Biofabrication of human skin with its appendages

Bilayer skin equivalent models have limited functional and anatomical relevance due to their simplicity, rarely forming mature structures such as skin appendages.

“However, these bilayer ‘skin equivalent’ models have limited functional and anatomical relevance due to their simplicity, rarely resulting in the formation of mature structures such as skin appendages, which are crucial for human skin function [7].”

The physiological relevance of hiPSC-derived SKOs remains limited by the absence of vascular and immune components, as SKOs are derived from differentiation of the surface ectoderm.

“Despite their experimental advantages over existing skin equivalents, the physiological relevance of hiPSC‐derived SKOs remains limited by the absence of vascular and immune components, as SKOs are derived from differentiation of the surface ectoderm.[ 36 , 37 , 38 ]”

Currently, SKOs lack vasculature and immune cells in a physiologically relevant context.

“Currently, SKOs lack vasculature and immune cells in a physiologically relevant context.[ 25 , 35 , 36 , 37 , 38 ]”

Hair follicles rely on epithelial-mesenchymal crosstalk to develop and are usually missing in other 2D or 3D skin culture systems.

“Hair follicles (HFs) are a key example of an appendage that relies on epithelial-mesenchymal crosstalk to develop and are therefore usually missing in other 2D or 3D skin culture systems [7].”

Hair placode epithelium invaginates into the dermis and signals surrounding mesenchymal cells to cluster and form the early dermal papilla.

“The hair placode epithelium invaginates into the dermis while signaling to surrounding mesenchymal cells to cluster and form the early dermal papilla.”

Further crosstalk between epithelium and early dermal papilla drives additional invagination and maturation, leading to a mature HF with sebaceous glands, inner and outer root sheath regions, and a hair shaft.

“Further crosstalk between the epithelium and the early dermal papilla drives additional invagination and maturation, eventually leading to the development of a mature HF with sebaceous glands, inner and outer root sheath regions, and a hair shaft [7, 10].”

De novo generation of skin substitutes with specialized cell types poses a significant challenge in the field.

“De novo generation of skin substitutes with specialized cell types poses a significant challenge in the field [7].”

Previous tissue-engineered constructs are limited in the generation of skin appendages.

“previous tissue-engineered constructs have shown promising outcomes in large full-thickness skin defects, preventing dehydration and infection, ultimately, they are limited in the generation of skin appendages [7].”

Although macrophage co-culture with SKOs has been reported, a physiologically relevant vascularized hiPSC-derived SKO has yet to be achieved.

“Although macrophage co‐culture with SKOs has been reported,[ 35 ] a physiologically relevant vascularized hiPSC‐derived SKO has yet to be achieved.[ 36 , 37 , 38 ]”