Conference Session A3
Bioengineering Topics 3 Paper #2093
Abstract— This paper delves into the most modern approaches to the tissue engineering of skin. We will first define skin engineering and the situations in which it is necessary, and then compare it to previous skin transplantation methods. Within skin engineering, we will evaluate two specific subsections: biomaterials and stem cells. Biomaterials will be evaluated in terms of a new substance, agarose-fibrin, that has the potential to be more biocompatible than any other current biomaterial. The idea of self-healing biomaterials will be discussed with respect to a longer lasting artificial skin sample. The two types of stem cells that will be discussed are mesenchymal stem cells, which are derived from adult bone marrow, and induced pluripotent stem cells, which are derived from adult stem cells, then manipulated. Other, non-common uses of skin engineering will be evaluated and discussed, as a means to promote the study of skin engineering. Finally, skin engineering will be related to the real world with regards to ethical and economical feasibility.
Key Words—Artificial skin, Biomaterials, Epidermis, Skin grafting, Stem cell engineering. epidermis is comprised of four layers: the strata basale, the spinosum, the granulosum and corneum [2]. The basal layer is the innermost layer that generates the remaining cells of the epidermis [2]. The stratum spinosum provides organization for the epidermis by contributing a structure for the cells [2]. Cells in the granulosum layer produce a lipid that binds the cells in the stratum corneum [2]. The corneum is the outermost layer of the epidermis [2]. The purpose of this layer is to provide a barrier for the remaining layers.
Skin engineering is the process of replicating each of these functions because the body can no longer perform the task unaided.
A N O VERVIEW OF S KIN E NGINEERING
In current military conflicts, burns make up five to twenty percent of all casualties [1]. The conventional treatment for severe burns is to perform a skin graft, a painful procedure that includes risks such as infection and nerve damage. This arduous surgery is not only used for burn patients, but also performed for an amalgam of other medical conditions including skin cancer, serious ulcers, and large wounds that are unable to be completely repaired by normal methods.
For a large part of the twentieth and twenty-first centuries, scientists have been trying to improve skin repair methods by engineering skin in the laboratory using materials such as collagen, fibronectin, and a variety of biomaterials.
Depending upon the depth of the wound, the body may be unable to heal itself naturally. Tissue engineering is the process of manipulating the body to heal itself by imitating the natural bodily processes. According to The
Williams Dictionary for Biomaterials, tissue engineering is
“the persuasion of the body to heal itself through the delivery to appropriate sites of molecular signals, cells, and supporting structures” [2] In sum, engineered organs must receive and deliver information from other parts of the body, regenerate cells, and maintain their shape. These three tasks prove difficult when attempting to regenerate the human epidermis, which consists of various layers and functions.
The structure of human skin, as illustrated in the diagram to the side, is fairly complicated. The human
FIGURE 1
A DIAGRAM OF HUMAN SKIN STRUCTURE [3]
In terms of skin engineering, biocompatibility is the ability of skin engineering efforts to resemble natural bodily processes. In skin grafting, the transferred skin already possesses the qualities of functioning skin, so biocompatibility is more easily achieved. Thus, the challenge of skin engineering is to produce artificial skin that will interact with the remainder of the body as natural skin. This artificial skin must contain pores for sweat glands, degrade and reproduce in sync with the remainder of the body, and maintain elasticity, just as real skin. Not only must the artificial skin function as skin for the host, it must also be durable enough to be manipulated by surgeons when the transplant occurs. Ultimately, skin engineering is a significant field within tissue engineering with various applications in today’s society.
University of Pittsburgh
Swanson School of Engineering March 1, 2012
1

Antonina Maxey
Nathalia Both
A PPLICATIONS OF A RTIFICIAL S KIN
Replacement skin is used in situations where the human body cannot regenerate the necessary amount of skin to continue functioning in a normal manner. The most common situations that require the use of skin engineering include burn injuries, large open wounds, giant nevi, or birthmarks, chronic ulcers, and incapacitating scars [1]. Artificial skin is developed outside of the body, and then placed onto the recipient site. It then assumes the role of living skin by protecting the body from bacteria, allowing the body to sweat, and moving in harmony with the rest of the body’s skin.
In some circumstances, artificial skin may be used for reasons other than skin transplant. Artificial skin that mirrors the composition of natural skin can be used in the medical or cosmetological testing of materials, or other circumstances that employ the use of skin. Artificial skin may replace the testing of cosmetics or other materials on animals.
With regards to skin transplanting, we believe that artificial skin outweighs its alternative, skin grafting, in situations where the patient does not have an adequate source of skin from which to extract. This occurs in babies, who do not have enough skin to be transferred, and the aged, who do not have durable skin that can be manipulated. This will be described in the following section.
S KIN G RAFTING : A N O UTDATED M ETHOD
Skin grafting is a method for wound regeneration that has been used in medicine for hundreds of years. According to
Practical Plastic Surgery for Nonsurgeons , skin grafting is the process of taking a piece of skin from the donor site and transferring it to the site of the wound on the patient [4]. The donor skin can come from multiple sources. The most common type of skin grafting, called autografting, uses skin from an uninjured site on the same patient who receives the skin [5]. Skin grafting can also utilize layers of skin taken from cadavers (called homografts), taken from pigs and other animal species (called xenografts), or taken from other human patients (called allografts) [5]. Doctors usually recommend patients have skin grafts for these conditions: skin infection leading to skin loss, burns, skin cancer surgery, surgeries that require skin to fully heal, venous ulcers, pressure ulcers, diabetic ulcers, and very large wounds [6].
There are several risks for skin grafting in any form. Because skin grafting requires the use of an anesthetic, skin grafting risks include anesthesia risks such as reactions to the medicine and breathing complications [6]. Some of the more rare risks associated with general anesthetic include temporary mental confusion, lung infections, stroke, heart attacks, and death [7]. However, these risks are very rare and generally occur in the aged and people with other medical problems. The risks for the surgery itself include bleeding, infection, chronic pain, infection, the graft not healing or healing slowly, reduced or lost skin sensation, increased skin sensitivity, scarring, skin discoloration, and uneven skin surface [6]. But these risks are generally overlooked as skin grafting is a reliable and established medical surgery. Furthermore, there are specific risks involved with the two individual types of skin grafts: full thickness skin grafts and split thickness skin grafts. All of these risks put together prove that skin grafting, despite the fact that it is established as the premier way of dealing with loss of skin, is an outdated and overly painful method to heal skin imperfections. Instead, we need to use stem cells and biomaterials to engineer artificial skin as a safer and improved alternative to skin grafting.
S PLIT -T HICKNESS S KIN G RAFTING
A split-thickness skin graft (STSG) only takes the epidermis and part of the dermis from the donor site [4]. This way, the donor site can heal on its own since some of the dermis still exists there. STSG’s are used for larger wounds that would take a long time to heal normally and for wounds that cannot be closed surgically [4]. Other wounds that require STSG’s include ulcers, burns, and abrasions [8]. STSG’s are used more often that full-thickness skin grafts because they can be applied to a broader range of wounds and conditions. One advantage of split-thickness skin grafts is that because the donor site heals by itself, it can be re-harvested for skin after it has healed [9].
There are several disadvantages to split-thickness skin grafts in addition to the general risks of skin grafting.
Often, STSG’s are unsuccessful because of the formation of a hematoma, or a collection of blood within tissue, under the graft [9]. Seromas, or clumps of clear bodily fluid, can form and prevent the STSG graft from healing [9]. Poor vascularity, bacteria, and harmful substances at the recipient site can also cause the graft to fail [9]. Errors on the medical practitioner’s side such as the application of the graft upside down, application of too much pressure on the graft, stretching of the graft, or poor handling of the graft can cause a partial or complete graft failure [9].
F ULL -T HICKNESS S KIN G RAFTING
A full thickness skin graft (FTSG) uses both the epidermis and the complete dermis as part of the skin graft [4]. The removal of all of the dermal material from the donor site means that the donor site cannot heal naturally and must instead be closed through surgery or receive a STSG from another recipient site [10]. FTSG’s are done much less regularly than STSG’s because FTSG’s require a very clean wound for a successful surgery [4]. Thus, these grafts are generally only used for wounds created surgically (such as a wound created through the excision of a skin lesion) or for open wounds on the palm side of the hands and fingers [4].
The advantage of FTSG’s is that the recipient site is more like normal skin when completely healed [10]. FTSGs allow
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Antonina Maxey
Nathalia Both the skin to retain such characteristics as color, texture, and thickness [10].
Just like with split-thickness skin grafts, fullthickness skin grafts have risks in addition to the ones from all skin grafts and the ones from STSG’s. If the growth of blood vessels in the skin is inhibited, then the graft will not survive [11]. Also, smoking during the recovery period will cause the graft to fail since smoking prevents the growth of small blood vessels [11].
Overall, split-thickness and full-thickness grafts both come with their advantages and disadvantages, as illustrated in Table 1. Although they do provide a solution for serious burns and injuries, both grafts result in pain and risks for the patient.
TABLE 1
A COMPARISON OF SPLIT-THICKNESS AND FULL-THICKNESS
TYPE OF GRAFT
Split-Thickness
GRAFTS
ADVANTAGES
Donor site can heal on
DISADVANTAGES
Hematoma risk,
Full-Thickness its own, broad range of uses, donor site can be re-harvested for skin seroma risk, poor vascularity, infection, delicate to handling
Donor site can’t heal
Recipient site heals more normally, used for surgical incisions, skin retains natural characteristics naturally, requires very clean wound, risks of failure when smoking, risk of failure when blood vessels inhibited
T
HE
O
RIGINAL
S
KIN
R
EPLACEMENTS
In tissue engineering, scaffolds are used as support structures for tissue [12]. The original skin substitutes were based around combining grafts with scaffolds. The scaffolds would provide the support and protection needed for the graft on top to heal and develop. In skin engineering, two natural scaffolds that are currently (and originally) used are collagen and fibronectin.
C OLLAGEN
A major fibrous protein, collagen is found in the extracellular matrix (a tissue support system) and in connective tissue [13]. There are at least 20 types of collagen, making it one of the most abundant natural proteins [13]. In skin, collagen particles form long fibrils, in order to support and provide a foundation for other tissues
[14]. The two most prevalent collagens in the skin are collagen 1 and collagen 3 [13]. Collagen 1 is often found in the dermis and in scar tissue [14]
As a skin substitute material, collagen is often used in many skin scaffolds. Collagen was one of the first materials used in skin engineering for matrix-based artificial skin. These initial skin substitutes used collagen to make porous matrices to provide the foundation for skin growth
[12]. However, these products couldn’t work to heal large wounds on their own. Once the matrix was placed on top of the wound, it would then have to be covered by an autograft.
Collagen-based skin substitutes are fairly common and two examples of such products are Integra and Alloderm [12].
Integra has two layers similar to natural skin. The bottom layer contains the collagen matrix and another carbohydrate molecule [15]. The top layer contains a flexible silicon sheet. The collagen in this product allows the natural skin cells to regenerate on the injured area [15]. However,
Integra does not look like natural skin nor does it have all the properties of natural skin. Likewise, Alloderm can effectively heal the wounded area but fails to provide the benefits of natural skin.
F IBRONECTIN
Fibronectin is another protein that is helpful in constructing extracellular matrices for tissue repair. Fibronectin is often considered for and used in artificial skin because it plays an important role in the process of tissue repair. As an extracellular matrix protein, fibronectin consists of fibroblasts, chondrocytes, endothelial cells, and macrophages [16]. One advantage of fibronectin is that it can be used along with collagen as a tool to bind the extracellular matrix made of collagen with the fibronectin receptors in tissue [16]. On the other hand, fibronectin does have disadvantages as a material for skin substitutes. The major disadvantage is that mechanical stretching weakens the functions of fibronectin and can cause a failure to vascularize [12]. A protein related to fibronectin that may help with the production of skin substitutes is fibrin, a protein known for its use in helping to clot blood. Fibrin has been found to support keratinocyte—the major cell type in the epidermis—and fibroblast—cells used in the extracellular matrix—growth in developing skin [12].
Certain reports also suggest that fibrin may help cell motility in wounds and that fibrin matrices can carry growth factors that can help the wound to heal [12]. Though these original skin replacement techniques have been employed throughout history, biomaterials are the next step with regards to skin transplanting.
B
IOMATERIALS
According to the Chemical and Materials Engineering department at the San Jose State University, a biomaterial is material that is either natural or man-made comprising whole or part of a living structure or biomedical device. It then performs, augments, or replaces a natural function. In terms of skin engineering, a biomaterial would need to be strong enough to cover a wound or connect tissue. It would also need to maintain a similar elasticity as natural skin. In addition, a biomaterial must be easy to store and manipulate at a low cost. [17]
The use of biomaterials is not a new idea, as there is evidence that they were used in the first century AD.
Biomaterials were initially used in places such as Egypt,
Greece, and India in plastic surgery operations to repair
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Antonina Maxey
Nathalia Both battle wounds [18]. Much of this information was lost until the Renaissance in which scientific inquiry was revived.
Because dental implants were less invasive than techniques such as transplanting a nose, the biomaterials used in dentistry were developed during the nineteenth century. The use of natural biomaterials began in the middle of the twentieth century and has since been developed.
In comparison to using the patient’s own skin to cover a wound site, as in skin grafting, the use of biomaterials eliminates the need to remove skin from another part of the body. The most important difference between the use of biomaterials and skin from another portion of the patient’s body is the level of biocompatibility.
Though biocompatibility cannot be specifically measured, it is evaluated in terms of performance or success at a specific task [19]. Skin transferred from another location of the patient’s body will automatically be more biocompatible than any biomaterial because the make-up of the transferred skin will have a similar structure and identical proteins as that of the wound site [18]. As previously mentioned, the challenge of engineering biomaterials is to make a product that will promote the healing of the wound site by performing the functions of natural skin.
There have been many advances in the field of biomaterials that allow engineers to make more accurate artificial skin. Advances have been made in the functions of the biomaterials being used and the substances being used to create those biomaterials. One new function, in addition to covering the wound site and sending and receiving messages from other cells, is the ability to regenerate.
S ELF -H EALING B IOMATERIALS
The biocompatibility of the artificial skin is not only determined by its ability to perform the immediate tasks of skin, but also its lifespan. Artificial skin that degrades at a fast rate is not biocompatible because it does not perform its intended function for the necessary amount of time. A new class of biomaterials that self heals is currently being studied. A self healing biomaterial is a substance that heals itself after undergoing the physical and chemical stress of replacing a part of the body. These biomaterials must sense, halt, and reverse damage without the use of outside aid. By repairing the small cracks that develop in the material, the lifespan of the material is increased [20]. This increased lifespan in conjunction with materials that emulate skin serve as the ideal skin substitutes.
A GAROSE -F IBRIN
Recent findings suggest that artificial skin made of fibrinagarose biomaterial is more lifelike and effective than current skin biomaterials. Agarose-fibrin biomaterial is a substance created of agarose and fibrin [21]. Agarose is a sugar obtained from seaweed and fibrin is a protein involved in the clotting of blood, collected from donors. This biomaterial, which has certain qualities of natural skin like water resistance and elasticity, was tested on the mice in the picture below. The mice exhibited no symptoms of either rejection or infection. In fact, the mice showed signs of healing after six days. The healing process was completed after twenty days.
FIGURE 2
MICE TESTED WITH AGAROSE FIBRIN SKIN [22]
As with other biomaterials, fibrin-agarose does not completely cover all of the characteristics of skin. For example, this biomaterial does not have the proper glands for sweat. It also lacks the melanin and pigmentation needed to completely mirror the properties of actual skin. Agarosefibrin is a promising biomaterial, and its deficiencies provide a need for the continuation of its study.
S
TEM
C
ELLS
When discussing tissue engineering, stem cells are often viewed as one of the most promising materials to work with.
Stem cells show such promise because of the fact that they are base cells which can differentiate into diverse types of cells. This allows researchers to use stem cells to make dermal cells without actually harvesting dermal cells.
Embryonic cells are the most prominent of stem cells since they are totipotent, which means they can be differentiated into almost all cell types. Thus, they are often viewed as a very viable, though controversial because they have to be harvested from human embryos, material for tissue engineering because they have to be harvested from human embryos. However, for skin engineering, other types of stem cells work just as well as embryonic stem cells. In fact, embryonic stem cell research in tissue engineering has encountered many technical difficulties that have lessened their importance to the field. One of the common problems
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Antonina Maxey
Nathalia Both of embryonic stem cells in skin engineering is that there are often rejection problems concerning the host [14].
Skin engineering is an excellent field for stem cell technologies because the skin contains a “wellcharacterized” adult stem cell called the keratinocyte [14]. In skin engineering with stem cells, one of the most important goals is to get the stem cells to commit to differentiating into keratinocytes. Of the multiple stem cell types available, adult mesenchymal stem cells and induced pluripotent stem cells are able to accomplish this with the most accuracy.
M ESENCHYMAL S TEM C ELLS
Adult mesenchymal stem cells or MSCs are stem cells that can be taken from adult bone marrow (among other sources) and can differentiate into multiple, but not all, types of cells
[23]. Specifically, MSCs have the ability to differentiate into connective tissue cells and dermis cells. Although they are more restricted in their ability to produce different cell types in comparison to embryonic stem cells, MSCs are efficient at producing cells for tissue repair [14]. Adult stem cells could also solve the problem associated with embryonic stem cells since adult stem cells can be transplanted back into the same individual with no rejection risks [14].
One clear advantage of bone marrow MSCs is that they can create larger amounts of collagen and more growth factors than natural dermal cells [12]. These traits can help to accelerate wound healing in patients. Skin keratinocytes from MSCs are useful because they can be kept and created in a laboratory without risks [14].On the other hand, the present skin substitutes made from these cells are missing some natural features like hair follicles and sweat glands
[14]. A disadvantage of MSCs is that bone marrow stem cells decrease with age so they often cannot be collected from the elderly [12].
I NDUCED P LURIPOTENT S TEM C ELLS
Induced pluripotent cells are a type of pluripotent cell ( a cell that can differentiate into all three germ layers) that originate from non-pluripotent cells (usually adult somatic cells) and are artificially changed to express certain genes and become pluripotent [12]. Induced pluripotent stem cells or iPS cells were first made in 2006 using mice and in 2007 using humans [12].
Like MSCs, iPS cells are able to solve the problem associated with embryonic stem cells since they are generally not rejected from the host [12]. Induced pluripotent cells do have one advantage over MSCs in that they are incredibly similar to embryonic stem cells in their ability to differentiate into numerous cell types. Current research into iPS cells show that iPS cell may be possdible to create without genetically altering the adult somatic cells.
Also, unlike mesenchymal stem cells, iPS cell may be able to be harvested from both the sick and the elderly [12].
Research regarding iPS cells and other types of stem cells have lead to further advances in the skin engineering field.
U
NUSUAL
A
SPECTS OF
S
KIN
A
PPLICATIONS
Advances in biomaterials and stem cells are significant to furthering the field of skin engineering. Some new branches of skin engineering include the strengthening of the skin and the discovery of new sources for the cells. One new idea for strengthening skin is bullet proof skin made of spider silk and goat milk. A new cell source being considered by engineers is the foreskin of infants [24]. Ultimately skin engineering is a significant part of tissue engineering that can lead to new breakthroughs on the medical front.
F ORESKINS AS A SOURCE OF CELLS
A German-based company has discovered a new source of cells to be used for biological applications: the foreskins of male babies [24]. The babies are preferably younger than the age of four because younger cells have better cell function.
This unique method is very practical because it gives purpose to a material that would otherwise be discarded. The
“skin factory” works by emulating the natural bodily conditions. The machine is heated to the temperature of the human body, giving the cells an ideal environment in which to grow. The cells that are extracted from the foreskin are incubated in tubes where they may reproduce[24]. The cells reproduce at the same rate that actual skin cells reproduce, which is six weeks. Once the process is completed, a gel of sorts is produced. The gel forces the cells to grow in to a sheet that simulates the epidermis. This gel can then be used in practical applications. Though this skin can be used for various biological projects, it is ideal for skin engineering because the levels of biocompatibility are likely to be high, due to the fact that the skin patch is made of human cells.
S PIDER S ILK
Though not fully developed, the idea of bulletproof skin is in the process of becoming a reality as opposed to a distant science fiction fantasy. Bulletproof skin employs the basics of skin engineering, with some additional factors. Instead of finding a material that resembles skin most closely, engineers have created a substance using the milk of a goat and spider silk [25]. This material is very strong, but lends itself to manipulation. The materials generally used in skin engineering can be grown around this strong substance, and then implanted into a host [25]. The problem currently facing engineers with regard to bulletproof skin is its strength in comparison to the speed of most bullets [25].
Though strong, the bulletproof skin would not currently withstand a shot from a standard bullet. Studies are in progress to increase the strength of the skin and improve the level of biocompatibility with the host [25].
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Antonina Maxey
Nathalia Both
E
THICS OF
S
KIN
E
NGINEERING
Though skin engineering has numerous benefits, there are certain aspects of the process that may be controversial. For instance, sourcing the cells to be used in the artificial skin requires the use of stem cells, a highly debated material.
Along with biocompatibility and the artificial skin’s ability to mimic natural bodily functions, the body must completely accept the skin. This means that there must be no inflammation or other reaction to the artificial skin.
Ultimately, skin engineering is the most ethical option with regards to skin replacement due to its affectivity and non-intrusive nature [26]. Artificial skin can also lead to developments that improve other controversial topics such as product testing on animals.
S TEM C ELL R ESEARCH
Stem cell research is a controversial topic in the United
States. The research itself does not cause the controversy, but the source of the cells is greatly debated. Stem cells can be sourced from adult tissue or from embryos. The controversy arises in the cell sourcing from embryos
[nursing]. Because embryonic stem cells are easier to isolate, they are more readily available. However, the artificial skin used in skin engineering can only be developed from adult cells because they are more durable and exhibit the characteristics necessary of skin to be transplanted.
S KIN E NGINEERING VERSUS O THER M ETHODS
Although many critics would argue against it, skin engineering is an ethical option for people dealing with burns and other large wounds. The process of skin engineering is painful and leaves scarring. Since the artificial skin of skin engineering is developed outside of the body, it does not cause pain to the patient and results in less scarring.
The two main processes currently in place for testing products that will later be used by humans are testing on animals and testing on human volunteers. As artificial skin begins to resemble human skin more closely, it can start to replace those methods, allowing for more ethical medical practices.
E
CONOMICS
The commercial expectations for artificial skin are high and unrealistic considering how long it takes to develop skin and the complexity of skin. The beginning stages of development of artificial skin are very costly for companies.
In fact, several smaller companies who work with developing skin replacements have had to file for bankruptcy because of these early stages [14]. After the product is developed, there are still several quality and safety regulations (such as an approval from the FDA) that the product has to pass [27]. Overall, the development and production of artificial skin is a difficult and costly process.
However, ideas for simplified medical treatment and better skin alternatives prove attractive to the market and, if pulled off correctly, could prove very profitable. In fact, there are already several commercially available skin substitutes. As shown in the table below, there are cellular epidermal replacements such as Epidex and Myskin, engineered dermal substitutes such as AlloDerm and Integra, and engineered dermo-epidermal substitutes such as
Apligraf or OrCel [27]. All of these products and the businesses that support them have been able to survive both commercially and medically, proving that skin engineering is an economically valid branch of engineering.
TABLE 1
COMMERCIAL SKIN SUBSTITUTES [14]
Epidermal
Substitutes
Engineered Dermal
Substitutes
Engineered Dermo-
Epidermal
Substitutes
Product
Epidex
Myskin
AlloDerm
Integra
Apligraf
Manufacturer
Modex Therapeutiques
CellTran
Life Cell Corporation
Johnson & Johnson
Organogenesis
Ortec International OrCel
T
HE
N
EXT
S
TEPS FOR
S
KIN
E
NGINEERING
Skin engineering is a promising, but challenging field within tissue engineering. Through the study of biomaterials and stem cells, the field will continue to prosper and develop an artificial skin product that is completely biocompatible.
Despite current skin substitutes and skin grafts, skin engineering research is important because it is more ethical, and with research, may eventually become more economical.
Research regarding stronger, more durable, and less costly artificial skin continues. With research, skin engineering will overcome current limitations and continue to improve the lives of patients.
R
EFERENCES
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A
DDITIONAL
S
OURCES
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(2010, July 6). “Closing In on the Formula for Artificial Skin.” The Wall
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ACKNOWLEDGEMENTS
We would like to thank Beth Newborg, Katy Rank Lev, and
Keely Bowers from the Writing Center for their help and instruction on the writing of this paper. We would especially like to thank Piaget Francois for meeting with us weekly to discuss and proofread our paper.
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