Reply to: Observation on the article “Long‐term follow‐up comparison of two different bilayer dermal substitutes in tissue regeneration: Clinical outcomes and histological findings”

Dear Editors,

We thank the author of the comment for the interest in our paper and for the possibility to clarify some critical points.

Nevelia has an appropriate pore size between 50 and 200 m, with a median pore size of 100 μm, and a degradation time of 21 days, both included in the optimal range indicated by Yannas et al. ¹ Optimal values of ligand densities for integrins α1β1 and α2β1 are not still available. ² Since the crosslinking treatment affects both the ligand density and the half‐life for degradation, future studies are required to understand these effects on the regenerative activity of dermal substitute. ¹ For all these reasons, in our opinion it is not correct to claim that only Integra has these important features that allow better interaction between cells and scaffold.

In particular,

• Glycosaminoglycans presence: Different studies have shown the use of collagen matrix with no glycosaminoglycans (GAG) and without loss of regenerative activity. ¹ , ³ Integra was originally developed in the 1990s, as a graft copolymer of collagen and GAG, in an attempt to simulate the extracellular matrix (ECM) that is present in many tissues. Yannas MIT laboratory eliminated the GAG from collagen matrix ¹ because of reported inhibition of peripheral nerve regeneration in the presence of GAG. ⁴ It has been observed that the reaction of collagen with GAG increases the half‐life for the degradation of collagen, ⁵ while it shows a moderate delaying effect on wound contraction ⁶ and it does not appear to affect at all the overall regenerative outcome. ⁶ Nevelia, which is a second‐generation dermal substitute, was developed a few years ago following the indications from all these researches and it contains no GAG.

• Scaffold immunomodulation: Macrophages are the first responders to biomaterial implantation and determine the success or failure of an implant through their polarisation into pro‐inflammatory (M1) through to anti‐inflammatory (M2) states. ⁷ , ⁸ , ⁹ Whiterel et al ¹⁰ showed in vitro that in Integra the expression of M2 anti‐inflammatory markers (CCL22 and TIMP3) was downregulated, suggesting a possible inhibition of ECM secretion. In a preliminary report, Nevelia implanted in critical limb ischaemia diabetic patients showed, on the contrary, a significant reduction of M1 and a significant increase of M2 macrophages after 30 days, observed both in immunohistochemical data using CD68+/CD163+ ratio and by confocal microscopy. ¹¹ This suggests that Nevelia, in addition to its action as a scaffold, may have a direct action on the healing processes as suggested from the shift of macrophage population from inflammatory M1 to regenerative M2 phenotype.

• Comparative studies: Nicoletti et al's ¹² comparative work clearly state that “Although our preliminary results with the Nevelia induced bioengineered skin would appear to be good, it is too short a clinical experience to make a long‐term assessment on a large sample of cases and to identify its most appropriate clinical indication.”

Clearly our study suffers from some weaknesses as the small sample size (n = 30) and the subjective assessment of Manchester Scar Scale. For this reason, we add to the clinical outcome the histological and immunohistochemical evaluation, which showed the good quality of the newly formed regenerated tissue. The fastest angiogenesis may occur due to increased M2 polarisation, which is more angiogenic than M1, ¹³ , ¹⁴ as observed from Uccioli et al. ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ Histological and immunohistochemical data obtained on traumatic lesion after Nevelia implants are comparable to the ones observed from our group in venous and arterial chronic ulcers treatment on 35 patients showing a regenerated skin architecture analogue to normal skin physiology. ¹⁶

Nevelia has a very limited number of studies ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ so far. We hope that many other Nevelia studies will also follow in comparison with other collagen matrices, especially in centres with a great experience on dermal substitutes.

The paper has been developed and structured uniquely displaying all scientific, clinical, histologic, and statistic data and their follow‐up as they have been achieved.

The comparison between Nevelia and Integra has become necessary as every time a new product is developed, to confirm its effectiveness, it is required to compare it with other similar products already in use. This process is part of the scientific research that is always in continuous development.

Finally, we believe that research should be based on data comparison of different centres, on different therapies and/or devices, to obtain clear and robust indication to treat patients in the best possible way.