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Microsurgical reconstruction affects the outcome in a translational mouse model for Achilles tendon healing.

ABSTRACT: Background:Animal models are one of the first steps in translation of basic science findings to clinical practice. For tendon healing research, transgenic mouse models are important to advance therapeutic strategies. However, the small size of the structures complicates surgical approaches, histological assessment, and biomechanical testing. In addition, available models are not standardized and difficult to compare. How surgery itself affects the healing outcome has not been investigated yet. The focus of the study was to develop a procedure that includes a transection and microsurgical reconstruction of the Achilles tendon but, unlike other models, preserves the sciatic nerve. We wanted to examine how distinct parts of the technique influenced healing. Methods:For this animal model study, we used 96 wild-type male C57BL/6 mice aged 8-12 weeks. We evaluated different suture techniques and macroscopically confirmed the optimal combination of suture material and technique to minimize tendon gap formation. A key element is the detailed, step-by-step illustration of the surgery. In addition, we assessed histological (Herovici and Alcian blue staining) outcome parameters at 1-16 weeks postoperatively. Microcomputed tomography (micro-CT) was performed to measure the bone volume of heterotopic ossifications (HOs). Biomechanical analyses were carried out using a viscoelastic protocol on the biomechanical testing machine LM1. Results:A modified 4-strand suture combined with a cerclage for immobilization without transection of the sciatic nerve reliably eliminated gap formation. The maximal dorsal extension of the hindlimb at the upper ankle joint from the equinus position (limited by the immobilization cerclage) increased over time postoperatively (operation: 28.8 ± 2.2°; 1 week: 54 ± 36°; 6 weeks: 80 ± 11.7°; 16 weeks: 96 ± 15.8°, p > 0.05). Histological staining revealed a maturation of collagen fibres within 6 weeks, whereas masses of cartilage were visible throughout the healing period. Micro-CT scans detected the development of HOs starting at 4 weeks and further progression at 6 and 16 weeks (bone volume, 4 weeks: 0.07604 ± 0.05286 mm3; 6 weeks: 0.50682 ± 0.68841 mm3; 16 weeks: 2.36027 ± 0.85202 mm3, p > 0.001). In-depth micro-CT analysis of the different surgical elements revealed that an injury of the tendon is a key factor for the development of HOs. Immobilization alone does not trigger HOs. Biomechanical properties of repaired tendons were greatly altered and remained inferior 6 weeks after surgery. Conclusion:With this study, we demonstrated that the microsurgical technique greatly influences the short- and longer-term healing outcome. When the sciatic nerve is preserved, the best surgical reconstruction of the tendon defect is achieved by a 4-strand core suture in combination with a tibiofibular cerclage for postoperative immobilization. The cerclage promotes a gradual increase in the range of motion of the upper ankle joint, comparable with an early mobilization rehabilitation protocol. HO, as a key mechanism for poor tendon healing, is progressive and can be monitored early in the model. The translational potential of this article:The study enhances the understanding of model dependent factors of healing. The described reconstruction technique provides a reproducible and translational rodent model for future Achilles tendon healing research. In combination with transgenic strains, it can be facilitated to advance therapeutic strategies to improve the clinical results of tendon injuries.

SUBMITTER: Michel PA

PROVIDER: S-EPMC7260609 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Microsurgical reconstruction affects the outcome in a translational mouse model for Achilles tendon healing.

Michel Philipp A PA Kronenberg Daniel D Neu Gertje G Stolberg-Stolberg Josef J Frank Andre A Pap Thomas T Langer Martin M Fehr Michael M Raschke Michael J MJ Stange Richard R

Journal of orthopaedic translation 20200511

<h4>Background</h4>Animal models are one of the first steps in translation of basic science findings to clinical practice. For tendon healing research, transgenic mouse models are important to advance therapeutic strategies. However, the small size of the structures complicates surgical approaches, histological assessment, and biomechanical testing. In addition, available models are not standardized and difficult to compare. How surgery itself affects the healing outcome has not been investigate ...[more]

PMID: 32489862

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Project description:PurposeThe relationship between the duration of operative time (DOT), healing response and patient outcome has not been previously investigated. An enhanced healing response related to DOT may potentiate repair processes, especially in hypovascular and sparsely metabolized musculoskeletal tissues such as tendons. This study aimed to investigate the association between DOT and the metabolic healing response, patient-reported outcome and the rate of post-operative complications after acute Achilles tendon injury.MethodsObservational cohort, cross-sectional study with observers blinded to patient grouping. A total of two-hundred and fifty-six prospectively randomized patients (210 men, 46 women; mean age 41 years) with an acute total Achilles tendon rupture all operated on with uniform anaesthetic and surgical technique were retrospectively assessed. At 2 weeks post-operatively, six metabolites were quantified using microdialysis. At 3, 6 and 12 months, patient-reported pain, walking ability and physical activity were examined using self-reported questionnaires, Achilles tendon total rupture score, foot and ankle outcome score and physical activity scale. At 12 months, functional outcome was assessed using the heel-rise test. Complications, such as deep venous thrombosis, infections and re-operations, were recorded throughout the study.ResultsPatients who underwent longer DOT exhibited higher levels of glutamate (p = 0.026) and glycerol (p = 0.023) at 2 weeks. At the 1-year follow-up, longer DOT was associated with significantly less loss in physical activity (p = 0.003), less pain (p = 0.009), less walking limitations (p = 0.022) and better functional outcome (p = 0.014). DOT did not significantly correlate with the rate of adverse events, such as deep venous thrombosis, infections or re-ruptures. Higher glutamate levels were associated with less loss in physical activity (p = 0.017). All correlations were confirmed by multiple linear regressions taking confounding factors into consideration.ConclusionThe results from this study suggest a previously unknown mechanism, increased metabolic response associated with longer DOT, which may improve patient outcome after Achilles tendon rupture surgery. Allowing for a higher amount of traumatized tissue, as reflected by up-regulation of glycerol in patients with longer DOT, may prove to be an important surgical tip for stimulation of repair of hypometabolic soft tissue injuries, such as Achilles tendon ruptures.Level of evidenceII.

Project description:BackgroundDuring the stance phase of running, the elasticity of the Achilles tendon enables the utilisation of elastic energy and allows beneficial contractile conditions for the triceps surae muscles. However, the effect of changes in tendon mechanical properties induced by chronic loading is still poorly understood. We tested the hypothesis that a training-induced increase in Achilles tendon stiffness would result in reduced tendon strain during the stance phase of running, which would reduce fascicle strains in the triceps surae muscles, particularly in the mono-articular soleus.MethodsEleven subjects were assigned to a training group performing isometric single-leg plantarflexion contractions three times per week for ten weeks, and another ten subjects formed a control group. Before and after the training period, Achilles tendon stiffness was estimated, and muscle-tendon mechanics were assessed during running at preferred speed using ultrasonography, kinematics and kinetics.ResultsAchilles tendon stiffness increased by 18% (P < 0.01) in the training group, but the associated reduction in strain seen during isometric contractions was not statistically significant. Tendon elongation during the stance phase of running was similar after training, but tendon recoil was reduced by 30% (P < 0.01), while estimated tendon force remained unchanged. Neither gastrocnemius medialis nor soleus fascicle shortening during stance was affected by training.DiscussionThese results show that a training-induced increase in Achilles tendon stiffness altered tendon behaviour during running. Despite training-induced changes in tendon mechanical properties and recoil behaviour, the data suggest that fascicle shortening patterns were preserved for the running speed that we examined. The asymmetrical changes in tendon strain patterns supports the notion that simple in-series models do not fully explain the mechanical output of the muscle-tendon unit during a complex task like running.

Project description:Mechano-regulation during tendon healing, i.e. the relationship between mechanical stimuli and cellular response, has received more attention recently. However, the basic mechanobiological mechanisms governing tendon healing after a rupture are still not well-understood. Literature has reported spatial and temporal variations in the healing of ruptured tendon tissue. In this study, we explored a computational modeling approach to describe tendon healing. In particular, a novel 3D mechano-regulatory framework was developed to investigate spatio-temporal evolution of collagen content and orientation, and temporal evolution of tendon stiffness during early tendon healing. Based on an extensive literature search, two possible relationships were proposed to connect levels of mechanical stimuli to collagen production. Since literature remains unclear on strain-dependent collagen production at high levels of strain, the two investigated production laws explored the presence or absence of collagen production upon non-physiologically high levels of strain (>15%). Implementation in a finite element framework, pointed to large spatial variations in strain magnitudes within the callus tissue, which resulted in predictions of distinct spatial distributions of collagen over time. The simulations showed that the magnitude of strain was highest in the tendon core along the central axis, and decreased towards the outer periphery. Consequently, decreased levels of collagen production for high levels of tensile strain were shown to accurately predict the experimentally observed delayed collagen production in the tendon core. In addition, our healing framework predicted evolution of collagen orientation towards alignment with the tendon axis and the overall predicted tendon stiffness agreed well with experimental data. In this study, we explored the capability of a numerical model to describe spatial and temporal variations in tendon healing and we identified that understanding mechano-regulated collagen production can play a key role in explaining heterogeneities observed during tendon healing.

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Microsurgical reconstruction affects the outcome in a translational mouse model for Achilles tendon healing.

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Microsurgical reconstruction affects the outcome in a translational mouse model for Achilles tendon healing.

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