BIOPRINTING FOR SKIN - 3D Bioprinting and Nanotechnology in Tissue Engineering and Regenerative Medicine - page 275

and sebaceous gland stem cells ( Koster, 2009 ). They are the source of all keratinocytes that form
the epidermis.
During their life span, the keratinocytes undergo terminal differentiation, which is accompanied by
many biochemical and morphological changes ( Koster, 2009; Houben et al., 2007; Proksch et al., 2008 ).
After a few more replications, the cells lose their replicative capability and start to produce different
proteins (e.g. cytokeratins 1 and 10). Filaggrin helps the cytokeratins form tight bundles of intermediate
filaments, which are important for the structural integrity of the cell and promote the collapse of the
cell into a flattened shape ( Houben et al., 2007 ). A so-called cornified envelope (CE) develops, includ-
ing proteins like involucrin, loricrin, and filaggrin as well as different lipids ( Houben et al., 2007 ). At
that stage, both proteins and lipids are covalently linked ( Eckert et al., 2005 ). During this transition
to so-called corneocytes, the cells undergo programmed cell death and are finally embedded in a self-
produced intercellular lipid matrix, comprising cholesterol, free fatty acids, and other lipids. These
tightly packed lipids are responsible for the low permeability of skin to water and the formation of a
permeability barrier. Nevertheless, the lower layers also contribute to the barrier function via the forma-
tion of a tight junction. Several cells together form horny flakes, the uppermost layer of the skin, which
are shed continuously in humans ( Houben et al., 2007 ).
If the balance between proliferation and differentiation is impaired, a disturbance of the skin barrier
may occur, resulting in the formation of inflammation, dermatitis, ichthyosis, and psoriasis, as well
as the entry of pathogens ( Proksch et al., 2008 ). Therefore, in healthy persons, this balance is tightly
controlled.
To form a stable epithelium, the cells are connected via cell-cell and cell-matrix junctions. Ad-
herens junctions and desmosomes provide a mechanical connection and thereby mechanical strength
between neighboring keratinocytes, while hemidesmosomes and actin-linked cell-matrix adhesions
are responsible for the coupling of cells to the underlying basement membrane. In adherens junctions,
so-called classical cadherins are found, especially e-cadherin in skin. The connection to the basement
membrane is realized by integrins. Tight junctions also contribute to the barrier function of the skin
by closing the intercellular space between the apical and the basal part of the epithelium. The barrier,
however, has a selective permeability that can be altered depending on the circumstances. Moreover,
gap junctions form channels between the cytoplasms of neighboring cells via transmembrane proteins
(connexins). They allow for the exchange of low molecular substances (e.g. hormones, glucose, or
vitamins) as well as ions (e.g. electrical coupling in the heart muscle), and are also essential for cell-
cell communication.
Other cell types in the epidermis include melanocytes, which reside in the basal layer. Due to their
production of melanin and their distribution to the surrounding keratinocytes, melanocytes are respon-
sible for skin color as well as protection against UV irradiation and corresponding mutagenesis. Lang-
erhans cells are also found in the epidermis. They belong to the adaptive immune system and represent
the antigen-presenting cells of the epidermis ( Michael, 2013c ).
Since the epidermis does not contain any blood vessels, it needs to be supplied with nutrition and
oxygen via diffusion from the dermis. At the dermal-epidermal junction both layers interdigitate, form-
ing the rete ridges (epidermal part) and the papillae (dermal part). The resulting high increase of the
available surface for diffusion enables the adequate supply of the epidermis. Furthermore, the rete
ridges/papillae are essential for the mechanical stability of the skin, as they greatly increase the resis-
tance of skin against shear forces ( Michael, 2013c ).