Long-term results of a clinical trial on dermal substitution.: A light microscopy and Fourier analysis based evaluation

doi:10.1016/S0305-4179(01)00085-7

Burns

Volume 28, Issue 2, March 2002, Pages 151-160

https://doi.org/10.1016/S0305-4179(01)00085-7 Get rights and content

Abstract

Although dermal substitution is a main topic of current wound healing research, there is a paucity of clinical trials with a long-term clinical and histopathological evaluation. A clinical trial was conducted to perform an intra-individual comparison of conventional treatment (split-thickness autograft) to a collagen/elastin dermal substitute in combination with an autograft. Promising results with this substitute were obtained with respect to dermal organisation and scar elasticity in animal studies and clinical trials with a short-term follow-up.

Twenty-nine of the 42 pairs of the burn wounds and 28 of the 44 pairs of the scar reconstructions enrolled in the study were biopsied after 1 year.

Promising but not statistically significant differences were found between substituted groups and control groups for epidermal thickness, basement membrane maturation, rete ridges (P=0.055), fibroblasts, myofibroblasts, inflammatory cells, vessels and extracellular matrix maturation.

An objective and accurate technique, Fourier analysis, was used to evaluate collagen bundle orientation and packing. However, no statistically significant differences were obtained for these parameters.

This microscopic evaluation provided no convincing evidence for a long-term effectiveness of a dermal substitute despite promising data over a short-term in in vitro and in vivo studies with the same material.

Introduction

The past decade has seen the emergence of tissue engineering as an increasingly more viable alternative for skin replacement. Artificial skin is considered beneficial for ‘difficult-to-heal’ chronic venous-ulcers, as well as for acute wounds such as burns and reconstructive wounds. Although a considerable number of papers have been published during the last decades regarding clinical trials using dermal and epidermal substitutes for acute wounds, only a few manuscripts with long-term follow-up and histopathological evaluations can be found [1], [2].

This paper describes the microscopic results of a clinical trial concerning a dermal substitute that is composed of collagen type I and elastin hydrolysate. Previously, this dermal substitute was shown to have a beneficial effect on wound healing in animal studies [3], [4] and in a clinical study concerning small punch biopsy wounds [5], demonstrating faster dermal maturation [3], [4], improved restoration of dermal organisation [5] and reduced contraction [3], [5].

More recently, a clinical trial was conducted to evaluate the collagen/elastin substitute by means of clinical and microscopic parameters for burns and reconstructive wounds. The clinical evaluation of the study showed that the elasticity of the reconstructive wounds was significantly improved by the dermal substitute after 3 months [6]. The elasticity was measured with an objective skin elasticity device measuring: the cutometer. Despite the promising short-term results, no statistically significant beneficial effect was shown after 1 year for reconstructive wounds [7]. For burn wounds, no statistically significant differences were shown for skin elasticity parameters in the short- and long-term. The microscopic evaluation of this clinical trial 1 year after surgery is presented in this paper.

Histopathological and immunohistochemical evaluation of the structure of epidermis, basement membrane and most importantly, the dermal architecture was utilised. We focused our attention on collagen as it is the most prevalent protein in the dermis that plays a crucial role in its function and strength [8]. In normal skin, collagen is arranged in a ‘basket weave’ pattern [9] in contrast to scar tissue which has collagen bundles orientated parallel to the epidermis [2], [10]. Morphometry was performed on collagen bundle orientation and packing by means of Fourier analysis. Previously, we established that this technique was convenient and more accurate than the ‘gold standard’ of multi-observer evaluation permitting quantification of collagen bundle orientation and packing [11].

Section snippets

Patients and methods

A clinical trial was performed based on intra-individual comparison of subjects. Patients were eligible if they were admitted to our hospital and needed excision and skin grafting for acute burn wounds or scar reconstruction after a burn injury. The patients, or their legal representatives, gave informed consent before surgery. The Ethics Committee from the Red Cross Hospital approved the protocol before the start of the trial.

Results

Twenty-nine of the 42 paired treatments for burn wounds (69%) were biopsied after 328 days post-surgery (S.D.: 73). Biopsies of 28 of the 44 paired treatments (64%) in the scar reconstruction category were harvested 302 days post-surgery (S.D.: 74).

Overviews of the results of both categories are listed in Table 1, Table 2. In both tables a column was added that indicated the reference value of normal skin. Of those patients who underwent scar reconstruction with the dermal substitute, the rete

Discussion

Dermal substitution is one of the main topics of acute and chronic wound healing research. Remarkably, clinical trials with large sized populations are lacking with respect to histopathological, immunohistochemical and objective long-term evaluation. We have used both subjective and objective methods to compare a dermal substitute with autograft to the conventional treatment (split skin autograft) in patients with burns and scar reconstructions.

In both acute burn and reconstructive wound

Acknowledgements

This study was supported by the Technology Foundation (Stichting Technische Wetenschappen), the Dutch Burns Foundation and The Netherlands Organisation for Scientific Research.

We gratefully acknowledge Adam Angeles M.D. for his valuable comments, Jos Vloemans, M.D, Toine van Trier M.D., and Frits Groenevelt M.D, Ph.D. for their clinical assistance during this study. Henk van Veen Ph.D. and Joris Ruurda are acknowledged for their technical assistance.

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As the healing process advances, the fibroblasts produce their own collagen matrix while collagen–elastin matrix is degraded. Experiences from a human clinical trial on the treatment of punch biopsy wounds demonstrated that collagen–elastin matrix is completely resorbed 6 weeks after implantation [35]. Nowadays, dermal substitutes are considered to play a more prominent role in burn surgery and have shown to minimize hypertrophic scarring, contractures and increase scar elasticity in acute burn wounds [9,10].
Management of full-thickness facial burns remains one of the greatest challenges. Controversy exists among surgeons regarding the use of early excision for facial burns. Unfortunately, delayed excision of deeper burns often results in more scarring and subsequent reconstruction becomes more difficult.
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We report the usage of a collagen–elastin matrix during single-step wound closure technique of severe full-thickness facial burns in 15 children with large burned body surface area, and also we review the literature about pediatric facial burns.
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In regard to early results, graft quality was close to normal skin in terms of vascularity, elasticity, pliability, texture and color. Esthetic and functional results have been encouraging.
This study shows us that the collagen–elastin matrix as a dermal substitute is a useful adjunct, which may result in quick healing with satisfying esthetic and functional results. It also may enhance short and long-term results in after burn facial wound closure in children.
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In reconstructive burn wounds, with this technique, an improvement in scar quality was found [4]. The use of dermal substitutes in acute burns, however, did not lead to improvement of scar quality in previous studies of our research group [4,8–10]. Thus, to improve the effectiveness of dermal substitutes in burns, additional strategies need to be investigated.
A recently performed randomised controlled trial investigated the clinical effectiveness of dermal substitutes (DS) and split skin grafts (SSG) in combination with topical negative pressure (TNP) in the surgical treatment of burn wounds. In the current study, medical and non-medical costs were investigated, to comprehensively assess the benefits of this new treatment.
The primary outcome was mean total costs of the four treatment strategies: SSG with or without DS, and with or without TNP. Costs were studied from a societal perspective. Findings were evaluated in light of the clinical effects on scar elasticity.
Eighty-six patients were included. Twelve months post-operatively, highest elasticity was measured in scars treated with DS and TNP (p = 0.027). The initial cost price of treatment with DS and TNP was €2912 compared to treatment with SSG alone €1703 (p < 0.001). However, mean total costs per patient did not differ significantly between groups (range €29 097–€43 774).
Costs of the interventional treatment contributed maximal 7% to the total costs and total costs varied widely within and between groups, but were not significantly different. Therefore, in the selection of the most optimal type of surgical intervention, cost considerations should not play an important role.
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Short-term follow-up revealed that skin elasticity was considerably improved by the collagen/elastin dermal substitute as analyzed by Cutometer measurements [478]. Long-term evaluations with respect to elasticity are consistent with the former findings, but the difference between controls was not significant after 1 year [479,480]. In the study of another group, the same collagen/3% α-elastin dermal matrix was used in ten patients as a dermal substitute in severe burn injuries of the hand.
Biomaterials play a critical role in engineering of tissue constructs, working as an artificial extracellular matrix to support regeneration. Because the elastic stretchability is a major mechanical property of many tissue types, huge efforts have been invested into the development of elastomeric biomaterials that mimic that of native tissue. Indeed, for the repair of most soft tissue types, one of the major problems encountered by biomaterials scientists has been difficulty in simply replicating this complex elasticity. This article provides a comprehensive review on the elastomeric biomaterials used in tissue engineering. Definitions of biomaterials, biocompatibility and elasticity in the context of tissue engineering are introduced. This is followed by systematic review of thermoplastic rubbers, chemically crosslinked elastomers, elastic proteins and elastomer-based ceramic-filled composites. Each section includes a detailed description of the chemical synthesis of the polymer critical to understanding of its unique properties, followed by discussion of its biocompatibility and biodegradability, two essential features of biomaterials in most tissue engineering applications. The mechanical properties and applications in tissue engineering are then reviewed for each polymer in great detail, with identification of specific challenges for its current and ongoing application in the field. Finally, the major achievements and remaining challenges for elastomeric biomaterials are summarized, with emphasis on the most important candidates to date.
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Le syndrome des « callosités douloureuses constitutionnelles » est une entité rare, s’intégrant dans le cadre des kératodermies palmoplantaires (KPP). C’est une hyperkératose plantaire douloureuse localisée aux points d’appui, invalidant la marche. Les traitements sont suspensifs et antalgiques. Nous rapportons les résultats d’un traitement chirurgical radical en un temps chez une patiente de 28 ans. Un traitement hautement tératogène par acitrétine et antalgique permet un contrôle satisfaisant de la symptomatologie. Face à un désir de grossesse, nous proposons alors le traitement suivant : exérèse, substitut dermique, greffe de peau mince (GPM) sécurisée par une thérapie par pression négative. À 12 mois, la cicatrisation était acquise sans troubles trophiques avec un très bon résultat fonctionnel. Le traitement chirurgical par excision des zones kératosiques suivie d’une greffe ou d’un lambeau cutané a été préalablement rapporté pour quelques cas de KPP. L’utilisation de substitut dermique n’a pas été décrite dans ce type de pathologie. Les substituts dermiques permettent de compenser la perte de substance en épaisseur et apportent une qualité d’élasticité appréciable sur cette localisation. L’utilisation de la thérapie par pression négative améliore la rapidité de la prise de greffe sur la matrice et l’adhérence de la matrice au sous-sol.
Constitutional painful callosities is an unusual pathology, integrated in the frame of “palmoplantar keratodermia” (PPK). Lesions are located at areas of support of the sole. These lesions are painful and disable the normal walking. Treatments are suspensive and painkillers. We report our experience of a single surgical treatment: surgical excision, split thickness skin graft applied on a dermal substitute and secured by negative wound therapy. A 28-year-old patient, affected by this disease, has a desire of pregnancy but her treatment is highly teratogen. A year post-op, wounds were healed. The walk was possible with a relief of the pain, without any ulcerations. The surgical treatment by excision and graft or flaps was previously reported for PPK. The use of dermal substitute was never described for this indication. Dermal substitute compensate the thickness of the soft tissue defect and give an accurate quality of elasticity in this localisation .The negative wound therapy enhances the quality and shortens the length of graft taking, and the adhesion of the dermal substitute on his bed.
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Also, wound contraction was significantly less in wounds treated with MatriDerm. Long-term follow-up showed that fibronectin formation of the dermis reconstructed with MatriDerm was comparable to normal, uninjured skin.11,12 MatriDerm also allows the clinician to simultaneously place an autologous split-thickness skin graft within the same procedure, which helps minimize the need for a second operation in burn surgery.13,14
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¹: Present address: IsoTis BV, Bilthoven, The Netherlands.

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Long-term results of a clinical trial on dermal substitution.: A light microscopy and Fourier analysis based evaluation

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

J. Invest. Dermatol.

Burns

Lab. Invest.

Histologic study of artificial skin used in the treatment of full-thickness thermal injury

J. Burn Care Rehabil.

Skin regenerated from cultured epithelial autografts on full-thickness burn wounds from 6 days to 5 years after grafting. A light electron microscopic and immunohistochemical study

Lab. Invest.

Dermal regeneration in native non cross-linked collagen sponges with different extracellular matrix molecules

Wnd. Rep. Reg.

Extracellular matrix characterization during healing of full-thickness wounds treated with a collagen/elastin dermal substitute shows improved skin regeneration in pigs

J. Histochem. Cytochem.

Reduced wound contraction and scar formation in punch biopsy wounds. Native collagen dermal substitutes. A clinical study

Br. J. Dermatol.

Graft survival and effectiveness of dermal substitution in burns and reconstructive surgery in a one-stage grafting model

Plast. Reconstr. Surg.

Morphological and immunochemical differences between keloid and hypertrophic scar

Am. J. Pathol.