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Artificial Skin The Skin Trade

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					     Artificial Skin: The Skin Trade

                  Alfredo Capps

                 351 Term Paper
                 Cindy Klevickis

                     4/18/00




Key words: Epicel, Integra, Apligraf, and AlloDerm




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                           TABLE OF CONTENTS



I. Abstract
II. Introduction
        a. Artificial Skin been here since the 17th Century
III. Discussion
        a. Skin is vital for existence
        b. Laboratory-grown skin
               1. Epicel
        c. Artificial Skin
               1. Integra
               2. Aligraf
               3. AlloDerm
IV. Closing
        a. Artificial Skin, a science for the future
V. Annotated Bibliography




                                                              2
Abstract

       Each year more than 2 million burn injuries demand medical attention in the

United States. Ten thousand of these burned victims die every year from the burn-related

infections taking over their bodies. Tragically, many of these burned victims are young

children. The idea of artificial skin was noted many years ago. It has not been until

recently that the medical technique of artificial skin has been allowed to aid these victims.

This new and innovative procedure will help mitigate the above statistics. Already the

combination of advanced technology and complex medications can even help patients

with 90% of their body survive.




                                                                                            3
Introduction

       The concept of artificial skin dates back to at least the late-seventeeth century,

during which water lizard skin was applied in wound care. This particular practice has

since been abandoned in modern times. However, the need for an effective skin substitute

has remained urgent, especially in the face of burn victims and skin cancer patients. Not

surprisingly, over the past few centuries, a host of possibilities have emerged in the field

of skin replacement. In addition to employing animal skin (or xenograft), researchers

experimented with plastic sprays, sponges, and fresh skin from cadavers (allograft).

Cadaver skin proved to be the most successful in temporarily covering large wounds.

Nevertheless, problems with availability, disease transmission, immunological rejection,

and limited shelf life forced researchers to develop different alternatives.

       This paper discuses four main products that have been developed to aid this field

of biotechnology. Epicel, Integra, Aligraf, and Alloderm are all different in their own way,

however they all have one thing in common; they are designed and manufactured to better

the lives of victims in need of replacement skin.




                                                                                               4
Discussion

         The human skin is vital for existence. The skin cools the body by secreting sweat

glands, maintains the perfect functional temperature for the body insulated by fat, protects

the internal organs from the outside environment, and fends off direct contact to disease

infested microbes. The body’s immune cells are resident in the skin as reserves to any

foreign invaders.




Figure 1- These are the vital components of skin.



        There are many reasons that patients may need artificial skin ranging from severe

burns to car accidents. Any loss of skin can weaken the body’s protective system. Blood

loss that results from skin loss can cause the body’s blood pressure to drop so low that it

will not be able to transport blood to vital organs such as the brain, heart and kidneys.

Insufficient amounts of blood in the system equals loss of the flow of oxygen in the body

and therefore the halt of the body’s functions. The skin’s specifications play a vital role

for human existence and, if the artificial skin is not capable of those needs, it could be

fatal to the patient.




                                                                                              5
       In such a case of a tragic burn, a burn surgeon must first come and remove the

damaged skin. The next step is to quickly cover the unprotected underlying tissue that is

now expose to the outside environment and bacteria. Two classes of biomaterials useful in

covering the wound are laboratory-grown skin cells and artificial skin. In some case the

two must be used together in order to secure the patient.

       Funding for these two methods of covering and additional research on the body,

especially the human skin, come from the National Institute of General Medical Sciences

(NIGMS). Laboratory-grown skins cells is mostly the method of growing the

keratinocytes (skin’s epidermal layer), in a culture. This is not a simple technique because

each cell requires a unique set of conditions. Even when all precautions are made, some of

the cells will not grow. Dr. Howard Green of Harvard Medical School is a pioneer in

laboratory-grown cells. In his technique, Dr. Green takes the human keratinocytes onto a

layer of lab mouse-derived fibroblast (connective tissue) cells in a plastic culture dish.

This is similar to what naturally happens in nature. The technique works because it mimics

what happens in actual skin, whose lower layer called the dermis is composed

predominantly of fibroblasts. The principle function of fibroblasts is to produce proteins

called collagen and elastin that provide structure to skin. The product that results from Dr.

Green’s work is called EpicelTM. This is used to treat deep wounds that would require

grafting. This treatment can be helpful when treating both burns and accidents that may

remove the body’s skin.

       EpicelTM is not artificial skin. EpicelTM must be taken from the patient in order to

initiate the culture growth. Artificial skin does not have to come from the patient. This is

an advantage to those tragedies that leave the patient with little or no remaining skin.




                                                                                               6
Artificial skin is very useful in covering the underlying tissue now exposed to the

environment and bacteria as well as promotes re-growth of natural skin instead of scar

tissue. This is an important distinction because scar tissue is less durable and flexible than

natural skin. The funding from the NIGMS established a reliable artificial skin system

called IntegraTM. IntegraTM is a successful result of the teamwork of two brilliant doctors

and their collaborating research teams. Dr. John Burke of the Burn Center at

Massachusetts General Hospital and Dr. Ioannas Yannas of MIT worked extensively

together in order to develop this helpful system.

       At, first Dr. Burke used the skin of relatives to graft the new skin for the patients.

It was important to find a donor with similar genetic markers, so that the patient’s immune

system will not reject the implant. As additional precaution, Dr. Burke used potent

immunosuppressant drugs, that weakens the immune system temporily to allow the

implant to set without being attack by the patient’s natural defenses. A setback from this

procedure is that it was dangerous to the patient as well as the results were not permanent.

This is when Dr. Burke decided that artificial skin would prove to be helpful and answer

his systems problem. That is when he turns to work with engineer, Dr. Yannas. The merge

of biomedical engineering and clinical medicine proves to be successful in developing

Integra.

       Integra does not come from any living organism. Its primary function is to provide

a protective covering that allows the patient’s own skin cells to regenerate the lower

dermal layer that was removed or damaged. In actuality the dermal layer of the skin is too

complex to regenerate. The dermal layer contains hair follicles, sweat glands, and many

blood vessels.




                                                                                                 7
       Dr. Burke and Dr. Yannas discovered a way to solve the problem of regenerating

the dermal layer. The remaining fibroblasts that lay deep within the skin can be instructed

through the lab to arrange themselves to resemble the dermis. This technique teaches the

existing fibroblasts and other supporting cells to act as healthy skin, not even scar tissue.

       Integra consist of two main layers, just as real skin has two main layers (epidermal

and dermal). The bottom layer is made of bovine collagen and a sticky carbohydrate

molecule called glycosaminoglycan (GAG). Collagen is part of the structural basis in

mammals, similar to cellulose in plants. GAG chemically binds collagen taken from

animal’s tendons. It can be found in the animal’s cartilage. These two ingredients called

collagen- GAG are interwoven in order to mimic the fibrous patterns of the human dermis.

This bottom layer is designed to regenerate the real dermal layer. The second layer is a

thin sheet of silicone. This upper layer acts similar to the human epidermal layer on the

surface of the skin. The end product of Integra looks like a plastic wrap around the patient.




 Figure 2- End product of Integra, looks like semi-transparent plastic wrap

       This plastic casting is left wrapped around the patient for 2-5 weeks. This allots

time for the patient’s cells to begin to form a new dermis underneath the sheet of Integra.



                                                                                                8
The collagen-GAG material has poses with carefully controlled diameters that permit cells

to grow through the scaffold, which eventually is broken down and dissolved by enzymes.

Cells synthesize a new dermis at the same time that the scaffold is being broken down.

Epidermis then grows naturally over the new dermis unless the wound area is especially

large, in which case the surgeon does an autograft of epidermis-a much less problematic

procedure than grafting dermis, because epidermis is one-tenth as thick and is constantly

being shed and regrown. After the 2-5 weeks have passed, the Inegra layer is removed and

a thin layer of the patient’s epithelial cells is applied to the wound. Over time the skin

excluding the hair follicles begins to regenerate into a functional epidermal layer.

        Apligraf is another product of artificial skin. Apligraf is used with standard

therapeutic compression for the treatment of noninfected partial- and full-thickness skin

ulcers due to venous insufficiency. Apligraf is only considered after conventional ulcer

therapy has failed and if the ulcer is present more than 1 month in duration. It is first tested

by analyzing Keratinocytes and fibroblasts derived from neonatal foreskin and expanded

in culture and then tested for infectious pathogens and immunogenicity. Like Integra,

Apligraf comes from bovine type I collagen used for the dermal matrix. Another similarity

is that they both are developed artificial skin construct that contains the important

elements of skin: extracellular matrix, dermal fibroblasts, and an epidermis containing a

protective stratum corneum.




                                                                                               9
Figure 3- Apligraf contains only the essential components of human skin covering.



       A bilayered viable skin construct that contains both an epidernmal layer, formed

by human keratinocytes (with a well-differentiated stratum corneum), and a dermal layer

composed of human fibroblasts in a bovine type 1 collagen lattice. Apligraf contains the

matrix proteins and cytokines like found in human skin. However Apligraf does not

contain Langerhans' cells, melanocytes, macrophages, lymphocytes, white blood cells,

blood vessels, hair follicles or sweat glands. This can be seen in Figure 3 above.

       On January 1999, this new product was put to a life or death test. Eight-week-old

Tori Cameron (picture on right) was born with a rare, painful and potentially deadly skin

disease called epidermolysis bullosa

that causes severe blistering with the

slightest touch. The disease causes

infections and raw spots, similar to

second-degree burns. Young Tori is

the first newborn that Apligraf has

been applied. 40% of her body was



                                                                                           10
covered with Apligraf. The surgery was so successful that even the doctors said that they

had a difficult time discerning the artificial skin to the new skin.

          Artificial skin is a fairly new technique that is practiced in the medical world

today. Along with Dr. Burke and Dr. Yannas there are many doctors devoted to this new

form of medication. Another product funded by the National Institute of General Medical

Sciences is called AlloDerm. Its main agenda is to preserve as much of the natural three-

dimensional structure of the dermis as possible. AlloDerm is produced by removing from

cadaver skin all cell components that cause a burn patient's immune system to reject a raft

from any other person. A key feature of the process is preserving to the greatest extent

possible the "natural," three-dimensional structure of the dermis. Properly approximating

this scaffold, whether from real dermis (as in AlloDerm™) or artificial dermis (as in

Integra™), is crucial to the ability of the patient's remaining cells to regenerate themselves

into a new, functioning skin.



            Name of Product                                         Origin
Epicel                                            Taking from patient-not artificial skin
Integra                                           Collagen- GAG
Apligraf                                          Bovine type I collagen
AlloDerm                                          Cadaver skin


Figure 4- This table summarizes the products and their main components



          The field of artificial skin is constantly expanding. With the direction of gifted

doctors and researchers and the advancements of biomedical technology, the art of skin




                                                                                               11
growth will be mastered. The damage caused by severe burns or a car accident will be

easily treated and patients can go on with their normal everyday lives.




Term                                          Abbreviations

National Institute of General Medical         NIGMS
Sciences
Glycosaminoglycan                             GAG




                                                                                       12
Dr. Cindy Klevickis,

        I have addressed all that Karen Hutherson, revised on my artificial skin paper. She
thoroughly edited my paper for grammar as well as the overall flow of the paper. I
especially appreciated her input about starting new ideas with each new paragraph. That
writing critique will help me with my papers and reports to come. I have added all the
missing parts to my paper. It now has all the required components. I hope that by the end
of the paper that the reader comes away with half the appreciation and knowledge that I
have gained about artificial skin just from writing this term paper.

                                                                    -Alfredo Capps




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                                     Annotated Bibliography

Current Surgical Diagnosis & Treatment, Lawrence W. Way, ed., Lange Medical Book, Appleton & Lange,
         1994
         This is another basic procedure book on burns and skin replacement.

Nursing Care of the Patient with Burns, Florence Greenhouse Jacoby, ed., The C.V. Mosby Company, 1976.
        This is an excellent handbook and guide to treatment for burns from the first contact all the way to
        the hospital operating room.

Wound Care, Cathy Thomas Hess, RN, BSN, CETN, Springhouse Corporation, 1995
       Handbook on burns and emergency care for burns.

http://www.pslgroup.com/dg/7d2e.htm
         Site informs about the UK acceptance of Integra

http://www.pslgroup.com/dg/6301e.htm
         This site provides background information on the CE Mark Certification

http://www.nando.net/newsroom/ntn/health/060997/health4_10033.html
         This site hosts many sites that provided useful information on Integra and Integra
         companies.

http://cwis.usc.edu/dept/biomed/bme490.981/artificial_skin.htm
         Internet site with useful and interesting background information about the origin of artificial
         skin. Also site where the Integra picture was located.

http://www.integralifesciences.com/index_java.html
         Integra website devoted to the LifeSciences Holding Corp.

http://web.mit.edu/newsoffice/tt/1996/apr03/41951.html
         MIT student, Alice Waugh, discusses the uses of artificial skin in journal TECH Talk.

http://www.um-jmh.org/Pages/Artificial_Skin.html
         This is website that provided the case of Tori Cameron and the successful application of
         Apligraf.

http://www.bae.ncsu.edu/bae/research/blanchard/www/465/textbook/otherprojects/cellular/project/skin.html
         This is another good journal site for a broad over view of artificial skin and its applications
         in the medical world.

http://www.channel2000.com/news/health/stories/news-health-990112-200231.html
         Another good site for the Cameron case and provided good pictures as well.

http://www.ri.cmu.edu/events/Faculty_Retreat_Pages/v99/Grace-Artificial_Skin.htm
         Expert, Richard Grace, gives his insight on the direction of artificial skin and the growing
         science in his personal journal.

http://www.apligraf.com/default_flash.htm
         This is the main website for Apligraf information. Impressive figures and statistics.

http://www.sciam.com/1097issue/1097infocus.html
         Journal Scientific American on artificail skin.



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