RESUMEN
BACKGROUND: The AGEs levels in tissues of diabetics and elderly tend to be higher than in normal individuals. This study aims to determine the effects of AGEs on Achilles tendon repair. MATERIALS AND METHODS: Thirty-six male eight-week-old Sprague Dawley rats were selected in this study. The rats were randomly divided into two experimental groups and a control group after the transection of the Achilles tendon. During the tendon repair, the experimental groups were injected around the Achilles tendon with 350mmol/L (low dose group) and 1000mmol/L (high dose group) D-ribose 0.2 ml respectively to increase the AGEs level, while in the control group were given the same amount of PBS. The injections were given twice a week for six weeks. Collagen-I, TNF-α, and IL-6 expression in the healed Achilles tendon was assessed. Additionally, macroscopic, pathological, and biomechanical evaluations of Achilles tendon repair were conducted. RESULTS: The repaired Achilles tendons in the high dose group showed severe swelling and distinctive adhesions. The histological score went up with the increase of the AGEs in the Achilles tendon (p<0.001). TNF- α and IL-6 in the Achilles tendon increased (p<0.001, p<0.001), and the production of collagen-I decreased with the accumulation of AGEs in the repaired Achilles tendon (p<0.001). The tensile strength of Achilles tendon in the high dose group was impaired significantly. CONCLUSION: In current study, the compromised tendon repair model induced by AGEs was successfully established in rat. The study demonstrated that AGEs significantly impair Achilles tendon repair.
Asunto(s)
Tendón Calcáneo , Productos Finales de Glicación Avanzada , Ratas Sprague-Dawley , Traumatismos de los Tendones , Cicatrización de Heridas , Animales , Masculino , Tendón Calcáneo/lesiones , Tendón Calcáneo/patología , Tendón Calcáneo/metabolismo , Tendón Calcáneo/cirugía , Tendón Calcáneo/efectos de los fármacos , Productos Finales de Glicación Avanzada/metabolismo , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/fisiopatología , Ratas , Cicatrización de Heridas/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Colágeno Tipo I/metabolismo , Interleucina-6/metabolismo , Modelos Animales de EnfermedadRESUMEN
OBJECTIVES: This study aimed to evaluate the biomechanical and histological effects of fluoroquinolones on surgically repaired tendon healing. MATERIALS AND METHODS: The Achilles tendons of 40 Wistar rats (mean weight: 213.5 g; range 201 to 242 g) were bilaterally surgically cut and repaired. The rats were randomly divided into four groups: the first and third groups were designated as control groups and did not receive drug therapy, whereas the second and fourth groups received 300 mg/kg ciprofloxacin for a week after the surgical procedure. The first and second groups had both tendons dissected at the end of the first week, while the third and fourth groups were dissected at the end of the third week. The left tendons were examined biomechanically, while the right tendons were examined histologically. RESULTS: Statistical analysis revealed that the mean maximum tensile forces of tendons in the first and second groups were 5.2±1.84 N (range, 2.9 to 8.5 N) and 11.1±2.65 N (range, 7.3 to 13.9 N), respectively, which was found to be statistically significant (p< 0.05). At the end of the third week, mean maximum tensile forces of the third and fourth groups were determined to be 20.7±5.0 N (range, 22.1 to 29.8 N) and 28.7±4.6 N (range, 22.1 to 36.8 N), respectively, which was also statistically significant (p< 0.05). Histologically, our results were compatible. CONCLUSION: This study demonstrated that ciprofloxacin did not exhibit the expected adverse effects on surgically repaired tendon healing in the early stages but likely contributed to healing in the short term by affecting the inflammatory phase.
Asunto(s)
Tendón Calcáneo , Ciprofloxacina , Ratas Wistar , Traumatismos de los Tendones , Resistencia a la Tracción , Cicatrización de Heridas , Animales , Cicatrización de Heridas/efectos de los fármacos , Tendón Calcáneo/cirugía , Tendón Calcáneo/lesiones , Tendón Calcáneo/efectos de los fármacos , Tendón Calcáneo/patología , Ratas , Ciprofloxacina/efectos adversos , Ciprofloxacina/farmacología , Resistencia a la Tracción/efectos de los fármacos , Traumatismos de los Tendones/cirugía , Traumatismos de los Tendones/tratamiento farmacológico , Traumatismos de los Tendones/patología , Antibacterianos/farmacología , Antibacterianos/efectos adversos , Fenómenos Biomecánicos/efectos de los fármacos , Masculino , Fluoroquinolonas/farmacología , Fluoroquinolonas/efectos adversosRESUMEN
Unveiling of the mechanism involved in the occurrence and development of trauma-induced heterotopic ossification (tHO) is highly demanding due to current ineffective clinical treatment for it. Previous studies proposed that hydrogen sulfide (H2S) was vital for fate determination of stem cells, suggesting a potential role in the regulation of tHO development. In the current study, We found that expression of metabolic enzyme within sulfur conversion pathway was enhanced after tendon injury, leading to H2S accumulation within the tHO region. Increased production of endogenous H2S was shown to promote aberrant osteogenic activity of tendon-derived stem cells (TDSCs), which accelerated tHO formation. The inhibition of metabolic enzyme of H2S production or directly absorption of H2S could abolished osteogenic induction of TDSCs and the formation of tHO. Mechanistically, through RNA sequencing combined with rescue experiments, we demonstrated that activation of Ca2+/ERK pathway was the downstream molecular event of H2S-induced osteogenic commitment of TDSCs and tHO. For treatment strategy exploration, zine oxide nanoparticles (ZnO) as an effective H2S elimination material was validated to ideally halt the tHO formation in this study. Furthermore, in terms of chirality of nanoparticles, D-ZnO or L-ZnO nanoparticles showed superiority over R-ZnO nanoparticles in both clearing of H2S and inhibition of tHO. Our study not only revealed the mechanism of tHO through the endogenous gas signaling event from a new perspective, but also presented a applicable platform for elimination of the inordinate gas production, thus aiding the development of clinical treatment for tHO.
Asunto(s)
Sulfuro de Hidrógeno , Sistema de Señalización de MAP Quinasas , Osificación Heterotópica , Osteogénesis , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/farmacología , Osificación Heterotópica/metabolismo , Osificación Heterotópica/patología , Osteogénesis/efectos de los fármacos , Animales , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Calcio/metabolismo , Masculino , Células Madre/metabolismo , Células Madre/citología , Diferenciación Celular/efectos de los fármacos , Óxido de Zinc/química , Óxido de Zinc/farmacología , Ratas , Tendones/metabolismo , Tendones/patología , Humanos , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/patología , Nanopartículas/química , Heridas y Lesiones/metabolismo , Heridas y Lesiones/patología , Heridas y Lesiones/complicacionesRESUMEN
BACKGROUND: The study aimed to determine the grade of retraction and atrophy according to the time elapsed in traumatic isolated full-thickness supraspinatus (SS) tears in young patients. METHODS: One thousand twenty-six patients, who underwent arthroscopic shoulder surgery, were retrospectively reviewed. Pre-operative magnetic resonance imaging (MRI) of 69 patients aged 18 to 40 years with isolated traumatic full-thickness SS lesions remaining after exclusion criteria were evaluated for tendon retraction and atrophy grades. SS retraction was determined from a T2-weighted oblique coronal MRI slice, and the atrophy grade was determined from the T1-weighted oblique sagittal MRI slice. The patients were divided into four groups 0-1 month, 1-3 months, 3-6 months, and 6-12 months according to the time between trauma and MRI. The relationship of tendon retraction and muscle atrophy with elapsed time was evaluated, in addition, comparisons between groups were made. RESULTS: Thirty-one (45%) of the patients were female and their mean age was 30 ± 7.3 (18-40) years. The mean age of men was 30.5 ± 6.9 (18-39) years (p = 0.880). The time between rupture and MRI was moderately correlated with retraction and strongly correlated with atrophy grades (r = 0.599, 0.751, respectively). It was observed that there was a statistically significant difference between the 1st (0-1 month) and 2nd (1-3 months) groups (p = 0.003, 0.001, respectively), and between the 2nd and 3rd (3-6 months) groups (p = 0.032, 0.002, respectively), but there was no significant difference between the 3rd and 4th (6-12 months) groups (p = 0.118, 0.057, respectively). In addition, there was a moderate correlation between tendon retraction and atrophy grades (r = 0.668). Power (1- b) in post hoc analysis was calculated as 0.826. CONCLUSIONS: The current study, supported by arthroscopy, showed that there is a moderate and strong positive correlation between the time elapsed after trauma and the level of retraction and degree of atrophy in traumatic full-thickness SS tears, and demonstrated the importance of early surgical intervention in young patients.
Asunto(s)
Imagen por Resonancia Magnética , Atrofia Muscular , Lesiones del Manguito de los Rotadores , Humanos , Femenino , Masculino , Adulto , Adolescente , Adulto Joven , Estudios Retrospectivos , Lesiones del Manguito de los Rotadores/cirugía , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Lesiones del Manguito de los Rotadores/patología , Atrofia Muscular/patología , Atrofia Muscular/diagnóstico por imagen , Atrofia Muscular/etiología , Factores de Tiempo , Manguito de los Rotadores/patología , Manguito de los Rotadores/diagnóstico por imagen , Manguito de los Rotadores/cirugía , Artroscopía/métodos , Traumatismos de los Tendones/diagnóstico por imagen , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/cirugíaRESUMEN
BACKGROUND: Tendons are important dense fibrous structures connecting muscle to bone, and tendon stem cells (TDSCs) affect their repair and regeneration. The role of TDSC-derived exosomes (TDSC-Exos) is still being unexplored; therefore, this study aimed to investigate the protective effect of TDSC-Exos on tenocytes. METHODS: The TDSCs and tenocytes were all derived from Sprague Dawley (SD) rats. The expression of positive and negative markers of TDSCs were detected by flow cytometry, and the multi-differentiation ability was also detected to identify TDSCs. Exos were derived from TDSCs using ultracentrifugation; furthermore, Exos enriched with microRNA(miR)-377-3p were generated from TDSCs stably overexpressing miR-377-3p after transfection, identified with transmission electron microscopy (TEM), western blot and PKH26 staining assay. Moreover, the cell functions of tenocytes were evaluated by MTT, EdU, transwell, and flow cytometry. Dual luciferase reporter and RNA pull-down assays were used to verify the binding sites of miR-337-3p and caspase3 (CASP3) predicted by Targetscan. RESULTS: Exos (miR-337-3p) were taken up by tenocytes, and promoted the proliferation, migration, and invasion and suppressed the apoptosis of tenocytes in a dose-dependent manner. Bioinformatics analysis showed that CASP3 was a target of miR-377-3p, which was further verified by luciferase and RNA pull-down assays. Moreover, over-expressed CASP3 reversed the effects of Exos (miR-337-3p) on cell functions of tenocytes. CONCLUSIONS: Our findings suggest that Exos derived from miR-337-3p over-expressing TDSCs could potentially protect against tenocyte apoptosis by regulating CASP3. This novel therapeutic approach holds promise for the treatment of tendon injury, offering a glimmer of hope for improved patient outcomes.
Asunto(s)
Apoptosis , Caspasa 3 , Exosomas , MicroARNs , Ratas Sprague-Dawley , Células Madre , Tendones , Tenocitos , Animales , MicroARNs/genética , MicroARNs/metabolismo , Exosomas/metabolismo , Exosomas/genética , Apoptosis/fisiología , Ratas , Caspasa 3/metabolismo , Caspasa 3/genética , Tenocitos/metabolismo , Células Madre/metabolismo , Tendones/metabolismo , Tendones/citología , Proliferación Celular/fisiología , Células Cultivadas , Masculino , Traumatismos de los Tendones/genética , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/patología , Movimiento CelularRESUMEN
Tendon calcification is a common clinical condition that frequently occurs as a complication after tendon injury and surgery, or as an expression of fibrodysplasia ossificans progressiva. This condition can be referred to by various names in clinical practice and literature, including tendon ossification, tendon mineralization, heterotopic ossification, and calcific tendonitis. The exact pathogenesis of tendon calcification remains uncertain, but current mainstream research suggests that calcification is mostly cell mediated. To further elucidate the pathogenesis of tendon calcification and to better simulate the overall process, selecting appropriate experimental animal models is important. Numerous animal models have been utilized in various clinical studies, each with its own set of advantages and limitations. In this review, we have discussed the advancements made in research on animal models of tendon calcification, with a focus on the selection of experimental animals, the sites of injury in these models, and the methods employed for modeling.
Asunto(s)
Calcinosis , Modelos Animales de Enfermedad , Tendones , Animales , Calcinosis/patología , Calcinosis/etiología , Tendones/patología , Tendinopatía/patología , Tendinopatía/etiología , Traumatismos de los Tendones/patología , HumanosRESUMEN
Beyond the sensation of pain, peripheral nerves have been shown to play crucial roles in tissue regeneration and repair. As a highly innervated organ, bone can recover from injury without scar formation, making it an interesting model in which to study the role of nerves in tissue regeneration. As a comparison, tendon is a musculoskeletal tissue that is hypo-innervated, with repair often resulting in scar formation. Here, we reviewed the significance of innervation in 3 stages of injury repair (inflammatory, reparative, and remodeling) in 2 commonly injured musculoskeletal tissues: bone and tendon. Based on this focused review, we conclude that peripheral innervation is essential for phases of proper bone and tendon repair, and that nerves may dynamically regulate the repair process through interactions with the injury microenvironment via a variety of neuropeptides or neurotransmitters. A deeper understanding of neuronal regulation of musculoskeletal repair, and the crosstalk between nerves and the musculoskeletal system, will enable the development of future therapies for tissue healing.
Accumulating evidence has shown that, across organs systems, peripheral nerves regulate the process of tissue repair and regeneration. This is particularly relevant in the context of musculoskeletal injuries such as those affecting the bone and tendon. The question then arises: what is the function of peripheral innervation in the repair of bone and tendon injuries? This review offers an in-depth look at the ways in which nerves regulate the healing of bone and tendon injuries at various stages of recovery. A deeper comprehension of the influence of nerves on the repair of these tissues could pave the way for the development of future therapeutic strategies for tissue healing.
Asunto(s)
Huesos , Traumatismos de los Tendones , Cicatrización de Heridas , Humanos , Traumatismos de los Tendones/fisiopatología , Traumatismos de los Tendones/patología , Animales , Huesos/patología , Neuronas/metabolismo , Neuronas/patología , Tendones/patología , Tendones/fisiopatologíaRESUMEN
OBJECTIVES: The study aimed to examine the histopathological and biomechanical effects of papaverine administered intraperitoneally and locally on Achilles tendon healing in a rat model. MATERIALS AND METHODS: Forty-eight adult male Sprague-Dawley rats (range, 300 to 400 g) were used in this study conducted between October and November 2022. The rats were divided into three groups, with each group further subdivided into two for sacrifice on either the 15th (early period) or 30th (late period) day after surgery. The first (control) group received no treatment following Achilles tendon repair, while papaverine was intraperitoneally administered every other day for 10 days in the second group and locally in the third group after surgery. On the 15th and 30th days, the rats were sacrificed, and their Achilles tendons were subjected to biomechanical testing and histopathological evaluation. RESULTS: Histopathologically, there were no significant differences among the groups on the 15th day. However, on the 30th day, the locally applied papaverine group exhibited superior histopathological outcomes compared to the control group (p<0.05). Concerning the highest tensile strength values before rupture, the biomechanical assessment showed that the group receiving local papaverine treatment in the early period and both the group with systemic papaverine treatment and the one with local papaverine treatment in the late period displayed a statistically significant advantage compared to the control group (p<0.05). CONCLUSION: Locally administered papaverine has positive biomechanical effects in the early period and exhibits a positive correlation both histopathologically and biomechanically in the late period. Novel therapeutic options may be provided for patients through these findings.
Asunto(s)
Tendón Calcáneo , Papaverina , Ratas Sprague-Dawley , Traumatismos de los Tendones , Cicatrización de Heridas , Animales , Tendón Calcáneo/lesiones , Tendón Calcáneo/efectos de los fármacos , Tendón Calcáneo/patología , Tendón Calcáneo/cirugía , Papaverina/farmacología , Papaverina/administración & dosificación , Papaverina/uso terapéutico , Masculino , Adherencias Tisulares/tratamiento farmacológico , Adherencias Tisulares/patología , Cicatrización de Heridas/efectos de los fármacos , Traumatismos de los Tendones/tratamiento farmacológico , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/cirugía , Ratas , Resistencia a la Tracción/efectos de los fármacos , Inyecciones Intraperitoneales , Fenómenos Biomecánicos/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
PURPOSE: This study aimed to evaluate whether cilostazol (phosphodiesterase III inhibitor) could enhance the healing of Achilles tendon ruptures in rats. MATERIALS AND METHODS: The Achilles tendons of 24 healthy male adult rats were incised and repaired. The rats were randomly allocated to cilostazol and control groups. The cilostazol group received daily intragastric administration of 50 mg/kg cilostazol for 28 days, while the control group did not receive any medication. The rats were sacrificed on the 30th day, and the Achilles tendon was evaluated for biomechanical properties, histopathological characteristics, and immunohistochemical analysis. RESULTS: All rats completed the experiment. The Movin sum score of the control group was significantly higher (p = 0.008) than that of the cilostazol group, with means of 11 ± 0.63 and 7.50 ± 1.15, respectively. Similarly, the mean Bonar score was significantly higher (p = 0.026) in the control group compared to the cilostazol group (8.33 ± 1.50 vs. 5.5 ± 0.54, respectively). Moreover, the Type I/Type III Collagen ratio was notably higher (p = 0.016) in the cilostazol group (52.2 ± 8.4) than in the control group (34.6 ± 10.2). The load to failure was substantially higher in the cilostazol group than in the control group (p = 0.034), suggesting that the tendons in the cilostazol group were stronger and exhibited greater resistance to failure. CONCLUSIONS: The results of this study suggest that cilostazol treatment significantly improves the biomechanical and histopathological parameters of the healing Achilles tendon in rats. Cilostazol might be a valuable supplementary therapy in treating Achilles tendon ruptures in humans. Additional clinical studies are, however, required to verify these outcomes.
Asunto(s)
Tendón Calcáneo , Cilostazol , Cicatrización de Heridas , Animales , Cilostazol/farmacología , Tendón Calcáneo/patología , Tendón Calcáneo/lesiones , Tendón Calcáneo/efectos de los fármacos , Masculino , Cicatrización de Heridas/efectos de los fármacos , Rotura/tratamiento farmacológico , Rotura/patología , Ratas , Traumatismos de los Tendones/tratamiento farmacológico , Traumatismos de los Tendones/patología , Ratas Sprague-Dawley , Fenómenos Biomecánicos/efectos de los fármacos , Tetrazoles/farmacologíaRESUMEN
Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26RtdTomato mice to lethally irradiated Ackr1-/- mice (Ackr1-/- chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.
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Movimiento Celular , Macrófagos , Regeneración , Humanos , Animales , Macrófagos/metabolismo , Ratones , Tendones/metabolismo , Tendones/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/genética , Proteómica , Femenino , MultiómicaRESUMEN
Heterotopic ossification (HO), the pathological formation of bone within soft tissues such as tendon and muscle, is a notable complication resulting from severe injury. While soft tissue injury is necessary for HO development, the specific molecular pathology responsible for trauma-induced HO remains a mystery. The previous study detected abnormal autophagy function in the early stages of tendon HO. Nevertheless, it remains to be determined whether autophagy governs the process of HO generation. Here, trauma-induced tendon HO model is used to investigate the relationship between autophagy and tendon calcification. In the early stages of tenotomy, it is observed that autophagic flux is significantly impaired and that blocking autophagic flux promoted the development of more rampant calcification. Moreover, Gt(ROSA)26sor transgenic mouse model experiments disclosed lysosomal acid dysfunction as chief reason behind impaired autophagic flux. Stimulating V-ATPase activity reinstated both lysosomal acid functioning and autophagic flux, thereby reversing tendon HO. This present study demonstrates that autophagy-lysosomal dysfunction triggers HO in the stages of tendon injury, with potential therapeutic targeting implications for HO.
Asunto(s)
Autofagia , Modelos Animales de Enfermedad , Lisosomas , Ratones Transgénicos , Osificación Heterotópica , Tendones , Osificación Heterotópica/metabolismo , Osificación Heterotópica/genética , Osificación Heterotópica/patología , Animales , Autofagia/fisiología , Ratones , Lisosomas/metabolismo , Tendones/metabolismo , Tendones/patología , Tendones/fisiopatología , Tenotomía/métodos , Masculino , Traumatismos de los Tendones/fisiopatología , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/patología , Ratones Endogámicos C57BLRESUMEN
The pathogenesis of trauma-induced heterotopic ossification (HO) in the tendon remains unclear, posing a challenging hurdle in treatment. Recognizing inflammation as the root cause of HO, anti-inflammatory agents hold promise for its management. Malvidin (MA), possessing anti-inflammatory properties, emerges as a potential agent to impede HO progression. This study aimed to investigate the effect of MA in treating trauma-induced HO and unravel its underlying mechanisms. Herein, the effectiveness of MA in preventing HO formation was assessed through local injection in a rat model. The potential mechanism underlying MA's treatment was investigated in the tendon-resident progenitor cells of tendon-derived stem cells (TDSCs), exploring its pathway in HO formation. The findings demonstrated that MA effectively hindered the osteogenic differentiation of TDSCs by inhibiting the mTORC1 signalling pathway, consequently impeding the progression of trauma-induced HO of Achilles tendon in rats. Specifically, MA facilitated the degradation of Rheb through the K48-linked ubiquitination-proteasome pathway by modulating USP4 and intercepted the interaction between Rheb and the mTORC1 complex, thus inhibiting the mTORC1 signalling pathway. Hence, MA presents itself as a promising candidate for treating trauma-induced HO in the Achilles tendon, acting by targeting Rheb for degradation through the ubiquitin-proteasome pathway.
Asunto(s)
Osificación Heterotópica , Complejo de la Endopetidasa Proteasomal , Proteína Homóloga de Ras Enriquecida en el Cerebro , Transducción de Señal , Ubiquitina , Animales , Ratas , Complejo de la Endopetidasa Proteasomal/metabolismo , Osificación Heterotópica/metabolismo , Osificación Heterotópica/etiología , Osificación Heterotópica/patología , Transducción de Señal/efectos de los fármacos , Proteína Homóloga de Ras Enriquecida en el Cerebro/metabolismo , Ubiquitina/metabolismo , Masculino , Osteogénesis/efectos de los fármacos , Tendones/metabolismo , Tendones/patología , Ratas Sprague-Dawley , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/complicaciones , Proteolisis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Tendón Calcáneo/metabolismo , Tendón Calcáneo/patología , Tendón Calcáneo/lesiones , Modelos Animales de Enfermedad , Ubiquitinación , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Células Madre/metabolismo , Células Madre/efectos de los fármacosRESUMEN
Cluster-like collective cell migration of fibroblasts is one of the main factors of adhesion in injured tissues. In this research, a microdot biomaterial system is constructed using α-helical polypeptide nanoparticles and anti-inflammatory micelles, which are prepared by ring-opening polymerization of α-amino acids-N-carboxylic anhydrides (NCAs) and lactide, respectively. The microdot biomaterial system slowly releases functionalized polypeptides targeting mitochondria and promoting the influx of extracellular calcium ions under the inflammatory environment, thus inhibiting the expression of N-cadherin mediating cell-cell interaction, and promoting apoptosis of cluster fibroblasts, synergistically inhibiting the migration of fibroblast clusters at the site of tendon injury. Meanwhile, the anti-inflammatory micelles are celecoxib (Cex) solubilized by PEG/polyester, which can improve the inflammatory microenvironment at the injury site for a long time. In vitro, the microdot biomaterial system can effectively inhibit the migration of the cluster fibroblasts by inhibiting the expression of N-cadherin between cell-cell and promoting apoptosis. In vivo, the microdot biomaterial system can promote apoptosis while achieving long-acting anti-inflammation effects, and reduce the expression of vimentin and α-smooth muscle actin (α-SMA) in fibroblasts. Thus, this microdot biomaterial system provides new ideas for the prevention and treatment of tendon adhesion by inhibiting the cluster migration of fibroblasts.
Asunto(s)
Materiales Biocompatibles , Movimiento Celular , Fibroblastos , Movimiento Celular/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/citología , Animales , Nanopartículas/química , Péptidos/química , Péptidos/farmacología , Apoptosis/efectos de los fármacos , Celecoxib/farmacología , Celecoxib/química , Cadherinas/metabolismo , Ratones , Traumatismos de los Tendones/tratamiento farmacológico , Traumatismos de los Tendones/patología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Adhesión Celular/efectos de los fármacos , Adherencias Tisulares/prevención & control , Adherencias Tisulares/tratamiento farmacológicoRESUMEN
BACKGROUND: Achilles tendon is composed of dense connective tissue and is one of the largest tendons in the body. In veterinary medicine, acute ruptures are associated with impact injury or sharp trauma. Healing of the ruptured tendon is challenging because of poor blood and nerve supply as well as the residual cell population. Platelet-rich plasma (PRP) contains numerous bioactive agents and growth factors and has been utilized to promote healing in bone, soft tissue, and tendons. OBJECTIVE: The purpose of this study was to evaluate the healing effect of PRP injected into the surrounding fascia of the Achilles tendon after allograft in rabbits. METHODS: Donor rabbits (n = 8) were anesthetized and 16 lateral gastrocnemius tendons were fully transected bilaterally. Transected tendons were decellularized and stored at -80°C prior to allograft. The allograft was placed on the partially transected medial gastrocnemius tendon in the left hindlimb of 16 rabbits. The allograft PRP group (n = 8) had 0.3 mL of PRP administered in the tendon and the allograft control group (n = 8) did not receive any treatment. After 8 weeks, rabbits were euthanatized and allograft tendons were transected for macroscopic, biomechanical, and histological assessment. RESULTS: The allograft PRP group exhibited superior macroscopic assessment scores, greater tensile strength, and a histologically enhanced healing process compared to those in the allograft control group. CONCLUSIONS: Our results suggest administration of PRP on an allograft tendon has a positive effect on the healing process in a ruptured Achilles tendon.
Asunto(s)
Tendón Calcáneo , Plasma Rico en Plaquetas , Traumatismos de los Tendones , Conejos , Animales , Tendón Calcáneo/cirugía , Tendón Calcáneo/lesiones , Tendón Calcáneo/patología , Traumatismos de los Tendones/terapia , Traumatismos de los Tendones/veterinaria , Traumatismos de los Tendones/patología , Cicatrización de Heridas , Aloinjertos/patologíaRESUMEN
AIM: To determine inter-reader analysis and diagnostic performance on digitally reconstructed virtual flexed, abducted, supinated (FABS) imaging from three-dimensional (3D) isotropic elbow magnetic resonance imaging (MRI). MATERIALS AND METHODS: Six musculoskeletal radiologists independently evaluated elbow MRI images with virtual FABS reconstructions, blinded to clinical findings and final diagnoses. Each radiologist recorded a binary result as to whether the tendon was intact and if both heads were visible, along with a categorical value to the type of tear and extent of retraction in centimetres where applicable. Kappa and interclass correlation (ICC) were reported with 95% confidence intervals. Areas under the receiver operating curve (AUC) were reported. RESULTS: FABS reconstructions were obtained successfully in all 48 cases. With respect to tendon intactness, visibility of both heads, and type of tear, the Kappa values were 0.66 (0.53-0.78), 0.24 (0.12-0.37), and 0.55 (0.43-0.66), respectively. For the extent of retraction, the ICC was 0.85 (0.79-0.91) when including the tendons with and without retraction and 0.78 (0.61-0.91) when only including tendons with retraction. For tear versus no tear, AUC values were 0.82 (0.74-0.89) to 0.96 (0.91-1.01). CONCLUSION: Digital reconstruction of FABS positioning is feasible and allows good assessment of individual tendon head tears and retraction with high diagnostic performance.
Asunto(s)
Codo , Traumatismos de los Tendones , Humanos , Codo/diagnóstico por imagen , Codo/patología , Hombro/patología , Antebrazo/diagnóstico por imagen , Antebrazo/patología , Traumatismos de los Tendones/patología , Imagen por Resonancia Magnética/métodosRESUMEN
Patellar tendinopathy is a common clinical problem, but its underlying pathophysiology remains poorly understood, primarily due to the absence of a representative experimental model. The most widely used method to generate such a model is collagenase injection, although this method possesses limitations. We developed an optimized rat model of patellar tendinopathy via the ultrasound-guided injection of collagenase mixed with a thermo-responsive Pluronic hydrogel into the patellar tendon of sixty male Wistar rats. All analyses were carried out at 3, 7, 14, 30, and 60 days post-injury. We confirmed that our rat model reproduced the pathophysiology observed in human patients through analyses of ultrasonography, histology, immunofluorescence, and biomechanical parameters. Tendons that were injured by the injection of the collagenase-Pluronic mixture exhibited a significant increase in the cross-sectional area (p < 0.01), a high degree of tissue disorganization and hypercellularity, significantly strong neovascularization (p < 0.01), important changes in the levels of types I and III collagen expression, and the organization and presence of intra-tendinous calcifications. Decreases in the maximum rupture force and stiffness were also observed. These results demonstrate that our model replicates the key features observed in human patellar tendinopathy. Collagenase is evenly distributed, as the Pluronic hydrogel prevents its leakage and thus, damage to surrounding tissues. Therefore, this model is valuable for testing new treatments for patellar tendinopathy.
Asunto(s)
Ligamento Rotuliano , Tendinopatía , Traumatismos de los Tendones , Humanos , Ratas , Masculino , Animales , Hidrogeles/efectos adversos , Poloxámero , Modelos Animales de Enfermedad , Ratas Wistar , Traumatismos de los Tendones/patología , Tendinopatía/tratamiento farmacológico , Tendinopatía/etiología , Tendinopatía/metabolismo , Ligamento Rotuliano/diagnóstico por imagen , Ligamento Rotuliano/lesiones , Ligamento Rotuliano/metabolismo , Colagenasas/farmacologíaRESUMEN
BACKGROUND: Both acute and chronic Achilles tendon ruptures are affected by alterations in the extracellular matrix during the healing process of the tendon. Yet, these alterations in gene expression patterns are not well characterized. PURPOSE: To characterize temporal and spatial differences in gene expression patterns after an Achilles tendon rupture and to evaluate if cells from chronic Achilles tendon ruptures have the same ability to form new tendon tissue (tendon constructs) as healthy tendon cells. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 35 patients with surgically treated Achilles tendon ruptures were included in the study and divided into 3 groups: acute (<4 weeks), short-term chronic (1-6 months), and long-term chronic (>6 months). Biopsy specimens were collected during surgical repair and were used to analyze the gene expression within the different groups and to compare mRNA levels in the proximal and distal tendon ends. A complementary in vitro experiment was performed to evaluate if cells from chronic Achilles tendon ruptures can form tendon constructs. RESULTS: The mRNA levels for COL1A1 and COL3A1 were significantly higher in the short-term chronic group compared with the acute group (P < .05). Both MMP-1 and MMP-13 had the highest mRNA levels in the acute group (P < .01) compared with the long-term chronic group, while MMP-2 had the highest mRNA level in the short-term chronic group. Significant differences between the proximal and distal tendon ends were only detected for the monocyte and macrophage marker CD163 (P < .05), which was more expressed proximally. Cells extracted from chronic Achilles tendon ruptures displayed a similar ability and effectiveness to form tendon constructs as healthy tendon cells. CONCLUSION: A high collagenase gene activity after an Achilles tendon rupture indicated possible rapid matrix degradation in the acute phase. Chronic ruptures appeared to initiate the healing process even before treatment, indicated by the higher expression of collagen in the short-term chronic group. Cells from chronic Achilles tendon ruptures also displayed an ability to form new tendon tissue in vitro. CLINICAL RELEVANCE: The study shows a rapid increase in collagenase gene expression, which could lead to matrix degradation that continues for months after an Achilles tendon rupture.
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Tendón Calcáneo , Traumatismos del Tobillo , Traumatismos de los Tendones , Humanos , Interleucina-6 , Tendón Calcáneo/cirugía , Traumatismos de los Tendones/genética , Traumatismos de los Tendones/cirugía , Traumatismos de los Tendones/patología , Rotura/cirugía , Colagenasas , ARN Mensajero , Expresión Génica , Resultado del TratamientoRESUMEN
Nonsurgical treatment and surgical repairment of injured Achilles tendons seldom restore the wounded tendon to its original elasticity and stiffness. Therefore, we hypothesized that the surgically repaired Achilles tendon can achieve satisfactory regeneration by applying multi-drug encapsulated hydrogels. In this study, a novel bupivacaine-eluting carbon dioxide-encapsulated Pluronic F127 hydrogel (BC-hydrogel) was developed for the treatment of Achilles tendon injuries. The rheological properties of BC-hydrogel were measured. A high-performance liquid chromatography assay was used to assess the release characteristics of bupivacaine in both in vitro and in vivo settings. Furthermore, the effectiveness of BC-hydrogel in treating torn tendons was examined in a rat model, and histological analyses were conducted. Evidently, the degradable hydrogels continuously eluted bupivacaine for more than 14 days. The animal study results revealed that the BC-hydrogel improved the post-surgery mobility of the animals compared with pristine hydrogels. Histological assay results demonstrated a significant reaction to high vascular endothelial growth factor in the surrounding tissues and expression of collagen I within the repaired tendon. This demonstrates the potential of this novel BC-hydrogel as an effective treatment method for Achilles tendon injuries.
Asunto(s)
Tendón Calcáneo , Traumatismos de los Tendones , Ratas , Animales , Hidrogeles/farmacología , Tendón Calcáneo/patología , Dióxido de Carbono/metabolismo , Poloxámero/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Traumatismos de los Tendones/patología , Bupivacaína/farmacologíaRESUMEN
The therapeutic role of tendon stem cells (TSCs) in tendon-related injuries has been well documented. Small extracellular vesicles (sEVs) are being increasingly used as new biotherapeutic agents for various diseases. Therefore, the potential function of TSC-sEVs in tendon injury repair warrants further investigation. In this study, we explored the effects of TSC-sEVs on TSC proliferation, migration, and differentiation in vitro in an autocrine manner. We further used a novel exosomal topical treatment with TSC-sEVs loaded with gelatin methacryloyl (GelMA) hydrogel in vivo; we mixed sufficient amounts of TSC-sEVs with GelMA hydrogel to cover the damaged molded Achilles tendon tissue and then exposed them to UV irradiation for coagulation. GelMA loading ensured that TSC-sEVs were slowly released at the injury site over a long period, thereby achieving their full local therapeutic effects. Treatment with TSC-sEVs loaded with GelMA significantly improved the histological score of the regenerated tendon by increasing the tendon expression while inhibiting the formation of excessive ossification and improving the mechanical properties of the tissue. Moreover, miRNA sequencing in TSC-sEVs, TSCs, and TSCs receiving sEVs revealed that TSC-sEVs altered the miRNA expression profile of TSCs, with increased expression of miR-145-3p. In conclusion, our study demonstrates that TSC-sEVs can play a key role in treating tendon injuries and that loading them with GelMA can enhance their effect in vivo. Moreover, miR-145-3p has a major functional role in the effect of TSC-sEVs. This study offers new therapeutic ideas for the local treatment of Achilles tendon injuries using sEVs. STATEMENT OF SIGNIFICANCE: In this study, we demonstrated that TSC-sEVs play a key role in treating tendon injuries and that loading them with GelMA hydrogel can act as a fixation and slow release in vivo. Moreover, it identifies the major functional role of miR-145-3p in the effect of TSCs that were identified and validated by miRNA sequencing. Our study provides a basis for further research on GelMA slow-release assays that have potential clinical applications. It offers new therapeutic ideas for the local treatment of Achilles tendon injuries using TSC-sEVs.