Skin cell gun

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The skin cell gun, also known as the skin gun or SkinGun™, is an medical device developed initially for use with self-donated (autologous) stem cell therapies to treat burn wounds. The skin gun is used in conjunction with a technique that isolates individual adult stem cells from the patient's uninjured skin for application to the wound site, where they differentiate into normal skin. This treatment can replace conventional methods of treating severe wounds, such as skin grafting. Early studies demonstrate that damaged skin tissue regenerates more quickly than with traditional methods. [1] [2] [3]

The skin cell gun, along with the cell isolation methodology, were acquired by RenovaCare, Inc. in 2013.[4] The company continues to develop the technology and treatment protocol for commercial distribution, with plans to enter into initial clinical trials in 2015. RenovaCare also is also exploring opportunities to apply its SkinGun™ treatments to additional indications, including chronic wounds, pigmentation disorders, and cosmetic applications. [5]

History[edit]

Early experimental versions of the device were developed by Dr. Jörg Gerlach and StemCell Systems GmbH in Berlin, Germany. Dr. Gerlach and SCS had already developed cell culture bioreactors for culturing useable liver and other solid organ tissues from stem cells, and were seeking a similar platform for culturing living skin. They soon realized that, compared to other organs, the skin is a special case. A skin wound itself is an excellent environment to culture new tissue in vivo, solving the problems of wait times and transplantation of delicate cultured tissue inherent to in vitro tissue generation technology.[6]

Researchers developed novel stem cell isolation techniques that maximize stem cell availability for transplantation.[7] To ensure minimal loss in transplanting the isolated stem cells, engineers at StemCell Systems designed a deposition device, the skin cell gun, to gently deliver the cell suspension without exposing cells to harsh forces in conventional spray devices.[7]

The skin cell gun method was first used experimentally at Charité – Universitätsmedizin Berlin on a group of nineteen patients. The clinician in that study determined that the results from the skin gun treatment was so significantly better than traditional grafting that he discontinued performing skin grafts on a control group on the basis of medical ethics.[1]

Subsequently there have been approximately thirty patients treated at UPMC Mercy Hospital in Pittsburgh, including patients who have been able to leave hospital within four days of treatment.[3]

Previous regenerative medicine approaches[edit]

The pursuit of tissue engineered products as skin substitutes began more than 20 years ago with improved culture methods for the growth of keratinocytes, and the production of natural and synthetic matrices used as delivery systems for cells or cell products.[8]

Any epidermal replacement must restrict the loss of water from underlying tissues, and provide a barrier against the introduction of chemical, physical, and microbial agents in the environment. Dermal replacements must be pliable and able to vascularize, in order to support the epidermis and fulfill other skin functions such as perspiration. Some earlier methods of skin regeneration include:

  1. Cultured epithelial autograft (CEA) involves the isolation of a patient's own epidermal keratinocytes, which are then cultured in sheets for subsequent transplantation. The long cultivation time and delicate nature of the sheets usually relegate use of this method to treatment in the most severe burns.
    1. Rheinwald and Green experimented with treating whole skin samples in vitro with enzymes to separate the layers of the skin then break down the epidermis into individual cells. The cells were then grown on a layer of non-living, irradiated mouse cells, producing sheets of epidermal cells were available for grafting after several weeks.[9][10]
    2. By 1988, CEA began to move into mainstream use for deep second and third degree burn injury, and congenital nevi. Individual keratinocytes cultured in a controlled setting produce colonies that fuse and form a multilayered epithelium, which may then be used as a skin substitute.[10]
  2. Skin glue has been used to successfully treat deep partial and full-thickness burn injuries. Histologically normal epidermis has been shown to develop in situ.[10]
  3. The direct application of keratinocyte cell suspensions has also shown promise. When delivered within a fibrin spray, keratinocytes promote the closure of deep partial and full-thickness burns, and of chronic wounds. The fibrin helps secure even placement of the keratinocytes. The keratinocyte spray technology is being commercialized for human use pending clinical trials and regulatory approvals (ReCell®, CellSpray®, CellSpray®XP).[10]
  4. “Acellular dermal substitutes have been evaluated for their ability to jumpstart neodermis formation and to provide a matrix compatible with reepithelialization and neovascularization.”[10]
    1. De-epidermized dermis is structurally identical to dermis and can be purchased as Alloderm ®. It can be used in conjunction with either STSG or CEA. De-epidermized dermis offers the advantage of being able to support engraftment of thin rather than thick STSG.
    2. Dermal matrix molecules require extensive remodeling to achieve normal dermal structure. Sold as Integra®, the pore size of the matrix is designed to be sufficient to allow fibroblast and endothelial cell migration to occur, and for the product to be remodeled by invading host cells. Neodermis is formed in about 3 weeks, at which time the silastic layer readily detaches. As with de-epidermized dermis, to achieve permanent wound closure, the treated area must be grafted with either a thin STSG or with CEA.[10]

Biological basis[edit]

Keratinocytes are epidermal cells that synthesize keratin and other proteins.[11] They are formed from undifferentiated (basal) cells and comprise 95% of the epidermis. Access to populations of keratinocytes that can be grown and expanded in vitro and still serve as stem cells subsequent to transplant is a requirement for producing epidermal skin substitutes.[10]

The overall goal of tissue engineering is the recapitulation of normal skin and normal skin function.

Operation[edit]

Stem cells from a biopsy of the patient's healthy skin are isolated, placed into a sterile syringe with a fitted nozzle, and sprayed directly through the nozzle into the wound. Using computer precision, the gun distributes cells at a uniform velocity throughout the wound. Then, a temporary artificial wound capillary system is applied. A tube is attached to each end of the dressings, one doing the work of an artery and the other of a vein. A bioreactor is attached to this artificial vascular system to provide nutrition such as glucose, sugar, amino acids, antibiotics and electrolytes; and support the fragile skin stem cells until they start to grow and generate new skin.

The newly introduced stem cells are able to regenerate and differentiate into their respective parts in a matter of days. The first phase of gathering the patient’s stem cells, creating a solution, and applying the stem cells takes approximately 1.5–2 hours. Within a week, the wound dressing procedure allows the stem skin cells to fully generate normal skin, and after a couple of months the skin regains its color and texture.[8][12]

Natural skin healing process[edit]

The natural skin healing process is a grouping of the mechanisms that allows the skin to repair itself after a tear, burn or other injury.[13] For healthy skin, the epidermis and dermis layers, together form a protective barrier that shields the inner body. Once that barrier is broken, the normal healing process is set in motion. Wound healing generally has three different stages: the inflammatory stage, the proliferative stage and the remodeling stage.[14] Once the skin is damaged, a series of interrelated events take place in close succession in order to repair the skin.[15] Within minutes after an injury occurs, blood platelets collect at the site of injury to form a clot. This clot limits bleeding at the injury site. The inflammatory phase causes bacteria and debris to be removed from the wound, and signals are released that result in the division of cells for repair. The proliferative phase is shown by the formation of new tissue at the injury site, the replacement of new skin at the site and the general shrinking and eventual disappearance of the wound.[16] New blood vessels are also established during the healing process. The wound is made smaller by myofibroblasts, which hold on to the edges of the wound and slowly get smaller by a system similar to the contraction of muscle cells. When cellular repair is complete unneeded cells are disposed of through apoptosis.

Comparison to traditional methods[edit]

Whereas it takes mere hours to prepare and administer stem cells with the stem cell gun, it takes 2–3 weeks to produce a skin sheet and harvest it from an external lab. Once the skin sheet has been attached to the wound, blisters form under the newly attached skin, pushing the sheet up, damaging the wound and increasing the risk of infection. The skin cell gun applies its stem cells directly to the patient's cells, which alleviates the concern of further tissue damage. The artificial vascular system network also provides a reliable source of protection to the skin stem cells. After the wound has been treated, it takes months for the skin sheet to heal over, yet only days for the skin cell gun to fulfill its function. Reducing the fragility of the cells and time frame of the operation by cleverly employing differentiated stem skin cells in such a way that offers a renewable source of replacement is an essential component of the skin cell gun’s capability.[8]

Applications[edit]

The current method is applicable to different burn damaged areas. Patients who have incurred second-degree burns, patients with infected wounds or patients with delay in wound healing are suitable for cell grafting treatment.[17] Third-degree burns, however, completely deprive victims of both their epidermis and dermis skin levels, which exposes the tissue surrounding the muscles. The skin cell gun has not progressed to the point where it can be used for such advanced wounds, and these patients must seek more traditional treatment methods. The skin cell gun is generally not used for burn victims with anything less than a second-degree burn either. First degree-burns still maintain portions of the epidermis and can readily heal on their own, thus they do not need this expensive technology.

Currently, the skin cell gun's applications have not been extended to include the regeneration of skin lost due to other injuries or skin diseases. It is also limited in that it is only effective immediately following the burn incident.[18]

Results[edit]

Since 2008 the skin cell gun has been under development for the treatment of second degree burns. It is not yet approved by the FDA. Stem cell damage during the spraying procedure is a current research hurdle.[19] This treatment is only for recently burned victims; it will not yet work for those who suffered the injury a few months prior.

A few days are required for the wounds to internally heal with this new process; but after those few days, the wound still looks damaged. The skin will not start to look as it did before the injury until months afterward. Because pigment cells are so much deeper in the part of the skin than keratinocytes are, pigment cells need much more time to develop.[20]

Benefits and side effects[edit]

The average healing time for patients with second degree burns takes weeks, which the skin cell gun reduces to days. Traditional skin grafting can be risky, in that chances for infection are relatively high. The skin cell gun alleviates this concern because the increased speed in which the wound heals directly correlates to the decreased time the wound can be vulnerable to infection. Although it takes several months for the skin to regain the exact texture and color before the incident, harmful side effects that can result from an open wound are not a factor.[21]

Applying the skin cells is quick and doesn't harm the patient because only a thin layer of the patients’ healthy skin is extracted from the body into the aqueous spray. The electronic spray distributes the skin cells uniformly without damaging the skin cells, and patients feel as if they are sprayed with salt water.[21]

Because the skin cells are actually the patient’s own cells, the skin that is regenerated looks more natural than skin grown from traditional methods. During recovery, the skin cells grow into fully functional layers of the skin, including the dermis, epidermis, and blood vessels.[22] The regenerated skin leaves little scarring. The basic idea of optimizing regenerative healing techniques to damaged biological structures demonstrated by the skin cell gun in the future may also be applied to engineering reconstruction of vital organs, such as the heart and kidneys.[22]

There are major limitations: the method will not work on deep burns that go through bone and muscle, specifically below the dermis. As of 2011, only several dozen patients have been treated; it remains an experimental, not a proven, method. As of 2011, the skin cell gun was still in its prototyping stage, since it has only treated a dozen patients in Germany and the US, compared to over 50,000 treated with Dermagraft bioengineered skin substitute. There is thus a lack of published peer reviewed clinical evidence, and no knowledge of long-term stability of the newly generated skin.

See also[edit]

Keratinocyte-fibrocyte concomitant grafting for wound healing by Mark B. Lyles United States Patent 7,641,898 Filed Mar 21, 2003. The first filing of a skin spray device in the United States.

References[edit]

  1. ^ a b Hartmann B., et al. Sprayed cultured epithelial autografts for deep dermal burns of the face and neck. Ann Plast Surg. 2007 Jan;58(1):70-3. (link retrieved Feb 4, 2015)
  2. ^ Gerlach, J. C. et al. Method for autologous single skin cell isolation for regenerative cell spray transplantation with non-cultured cells. Int J Artif Organs 2011; 34(3): 271 - 279 (link retrieved Feb 4, 2015)
  3. ^ a b Gerlach, J. C. et al. Autologous skin cell spray-transplantation for a deep dermal burn patient in an ambulant treatment room setting. Burns 37, e19-e23 (2011) (link retrieved Feb 4, 2015)
  4. ^ RenovaCare, Inc. (formerly Janus Resources, Inc.) SEC form 8-K/A filed on November 21, 2013.. (link retrieved Feb 4, 2015)
  5. ^ RenovaCare, Inc. Website Technology Q&A (link retrieved Feb 4, 2015)
  6. ^ RenovaCareInc.com 'About' page(link retrieved Feb 10, 2015)
  7. ^ a b Gerlach, Johnen et al. Method for autologous single skin cell isolation for regenerative cell spray transplantation with non-cultured cells. Int J Artif Organs. 2011 Mar;34(3):271-9.
  8. ^ a b c Ellis, Bob (3 Feb 2011). "Skin Gun Uses Adult Stem Cells". Dakota Voice. Retrieved 20 April 2011. 
  9. ^ Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell. 1975 Nov;6(3):331-43.
  10. ^ a b c d e f g O'Connor NE, Mulliken JB, Banks-Schlegel S, Kehinde 0, Green H (1981). Grafting of burns with cultured epithelium prepared from autologous epidermal cels. Lancet. pp. 75–8. 
  11. ^ keratinocyte. (2011). In Encyclopædia Britannica. Retrieved from
  12. ^ Lorianna De Giorgio, "Skin gun that sprays stem cells being used on burn victims", Toronto Star, February 7, 2011
  13. ^ Nguyen, D.T., Orgill D.P., Murphy G.F. (2009).The Pathophysiologic Basis for Wound Healing and Cutaneous Regeneration. New York pg. 234 .
  14. ^ Quinn, J.V. . Tissue Adhesives in Wound Care. B.C. Decker. Hamilton Decker Inc., Ont. B.C. ,1998
  15. ^ Stadelmann, WK; Digenis, AG; Tobin, GR . "Physiology and healing dynamics of chronic cutaneous wounds.". American journal of surgery 1998. pg 176
  16. ^ N/A Biomaterials For Treating Skin Loss. Woodhead Publishing (UK/Europe) & CRC Press (US), Cambridge/Boca Raton, pg 25-57.
  17. ^ Gerlach, J. C. et al. Autologous skin cell spray-transplantation for a deep dermal burn patient in an ambulant treatment room setting. Burns 37, e19-e23 (2011
  18. ^ "Skin cell gun sprays stem cells for fast recovery from serious burns." RobAid, February 6, 2011. Accessed March 26, 2011. [1]
  19. ^ Edwards 2011
  20. ^ RobAid 2011
  21. ^ a b Hanlon, Tegan. "Skin-cell Gun Expedites Burn Victim Recovery Time." The Pitt News (Pittsburgh), February 2, 2011. Accessed March 29, 2011. [2]
  22. ^ a b Underwood, Anne. "Military Medicine: The War on Wounds - Newsweek." Newsweek. 10 May 2008. Web. 10 May 2011. [3].