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Integra™ - a therapeutic alternative in reconstructive surgery. Our first experience
Sidonia Popescu, N. Ghetu, Oana Grosu, Mihaela Nastasa, D. Pieptu (Chirurgia, 102 (2): 197-204)
Introduction
Coverage is one of the most important issues in plastic surgery. The both acute and reconstructive surgery can often face with limited donor site availability requiring additional therapeutic options. Surgeons are in a struggle to find the best (functional and esthetic) solution for closing a tissue defect after a trauma, for skin replacement in a severe burn patient or for removing a scar with functional impairment or esthetic involvement. Grafts and flaps were developed for each clinical situation. But all have a price. One can never cover a defect without creating another. The surgeon has only the option to find some "spare parts" in other region of the patient's body. And in most situations, the plastic surgeons are more than happy to find that "unique" solution, the most adequate for a specific case. However the patients will always wait for the day when these "spare parts" will be readily available.
One of the research direction developed in the last 30 years is the quest for the "artificial skin". This goal is not yet reached but lots of progress has been made. Although technically it is not a real an artificial skin, the most important break through in the field is Integra™, a permanent skin substitute used in acute full thickness burns, after injuries and also in reconstructive surgery. Described for the first time in 1981 by Bruke and Yannas (1-5), Integra™ is an artificial bilayer acellular skin substitute, a dermal regeneration template, covered by a silicone sheet. The dermal layer is organized as a matrix of fibers of cross-linked bovine tendon collagen (collagen type I) and shark glycoso-aminoglican (chondroitin-6-sulfate) (1). It has a porous structure similar to the normal human dermis. The size of the pores ranges from 70 to 200 microns (6) that allows the migration of the host cells. This dermal template becomes the host for the migrating cells originated in the wound bed - endothelial cells, fibroblasts and macrophages (1-5, 7). While the macrophages degrade the artificial collagen, host fibroblasts synthesize endogenous collagen and neovessels develop from the endothelial cells. In this manner, after 3 to 6 weeks, the artificial dermal scaffold is completely replaced by a "neodermis" with a structure almost similar with normal human derm (6). The epidermal-like layer consists of synthetic polysiloxane polymer (silicone) (8). It acts as a barrier against bacterial invasion and prevents the fluid lost (1-5, 8, 9). Once the neodermis is completely integrated into the wound bed, the silicon layer can be peeled away atraumatically, without bleeding and should be replaced with an ultra-thin autoepidermal graft (0.1 mm). The histological studies demonstrated the same four phases of derm regeneration: imbibition, fibroblast migration, neovascularisation and remodeling and maturation (10).
Senior author's previous experience with various skin substitutes and Integra™ (11, 12) determined us to use the product in our department. This is the first report on the use of Integra™ in Romania. Since by the end of this study the product became available in our country too, we think that our preliminary experience might be of an interest for our colleagues.

Material and Method
Being the first use of Integra™ in Romania we decided to start with small area defects. Three patients were selected. The selection's criteria were - localized defects, no larger than 10 x 25 cm (the size of one piece of Integra™) with no other diseases, wiling to cooperate and accepting two operations and long period of hospitalization.
The surgical technique is simple: excision of the scar or defect debridment followed by thorough hemostsis of the receiving bed; Integra™ preparing - aseptic removal from the package, cleaning with saline until the alcohol smell disappears, small perforation with scalpel blade no11, suture or staples, tie-over dressing; careful immobilization as requested. Dressing is changed under operative condition as often as requested. Careful searching for haematoma, infection, or Integra™ displacement is mandatory. Skin grafting (ultra-thin unmeshed split-thickness) is performed in the 21-st day. Antibiotics are administrated for short terms (72 hours) pre and postoperatively both for Integra™ placing and grafting.
Results
All the three cases were solved without problems. Even the anatomic regions were demanding (cervical area, frontal area and penis) we had no Integra™ displacement. The skin graft take was 100% in all the cases. We had no haema-toma, no infection. Follow up period is 3 to 8 month.
Cases reports:
Case 1 (Fig. 1). A 28-years old man was admitted in our department with severe scar contracture of the cervical area after a 40 % TBSA deep burn located mainly on his neck, anterior chest and shoulders. Upon arrival, one and a half years after the accident, the mouth opening was less than 3 cm and the extension of the neck almost impossible. Tissue expanders were considered inappropriate for three reasons. First he had good quality skin in less advantageous areas. Second, his occupation (farmer in a remote village) did not allow weekly expander filling. Third, he developed repeated cervical area infections with numerous fistulous trajects due to the hair follicles growth through the scar tissue. Free tissue transfers were difficult to plan due to the scarred disseminated on various regions. In the first step, the hypertrophyc cervical scar was removed, followed by cervical angle relaxation and revealing of the size of the defect. Care was taken to remove all the infected tissues. After meticulous haemostasis one Integra™ sheet was applied and fixed with tie-over dressing. Preoperative intravenous antibiotics were administered (Cefort R, 3 g / day). The dressing was changed on the postoperative day 3 and all signs of localized infection were traced and treated using topical antiseptics. Further dressings were repeated at 3 days interval, all under surgical condition. In the 21-st postoperative day the second operation was performed. The neovascularisation of the dermis had taken place and an ultra-thin unmeshed split-thickness skin graft was placed. The autograft take was 100 %. One week later, after skin graft take, a Minerva type immobilization was placed. The patient was discharged and asked to use this immobilization for three month day and night, and additional three only by night. He refused to use it. At 3 months follow-up the extension of the neck was significant improved, the mouth opening was almost normal, skin was flexible, pliable and normally pigmented, with no signs of hypertrophyc scar. However, we did notice some contracture under the new skin. After 6 month the contact with the patient was lost.
Figure 1a
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Figure 1e

Case 2 (Fig. 2). A 12 years young girl was admitted in our department for the treatment of an alopecia due to a severe contact burn in early childhood (6 months old), when she felt down to an oven. In a first step we used a tissue expander to advance the hairy skin up to the hairline. One year later was scheduled the second reconstructive step - frontal scarred skin replacement with full thickness skin graft taken from the abdominal area. In order to conceal better the donor area we placed another tissue expander under the abdominal skin. The expansion went uneventfully, and skin grafting was scheduled after 3 months during the school holiday. However upon admission we realized that the expanded skin was useless due to a scar (poststaphiloccocyc infection) that occurred exactly in the middle of the expanded area. After discussion with the family we decided to use Integra™. The forehead scarred skin was removed down to the periosteum since frontalis muscle was almost absent being replaced by scar tissue. The principle of esthetic frontal unit was respec-ted and some good skin was also discarded. After thorough hemostasis a sheet of Integra™ was applied and tailored on the remaining bed and fixed with separated sutures. Betadine moistened gauzes were applied and a tie-over dressing assured the permanent contact between the dermal layer and the wound bed. First inspection and dressing change was performed in the operation room in the 5th postoperative day. A small haematoma above the middle of the right eyebrow was removed as in usual skin grafts. In the day 21st the skin grafting was scheduled. The vascularised neodermis had formed and the deffect was grafted with one piece of an ultra-thin non meshed split-skin graft. The graft take and the donor site healing were complete within 10 days. After 4 months, the follow up shows good cosmetic result, with normally pigmented, pliable, non-adherent skin. At 6 month the patient and her family are completely satisfied. She is currently waiting to continue the surgical treatment in the orbitopalpebral area.

Figure 2a
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Figure 2g
Figure 2h

Case 3 (Fig. 3). A 31-years old man was admitted in our unit immediately after suffering a traumatic avulsion (chain mechanism) of the skin over all the anterior perineum with full degloving of the external genitals, penis and both testicles. Upon admission the first surgical debridment was performed with complete removal of the compromised tissue and thorough cleansing. A urethral catheter was placed. The coverage was performed 48 hours later. After meticulous repeated cleansing and haemostasis, the testicles were grafted with meshed split-thickness skin graft harvested from the left thigh. The penis was circumferential grafted with one sheet of Integra™. Since 85% of the preputial mucosa was intact we decided to reconstruct this segment too. A special immobilization device was designed and a tie over dressing was placed. The penis was immobilized in a perpendicular manner as in erection. The dressing was changed in the third postoperative day, when a small seroma had to be evacuated. Dressings were repeated at 3 to 4 days interval. Careful cleaning of the urethral catheter was performed twice daily. In the 21th postoperative day the silicon layer could be peeled away and whole penis was grafted with thin split-thickness skin graft. Immobilization with the same method and the urethral catheter were maintained. Further healing was uneventful and the graft take was 100 %. At 3 months follow-up the patient has satisfactory cosmetic results - the skin start to regain its flexibility and supplesse. There are no signs of hypertrophic scars.

Figure 3a
Figure 3b
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Figure 3d
Figure 3e

Discussion
The wound healing process may lead to tight, painful, mutilating scars or debilitating contractures that require reconstructive surgery. Integra™ is a therapeutic concept suitable both for acute and reconstructive surgery, and it became extensively used in the last five years in burns (9, 13-15) and in reconstructive surgery - cervical area (16), breast area (17), donor areas (7), various flaps (18, 19), after tumor resection (20), or even trauma (21). Its main advantages are the unlimited, immediate availability, associated with simplicity and reliability of the surgical technique (22). One should also consider the superior cosmetics results, with a grater flexibility and suppleness of the resulted skin, leading also to increasing range of movement on functional area (9). Its biocompatibility with low antigenicity and decreased host inflammatory response limit the granulation tissue and hypertrophyc scar formation (13). The contraction of the miofibroblasts is inhibited (13) thus preventing wound contractions. Using this material in coverage of exposed structure might avoid the need of local or free flaps. The ultra-thin split-thickness skin graft decreases the morbidity of the donor site, with rapid reepithelialization.
There are also some disadvantages. The price (23) is the main one. A sheet measuring 25 cm x 10 cm, similar with those utilized in each of our cases costs about 2100 EUR in Romania. The method requires also a two-stage procedure that demands a good cooperation with the patient. The third main disadvantage is the long hospitalization. All our cases stayed in hospital four to five weeks. One may shorten this period down to three weeks by grafting after only 14 days and discharging one week later. We do not think this is an option for most of the patients in our country. That is why we consider that a careful patient selection is mandatory, regular follow-up being important for the success of the reconstruction. However, in our opinion the advantages outweigh the disadvantages of the two-staged procedure which is comparable to many flap placing and pedicle detaching procedures.
Some authors argue that Integra™ is particularly susceptible to infections because it has no intrinsic immunological defense (19). Careful debridement, good excision, thorough haemostasis of the wound bed and frequent inspection are easy and straightforward steps to perform. Minor and major haematoma should be avoided by meticulous haemostasis. Should they appear, easy pressure and puncture are the best way to cure it. Infection should be prevented and not cured. As in classical skin grafting the best way to prevent infection is careful hemostasis and adequate immobilization. A short term preoperative antibiotherapy is advisable. We strongly consider that a very important point is the follow-up and the dressing change under surgical condition. Care should be taken to avoid collapsing the structures of the dermal matrix by compression (10) or silicon detachment.
The patients' complains are most frequently: pain, prurit and dry skin (17). None of our patients claimed such reactions. However in all the cases we advised free use of hydratating ointment starting two week after skin grafting.

Conclusions
Integra™ is a very attractive coverage solution in a large spectrum of clinical situation. It represents a functional and esthetic benefit for the patient and also a safe boat for surgeons. A meticulous surgical technique, with careful debridment of the wound, thorough haemostasis, and standardized dressing protocols are mandatory for a very good result.
The final qualities of the skin achieved with Integra™ dermal regeneration template are comparable to those with full-thickness skin graft. It adds however some other advantages: non adhesion to deep tissue, no hypertrophyc donor site scarring, less retraction.

Disclosure
In conducting this study, none of the authors had any kind of financial / material support and / or endorsement from any medical company from Romania or abroad.

References
1. YANNAS, I.V., BURKE, J.F. - Design of an artificial skin: I. Basic design principles. J. Biomed. Mat. Res., 1980, 14:65.
2. YANNAS ,I.V., BURKE, J.F., GORDON, P., HUANG, C., RUBENSTEIN, R. - Design of an artificial skin: II. Control of chemical composition. J. Biomed. Mat. Res., 1980, 14:107.
3. YANNAS, I.V., BURKE, J.F., QUINB, W., JUNG, W. - Successful use of a physiologically acceptable skin in the treatment of extensive burn injury. Ann. Surg., 1981, 194:413.
4. YANNAS, I.V., LEE, E., ORGIL, D., SKRABUT, E., MURPHY, G. - Synthesis and characterization of a model extracellular matrix that induces partial regeneration of adult mammalian skin. Proc. Natl. Acad. Sci., 1989, 86:933.
5. BURKE, J.F. - Observations on the devlopement and clinical use of artificial skin an attempt to employ regeneration rather than scar formation in wound healing. Jpn. J. Surg., 1987, 6:431.
6. GRANT, I., GREEN, C., MARTIN, R. - Strategies to improve the take of commercially available collagen/glycosaminoglycan wound repair material investigated in an animal model. Burns, 2001, 27: 699.
7. WANG, J. C.Y., TO, E.W.H. - Application of dermal substitute (Integra™) to donor site defect of forehead flap. Brit. J. Plast. Surg., 1999, 55:70.
8. HORCH, E., KOPP, J., KNESSER, U., BEIER, J., BACH, D.A. - Tissue engineering of cultured skin substitutes. J. Cell. Mol. Med., 2005, 9:592.
9. FITTON, A.R., DREW, P., DICKSON, W.A. - The use of a bilaminate artificial skin substitutes (Integra™) in acute resurfacing of burns: an early experience. Brit. J. Plast. Surg., 2001, 54:2008.
10. MOINEM, S.N., STAINO, J.J., OJEH, O.N., THWAY, Y., FRAME, D.J. - Reconstructive surgery with a dermal regeneration template: clinical and histologic study. Plast. Reconstr. Surg., 2001, 108:93.
11. PIEPTU, D., BRAYE, F., LUCHIAN, S., DAMOUR, O. - Skin substitutes for the permanent coverage of burned patient, Rom. J. Plast. Surg., 1999, 7:144.
12. BRAYE, F., STEFANI, A., VENET, E., PIEPTU, D., TISSOT, E., DAMOUR O. - Grafting of large pieces of human reonstructed skin in a porcine model, Brit. J. Plast. Surg., 2001, 54:532.
13. CHOU, T.-D., CHEN, S.-L., LEE, T.-W., CHEN, S.-G., CHENG, T.-Y., LEE, C.-H., CHEM, T.-M., WANG, H.-J. - Reconstruction of burn scar of the upper extremities with artificial skin. Plast. Reconstr. Surg., 2001, 108:378.
14. DANZER, E., QUERUEL, P., SALINIAER, L., PALMIER, B., QUINOT, J.F. - Dermal regeneration template for deep hand burns: clinical utility for both early grafting and reconstructive surgery. Brit. J. Plast. Surg., 2003, 56:764.
15. LOSS, M., WEDLER, V., KUENZI, W., MEULI-SIMMEN, C., MEYER, V.E. - Artificial skin, split-thickness autograft and cultured autologous keratinocytes combined to treat a sever burn injury of 93% of TBSA. Burns, 2000, 26:644.
16. HUNT, J.A., MIOSIDIS, E., HAERSCH, P. - Initial experience of Integra in the treatment of post-burn anterior cervical neck contracture. Brit. J. Plast. Surg., 2000, 53:652.
17. PALAO, R., GOMEZ, P., HUGUET, P. - Burned breast reconstructive surgery with Integra dermal regeneration template. Brit. J. Plast. Surg., 2003, 56:252.
18. GIOVANINNI, U.M., TEOT, L. - Aesthetic complex reconstruction of the lower leg: application of a dermal substitute (Integra) to an adipofascial flap. Brit. J. Plast. Surg., 2001, 55:171.
19. MOORE, C., LEE, S., HART, A., WATSON, S. - Use of Integra to resurface a latissimus dorsi free flap, Brit. J. Plast. Surg., 2003, 56:66.
20. KOPP, J., NOAH, M.E., RUEBBEN, A., MERK, H.F., PAULLA, N. - Radical resection of giant congenital melano-cytic nevus and reconstruction with Meek-graft covered Integra dermal template. Dermatol. Surg., 2003, 29:653.
21. WOLTER, T.P., NOAH, M.E, PAULLA, N. - The use of Integra™ in an upper extremity avulsion injury. Brit. J. Plast. Surg., 2005, 58:416.
22. PAPP, A., HAERMA, M. - A collagen based dermal substitute and the modified Meek technique in extensive burns. Report of three cases. Burns, 2003, 167-171.
23. JOENS, I., JAMES, S.E., RUBIN, P., MARTIN, R. - Upward migration of cultured autologous keratinocytes in Integra™ artificial skin: a preliminary report. Wound Repair and Regeneration, 2003, 11:132-138.


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