Long‐term follow‐up comparison of two different bi‐layer dermal substitutes in tissue regeneration: Clinical outcomes and histological findings

Dear Editors,

We read with attention the study entitled “Long‐term follow‐up comparison of two different bi‐layer dermal substitutes in tissue regeneration: Clinical outcomes and histological findings,” and we want to emphasise that our clinical experience with the two devices Integra and Nevelia is different.

Dermal substitutes are becoming more essential in the treatment of acute and chronic wounds. A dermal substitute improves functional and cosmetic results in the long term and outcome. They allow the formation of a new dermis with chemical and elasticity characteristics like normal skin. According to Yannas et al,1, 2 a dermal substitute with regenerative activity must have an appropriate pore size, which is critical to the optimal in‐growth of patients' fibroblasts and endothelial cells. Yannas et al define this pore size as between 20 and 125 μm. Another important characteristic of a regenerative dermal substitute is the controlled half‐time degradation time of 14 ± 7days. Finally, another important feature of a dermal substitute (DS) to create dermis is surface chemistry. For Yannas et al, in DS the ligand densities of myofibroblasts (MFB) should 200 μM α1β1 or α2β1 ligands. This important feature allows these cells to anchor in a better way to the scaffold, and therefore the MFB can create a better dermis pattern. ³

Only Integra integra dermal regeneration template (IDRT) has these important features that allow a better interaction between cells and scaffold.

Concerning of the scaffold composition, we also want to emphasise that the glycosaminoglycan (GAG) and chondroitin 6 sulfate are important constituents for a regenerative scaffold. Chondroitin 6 sulfate increases the half‐life of the scaffold and allows a better interaction between cells and scaffold. ⁴

The degradation rate of scaffolds for wound repair is usually controlled by glutaraldehyde‐induced cross‐links. This chemical cross‐link can lead to an immunogenic response to the scaffold. In the manufacturing process of Integra IDRT, the collagen is cross‐linked with GAG and allows for the use of a less quantity of the solvent compared with the scaffolds that are composed only with collagen. Yannas et al show that chondroitin 6 sulfate increases the modulus of resistance and elasticity of the scaffold GAGs Cross‐linking and maintaining allows to keep the degradation duration half‐time faster compared with the one of scaffold without GAG, that needs more glutaraldehyde, leading to higher foreign response.

In this study, the authors make a comparison between Integra and Nevelia in traumatic wounds. The authors observed a difference at 3 years of follow‐up measured with MSS, which is a subjective assessment scar scale. First, we want to emphasise that the sample size is limited.

Moreover, Integra Dermal Regeneration Template is the only dermal substitute that has a long and significant clinical history in several indications. Several randomised control trials (RCT) show that Integra showed better functional and aesthetic outcomes at long follow‐up not only with subjective scar scales but also instrumentally. Lagus et al, ⁵ in a randomised controlled trial, showed that patients reported favourable aesthetic outcomes as measured by the Vancouver Scar Scale. In another randomised clinical trial in paediatric patients, Branski et al ⁶ evaluated the long‐term cosmetic and functional results (18‐24 months). Also in this study, Integra showed significant improvement in the Hamilton Burn Scar scale. Integra has also other studies that showed its efficacy in terms of functional and cosmetic outcome in burned hands. Among them, Danin ⁷ employed a Cutometer to evaluate the quality of the scars obtained after using Integra Dermal Regeneration Template. When data and elasticity (cutometrical data) were compared for Integra Dermal Regeneration Template‐treated burns and normal skin, there were no statistically significant differences between the Integra and normal skin. Another study by Dantzer ⁸ assessed the safety and performance of Integra Dermal Regeneration Template when used to treat deep hand burns and reconstruct scars; there was 100% Integra Dermal Regeneration Template graft take improvement of Vancouver Scar Scale and favourable cosmetic and functional outcomes.

After our searches (PubMed, Medline) we noticed that Nevelia has a limited number of studies (only four observational retrospective studies) to show its systematic efficacy in terms of aesthetics and functional outcomes, and in terms of artificial dermis take a percentage that is an important feature of a dermal implant.

Integra IDRT has shown in RCT a high take rate even in traumatic wounds. ⁹

Another limitation of this study is that wounds with, exposed tendons or bones, are excluded. One important function of a dermal substitute is the ability to cover avascularised tissue, such as tendons and bones. When we have soft tissue defects overlying exposed tendon, it is important to avoid adhesions, restoration of functionality, and getting good aesthetic outcomes. Shores et al showed that Integra IDRT in the reconstruction of soft tissue with exposed tendons of paratenon in upper and lower extremity allows immediate tendon coverage with good cosmesis and tendon function and a high split‐thickness skin graft take rate of 92.5%. ¹⁰

Yeong et al ¹¹ found the same results in the treatment of bone‐exposed wounds in burn patients with Integra. In conclusion, Integra has shown the ability to cover poor avascularised structures that allow high split‐thickness skin graft take rates.

From our experience, a dermal substitute should promote neodermis suitable to be grafted, even in a wound with poor vascularization. Due to the exclusion criteria of this study, we cannot evaluate the efficacy of Nevelia on these wounds.

Nicoletti et al in an observational study to treat scalp defects, describe better cosmetic outcomes using Integra comparing with Hyalomatrix and Nevelia. ¹²

An RCT on Integra in chronic wounds ¹⁷ also showed higher complete healing of wounds.

Integra has also several studies on the traum wounds a higher take rate, and the scars outcomes measured with Vancouver scale gave better scores13, 14, 15 (Vakerio, Seavey, Weigert).

Regarding the histological findings, we also have some concerns. In this study, they claim that Integra collagen was still present after 3 weeks, while Nevelia was completely resorbed. Stern et al ¹⁶ in their histologic study on 131 patients found the same discovery and identified six phases of repair with Integra. The presence of a scaffold after 3 weeks is a clear sign that the structure of the scaffold is strong.

We think that the presence of the scaffold after 3 weeks is an important feature because Integra continues to act as a scaffold during the process of wound healing. Moreover, the presence of Integra collagen means that the chemical cross‐link associated with GAGs is a better choice for a regenerative scaffold.

In this study, the authors talk about the findings of Agrawal et al. We want to emphasise that according to Agrawal et a's findings, Integra showed a mixed M1/M2 macrophage in histologic samples of Sprague Dawley rats and that this response is associated with a more constructive tissue remodelling response. This is confirmed by the functional and aesthetic outcomes of several studies of Integra that show Integra creates a dermis similar to normal skin.

Due to the low clinical and preclinical literature of Nevelia, there is no evidence of macrophage polarisation and tissue remodelling of this device.

In our clinical experience with Nevelia, we have had some difficulty to remove the reinforced polyester silicon sheet, because of its tendency to encapsulation. For the clinical outcomes in some cases with Nevelia, there was a rapid degradation of the scaffold. This rapid degradation led to the formation of granulation tissue and led to a contracted scar.

In conclusion, considering that most significant literature and clinical use of Integra in several indications (burns, traumatic, chronic wounds, reconstructive surgery) and the aesthetic and functional outcomes, we continue to consider Integra the only dermal substitute able to create dermis with aesthetic and functional outcomes similar to normal skin and the only dermal substitute for regenerative medicine.