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      Tibial cortex transverse transport accelerates wound healing via enhanced angiogenesis and immunomodulation

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          Abstract

          Aims

          Treatment for delayed wound healing resulting from peripheral vascular diseases and diabetic foot ulcers remains a challenge. A novel surgical technique named ‘tibial cortex transverse transport’ (TTT) has been developed for treating peripheral ischaemia, with encouraging clinical effects. However, its underlying mechanisms remain unclear. In the present study, we explored the potential biological mechanisms of TTT surgery using various techniques in a rat TTT animal model.

          Methods

          A novel rat model of TTT was established with a designed external fixator, and effects on wound healing were investigated. Laser speckle perfusion imaging, vessel perfusion, histology, and immunohistochemistry were used to evaluate the wound healing processes.

          Results

          Gross and histological examinations showed that TTT technique accelerated wound closure and enhanced the quality of the newly formed skin tissues. In the TTT group, haematoxylin and eosin (H&E) staining demonstrated a better epidermis and dermis recovery, while immunohistochemical staining showed that TTT technique promoted local collagen deposition. The TTT technique also benefited to angiogenesis and immunomodulation. In the TTT group, blood flow in the wound area was higher than that of other groups according to laser speckle imaging with more blood vessels observed. Enhanced neovascularization was seen in the TTT group with double immune-labelling of CD31 and α-Smooth Muscle Actin (α-SMA). The number of M2 macrophages at the wound site in the TTT group was also increased.

          Conclusion

          The TTT technique accelerated wound healing through enhanced angiogenesis and immunomodulation.

          Cite this article: Bone Joint Res 2022;11(4):189–199.

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          Most cited references46

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          Exploring the full spectrum of macrophage activation.

          Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.
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            Role of YAP/TAZ in mechanotransduction.

            Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.
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              Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.

              Mononuclear phagocytes are versatile cells that can express different functional programs in response to microenvironmental signals. Fully polarized M1 and M2 (or alternatively activated) macrophages are the extremes of a continuum of functional states. Macrophages that infiltrate tumor tissues are driven by tumor-derived and T cell-derived cytokines to acquire a polarized M2 phenotype. These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.
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                Author and article information

                Contributors
                Role: PhD student
                Role: Doctor
                Role: Doctor
                Role: PhD student
                Role: Doctor
                Role: Doctor
                Role: Doctor
                Role: Doctor
                Journal
                Bone Joint Res
                Bone Joint Res
                bjr
                Bone & Joint Research
                The British Editorial Society of Bone & Joint Surgery (London )
                2046-3758
                April 2022
                31 March 2022
                : 11
                : 4
                : 189-199
                Affiliations
                [1 ] org-divisionDepartment of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences , org-divisionThe Chinese University of Hong Kong, Prince of Wales Hospital , Hong Kong, China
                [2 ] org-divisionDepartment of Pediatric Orthopaedics, South China Hospital, Health Science Center , org-divisionShenzhen University , Shenzhen, China
                [3 ] org-divisionDepartment of Orthopaedics and Traumatology , org-divisionThe Second Affiliated Hospital of Shenzhen University (Shenzhen Bao'an People's Hospital) , Shenzhen, China
                Author notes
                Gang Li. E-mail: gangli@ 123456cuhk.edu.hk

                Y. Yang and Y. Li contributed equally to this work.

                X. Pan, K. Ling, and G. Li are joint senior authors.

                Author information
                https://orcid.org/0000-0002-3981-2239
                Article
                BJR-11-189
                10.1302/2046-3758.114.BJR-2021-0364.R1
                9057526
                35358393
                9ac1cfa8-dfb1-4ec2-b96a-5d4de5a44c6f
                © 2022 Author(s) et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                Categories
                Foot & Ankle
                Trauma
                Orthopaedics
                Tibial Pilon
                Distal Tibial
                Ilizarov
                Circular Frame
                External Fixation
                Calcaneum
                Hindfoot
                Foot & Ankle, foot-ankle
                bj731, Anatomy
                bj1763, Basic science
                bj17439, Trauma
                bj11386, Orthopaedic devices
                bj11388, Orthopaedic diseases
                bj17016, Tibial cortex
                bj18359, Wound-healing
                bj765, Angiogenesis
                bj9357, Macrophage
                bj18360, Wounds
                bj13752, Rat model
                bj5409, External fixators
                bj2079, Blood
                bj2092, Blood vessels
                bj4433, Diabetic foot
                Custom metadata
                2.0
                $2.00
                The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
                Foot & Ankle
                The authors have no conflicts of interest to disclose in relation to this article.

                tibial cortex transverse transport technique,wound healing,angiogenesis,distraction histogenesis,immunomodulation,tibial cortex,macrophages,wounds,rat model,external fixator,blood,blood vessels,diabetic foot ulcers

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