RESUMEN
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.
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Tendón Calcáneo/metabolismo , Transducción de Señal/fisiología , Factor D de Crecimiento Endotelial Vascular/metabolismo , Animales , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Matriz Extracelular/metabolismo , Femenino , Humanos , Masculino , Ratones , Neovascularización Patológica/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
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.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Fibroblastos/metabolismo , Inflamación/metabolismo , Esclerótica/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/análisis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Fibroblastos/patología , Proteínas Fluorescentes Verdes/análisis , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerótica/patologíaRESUMEN
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.
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Depresión , Calidad de Vida , Ansiedad/diagnóstico , Ansiedad/epidemiología , Ansiedad/etiología , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/etiología , Depresión/diagnóstico , Depresión/epidemiología , Depresión/etiología , Femenino , Humanos , Psicometría , Encuestas y CuestionariosRESUMEN
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.
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Apatitas/farmacología , Proteína Morfogenética Ósea 2/farmacología , Regeneración Ósea/efectos de los fármacos , Huesos/fisiología , Fibroínas/farmacología , Andamios del Tejido/química , Factor de Crecimiento Transformador beta/farmacología , Adenosina Trifosfato/metabolismo , Animales , Anisotropía , Materiales Biomiméticos/farmacología , Huesos/efectos de los fármacos , Huesos/ultraestructura , Caspasa 7/metabolismo , Caspasas/metabolismo , Fémur/diagnóstico por imagen , Fémur/efectos de los fármacos , Congelación , Humanos , Masculino , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacología , Microtomografía por Rayos XRESUMEN
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.
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Envejecimiento/fisiología , Células Madre Mesenquimatosas/fisiología , Oligodendroglía/fisiología , Remielinización/fisiología , Animales , Células Cultivadas , Enfermedades Desmielinizantes/fisiopatología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: The purpose of this retrospective study was to evaluate the clinical and radiologic long-term results of medium-sized (Ellman grade 2) partial-thickness articular-sided supraspinatus tendon avulsion (PASTA) lesions treated arthroscopically. METHODS: Of 22 patients, 18 (82%) were available for follow-up evaluation after a mean of 15 ± 2 years (range, 12-17 years). The mean age at time of surgery was 55 ± 9 years (range, 35-66 years). The Constant score was used as the primary outcome instrument to evaluate shoulder function. Furthermore, the University of California-Los Angeles shoulder score, the American Shoulder and Elbow Surgeons score, and the Subjective Shoulder Value were collected. The patients' satisfaction with the outcome was investigated. Tendon integrity of the affected shoulder at final follow-up was assessed with magnetic resonance imaging or ultrasound in 89% of the cohort. RESULTS: Overall, 94% of the patients were very satisfied or satisfied with the outcome. The average Constant score of the affected shoulder was 78 ± 21 points; the University of California-Los Angeles score, 31 ± 7 points; the American Shoulder and Elbow Surgeons score, 85 ± 24 points; and the Subjective Shoulder Value, 83% ± 21%. Radiologic evaluation showed progression to a full-thickness rotator cuff tear in 6% (1/16), and 60% of the patients (6/10) showed persistent signs of partial tearing evaluated by magnetic resonance imaging. CONCLUSION: At long-term follow-up, arthroscopic treatment of medium-sized PASTA lesions resulted in good clinical results together with a high satisfaction level of the patients.
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Lesiones del Manguito de los Rotadores/cirugía , Articulación del Hombro/fisiopatología , Articulación del Hombro/cirugía , Adulto , Anciano , Artroscopía/métodos , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Estudios Retrospectivos , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Lesiones del Manguito de los Rotadores/fisiopatología , Articulación del Hombro/diagnóstico por imagen , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The purpose of this study was to evaluate the long-term clinical and radiologic results after arthroscopic transosseous rotator cuff repair (TORCR). METHODS: A total of 69 patients with full-thickness supraspinatus tendon tears with or without infraspinatus tendon tears treated with arthroscopic TORCR by a single surgeon between 1998 and 2003 were included. Among them, 56 patients (81%) with a mean age of 58 ± 5 years (range, 42-70 years) were available for final follow-up examination after an average of 15 ± 2 years (range, 12-18 years). The Subjective Shoulder Value, Constant score (CS), University of California at Los Angeles score, and American Shoulder and Elbow Surgeons score were recorded. Magnetic resonance imaging (MRI) was performed to visualize tendon integrity in 66% of patients. RESULTS: At final follow-up, the mean CS was 84 ± 8 points; mean University of California at Los Angeles score, 33 ± 2 points; mean American Shoulder and Elbow Surgeons score, 92 ± 10 points; and mean Subjective Shoulder Value, 89% ± 17%. MRI revealed asymptomatic repair failure in 9 patients (27%). Moreover, 4 patients (7%) underwent revision surgery because of a symptomatic rerupture, resulting in an overall retear rate of 33%. Patients with intact repairs at final follow-up showed a significantly higher CS (P = .019) and abduction strength (P = .016) than patients with retears. CONCLUSION: Arthroscopic TORCR for the treatment of full-thickness rotator cuff tears provided good clinical results 12 to 18 years after surgery. Cuff integrity on follow-up MRI scans had a positive effect on the clinical outcome.
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Artroscopía/métodos , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Lesiones del Manguito de los Rotadores/cirugía , Articulación del Hombro/fisiopatología , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia , Reoperación , Articulación del Hombro/diagnóstico por imagen , Factores de Tiempo , Insuficiencia del TratamientoRESUMEN
With age, our cognitive skills and abilities decline. Maybe starting as an annoyance, this decline can become a major impediment to normal daily life. Recent research shows that the neurodegenerative disorders responsible for age associated cognitive dysfunction are mechanistically linked to the state of the microvasculature in the brain. When the microvasculature does not function properly, ischemia, hypoxia, oxidative stress and related pathologic processes ensue, further damaging vascular and neural function. One of the most important and specialized functions of the brain microvasculature is the blood-brain barrier (BBB), which controls the movement of molecules between blood circulation and the brain parenchyma. In this review, we are focusing on tight junctions (TJs), the multiprotein complexes that play an important role in establishing and maintaining barrier function. After a short introduction of the cell types that modulate barrier function via intercellular communication, we examine how age, age related pathologies and the aging of the immune system affects TJs. Then, we review how the TJs are affected in age associated neurodegenerative disorders: Alzheimer's disease and Parkinson's disease. Lastly, we summarize the TJ aspects of Huntington's disease and schizophrenia. Barrier dysfunction appears to be a common denominator in neurological disorders, warranting detailed research into the molecular mechanisms behind it. Learning the commonalities and differences in the pathomechanism of the BBB injury in different neurological disorders will predictably lead to development of new therapeutics that improve our life as we age.
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Envejecimiento , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Microvasos/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Uniones Estrechas/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/irrigación sanguínea , Humanos , Enfermedad de Parkinson/metabolismoRESUMEN
BACKGROUND/AIMS: Effective wound-healing generally requires efficient re-vascularization after injury, ensuring sufficient supply with oxygen, nutrients, and various cell populations. While this applies to most tissues, tendons are mostly avascular in nature and harbor relatively few cells, probably contributing to their poor regenerative capacity. Considering the minimal vascularization of healthy tendons, we hypothesize that controlling angiogenesis in early tendon healing is beneficial for repair tissue quality and function. METHODS: To address this hypothesis, Bevacizumab, a monoclonal antibody blocking VEGF-A signaling, was locally injected into the defect area of a complete tenotomy in rat Achilles tendon. At 28 days post-surgery, the defect region was investigated using immunohistochemistry against vascular and lymphatic epitopes. Polarization microscopy and biomechanical testing was used to determine tendon integrity and gait analysis for functional testing in treated vs non-treated animals. RESULTS: Angiogenesis was found to be significantly reduced in the Bevacizumab treated repair tissue, accompanied by significantly reduced cross sectional area, improved matrix organization, increased stiffness and Young's modulus, maximum load and stress. Further, we observed an improved gait pattern when compared to the vehicle injected control group. CONCLUSION: Based on the results of this study we propose that reducing angiogenesis after tendon injury can improve tendon repair, potentially representing a novel treatment-option.
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Bevacizumab/uso terapéutico , Traumatismos de los Tendones/tratamiento farmacológico , Tendón Calcáneo/patología , Animales , Bevacizumab/farmacología , Modelos Animales de Enfermedad , Módulo de Elasticidad , Femenino , Marcha/fisiología , Neovascularización Fisiológica/efectos de los fármacos , Ratas , Ratas Endogámicas Lew , Traumatismos de los Tendones/patología , Resistencia a la Tracción , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Tendons lack sufficient blood supply and represent a bradytroph tissue with prolonged healing time under pathological conditions. While the role of lymphatics in wound/defect healing in tissues with regular blood supply is well investigated, its involvement in tendon defects is not clear. We here try to identify the role of the lymphatic system in a tendon lesion model with morphological methods. A rat Achilles tendon lesion model (n = 5) was created via surgical intervention. Two weeks after surgery, animals were killed and lesioned site removed and prepared for polarization microscopy (picrosirius red) and immunohistochemistry using the lymphatic markers PROX1, VEGFR3, CCL21, LYVE-1, PDPN, and the vascular marker CD31. Additionally, DAPI was applied. Untreated tendons served as controls, confocal laser-scanning microscopy was used for documentation. At the lesion site, polarization microscopy revealed a structural reintegration while immunohistochemistry detected band-like profiles immunoreactive for PDPN, VEGFR3, CCL21, LYVE1, and CD31, surrounding DAPI-positive nuclei. PROX1-positive nuclei were detected within the lesion forming lines and opposed to each other. These PROX1-positive nuclei were surrounded by LYVE-1- or VEGFR3-positive surfaces. Few CD31-positive profiles contained PROX1-positive nuclei, while the majority of CD31-positive profiles lacked PROX1-positive nuclei. VEGFR3-, PDPN-, and LYVE-1-positive profiles were numerous within the lesion site, but absent in control tissue. Within 2 weeks, a structural rearrangement takes place in this lesion model, with dense lymphatic supply. The role of lymphatics in tendon wound healing is unclear, and proposed model represents a good possibility to study healing dynamics and lymphangiogenesis in a tissue almost completely lacking lymphatics in physiological conditions.
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Tendón Calcáneo/patología , Linfangiogénesis , Vasos Linfáticos/patología , Traumatismos de los Tendones/patología , Cicatrización de Heridas , Tendón Calcáneo/lesiones , Tendón Calcáneo/metabolismo , Tendón Calcáneo/cirugía , Animales , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Vasos Linfáticos/metabolismo , Microscopía Confocal , Microscopía de Polarización , Ratas Endogámicas Lew , Traumatismos de los Tendones/metabolismo , Factores de TiempoRESUMEN
Tears of the anterior cruciate ligament (ACL) are very frequent injuries, particularly in young and active people. Arthroscopic reconstruction using tendon auto- or allograft represents the gold-standard for the management of ACL tears. Interestingly, the ACL has the potential to heal upon intensive non-surgical rehabilitation procedures. Several biological factors influence this healing process as local intraligamentous cytokines and mainly cell repair mechanisms controlled by stem cells or progenitor cells. Understanding the mechanisms of this regeneration process and the cells involved may pave the way for novel, less invasive and biology-based strategies for ACL repair. This review aims to focus on the current knowledge on the mechanisms of ACL healing, the nature and potential of ligament derived stem/progenitor cells as well as on the potential and the limitations of using mesenchymal stem cells (MSCs) for treating injured ACL.
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Lesiones del Ligamento Cruzado Anterior , Trasplante de Células Madre , Cicatrización de Heridas , Reconstrucción del Ligamento Cruzado Anterior/métodos , Humanos , Traumatismos de los Tejidos Blandos/terapiaRESUMEN
Aside from human bones, epoxy-based synthetic bones are regarded as the gold standard for biomechanical testing os osteosyntheses. There is a significant discrepancy in biomechanical testing between the determination of fracture stability due to implant treatment in experimental methods and their ability to predict the outcome of stability and fracture healing in a patient. One possible explanation for this disparity is the absence of population-specific variables such as age, gender, and ethnicity in artificial bone, which may influence the geometry and mechanical properties of bone. The goal of this review was to determine whether commercially available artificial bones adequately represent human anatomical variability for mechanical testing of femoral osteosyntheses. To summarize, the availability of suitable bone surrogates currently limits the validity of mechanical evaluations of implant-bone constructs. The currently available synthetic bones neither accurately reflect the local mechanical properties of human bone, nor adequately represent the necessary variability between various populations, limiting their generalized clinical relevance.
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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) ≥â¯16, an age ≥â¯16 years, and who were primarily admitted to an Austrian (nâ¯= 4186) or German (nâ¯= 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 (62â¯min in Austria, 65â¯min in Germany). Overall, 53% of all trauma patients in Austria were transported to the hospital with a helicopter compared to 37% in Germany (pâ¯<â¯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 (Φâ¯= 0.00). Hemodynamic instability (systolic blood pressure, BP ≤â¯90â¯mmHg) upon arrival in the TC was higher in Austria (20.6% vs. 14.7% in Germany; pâ¯< 0.001). A median of 500â¯mL of fluid was administered in Austria, whereas in Germany 1000â¯mL was infused (pâ¯< 0.001). Patient demographics did not reveal a relationship (Φâ¯= 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 >â¯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.
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Servicios Médicos de Urgencia , Traumatismo Múltiple , Humanos , Adolescente , Traumatismo Múltiple/terapia , Aeronaves , Alemania/epidemiología , Estudios EpidemiológicosRESUMEN
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.
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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.
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Proteína Morfogenética Ósea 2 , Vesículas Extracelulares , Fémur , Osteoporosis , Proteínas Recombinantes , Cordón Umbilical , Animales , Proteína Morfogenética Ósea 2/farmacología , Proteína Morfogenética Ósea 2/genética , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/genética , Osteoporosis/patología , Ratas , Femenino , Humanos , Fémur/patología , Fémur/efectos de los fármacos , Fémur/diagnóstico por imagen , Cordón Umbilical/citología , Vesículas Extracelulares/metabolismo , Regeneración Ósea/efectos de los fármacos , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta/farmacología , Modelos Animales de Enfermedad , Microtomografía por Rayos X , Células Madre Mesenquimatosas/metabolismoRESUMEN
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.
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Vesículas Extracelulares , Células Madre Mesenquimatosas , Lesiones del Manguito de los Rotadores , Animales , Ovinos , Humanos , Manguito de los Rotadores/cirugía , Proyectos Piloto , Colágeno Tipo I/metabolismo , Lesiones del Manguito de los Rotadores/cirugía , Células Madre Mesenquimatosas/metabolismo , Vesículas Extracelulares/patología , Cordón UmbilicalRESUMEN
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.
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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.
Asunto(s)
Fracturas Óseas , Apófisis Odontoides , Fracturas de la Columna Vertebral , Anciano , Tornillos Óseos , Fijación Interna de Fracturas/métodos , Humanos , Apófisis Odontoides/diagnóstico por imagen , Estudios Retrospectivos , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/cirugía , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Esclerótica , Tendones , Colágeno , Tejido Conectivo , Matriz Extracelular , HumanosRESUMEN
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.