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Biofabrication of thick vascularized neo-pedicle flaps for reconstructive surgery

      Wound chronicity due to intrinsic and extrinsic factors perturbs adequate lesion closure and reestablishment of the protective skin barrier. Immediate and proper care of chronic wounds is necessary for a swift recovery and a reduction of patient vulnerability to infection. Advanced therapies supplemented with standard wound care procedures have been clinically implemented to restore aberrant tissue; however, these treatments are ineffective if local vasculature is too compromised to support minimally-invasive strategies. Autologous “flaps”, which are tissues equipped with their own hierarchical vascular supply, can be harvested from one region of the patient and transplanted to the wound where it is reperfused upon microsurgical anastomosis to appropriate recipient vessels. Despite the success of autologous flap transfer, these procedures are extremely invasive, incur obligatory donor-site morbidity, and require sufficient donor-tissue availability, microsurgical expertise, and specialized equipment. 3D-bioprinting modalities, such as extrusion-based bioprinting, can be used to address the clinical constraints of autologous flap transfer, primarily addressing donor-site morbidity and tissue availability. This advancement in regenerative medicine allows the biofabrication of heterogeneous tissue structures with high shape fidelity and spatial resolution to generate biomimetic constructs with the anatomically-precise geometries of native tissue to ensure tissue-specific function. Yet, meaningful progress toward this clinical application has been limited by the lack of vascularization required to meet the nutrient and oxygen demands of clinically relevant tissue volumes. Thus, various criteria for the fabrication of functional tissues with hierarchical, patent vasculature must be considered when implementing 3D-bioprinting technologies for deep, chronic wounds.

      Abbreviations:

      ECM (Extracellular Matrix), MSC (Mesenchymal stromal cells), SMC (Smooth muscle cells), HUVEC (Human Umbilical Vein Endothelial Cells), PIU (Pressure-Induced Ulcer), DFU (Diabetic Foot Ulcers), AIU (Arterial Insufficient Ulcers), GFT (Growth Factor Therapy), EBB (Extrusion-based Bioprinting), iPSC (Induced Pluripotent Stem Cells), VEGF (Vascular Endothelial Growth Factor), VEGFR (Vascular Endothelial Growth Factor Receptor), Ang (Angiopoietin), Tie2 (Tyrosine Protein Kinase Receptor-2), PDGF (Platelet-Derived Growth Factor), EGF (Epidermal Growth Factor), TGF-β (Transforming Growth Factor - beta), S1P (Sphingosine-1-phosphate), MVEC (Microvascular Endothelial Cells), HDF (Human Dermal Fibroblasts), Cad (Cadherin), PECAM-1 (Platelet/Endothelial Cell Adhesion Molecule-1), vWF (von Willebrand factor), BM (Bone Marrow), ASC (Adipose-Derived Stromal Cells), AT (Adipose Tissue), HGF (Hepatocyte Growth Factor), α-SMA (Smooth Muscle Actin - alpha), BMP (Bone Morphogenetic Protein), FGF (Fibroblast Growth Factor), EpSCs (Epidermal Stem Cells), HIF-1α (Hypoxia Inducible Factor - 1 alpha), INF-γ (Interferon-gamma), EPC (Endothelial Progenitor Cells), MMP (Matrix Metalloprotease)
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