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Research Report Shawn Fletcher .pdf

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Developments in Engineered Skin Tissue- Fletcher

Developments in Engineered Skin Tissue
This paper will discuss the pros and cons of tissue-engineered skin and will delve into the
development and history of said technology.

As of 2013, 450,000 burn cases received medical attention worldwide. Many of these
burns caused intensive and life lasting injuries [American Burn Association National Burn
Repository, 2013]. Tissue-engineered skin has been investigated and researched widely since the
90’s as a solution to this problem. This paper will investigate the development and advances in
skin-regenerative technologies and will explain the immense need for this technology. It will
delve into the multiple applications in the medical industry as well as the many different
approaches to the development of engineered skin tissue. Research into this topic took off in the
early 90’s, but skin research dates back to before the Bronze Age. 1990-2000 was filled with
attempts to develop tissue engineered products, biological and non-biological [Mansbridge,
2009]. The field has broadened since then; applications can range from genetically modified skin
substitutes to induced skin stem cells. For any of these methods to work however, the engineered
tissue must meet a certain criteria; it must provide a protective, regenerative upper layer of cells
called keratinocytes, it must be attached to a lower layer called the dermis (this layer gives the
skin its flexibility), well vascularized, and the tissue must have a sturdy, but elastic structural
support [Macneil, 2008, pg.26]. The idea of skin regenerative technology is beneficial to society
for many reasons, including clinical applications such as regenerating skin after serious burns or

Developments in Engineered Skin Tissue- Fletcher

injuries. There is much potential of clinical usage, but there are also many non-clinical uses that
are often overlooked. Being able to 3-D model generated skin cells allows for testing on said
skin cells, greatly reducing animal experimentation as well as creating the ability to run tests
such as skin penetration, healing of burns and other injuries, skin pigmentation regulation, skin
contraction, investigation of skin diseases and much more [Macneil, 2007, pg. 874]. Though the
benefits greatly outweigh the cons, there are still concerns. Safety is a main point brought up
when discussing regenerative tissue. There is a possibility that cells contain viruses that are able
to transform human cells. These cells are subject to lethal gamma radiation in hopes to kill any
viruses [Macneil, 2007, pg. 879]. The efforts of scientists are focussed on ensuring clean cells
before they work with any living creature.

History and Background Information
Skin technology research has been investigated on a large scale, dating all the way back
to 3000 BCE. Tissue-engineered skin, however, is a fairly new field. This technology uses
physical and biochemical properties, as well as living cells to create structures similar to human
tissue. Large steps were made in this field through the 80’s and 90’s that have become the
foundation of research today [Mansbridge, 2009, pg.563]. The term, tissue engineering, was
coined in 1987, which many believe to be the beginning of modern tissue engineering, but it
wasn’t until the 90’s that progress rapidly increased. The figure below provides background
information and developments over the years, in the form of a table. Major dates include 1975,
when Howard Green from Harvard Medical School, first described methods to grow skin
epidermis thus leading to the first tissue-engineered based product called Epicel. Another early

Developments in Engineered Skin Tissue- Fletcher

development includes the work of Ioannis Yannas. Yannas was a mechanical engineer at the
Massachusetts Institute of Technology (MIT). Working with burn surgeon, John F. Burke, they
developed a porous matrix and epidermis like structure that is capable of covering wounds where
there is extensive damage deep into the dermis. This technology was marketed under Dermal
Regeneration Template by Integra Life Sciences. Throughout the 90’s, many skin regeneration
technologies were successfully commercialized. It wasn’t until the early 2000’s that progress
came to a seemingly abrupt halt. This was about the time when the “high tech bubble” burst.
Investors saw skin regeneration as a high risk venture and stopped funding. Significant advances
have occurred since then, but now the field is leading more into stem cell research. [Berthiaume,
2011, pg. 404]

Above is a table documenting the history of research in tissue engineering. From Tissue
Engineering and Regenerative Medicine: History, Progress, and Challenges by
Berthiaume, F., Maguire, T. J., & Yarmush, M. L. (2006). Copyright © 2011 by Annual
Reviews. All rights reserved. Reprinted with permission.


Developments in Engineered Skin Tissue- Fletcher

Methods and Applications
Experimentation and research have led to several applications of tissue engineered skin.
These applications include clinical uses (used in laboratories and directly pertain to medical
usage) and non-clinical uses. Non-clinical uses concern the economic standpoint, which include
product testing and 3D modelling of skin. There are many methods, but only three will be
discussed within this section; genetically modified skin substitute, skin constructs as models, and
induced skin cells.


Genetically Modified Skin Substitute
Genetically modified skin substitutes are vitally important to the medical world. Skin

substitutes allow a patient who has loss a substantial amount of skin to regenerate skin by
stretching a graft of their own skin over the wound. Many medical companies, such as Integra,
have utilized this technology to their advantage. The figure below shows the process of skin
regeneration using the Integra system. The process of skin regeneration is rigorous and requires
various steps. Firstly, a patch of synthetic skin is placed on top of the damaged skin which acts as
the subject’s epidermis (outermost layer of skin cells). The patch contains chemicals which
trigger the production of red blood cells and protein to repair the skin. The silicone piece protects
from heat loss and infection. The silicone is then removed and a small graft of the patient’s skin
is placed on top. The graft creates a smooth surface after 35+ days. This process can be used to
treat anything from burns to scars. This revolutionary technology has already treated 10,000
patients (as of 2011) [Bartis & Pongrác, 2011]. The Integra generated skin was designed
extremely durable but at the same time made to be flexible, pliable and biodegradable, made
possible by using a specific skin template designed by Integra. Skin substitutes like the Integra

Developments in Engineered Skin Tissue- Fletcher

system, are only used in extreme cases where 30-40 % of body surface is burned. So far this
product has only been FDA approved for burns and minimal skin injuries, but with the rapid
development that is happening in this industry, humans could soon see full regeneration of skin
with little to no scarring [Bartis & Pongrác, 2011].

Above is a diagram of genetically modified skin using the Integra System. From Three
dimensional tissue cultures and tissue engineering by Bartis, D., & Pongrác, J. (2011).
http://www.Tankonyvtar.hu/en Copyright © 2011 University of Pécs. Reprinted with
There are also many other systems of regenerating skin including dermo-epidermal skin
substitutes. The aim of this method is to mimic the structure and process of regeneration of
normal skin. These are the most expensive, but also the most advanced skin substitute. Until this


Developments in Engineered Skin Tissue- Fletcher

method is designed to be inexpensive and more easily producible, then it seems this process is
too far out of our reach. [Shevchenko, 2010, pg.230]


Skin Constructs as Models
Skin constructs are similar to genetically modified skin tissue, though skin constructs are

used specifically for modelling and experimentation purposes. Reconstruction of skin strictly for
models can be extremely useful to the domestic market and on a scientific standpoint. The ability
to use skin constructs for testing of skin diseases, household products, as well as experiments
relating to development of skin due to aging can be valuable to a lab technician or even an
average consumer [Mansbridge, 2008, pg. 565]. The construction of rat skin, for example, is
particularly important to animal testing, as it allows a non-living subject to be tested on. An
experiment was conducted in 2002 involving constructed skin. Rat skin, formed using
undifferentiated keratinocytes (dead skin cells that form the outer, tougher layer of skin),
underwent 72 hours of electrical stimulation and was attached to the lab-made dermis. The result
was skin that was similar to that of a newborn rat. The findings are of great significance since
they show resemblance towards the structure of human tissue, making a large stride towards the
goal of clinical application of tissue engineered human skin [Han, 2002, pg.367].


Developments in Engineered Skin Tissue- Fletcher


Induced Skin Stem Cells

Skin stem cells research has expanded rapidly and become a vital portion of tissue engineering.
Stem cells are undifferentiated cells that are capable of replicating and creating more of a certain
cell [Mansbridge, 2009, pg.565]. This is especially important to tissue engineering, as a scientist
can take a piece of undamaged skin from a subject and use it to replicate more cells in order to
heal the wound. Possibilities continue to open up as skin stem cell research continues to develop,
possibilities like full limb regeneration, similar to the salamander. The salamander is able to use
stem cells to re-differentiate the cells and completely regenerate a lost limb [Mansbridge, 2009,
pg.565]. Another aspect of the study of skin stem cells is hair follicles. Recently, hair follicles have
been found to contain properties that promote epidermal and dermal repopulation. There is still
much work to be done to determine if this research can be applied to tissue engineering [Shi, 2006,
pg. 48].

Safety Concerns
Tissue engineered skin is a work in progress, and with any work in progress there will be
flaws. Since tissue engineering is relatively new field there have been few flaws that have
emerged. Some may argue that tissue engineering poses potential risk to the subject being tested
on but in the bigger scheme of things, tissue engineering poses much less of a threat than most
medical apparatus since most are mass produced and can affect thousands of patients. Since
tissue engineering is directed towards a smaller demographic, it has minimal hazardous potential.
Yet there is still concerns. Tissue engineering manipulates subject’s cells therefore leading to the


Developments in Engineered Skin Tissue- Fletcher

possibility of contamination or other errors that can have serious repercussions. Scientists are
working hard to minimize this risk [Williams, 2004, pg. 24-29].

Skin tissue research has been active for years and years, though it has just recently
become a field of its own in the last thirty years. Research into tissue engineering has taken many
different routes of which include genetically modified skin substitutes which uses the method of
skin grafts to heal wounds, skin models used for experimentation and research, and finally stem
cells which are used to “copy” and mass produce cells. These methods all produce amazing
results, yet there are still problems that need to be solved. In the next 10-20 years, if research
continues to progress as it has, we could see humans capable of restoring full limb, an exciting


Bartis, D., & Pongrácz, J. (2011, January 1). Three dimensional tissue cultures and tissue
engineering (Z. Bencze, V. Csöngei, & S. Czulák, Eds.). Retrieved October 19, 2014,
from http://www.Tankonyvtar.hu/en
Berthiaume, F., Maguire, T. J., & Yarmush, M. L. (2006). Tissue engineering and regenerative
medicine: History, progress, and challenge. Annual Review of Chemical and
Biomolecular Engineering, 2, 403-430.


Developments in Engineered Skin Tissue- Fletcher

Burn Incidence and Treatment in the United States: 2013 Fact Sheet. (2013). Retrieved October
19, 2014, from http://www.ameriburn.org/
Gibson, A., Schurr, M. J., Schlosser, S. J., Comer, A. R., & Allen-Hoffmann, B. L.
(2008). Comparison of therapeutic antibiotic treatments on tissueengineered human skin substitutes. Tissue Engineering, 14(5), 629-638.
Han, Y., Pu, Y., Li, Y., Yin, L., & Ge, C. (2002). Reconstruction of tissue
engineered rate skin. Dongnan Daxue Xuebao, 32(3), 367-370.

Macneil, S. (2007). Progress and opportunities for tissue-engineered skin. Nature, 445(7130),

Macneil, S. (2008). Biomaterials for tissue engineering of skin. Materials Today, 11(5), 26-35.

Mansbridge, J. (2009). Tissue-engineered skin substitutes in regenerative medicine. Current
Opinion in Biotechnology, 20(5), 563-567.

Shevchenko, R., James, S. L., & James, S. E. (2010). A review of tissue-engineered skin bio
constructs available for skin reconstruction. Journal of the Royal Society Interface, 7(43),
Shi, C., Zhu, Y., Su, Y., & Cheng, T. (2006). Stem cells and their applications in skin-cell
therapy. Trends in Biotechnology, 24(1), 48-52.
Williams, D. (2004). Benefit and risk in tissue engineering. Materials Today, 7(5), 24-29.


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