Bioprinting and plastic compression of large pigmented and vascularized human dermo-epidermal skin substitutes by means of a new robotic platform

Abstract

Extensive availability of engineered autologous dermo-epidermal skin substitutes (DESS) with functional and structural properties of normal human skin represents a goal for the treatment of large skin defects such as severe burns. Recently, a clinical phase I trial with this type of DESS was successfully completed, which included patients own keratinocytes and fibroblasts. Yet, two important features of natural skin were missing: pigmentation and vascularization. The first has important physiological and psychological implications for the patient, the second impacts survival and quality of the graft. Additionally, accurate reproduction of large amounts of patient’s skin in an automated way is essential for upscaling DESS production. Therefore, in the present study, we implemented a new robotic unit (called SkinFactory) for 3D bioprinting of pigmented and pre-vascularized DESS using normal human skin derived fibroblasts, blood- and lymphatic endothelial cells, keratinocytes, and melanocytes. We show the feasibility of our approach by demonstrating the viability of all the cells after printing in vitro, the integrity of the reconstituted capillary network in vivo after transplantation to immunodeficient rats and the anastomosis to the vascular plexus of the host. Our work has to be considered as a proof of concept in view of the implementation of an extended platform, which fully automatize the process of skin substitution: this would be a considerable improvement of the treatment of burn victims and patients with severe skin lesions based on patients own skin derived cells.

Full Skin Equivalent Models for Simulation of Burn Wound Healing, Exploring Skin Regeneration and Cytokine Response

“…The next step in the development of in vitro skin models will be the integration of immune cells, blood vessels, or other relevant skin appendages [ 50 , 51 , 52 , 53 ] and developing models suitable for drug discovery and testing [ 54 ]. Cells from different (disease-related) origins, such as skin cells derived from fetal, burn, or scar tissue, could be used to study their effect on skin regeneration.…”

Advances in 3D skin bioprinting for wound healing and disease modeling

“…Melanocytes are given great hope to construct 3D-printed skin with pigmentation. They reside in the stratum basal layer and produce pigment, which helps to protect the skin from ultraviolet rays [ 78 ]. Melanocytes are also part of the skin immunological response and display extensive interactions with other immune cells [ 79 ].…”

“…The 3D-bioprinted skin showed resembling morphology and similar pigmentation as the natural skin [ 21 ]. It might help to address the psychological and physical problems caused by abnormal pigment after skin substitutes transplantation on patients [ 78 ].…”

3D Bioprinting: An Enabling Technology to Understand Melanoma

“…As bioprinting technologies and bioink design have progressed, the ability to bioprint complex full-thickness HSE models has become possible [ 1 , 86 , 116 , 209 , 210 , 211 ]. These models include not only dermal and epidermal compartments, but additional aspects of skin, such as the hypodermis (trilayer), a vascular network, and appendages.…”

“…Despite existing skin and melanoma models having been proved to be useful for understanding disease pathology, performing drug screening, and even providing scientific support to clinical trials, a major challenge remains in the development of a melanoma model capable of better reproducing the different features of the tumour microenvironment underlying the in vivo resistance and differential responses in human patients. This As bioprinting technologies and bioink design have progressed, the ability to bioprint complex full-thickness HSE models has become possible [1,86,116,[209][210][211]. These models include not only dermal and epidermal compartments, but additional aspects of skin, such as the hypodermis (trilayer), a vascular network, and appendages.…”