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WIREs Nanomed Nanobiotechnol
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2D and 3D electrospinning technologies for the fabrication of nanofibrous scaffolds for skin tissue engineering: A review

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Abstract This review provides insights into the current advancements in the field of electrospinning, focusing on its applications for skin tissue engineering. Furthermore, it reports the evolvement and present challenges of advanced skin substitute product development and explores the recent contributions in 2D and 3D scaffolding, focusing on natural, synthetic, and composite nanomaterials. In the past decades, nanotechnology has arisen as a fascinating discipline that has influenced every aspect of science, engineering, and medicine. Electrospinning is a versatile fabrication method that allows researchers to elicit and explore many of the current challenges faced by tissue engineering and regenerative medicine. In skin tissue engineering, electrospun nanofibers are particularly attractive due to their refined morphology, processing flexibility—that allows for the formation of unique materials and structures, and its extracellular matrix‐like biomimetic architecture. These allow for electrospun nanofibers to promote improved re‐epithelization and neo‐tissue formation of wounds. Advancements in the use of portable electrospinning equipment and the employment of electrospinning for transdermal drug delivery and melanoma treatment are additionally explored. Present trends and issues are critically discussed based on recently published patents, clinical trials, and in vivo studies. This article is categorized under: Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanomaterials and Implants
The skin. (a) Schematic representation of the skin layers and appendages; (b) The wound healing cascade. The major phases of the wound healing cascade are the homeostasis, inflammatory response, proliferation, and maturation, and on these phases various cell lineages and ECM components contribute to a coherent wound closure; (c) Classification of Burns: (i) First degree, (ii) Superficial and (iii) deep second‐degree, and (iv) third‐degree burns (Kordestani, )
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3D electrospinning techniques. (a) Schematic of wet electrospinning technique; (b) SEM image of chitosan/sodium alginate 3D‐bioprinted hydrogel scaffold to be used as a template for electrospinning (Miguel et al., ); (c) schematic of a sequential multilayering process; (d) cold‐plate electrospinning process with (i) graphical depiction and (ii) experimental setup for PCL and PCL/SF electrospinning (Lee et al., ); (e) process for forming 3D electrospun sponges via post‐process freeze‐drying short fiber dispersions (Jiang, Gruen, et al., ); (f) Single‐step 3D electrospinning, using a modified 3D printer, with 3D structure self‐assembly (Vong et al., )
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Functional electrospun NFs for treatment of melanoma and cancer cell capture. (a) Schematic representation of the different forms of skin cancer (permission to reuse by Mayo Clinic Foundation for Medical Education and Research) (b) The correlation between the Fitzpatrick phenotype and skin cancer risk (D'Orazio, Jarrett, Amaro‐Ortiz, & Scott, ); (c) Smart hyperthermia poly(NIPAAmco‐HMAAm) NFs, (i) design concept of the smart hyperthermia NF system utilizing magnetic nanoparticles (MNPs) dispersed in temperature‐responsive polymers for the release of heat and doxorubicin (DOX), (ii) “On–off” switchable and reversible heat profile and swelling ratio toward the cumulative release of DOX, (iii) TEM image where the MNPs are visible in the core of the NFs, (iv‐v) AFM images of the nanofibrous mats after being immersed in 20 and 50°C water, respectively (Kim, Ebara, & Aoyagi, )
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In situ portable electrospinning models. (a) Hand‐held electrospinning apparatus incorporating Ag‐NPs, (i) Schematic illustration of the portable device (ii) in vivo Wistar rat wound‐healing model of in situ electrospun mesh, (iii) Histological evaluation blue, red, and yellow arrows designate inflammatory cells, tissue granulation, and regenerated epidermal layers, respectively. PCL: polycaprolactone, Ag‐MSNs: Silver‐mesoporous silica nanoparticles. Adapted from RSC Publications (Dong et al., ). (b) Battery‐operated electrospinning apparatus (BOEA), (i) Schematic diagram, (ii) Slow‐motion Taylor cone formation, (iii) Optical images showing PLA nanofibers being directly electrospun onto a hand, (v) Optical images of a 2 cm gash, (vi) Appling the BOEA nanofiber glue and (vii) Rapid coagulation of the wounded area (rat model). Adapted from RSC Publications (Xu et al., ) (c) Nanomedic's SpinCare™, (i) Schematic representation of the Spincare™ hand‐held electrospinning device (Nicast). (ii) Direct deposition of electrospun fibers onto the skin, (iii) Results obtained from the clinical trial NCT02997592 (“Evaluation of the SpinCare™ System in the Treatment of Partial Thickness Burns”), where Spincare™ is used to treat a donor site wound. Adapted with the written permission of Nanomedic Technologies Ltd. (Nanomedic Technologies Ltd, )
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The electrospinning technique. (a) Conventional needle‐spinneret electrospinning setup. (b) Cylindrical (Keirouz, Fortunato, Zhang, Callanan, & Radacsi, ), (c) wire (Li et al., ), and (d) annular spinneret multi‐jet electrospinning schematic (Wei, Sun, et al., ). Fibers woven in an arrangement of a (e) nanoweb (S. Wang, Zhong, Lim, & Nie, ), (f) aligned (S. Wang, Zhong, et al., ), and (g) crossed array (Laudenslager & Sigmund, )
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Electrospun skin grafts. (a) Poly(hydroxybutyrate) (PHB) electrospun dermo‐epidermal skin equivalent (i) Cross‐section of epidermal and dermal tissue stained with Masson's trichrome (scale bar 200× magnification). White arrows denote implanted scaffold and white stars multinuclear giant cells. (ii) Kinetics of macrophage polarization of Matriderm® (MD), PCL, and PHB electrospun mats in the wound site. DAPI nucleic acid staining (blue) was used. (ii) M1 (markers CCR7+ and CD68+) / M2 (CD206+ and CD68+) ratio in the biopsies acquired by the wound region 14 d post‐implantation. Scale bars = 50 μm, significant difference of *p < .05 and **p < .01 (Castellano et al., ). (b) Wound contraction on mice treated with PLCL, fibronectin‐coated PLCL, human fibroblast‐derived extracellular matrix‐PLCL (hfDM‐PLCL) NF mats. (i) Gross appearance shows wound repair progress over 28 days. (ii) Wound size closure (%). The initial wound size was 8 mm (Du et al., )
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2D Electrospun NFs for wound healing applications. (a) Collagen‐coated ostholamide (OSA) electrospun NF mats (i) Wound contraction of the untreated, collagen, PHB‐GEL‐COL, and PHB‐GEL‐OSA‐COL electrospun scaffolds in Wistar rats for 15 days. (ii) Hematoxylin and eosin staining of the PHB‐GEL‐OSA‐COL group. (iii) Release profile of the PHB‐GEL collagen‐coated OSA containing fibers versus the collagen OSA loaded cast films. Adapted from Kandhasamy et al. (). (b) The effect of Tazarotene released from aligned and randomly oriented PCL electrospun membranes (i) Posterior images of the wounds on Sprague–Dawley rats at different time points after implementation (3–14 days); (ii) Cell proliferation assessed by CCK‐8 assay after HUVECs were cultured on the variant membranes for 1, 3 and 7 days; (iii) Statistics based on the CD31 immunohistochemical staining, correlating the number of new blood vessels formed on the examined biopsies. For all the groups: Blank, PCL/Aligned, PCL/Random, PCL/Aligned Tazarotene loaded, PCL/Random Tazarotene loaded. Adapted from Zhu et al. (). (c) The effect of patterned nanomats orientation, consisting of PCL/collagen NFs, toward wound healing. (i) Wound contraction in a rat model; (ii) SEM images of the different nanotopographies; (iii) Confocal images of fibroblast attachment 3 days post‐culture. Actin Green 488 (green) and DAPI (blue) for actin filaments and nuclei staining, respectively; (iv) Changes in the actin length on day 3 between the variant groups. RONM: Randomly‐oriented nanofibrous membrane, ANM: Aligned nanofibrous membrane, GPN‐95M: Grid‐patterned nanofibers with the angle of 95°, GPN‐30M: Grid‐patterned nanofibers with angle of 30°. Adapted from Kim and Kim ()
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Implantable Materials and Surgical Technologies > Nanomaterials and Implants
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement

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