EXPERIENCE WITH INTEGRA^® AT THE PRAGUE BURNS CENTRE 2002–2016

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Authors: R. Zajíček; I. Grossová; H. Šuca; R. Kubok; I. Pafčuga
Authors‘ workplace: Prague, Czech Republic ; Clinic of Burns Medicine, Královské Vinohrady Teaching Hospital and 3rd Faculty of Medicine, Charles University
Published in: ACTA CHIRURGIAE PLASTICAE, 59, 1, 2017, pp. 18-26

INTRODUCTION

Integra^® (Dermal regeneration template, Integra Life Sciences, Plainsboro, USA) is a biosynthetic skin replacement made of network of bovine collagen fibres and glycosaminoglycane (GAG) that is covered by a semipermeable silicone foil serving as a temporary epidermal cover. After placing the template into a skin defect, a gradual vascularization and replacement of bovine collagen by patient´s own collagen takes place, and so-called „neodermis“ is formed within several weeks. The silicone foil cover of a fully vascularized tissue is then removed and a thin dermoepidermal (DE) graft is applied. When the DE graft successfully heals in, the bilaminar tissue has better functional and cosmetic features as compared to the standard method of DE grafting.^1,2 The main advantages of Integra^® include a better coverage of extensive skin losses, transplantation of thin DE grafts with a minimal morbidity of a harvested area, excellent cosmetic and functional effects due to a high elasticity of bi-laminar tissue, zero immunological intolerance and a reduced number of follow-up reconstructive surgeries.^3,4 The application of Integra^®is indicated in burns medicine as well as in reconstructive surgery and traumatology for the coverage of soft tissue defects.⁵

Integra^® was first used in the Czech Republic in 2002 at the Prague Burns Centre, Královské Vinohrady Teaching Hospital to manage an extensive burn trauma in a child. Since then it has become an inseparable part of treatment of burn patients.⁶This article presents our experience with the use of Integra^® skin replacement in clinical practice since 2002. We evaluated even the early patients after a long period from the first application. The obtained clinical data were correlated with the results of histological assessment of scar tissue after the application of Integra^® and DE graft.

Study groupIntegra^® was applied in total in 47 patients from July 2002 till May 2016 (Table 1). Two patients from this group were treated in another workplace. A 4-year-old girl after a car accident with skin avulsion of 25% body surface area was operated on in the Child Trauma Centre of Thomayer Hospital and a 10-year-old girl with an extensive pigment naevus on her knee was operated on at the Clinic of Plastic Surgery, Královské Vinohrady Teaching Hospital, both in Prague.

**Table 1. The group of patients treated by Integra<sup>®</sup> skin replacement in 2002–2016**

In total, there were 28 patients of child age at the time of application, another 19 patients were adults. The main indication for the child group was reconstruction of scar contractures following a burn trauma. Eight children were treated by skin replacement within the surgical management of an acute trauma. In these cases, Integra^®was used to quickly cover the body surface in patients loosing over 50% of their skin and with limited harvesting possibilities. In adult patients, we used Integra^® to treat an acute burn trauma in 11 patients. Another 9 patients received it to cover defects following a release of scar contractures. Of the paediatric patients, three had Integra^® applied both in acute and reconstruction periods. Three patients were operated on with a repeated application of Integra^® on different body parts in various time intervals. Three adult patients from our group died of the complications of their burn injury.

During 2016, we invited 11 patients treated by Integra^® in the past for a follow-up visit. The interval from the last application was at least 2 years. The average time since application was 9 years. Originally, our subjects were 3 adults and 8 children. At the follow-up visit, their average age was 30 years. All these patients had primarily received Integra^® during acute trauma management. Their scars were objectively evaluated by the modified Vancouver Scar Scale (VSS). A subjective assessment of scar quality was performed by means of a questionnaire. The area covered by Integra^® was compared with the scar after the application of DE graft in anatomically similar localisation. Questions of the subjective assessment were focused on a functional result, cosmetic effect and innervation, always in com-parison with the scar after DE transplantation. Having signed an informed consent, patients then underwent a punch biopsy of 2–5 mm in diameter (according to the localisation), which was later evaluated histologically. (Table 2.)

**Table 2. Scar follow-up in patients after at least 2 years since the application of Integra<sup>®</sup>**

RESULTS

On the subjective assessment, all patients reported an improvement of functional and aesthetic perception of the Integra^®-covered sites in comparison with the scars where the primary treatment consisted of DE grafting only. Patients observed no significant difference in the innervation between these sites. One of the patients operated on in 2002 noticed absent perception of warmth in lower limbs where the replacement had been used.

On the objective assessment by means of VSS, sites covered by Integra^® scored 1.4 points on average, whereas scars after DE transplantation scored on average 4 points on the same scale.

Case report No.1

Male, 33 years old, injured in 2003, suffered 2^nd and 3^rd degree burns from burning of construction foam on 75% body surface area. Integra^® had been applied after a fascial necrectomy to cover an area on his left lower limb (Fig.1A). The healing was complicated by Staphylococcus aureus infection resulting in the loss of coverage on and under the poples (Fig. 1B). Thirteen years after the injury, a cosmetic difference of scars was obvious between the right lower limb, where medium-thickness dermoepidermal grafts were used, and the left one, where Integra^® was applied (Fig.1C). The left side exhibited a clearly visible border at the proximal part of crus between the scar, where Integra^® successfully healed, and the site where Integra^® was rejected due to an infection with a subsequent transplantation of skin grafts on the basis lacking neodermis (Fig.1D). On histological assessment, we found characteristic differences between the scars on the left and right lower limbs (Fig. 2).

Fig.1. Comparison of scars after the application of Integra<sup>®</sup> 13 years after the injury in the patient with 2nd–3rd degree burns of 75% body surface area — **Fig.1. Comparison of scars after the application of Integra^® 13 years after the injury in the patient with 2nd–3rd degree burns of 75% body surface area**
A. The condition after placing Integra^® on the left lower limb in an extensively burnt patient, B. The site of infectious complication in poples resulting in Integra^® rejection from the wound bed, C. The condition after 13 years since application with a visible cosmetic difference between scars on the left lower limb (Integra^®) and right lower limb (DE graft), D. The site of transition (arrow) from the healed Integra^® and the area where the DE graft was applied after rejection

Fig. 2. The comparison of histological structure of the scar after the application of Integra<sup>®</sup> 13 years ago with the scar after the transplantation of DE grafts — **Fig. 2. The comparison of histological structure of the scar after the application of Integra^® 13 years ago with the scar after the transplantation of DE grafts**
**Fig. 2A.** The scar after application of Integra^® with collagen fascicles oriented roughly in parallel to the skin surface. Deeper parts of neodermis contained detectable residues of original bovine collagen matrix even after 13 years (inserted image). Stained by haematoxylin & eosin, original image scale 100x, image insert 600x **Fig.2B.** Chaotic course of collagen fibres in the scar after DE grafting. Stained by haematoxylin & eosin, original image scale 100x **Fig. 2C.** Elastic fibres are thin and often fragmented in case of Integra^® application with relatively even distribution in the sample (arrows). Stained by orcein, original image scale 200x **Fig. 2D.** The scar after DE grafting contains thick, fragmented and unevenly distributed elastic fibres (arrows). Stained by orcein, original image scale 200x

Case report No. 2, extensive burn trauma

A 9-year-old boy was burnt in 2002 on 85% of body surface area, of which 75% were 3^rd degree burns. In his case, Integra^® was used for the first time in the Czech Republic to cover lower extremities (Fig. 3A–3C).

Fig. 3. The course of treatment by Integra<sup>®</sup> on lower limbs in the patient with 75% burns of 3<sup>rd</sup> degree — **Fig. 3. The course of treatment by Integra^® on lower limbs in the patient with 75% burns of 3^rd degree**
A. The area with 3^rd degree burns on both lower limbs, B. The condition following fascial necrectomy of burnt area, C. The healed Integra^® prior to the transplantation of DE grafts

No scar contracture on the lower limbs has developed during the growth of this child. On the out-patient follow-up, after 14 years, there is a visible cosmetic difference between the scars on the lower limbs and the upper limb, where a mixed transplantation of DE grafts and allografts from his father was performed (Fig. 4A, 4B).

Fig. 4. Comparison of scars on lower limbs (Integra<sup>®</sup>) and upper limb (mixed transplantation of autografts and paternal allografts on wound bed without Integra<sup>®</sup>). Condition after 14 years — **Fig. 4. Comparison of scars on lower limbs (Integra^®) and upper limb (mixed transplantation of autografts and paternal allografts on wound bed without Integra^®). Condition after 14 years**
A. Scars on lower limbs after the application of replacement in 2002, B. The scar on the upper limb after the transplantation of DE grafts with a visible pattern of the original graft mesh

On immunohistochemical comparison of revascularization and reinnervation of Integra^®, we were surprised to find a reconstituted superficial dermal plexus in a virtually normal quality. The restitution of superficial vascular plexus within the scar was imperfect. The reinnervation was observed in both samples. The scar after Integra^® application had less peripheral nerve fibres in comparison with the scar after application of DE grafts. No clinical change was observed (Fig. 5A, 5B).

Fig. 5. The histological comparison of tissue revascularization after the application of Integra<sup>®</sup> and DE graft — **Fig. 5. The histological comparison of tissue revascularization after the application of Integra^® and DE graft**
A. Neodermis following Integra^® application with a reconstituted superficial dermal plexus (of virtually normal quality), B. The restitution of superficial vascular plexus is imperfect in the scar without Integra^®. Immunohistochemical staining with primary monoclonal antibody anti-CD31/PECAM-1 marking endothelium, original image scale 400x

Case report No. 3, chemical trauma

Female, 39 years, suffered a 3^rd degree chemical burn on 30% body surface from a mixture of acids and lyes in a car accident in 2013. On surgical examination, we found a full-thickness skin loss on her face and neck. These areas were treated by Integra^®replacement. In the frontoparietal area, the wound reached even the skull on approx. 4x3 cm. Following several drills into lamina externa, the defect was also covered by Integra^®. (Fig. 6A–6D; Fig. 7A, 7B; Fig. 8A–8F.)

Fig. 6. The application of Integra<sup>®</sup> in the management of deep skin loss in face after a chemical burn by mixture of acids and lyes — **Fig. 6. The application of Integra^® in the management of deep skin loss in face after a chemical burn by mixture of acids and lyes**
A. A 39-year-old patient with chemical burns of 3^rd degree on her face due to a leakage of mixed acids and lyes during a car accident. 48 hours after admission a fascial necrectomy of burnt facial and neck areas was performed, B. Condition after necrectomy in face, head and neck 48 hours from the injury, C. The wound bed was covered by Integra^® (an arrow indicates the site of bone defect coverage), D. On day 25 since the application of Integra^®, vascularized neodermis was covered by thin non-meshed dermoepidermal grafts

**Fig. 7A, B. A cosmetic and functional result 3 years later**

Fig. 8. The coverage of exposed skull by Integra<sup>®</sup> replacement — **Fig. 8. The coverage of exposed skull by Integra^® replacement**
A. The wound in frontal area reached to the skull, B. Several drills of lamina externa were carried out, C. The wound was covered by Integra^® after drilling, D. The bone defect was rebuilt in course of maturation, E. The same area after coverage by DE graft, F. The result 2 years since application – no visible deformity

Case report No. 4, high-voltage electric injury

A 14-year-old girl was burnt by high-voltage electric current when climbing train wagons in 2003. She suffered burn injuries of 2^nd b–3^rd degree on 43% body surface area. Areas on the left part of the face, neck and adjacent head parts were managed by the application of Integra^®. (Fig. 9, Fig. 10.)

Fig. 9. A 14-year- old patient after an electric injury with 3<sup>rd</sup> degree burns on her face and head — **Fig. 9. A 14-year- old patient after an electric injury with 3^rd degree burns on her face and head**
A. Deep burns on the left half of face after the passage of high-voltage electric current, B. A condition after fascial necrectomy, C. A defect covered by Integra^®, D. A successfully healed thin non-meshed DE graft 2 weeks after the application

**Fig. 10. A cosmetic and functional effect 10 years later**

DISCUSSION

Published papers have unanimously confirmed favourable functional and cosmetic results of Integra^® in burn trauma.^7,8,9 The multicentre study conducted by Frame (2004) lists Integra^® as an adequate equivalent to the use of full-thickness transplants in the management of scar contractures due to burns.¹⁰ One of the main disadvantages of full-thickness grafts mentioned is the resulting scar at a harvested site. Our experience at Clinic of Burns Medicine, Královské Vinohrady Teaching Hospital in Prague confirm that Integra^® is very effective in the management of extensive burn injuries in childhood with a limited size of harvesting site. Integra^® was used in our workplace to successfully treat 90% burn injuries of 3^rd degree in a 9-year-old boy and to quickly cover 60% of his body surface. Only a few clinical case studies report on the application of Integra^® on a wound bed after a chemical or electric trauma.¹¹Despite the fact that the wound bed after a chemical trauma carries a high risk of deepening and subsequent excessive scarring, we applied Integra^® even in such a case of the patient with deep chemical burns of face by the mixture of acids and lyes.

The study by Graham published in the Journal of Burn Care and Research presents successful usage of Integra^® for definitive coverage of soft tissue defects with exposed deep structures such as bones or sinews.¹² Gonzales Alaña et al. confirm in their paper that usage of Integra^® in combination with V.A.C. (Vacuum Assisted Closure) system on denuded skeleton after burns is an adequate alternative to a surgical approach with free flaps, namely in patients with a serious contraindication of free tissue transfer.¹³We have not gained a clinically relevant experience with the combination of negative pressure and Integra^® at our workplace. Yet we applied Integra^® to cover the exposed bone in the aforementioned patient.

Injuries by electric current are one of the most severe ones in burn medicine. A definitive wound closure is often delayed even up to 6 weeks after the trauma because of wound depth progression. This is due to the influence of electric current foremost on blood vessels.¹⁴ In case of the electric trauma of the 14-year-old girl, we used Integra^® to cover areas of face and neck. Healing proceeded without complications and after the take of a thin DE graft, an intensive multimodal rehabilitation started. No scar contracture requiring surgical treatment has developed in subsequent years.

Regeneration of skin adnexa was not found in any analysed histological samples. Some published papers even refute the presence of elastic fibres in scars after Integra^® application. ¹⁵ Moiemen proved the presence of elastic fibres in all samples included in his group of biopsied patients. Elastic fibres however had abnormal morphology as our findings also confirm.^16,17 The presence of residue of the original bovine matrix was documented by Jeng 2 years after the application.¹⁸ Remnants of the original matrix in the biopsy sample of the patient from our group were found 13 years after skin replacement. The presence of peripheral nerve fibres in assessed samples was confirmed by an immunohistochemical analysis. The fibres were localized in the reticular part of dermis and their uneven distribution is likely responsible for the difference in sensitivity of scars after dermal replacement in comparison with healthy skin.

CONCLUSION

Our clinical experience with the use of dermal replacement confirms the positive effect of Integra^® coverage on the resulting functional and cosmetic effect on post-burn scars in comparison with the standard method of DE graft transplantation. The main indication of Integra^® application are extensive burn injuries with limited harvesting sites. It is also advantageous to use Integra^® to cover large skin defects after the release of scar contractures, namely in patients with limited possibility to harvest a full-thickness skin graft. It seems that the Integra^® artificial skin is suitable even in case of deep skin losses caused by electric current or by chemical burns. From the long-term perspective, we prefer applicationof Integra^® in facial injuries because of cosmetic reasons as we have not observed any occurrence of scar contractures. Our histological and immunohistochemical analyses confirm that the tissue after application of Integra^® markedly differs from the scar after the transplantation of dermoepidermal graft. Deeper understanding of the clinical and histological processes involved in the rebuilding of the artificial dermal replacement like Integra^® may play an important role in the development of a new generation of full-bodied dermoepidermal skin replacements.

Acknowledgment:

We acknowledge the Department of Pathology, Královské Vinohrady Teaching Hospital and The 3^rd Faculty of Medicine, Charles University in Prague for granting the photographs for this paper.

Grant support:

Our work was supported by the Programme of Scientific Development at Charles University, Prvouk-P33.

Corresponding author:

Robert Zajíček, M.D., PhD.

Clinic of Burns Medicine,

Královské Vinohrady

Teaching Hospital and 3^rd Faculty of Medicine, Charles University

Šrobárova 50,

100 34 Prague 10,

Czech Republic

E-mail: robert.zajicek@fnkv.cz

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