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International Journal of Bioprinting 3D bioprinting for vascularized skin tissue engineering

materials. A few strategies to accelerate vascularization transplanted with native HSEs. In grafts, vHSEs promoted
include enhancing wound healing, promoting blood vessel host neovascularization. Neovascularization was directed
regeneration before transplantation, optimizing scaffold by micropatterned vasculature by facilitating the perfusion
properties, and incorporating growth factor delivery of labeled dextran into host vessels, as shown in Figure
systems. However, fast microvascular formation within the 7A-c–g. Taken together, the results indicate that the
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large construct presents challenges for the host immune micropatterned vasculature in vHSEs promotes and directs
response, which could reduce the duration required for neovascularization during graft integration into wounds,
effective vascularization. According to Yanez et al., pre- possibly improving the engraftment of engineered skin
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vascularization of constructs is a strategy to promote in vivo structures. A vascularized and pigmented dermoepidermal
blood vessel formation after transplantation. By developing skin substitute (DESS) was developed in vitro by Pontiggia
a 3D cell printing technique that develops mature, et al. using a robotic 3D bioprinter called SkinFactory
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perfusable, and vascularized human skin substitutes, Kim (Figure 7B-a). As shown in Figure 7B-b and c, the bioink,
et al. successfully achieved a significant breakthrough. By type I collagen hydrogel, was utilized to distribute different
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precisely distributing cells with biomaterials, this technique human skin-derived cells by patterned inkjet and extrusion-
provides structural complexity that mimics human skin, based bioprinting to develop in vitro blood and lymphatic
comprising the epidermis, dermis, and hypodermis. The vascular networks. Afterward, the biofabricated DESS was
vascularized dermal and hypodermal compartments placed into a frame and inside a cell culture flask with the
combine to provide an ideal microenvironment, which appropriate media, followed by the sealing of the lid. The
leads to enhanced epidermal morphogenesis and skin two main parts of the DESS were fibroblasts mixed with
recapitulation. The full-thickness skin model demonstrated melanocytes and keratinocytes to provide the necessary
superior performance in a comparison study compared to epidermal layer for skin substitute and fibroblasts integrated
normal dermal and epidermal skin models, which showed into collagen-based hydrogels for the dermal structure. One
the potential to enhance the in vitro platform for skin week later, the DESS showed satisfactory dermal motility
disease modeling, pathological research, and sustainable and cell survival of the fibroblasts within the collagen matrix.
instruments for research. For example, Yanez et al. Dense patterns of melanocytes and keratinocytes were jetted
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enhanced vascularization in 3D-bioprinted skin grafts onto the hydrogel-based bioink using a 3D bioprinting
implanted on mice by using inkjet printing technology with process, developing layers with excellent skin structural
collagen and fibrinogen matrix containing fibroblasts from organization. After 4 weeks, CD31 expression could be
neonatal dermis, keratinocytes, and HUVECs as seeding observed in a vascular network within the dermal layer, with
cells. Within 2 weeks following surgery, the results showed CD90-positive mural cells and CD31-positive capillaries,
improved wound healing and neovascularization in the skin as demonstrated by immunofluorescence staining. After 3
graft. Abaci et al. developed a unique bioengineering weeks, compression did not show any significant effect on
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method for creating micropatterned, spatially controlled, the formation of vascular plexuses in lymphatic and blood
and perfusable vascular networks within 3D human skin capillaries (Figure 7B-d and e). 129
substitutes using primary and induced pluripotent stem cell
(iPSC)-derived ECs. They regulated the geometries of The significance of vascularized skin construction
micropatterned vascular networks using 3D printing requirements has been increasingly recognized owing to its
technology. Vascularized human skin equivalents (vHSEs) progressive function in regulating the biological activities
based on this approach can enhance neovascularization of implants, which is vital for the survival of implants in
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during wound healing (Figure 7). 3D printing was the host body. The in vitro fabrication of vascularized
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utilized to develop molds for establishing vascular networks networks of channels into 3D-bioprinted skin constructs
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in human skin equivalents (HSEs), as well as the inlet is essential for providing nutrition to surrounding cells.
and outlet tubes and ring-shaped holders (Figure 7A-a). In addition, angiogenesis significantly contributes to the
Researchers investigated the formation of the epidermal efficacy of skin grafts. However, adding layers may reduce
layer along with the endothelial barrier in vHSEs using the survivability of the graft in low-oxygen (hypoxic)
GFP-tagged HUVECs and induced endothelial cells environments because of the distance between the cell
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(iECs). The HUVEC-lined hollow microchannels were layers and the wound surface. Pre-vascularization of
observed in vHSE sections, including vasculature, with a 3D-bioprinted structures using HUVECs and fibroblasts, as
physiological pattern. Histological and immunostaining well as mesenchymal stem cells (MSCs) and HUVECs, has
investigations confirmed the development of an epidermal been demonstrated in in vivo models to improve integration
layer (Figure 7A-b). Proliferation of basal keratinocyte and with the host tissue, enhance graft survival, and promote
blood perfusion were observed in vHSEs-transplanted re-epithelialization after implant placement. 63,131 Several
immunodeficient mice, as compared to their counterparts researchers conducted in vitro bioprinting experiments

Volume 10 Issue 3 (2024) 101 doi: 10.36922/ijb.1727