Michael QuintanaProf. TownsendMay 2, 2014Writing 340A2- Illumin

Why Graft Skin When You Can Spray It On?

AbstractFor the past five thousand years, skin grafts have been the primary treatment for severe

burns. Skin grafting is the process of taking skin from either the patient or an animal and transplanting it onto the burn surface with the hopes of it permanently replacing the skin that was lost or damaged. The downside of this method is that the skin grafts are often rejected by the body or leave terrible scarring and discoloration. However, just this decade a new innovation has arisen that solves all these problems: Avita Medical’s ReCell Spray-On Skin. This technology involves taking the stem cells from the patient’s own healthy skin and spraying them over the patient’s burn surface to stimulate a quick and natural regrowth of normal, seamless skin. Though Spray-On Skin technology is currently incompletely developed, it has great potential to change future healing practices.

Introduction

For about 5,000 years, humans have used skin grafts to replace damaged or lost skin [1].

However, even the use of the most up-to-date skin grafts

can result in many complications, such as texture

deformation, discoloration (as seen in Figure 1), and

tissue rejection [2]. Very recently, the biotech company

Avita Medical has been developing a new technology

called ReCell Spray-On Skin, which uses the patient’s

own healthy skin cells to repair the damaged ones. In

comparison to skin grafts, ReCell technology repairs skin much more efficiently. Where skin

grafts take weeks to months to fully heal, spray-on skin takes just days; where skin grafts run the

risk of being rejected by the patient’s body, spray-on skin will always be accepted because it is

the patient’s own skin; and where skin grafts usually require the patient to undergo surgery and

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Healed Skin Graft

Figure 1 Fully healed and accepted skin graft

Epidermis-melanocytes, keratinocytes

Dermis-fibroblasts

Subcutaneous Layer

tissue sewing, spray-on skin needs just a small skin sample. As a quicker, safer, and less invasive

method of skin reparation, spray-on skin technology has the potential to someday replace skin

grafts entirely and be the sole treatment for burn and surface wound victims.

Background

Importance of Skin

As the first line of defense against infections and pathogens entering our bodies, skin

plays a vital role in our wellbeing. It is made

up of three layers, the epidermis, the dermis

and the subcutaneous layer [3]. The outermost

layer, the epidermis, consists of melanocytes

and keratinocytes, which are responsible for

skin pigmentation and for attracting white

blood cells to fight pathogens at the surface, respectively [3]. The dermis, the next layer, contains

fibroblasts, which are vital for wound healing and tissue regeneration. Therefore, as long as the

dermis remains intact, skin can heal and regrow [4]. When lacerations and other wounds damage

both the epidermis and the dermis, the skin can sometimes heal through scar formation [5].

However, when the wounds cover large areas of skin, such as in cases with severe burns, the skin

cannot heal by itself. These situations call for skin grafts.

History of Skin Grafts

Skin grafting, autografting to be precise, is the practice of cutting off skin from a

different part of a patient’s body, usually from the buttocks, the thigh, or the back of the arm, and

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Figure 2 The three layers of skin and other components.

using it to replace the skin lost or damaged at a wound site [5]. The first records of skin

autografts originated from ancient India in 3000-2500BC. Interestingly enough, Hindu potters

and tilemakers were the ones responsible for the first attempts at skin reparation, not the healers.

The potters and tilemakers regularly reconstructed noses, which were frequently maimed as

punishment for minor crimes, such as adultery and theft [1]. Their ancient technique involved

obtaining skin from the buttocks, slapping it with a wooden paddle until it was red and inflamed,

cutting it to size, and transplanting it onto the patient’s face [1]. Although this method was very

crude and often resulted in infections and tissue rejection, many people still relied on that method

because it was the only way to patch damaged skin. It would take another few thousand years for

the practice to develop a cleaner and more effective technique.

Since the frequency of widespread skin diseases, such as syphilis, and nasal mutilation

punishments have greatly declined since the skin graft’s origins, most skin grafts have been

implemented to heal burn wounds since the nineteenth century. The very idea of using skin grafts

to treat burn wounds was introduced in 1871 [1]. By this point not much had changed in the

practice of skin grafting. In the aforementioned case of nasal mutilation, the patient would

receive a skin graft taken from his own body; however this technique would need to be adjusted

for most burn treatments. Autografts were very common for nasal reconstruction because a very

small graft of skin was required. However, large burn wounds require a much larger skin graft.

Evidently, taking skin from the leg, for example, to cover a large area of skin on the arm would

not be favorable as the leg would then need its own skin graft to heal. Instead of using autografts,

skin grafts taken from the patient’s own body, these burn wounds would often require allografts,

which were skin grafts taken from animals such as sheep or even preserved cadavers. Allografts

presented the solution to this problem as the patient could receive as much skin as needed

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without losing more of his own. The use of skin grafts to tend to burns transformed the treatment

of burn victims and greatly improved their survival rate [1]. However, there were issues with the

survival rate of the skin graft themselves.

In most cases, the skin allografts would mysteriously rot and die after implantation.

Decades later in 1943, surgeon Thomas Gibson and biologist Peter Medawar discovered that the

patients’ own immune systems were responsible for the graft rejection [6]. Essentially, the

patient’s immune system would not recognize the skin graft as its own skin, but as a foreign

object and would remove it. Unfortunately, this problem has yet to be fixed and still exists today,

decades later. Even so, allografts are still currently used as the primary treatment for large burns.

Clearly, new techniques need to be implemented to improve burn treatment without risk of

rejection.

One innovation that is currently in development, but has yet to be practiced in clinical

trials, is the tissue engineering of cultured epithelial autografts. Essentially, the practice involves

culturing, or growing, epithelial cells, which are the cells responsible for the regrowth of lost

skin cells. This technology artificially replicates the natural process of skin replacement and is

individualized for every patient, assuring that the graft will not be rejected by the patient’s

immune system. Although this is an improvement, these epithelial cells take three to four weeks

to culture alone. This technology can only really handle small burns, too, since producing large

quantities of these autografts is extremely time consuming and expensive. On top of this, the

recovery time of these autografts is another three to four weeks. In this time the patient’s wound

could get infected, fester, and even cause death [2]. As of now this technology cannot be

considered an alternative or replacement to normal skin grafts, until the culturing time and

production are improved.

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New and Improved Alternative – ReCell Spray-On Skin

What is it?

The future of burn treatment does

not involve grafting skin, but spraying it.

The regenerative medicine company

Avita Medical is currently developing

their product called ReCell Spray-On

Skin [7]. Unlike skin grafts, ReCell

technology repairs skin quickly and

efficiently without scarring, tissue

deformation, or pigment discoloration. While skin grafts generally take weeks to heal

completely, spray-on skin takes just five to seven days [8]. Although the skin is considered

completely healed, having achieved full functionality and regrowth, it will not look completely

normal for a few months. Still, with such a short recovery time, scar formation does not occur

resulting in an unblemished and aesthetically-pleasing recovery, as seen in Figure 3.

How does it work?

Avita Medical’s ReCell Spray-On Skin replicates the patient’s own natural skin

regeneration process to reproduce functional and aesthetically appealing skin. The doctor takes a

small skin sample about the size of a postage stamp (2cmx2cm in area, 0.15-0.20mm thick) from

the patient’s healthy, undamaged skin near the wound site. This small sample will be sufficient

to cover an area up to 80 times its own size [9].

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Before treatment Four months afterFigure 3 Toddler Zed Merrick’s ReCell recovery.

Special enzymes are added to this skin sample to split the epidermis and the dermis. The

epidermal-dermal junction, where the two layers of skin connect, is then scraped for

keratinocytes, melanocytes, fibroblasts, and Langerhans cells, which are responsible for

protection from pathogens, skin pigmentation, the actual tissue regeneration, and microbe

elimination, respectively. These cells are basal and undifferentiated, meaning they have not yet

developed into a specific type of cell. These cells will be responsible for differentiating into and

reproducing the new skin cells that the wound needs.

These cells are then mixed into a

balanced salt solution to form the ReCell

suspension, which is then loaded into the ReCell

Spray-On Skin nozzle, which is shown in Figure

4. The ReCell suspension is then sprayed over

the wound site, followed by bandaging. At this

time, the metabolically responsive ReCell

suspended cells cover the wound site and differentiate. This method of skin regeneration is much

faster than the natural method as it repairs the wound differently. In natural skin repair, the

wound heals from the outside in, which is

a slow process, especially for large

wounds. Alternatively, in ReCell-mediated

skin repair, the wound heals from islets of

regeneration, drastically increasing the

speed of recovery for wounds of all sizes. These different methods are clearly depicted in Figure

5.

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Figure 4 Avita Medical's ReCell Spray-On Skin nozzle

Figure 5 Natural Skin Repair (left) vs. ReCell Skin Repair (right)

Islets of RegenerationOutside-in Regeneration

Since this is an autologous procedure, meaning these cells were taken from the patient’s

healthy skin near the wound site, they will produce new skin that looks just like the original skin

without pigment discoloration, tissue deformation, or tissue rejection. The process of taking the

biopsy, preparing the ReCell suspension, and spraying it onto the wound surface takes just about

half an hour to complete [7].

Benefits

As a quicker, safer, and easier-to-use method of skin reparation without risk of tissue

rejection, ReCell Spray-On Skin proves to be a vast improvement from skin grafts. Furthermore,

ReCell greatly reduces the risk of infection at the wound site. In most burn cases, infections can

settle in the wound area in just five to seven days if not cleaned thoroughly and frequently [10].

The great advantage of ReCell technology is that it creates new skin cells in just 20 to 30

minutes, and fully heals the skin in just a few days.

Imperfections

Although ReCell Spray-On Skin might initially seem like the perfect method of repairing

skin, it does not come without flaws. As of now, ReCell technology is limited to being able to

handle only first- and second-degree burns since they only damage up to the second layer of

skin, the dermis [3]. It is not a stand-alone treatment for severe skin damage. Third-degree burns

harm the third layer, the subcutaneous layer, which cannot be replaced by the body alone nor

through current ReCell methods. A skin graft of this subcutaneous layer needs to be implanted

prior to the ReCell treatment [12]. This method, however, leads to the same issues of infection

and tissue rejection accompanied with skin grafts. The ability to heal third-degree burns would

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greatly improve ReCell Spray-On Skin and further help to establish it as the primary method of

burn treatment.

Furthermore, there are risks of unlikely, but serious, pathophysiological problems

associated with the use of ReCell Spray-On Skin, such as the formation of fluid blisters between

the newly grown skin and the original wound surface, and poor cell nutrition in the early stages

of cell regeneration [14]. The fluid blisters form due to the lack of connective tissue between the

regenerated skin and the subcutaneous layer below. Without connective tissue, fluid, most often

blood, tends to just bubble up and pool between the layers instead of flowing through both the

old skin and the new [14]. This lack of connective tissue also leads to the second problem of cell

malnutrition since an insufficient amount of blood reaches all parts of the skin [14]. Dr. Jörg C.

Gerlach, a regenerative medicine researcher at the University of Pittsburgh, is currently

researching and developing two solutions to these problems: a cell biology approach and a

wound healing approach, both of which have proven success in their development [14].

The cell biology approach involves the use of connective tissue fibroblasts. To

recapitulate, undifferentiated fibroblasts are cells that can differentiate and become almost any

other cell that is needed. The use of these cells will create more connective tissue between the

regenerated skin and the burn surface below [14]. On the other hand, the wound healing

approach uses a temporary medium to supply the developing skin with the nutrients it needs. The

medium is a temporary hollow fiber membrane capillary bed, which is essentially a biologically-

degradable layer that would be placed over the wound surface prior to using the ReCell Spray-

On Skin. The capillary bed contains oxygenated nutrition to supply the cells with the oxygen it

needs to develop, and a dialysis medium, which is responsible for removing waste and excess

water from the blood to ensure less buildup of blood and toxins [14].

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Fortunately, with these proven solutions to the ReCell treatment’s main flaws, the

treatment has been established as a safe and viable alternative and even replacement for current

skin reparation methods.

Availability

As of 2011, more than 3,500 patients

had been treated by ReCell [11]. However, the

vast majority of these cases were carried out in

Canada, France, the United Kingdom,

Germany, and Australia. This treatment has yet

to be approved by the Food and Drug

Administration (FDA) in the United States

[11]. The treatment has, however, attracted the attention of the United States Armed Forces

Institute of Regenerative Medicine, which provided 100 patients and $1.45 million for the testing

of the ReCell technology in 2009 in hopes of hastening ReCell’s approval from the FDA. In

2012, Avita Medical initiated testing to get its ReCell Spray-On Skin kit, as seen in Figure 6, and

treatment approved by the FDA [11]. On April 10, 2014, the United States FDA finally granted

Investigational Device Exemption (IDE) for compassionate use of ReCell Spray-On Skin to

Avita Medical [13]. If a physician believes that a patient has life-threatening burn or trauma

wounds and insufficient healthy skin necessary for a skin graft, he can request Avita Medical’s

ReCell Spray-On Skin, a compassionate use of the treatment. The IDE allows Avita Medical to

exclusively manage these requests within FDA guidelines [13].

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Figure 6 ReCell Spray-On Skin kit with Spray-On nozzle and ReCell suspension mixture sites.

Future

Avita Medical’s ReCell Spray-On Skin technology has proven itself to be a permanent

replacement for skin grafts as the primary method of burn treatment. But in addition, it could

potentially extend to nonclinical areas of skin treatment, such as the cosmetic. ReCell technology

shows great promise as a method of not only regenerating burned or damaged skin, but also in

removing scars and tattoos, treating hypo- and hyper-pigmentation (such as in patients with

Vitiligo), and general aesthetic skin rejuvenation, such as wrinkle removal. Once the technology

is approved by the U.S. FDA, ReCell technology will change skin treatment for the better,

forever.

About the Author

Michael Quintana is a junior Biomedical Engineering major at the University of

Southern California. Outside of his academic life, he plays trombone in the USC Trojan

Marching Band. He also eats a lot of hot dogs.

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http://www.woundsresearch.com/article/9002[3] W. Montagna "Human Skin (anatomy)." Britannica Online Encyclopedia. Available:

http://www.britannica.com/EBchecked/topic/547591/human-skin[4] “Skin Substitutes." Biotechnology: Changing Life Through Science. Science in Context. [5] P. Lagassé. "Skin." The Columbia Encyclopedia, 6th ed. New York: Columbia University

Press, 2000. http;//www.galegroup.com [6] T. Gibson, P.B. Medawar. “The fate of skin homografts in man” Journal of Anatomy.

July 1943; 77(Pt 4): 299-310.[7] "Avita Medical." Avita Medical . Available: http://www.avitamedical.com[8] “Tea-scald toddler Zed Merrick given spray-on skin.” BBC News. (2012, February 27).

Available: http://www.bbc.co.uk/news/uk-england-lincolnshire-17181073[9] “Study Demonstrates That Avita Medical’s ReCell Spray-On Skin in Combination with a

Biological Wound Dressing Has ‘a Number of Benefits Compared to Standard Skin-Grafting Techniques.’” Business Wire. (2011, April 27. Available: http://www.businesswire.com/news/home/20110427007111/en/Study-Demonstrates-Avita-Medical%E2%80%99s-ReCell%C2%AE-Spray-On-Skin%E2%84%A2#.Ux-M6vldX84

[10] D. Church, et al. “Burn Wound Infections” Clinical Microbiology Reviews. April 2006. 19(2): 403-434.

[11] P. Dimberu. "Miraculous New Spray On Skin Technology Treats Burns Without Scars." Singularity Hub, June 14, 2011. Available: http://singularityhub.com/2011/06/14/miraculous-new-spray-on-skin-technology-treats-burns-without-scars/

[12] L. Gravitz. "Spraying on Skin Cells to Heal Burns." Technology Review. November 5, 2009. Available: http://www.technologyreview.com/biomedicine/23876/page1/

[13] “United States Food and Drug Administration Grants an Investigational Device Exemption for Compassionate Use of ReCell” Avita Medical. April 10, 2014. Available: http://www.avitamedical.com/index.php?ob=2&id=272

[14] B. Christensen. "Spray-On Skin With Skin Cell Spray-Transplantation." Technovelgy. May 7, 2010. Available: http://www.technovelgy.com/ct/Science-Fiction-News.asp?NewsNum=2886

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