendon homeostasis by SPARC, a genetic predisposition factor for tendon and ligament injuries.

Tendons and tendon interfaces have a very limited regenerative capacity, rendering their injuries clinically challenging to resolve. Tendons sense muscle-mediated load; however, our knowledge on how loading affects tendon structure and functional adaption remains fragmentary. Here, we provide evidence that the matricellular protein secreted protein acidic and rich in cysteine (SPARC) is critically involved in the mechanobiology of tendons and is required for tissue maturation, homeostasis, and enthesis development. We show that tendon loading at the early postnatal stage leads to tissue hypotrophy and impaired maturation of Achilles tendon enthesis in Sparc -/- mice. Treadmill training revealed a higher prevalence of spontaneous tendon ruptures and a net catabolic adaptation in Sparc -/- mice. Tendon hypoplasia was attenuated in Sparc -/- mice in response to muscle unloading with botulinum toxin A. In vitro culture of Sparc -/- three-dimensional tendon constructs showed load-dependent impairment of ribosomal S6 kinase activation, resulting in reduced type I collagen synthesis. Further, functional calcium imaging revealed that lower stresses were required to trigger mechanically induced responses in Sparc -/- tendon fascicles. To underscore the clinical relevance of the findings, we further demonstrate that a missense mutation (p.Cys130Gln) in the follistatin-like domain of SPARC, which causes impaired protein secretion and type I collagen fibrillogenesis, is associated with tendon and ligament injuries in patients. Together, our results demonstrate that SPARC is a key extracellular matrix protein essential for load-induced tendon tissue maturation and homeostasis.

Anxiety and depression in patients wearing prosthetic eyes.

PURPOSE: To investigate anxiety and depression levels in prosthetic eye-wearing patients using standardized psychometric instruments, to define factors associated with these psychological diseases, and to identify a potential healthcare gap. METHODS: A total of 295 prosthetic eye wearers were screened using the 7-item generalized anxiety disorder scale (GAD-7) and the 9-item patient health questionnaire (PHQ-9). Scores of GAD-7 and PHQ-9 were correlated with scores of general physical and mental health functioning, vision-related quality of life, appearance-related distress, appearance-related social function, and further biosocial factors. RESULTS: Five patients (2%) had a pre-diagnosed anxiety disorder, and 20 patients (7%) had a pre-diagnosed depression. However, our screening revealed 26 patients (9%) with anxiety symptoms, 31 patients (11%) with depression symptoms, and 40 patients (14%) suffering from both anxiety and depression symptoms. This underdiagnosing for both anxiety and depression disorders was significant (p < 0.001, respectively). Higher GAD-7 scores were significantly associated with higher PHQ-9 scores, lower appearance-related social function, lower mental health functioning, and female gender (p ≤ 0.021, respectively). Higher PHQ-9 scores were significantly associated with lower physical and mental health functioning, higher educational degree, and non-traumatic eye loss (p ≤ 0.038, respectively). CONCLUSIONS: Anxiety and depression disorders seem to be underdiagnosed in prosthetic eye wearers and to have higher incidence compared with the general population. Therefore, a psychometric screening should be routinely implemented in the clinical care. For a successful long-term rehabilitation, integrated care by a multidisciplinary team including ophthalmic plastic surgeons, ophthalmologists, ocularists, general practitioners, and psychologists is essential.

Enhanced BMP-2-Mediated Bone Repair Using an Anisotropic Silk Fibroin Scaffold Coated with Bone-like Apatite.

The repair of large bone defects remains challenging and often requires graft material due to limited availability of autologous bone. In clinical settings, collagen sponges loaded with excessive amounts of bone morphogenetic protein 2 (rhBMP-2) are occasionally used for the treatment of bone non-unions, increasing the risk of adverse events. Therefore, strategies to reduce rhBMP-2 dosage are desirable. Silk scaffolds show great promise due to their favorable biocompatibility and their utility for various biofabrication methods. For this study, we generated silk scaffolds with axially aligned pores, which were subsequently treated with 10× simulated body fluid (SBF) to generate an apatitic calcium phosphate coating. Using a rat femoral critical sized defect model (CSD) we evaluated if the resulting scaffold allows the reduction of BMP-2 dosage to promote efficient bone repair by providing appropriate guidance cues. Highly porous, anisotropic silk scaffolds were produced, demonstrating good cytocompatibility in vitro and treatment with 10× SBF resulted in efficient surface coating. In vivo, the coated silk scaffolds loaded with a low dose of rhBMP-2 demonstrated significantly improved bone regeneration when compared to the unmineralized scaffold. Overall, our findings show that this simple and cost-efficient technique yields scaffolds that enhance rhBMP-2 mediated bone healing.

Macromechanics and polycaprolactone fiber organization drive macrophage polarization and regulate inflammatory activation of tendon in vitro and in vivo.

Appropriate macrophage response to an implanted biomaterial is crucial for successful tissue healing outcomes. In this work we investigated how intrinsic topological cues from electrospun biomaterials and extrinsic mechanical loads cooperate to guide macrophage activation and macrophage-tendon fibroblast cross-talk. We performed a series of in vitro and in vivo experiments using aligned or randomly oriented polycaprolactone nanofiber substrates in both mechanically loaded and unloaded conditions. Across all experiments a disorganized biomaterial fiber topography was alone sufficient to promote a pro-inflammatory signature in macrophages, tendon fibroblasts, and tendon tissue. Extrinsic mechanical loading was found to strongly regulate the character of this signature by reducing pro-inflammatory markers both in vitro and in vivo. We observed that macrophages generally displayed a stronger response to biophysical cues than tendon fibroblasts, with dominant effects of cross-talk between these cell types observed in mechanical co-culture models. Collectively our data suggest that macrophages play a potentially important role as mechanosensory cells in tendon repair, and provide insight into how biological response might be therapeutically modulated by rational biomaterial designs that address the biomechanical niche of recruited cells.

The lymphangiogenic and hemangiogenic privilege of the human sclera.

PURPOSE: Most organs of the human body are supplied with a dense network of blood and lymphatic vessels. However, some tissues are either hypovascular or completely devoid of vessels for proper function, such as the ocular tissues sclera and cornea, cartilage and tendons. Since many pathological conditions are affecting the human sclera, this review is focussing on the lymphangiogenic and hemangiogenic privilege in the human sclera. METHODS: This article gives an overview of the current literature based on a PubMed search as well as observations and experience from clinical practice. RESULTS: The healthy human sclera is the outer covering layer of the eye globe consisting mainly of collagenous extracellular matrix and fibroblasts. Physiologically, the sclera shows only a superficial network of blood vessels and a lack of lymphatic vessels. This vascular privilege is actively regulated by balancing anti- and proangiogenic factors expressed by cells within the sclera. In pathological situations, such as open globe injuries or ciliary body melanomas with extraocular extension, lymphatic vessels can secondarily invade the sclera and the inner eye. This mechanism most likely is important for tumor cell metastasis, wound healing, immunologic defense against intruding microorganism, and autoimmune reactions against intraocular antigens. CONCLUSIONS: The human sclera is characterized by a tightly regulated vascular network that can be compromised in pathological situations, such as injuries or intraocular tumors affecting healing outcomes Therefore, the molecular and cellular mechanisms underlying wound healing following surgical interventions deserve further attention, in order to devise more effective therapeutic strategies.

MicroRNA Profiling Reveals Distinct Signatures in Degenerative Rotator Cuff Pathologies.

MicroRNAs (miRNAs) have emerged as key regulators orchestrating a wide range of inflammatory and fibrotic diseases. However, the role of miRNAs in degenerative shoulder joint disorders is poorly understood. The aim of this explorative case-control study was to identify pathology-related, circulating miRNAs in patients with chronic rotator cuff tendinopathy and degenerative rotator cuff tears (RCT). In 2017, 15 patients were prospectively enrolled and assigned to three groups based on the diagnosed pathology: (i) no shoulder pathology, (ii) chronic rotator cuff tendinopathy, and (iii) degenerative RCTs. In total, 14 patients were included. Venous blood samples ("liquid biopsies") were collected from each patient and serum levels of 187 miRNAs were determined. Subsequently, the change in expression of nine candidate miRNAs was verified in tendon biopsy samples, collected from patients who underwent arthroscopic shoulder surgery between 2015 and 2018. Overall, we identified several miRNAs to be progressively deregulated in sera from patients with either chronic rotator cuff tendinopathy or degenerative RCTs. Importantly, for the several of these miRNAs candidates repression was also evident in tendon biopsies harvested from patients who were treated for a supraspinatus tendon tear. As similar expression profiles were determined for tendon samples, the newly identified systemic miRNA signature has potential as novel diagnostic or prognostic biomarkers for degenerative rotator cuff pathologies. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. Inc. J Orthop Res 38:202-211, 2020.

Risk Factors for Rotator Cuff Disease: An Experimental Study on Intact Human Subscapularis Tendons.

Although several studies revealed a multifactorial pathogenesis of degenerative rotator cuff disorders, the impact and interaction of extrinsic variables is still poorly understood. Thus, this study aimed at uncovering the effect of patient- and pathology-specific risk factors that may contribute to degeneration of the rotator cuff tendons. Between 2015 and 2018, 54 patients who underwent arthroscopic shoulder surgery at three specialized shoulder clinics were prospectively included. Using tendon samples harvested from the macroscopically intact subscapularis (SSC) tendon, targeted messenger RNA expression profile analysis was performed in the first cohort (n = 38). Furthermore, histological analyses were conducted on tendon tissue samples obtained from a second cohort (n = 16). Overall, both study cohorts were comparable concerning patient demographics. Results were then analyzed with respect to specific extrinsic factors, such as patient age, body mass index, current as well as previous professions and sport activities, smoking habit, and systemic metabolic diseases. While patient age, sports-activity level, and preexisting rotator cuff lesions were considered to contribute most strongly to tendinopathogenesis, no further coherences were found. With regards to gene expression analysis, change in expression correlated most strongly with patient age and severity of the rotator cuff pathology. Further, chronic disorders increased overall gene expression variation. Taken together, our study provides further evidence that tendon degeneration is the consequence of a multifactorial process and pathological changes of the supraspinatus tendon affect the quality of SSC tendon and most likely vice versa. Therefore, the rotator cuff tendons need to be considered as a unit when managing rotator cuff pathologies. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:182-191, 2020.

Mesenchymal Stromal Cell-Based Bone Regeneration Therapies: From Cell Transplantation and Tissue Engineering to Therapeutic Secretomes and Extracellular Vesicles.

Effective regeneration of bone defects often presents significant challenges, particularly in patients with decreased tissue regeneration capacity due to extensive trauma, disease, and/or advanced age. A number of studies have focused on enhancing bone regeneration by applying mesenchymal stromal cells (MSCs) or MSC-based bone tissue engineering strategies. However, translation of these approaches from basic research findings to clinical use has been hampered by the limited understanding of MSC therapeutic actions and complexities, as well as costs related to the manufacturing, regulatory approval, and clinical use of living cells and engineered tissues. More recently, a shift from the view of MSCs directly contributing to tissue regeneration toward appreciating MSCs as "cell factories" that secrete a variety of bioactive molecules and extracellular vesicles with trophic and immunomodulatory activities has steered research into new MSC-based, "cell-free" therapeutic modalities. The current review recapitulates recent developments, challenges, and future perspectives of these various MSC-based bone tissue engineering and regeneration strategies.