YSM Issue 93.1

Biomedical Engineering
FOCUS
bioinks. The first dermal layer combines
human foreskin dermal fibroblasts,
which are the cells responsible for
synthesizing structural proteins such
as collagen, as well as endothelial
(skin) cells and placental pericytes,
cells which wrap around vascularized
endothelium, to form the dermal layer.
The second epidermal layer contains
human foreskin keratinocytes, cells
which produce keratin, which typically
composes hair, skin and nails. These
keratinocytes form a barrier, protecting
the vascularized tissue. Keratin itself is
particularly resistant to scratching and
tearing. After implanting these tissue
constructs into immunodeficient mice,
the micro vessels of the mouse inoculate
with the implant and fully perfuse after
about a month, ‘fusing’ the tissues from
the graft and mouse.
IMAGE COURTESY OF WIKIMEDIA COMMONS
Transmission electron microscope image of a
red blood cell within a capillary.
This process is carried out through
a relatively new technology known
as bioprinting. Various forms of
bioprinting, including inkjet and laser
assisted printing, can be used to better
replicate the minutiae of human skin,
such as the capillaries. Inkjet printers
are primarily used in large-scale
products, while laser assisted printing is
expensive and used for higher resolution
projects. Bioprinting can be thought
of as 3D printing using biomaterials,
where structures are formed layerby-layer
through the deposition of
bioinks—substances comprised of a
variety of living cell types. These bioinks
can mimic the extracellular matrix,
have the unique capability to be printed
as a filament, and can be produced at
relatively mild conditions.
Off-the-Shelf Product
Finding solutions to the issue of skin
ulcers is a crucial scientific endeavor,
with more than seven million Americans
suffering from the condition each year.
Many of these cases result from venous
stasis and diabetes, with patients often
lacking the ability to efficiently heal their
wounds. According to the researchers,
while the generation and implementation
of 3D bioprinted vascularized skin grafts
has yet to be fully realized, it has the
potential to become an ‘off-the-shelf ’
clinical product with wide availability to
the public.
To this end, the produced grafts must
be compatible with the host immune
systems. One method by which the
research team has worked to eliminate
immune responses to ‘non-self ’ antigens
from members of the same species is
the implementation of CRIPSR/Cas9
gene editing. Within human endothelial
cells, a gene codes for the expression of
the human leukocyte antigen, or HLA,
protein, which plays a critical role in
the regulation of the human immune
system. The research team has shown
it is possible to delete this section of
the genome within their skin grafts,
potentially leading to implants which
would altogether avoid host rejection.
“One of the challenges is compatibility:
ABOUT THE AUTHOR
PHOTOGRAPH COURTESY OF YIMING ZHANG
Close-up photograph of a CELLINK 3D printer.
is this skin graft going to be rejected
when we implant it into a patient.
We are trying to make a universal
immuno-evasive vascularized skin graft,
something you could have available as
an off-the-shelf product,” Baltazar said.
Saltzman, whose background is in
chemical engineering, is particularly
excited by the potential integration of
drug delivery systems into printed skin
grafts and has already worked alongside
Prober to publish works covering the
delivery of drugs such as VEGF, or
vascular endothelial growth factor.
“This 3D printing technique allows us
to apply drug delivery technologies, but
in a much more sophisticated way. We
can make gradients of delivery systems,
deliver the drugs in different patterns,
and I think that is going to be a very
powerful part of the approach worth
exploring,” Saltzman said. ■
MATT SPERO
MATT SPERO is a junior in Morse College pursuing the simultaneous B.S./M.S. degree in
Biomedical Engineering. In addition to writing for the YSM, he is the president of both Yale
Biomedical Engineering Society & Taps at Yale and is a researcher in the Human Nature Lab.
THE AUTHOR WOULD LIKE TO THANK Tânia Baltazar and W. Mark Saltzman for their time
and enthusiasm.
FURTHER READING
Baltazar, T., Merola, J., Catarino, C., Xie, C., Kirkiles-Smith, N., Lee, V., … Karande, P. (2019). Three
Dimensional Bioprinting of a Vascularized and Perfusable Skin Graft Using Human Keratinocytes,
Fibroblasts, Pericytes, and Endothelial Cells. Tissue Engineering. Advanced online publication.
www.yalescientific.org
March 2020
Yale Scientific Magazine
17