Macrophage Activation and M2 Polarization in Wound Bed of Diabetic Patients
Treated by NEVELIA®

Macrophage Activation and M2 Polarization in Wound Bed of Diabetic Patients Treated by Dermal/Epidermal Substitute NEVELIA

Manuela Montanaro, PI, PhD, Marco Meloni, MD, PhD , Lucia Anemona, PhD, Laura Giurato, MD, PhD, Manuel Scimeca, PhD, Valentina Izzo, MD, PhD, Francesca Servadei, PhD, Artem Smirnov, PhD, Eleonora Candi, PhD, Alessandro Mauriello, MD, and Luigi Uccioli, MD

Principal Investigator
Pr Uccioli

Published in

The International Journal of Lower Extremity Wounds 1-7
First Published August 20, 2020

Clinical evidences have shown the usefulness of Dermal/Epidermal Substitutes to treat Diabetic foot ulcers.
Recent studies suggest that in addition to their action as a scaffold, wound healing by influencing inflammatory cells in the wound bed.


This study aims to investigate whether Dermal Substitute NEVELIA® may influence the inflammatory infiltrate and macrophages polarization toward a reparative phenotype.
Fifteen diabetic patients with chronic Diabetic foot ulcers have been randomly enrolled:

Study Design

  • Type of study: randomized controlled
  • CG: control group 5 patients – debridement and weekly dressings,
    off loading
  • TG: treated group 10 patients – debridement and Nevelia graft,
    off loading
  • Type of lesions studied: non-ischemic, uninfected, chronic (reduction <50% in 4 weeks), size > 5 cm2
  • Biopsy at T0, and 30 days
  • Immunohistochemistry: Monoclonal antibodies used: CD38 for M1, CD68 for MF, CD163 for M2

Histological Findings

Immunohistology analysis at Baseline “T0” shows that whatever the group, the same inflammatory scenario is observed, M1 density prevails over M2.
At 30 days “T1”, the control group did not change the scenario, while the NEVELIA® grafted group significantly changed: there is a prevalence of macrophages M2 on M1 that express an anti-inflammatory phenotype.

Confocal Microscopy

Microscopic observation confirms the significant increase of M2 cells in the the NEVELIA® group after 30 days. At T0, bioptic samples showed that M2 were 27,3% of the whole macrophage population.
At T1, M2 have significantly increase becoming 63,9% of the whole macrophage population.

This clinical study demonstrates that NEVELIA® is able to stimulate healing in chronic wounds by inducing the polarization of M1 macrophages toward the repairing phenotype M2.

Key Take Aways

A human study that shows NEVELIA® Dermal Substitute is able to polarize Macrophages from M1 to M2 phenotype with M2 prevailing highly over M1 [1].

Key Take Aways

1 in 11 adults have diabetes = 463 million people worldwide.
Diabetic foot and lower limb complications, which affect 40 to 60 million people with diabetes globally [2].

Key Take Aways

The global chronic wound care market size was valued at $10.12 B in 2019 & is projected to reach $16.36 by 2027 [3].

Key Take Aways

Non-healing ulcers are chronically inflamed and are characterized by high M1/M2 ratio.
The goal for tissue regeneration is to resolve inflammation, that means decrease M1/M2 ratio.

Key Take Aways

The clinical study demonstrates that NEVELIA® is able to stimulate healing in chronic wounds by inducing the polarization of M1 macrophages toward the repairing phenotype M2.

60% of the NEVELIA® group completely healed, while only 20% healed with standard of care after 6 months of observation [1].

Key Take Aways

Regeneration over inflammation.
In clinical practice, NEVELIA® inhibits inflammation and promotes tissue regeneration.
This capacity is crucial in chronic ulcers [1].


Professor Luigi UCCIOLI

  • Associate Professor of Endocrinology at
    the Universityof Rome TorVergata
  • Head Diabetic Foot Unit Tor Vergata Teaching Hospital
  • Chairman Master on Diabetic Foot University
    of Rome Tor Vergata

He has a long research experience on diabetic late complications as neuropathy and diabetic foot.
Recently his interest has been focused on the treatment
of diabetic patients with peripheral vascular disease and critical limb ischemia at risk of major amputation.
Another area of interest is regenerative medicine applied to Diabetic Foot Ulcers, with special interest on dermal substitutes and PBMNC cell Therapy, focused on their immune-modulation activity in chronic wounds.
He is a former member of the IWGDF, the International Working Group that has developed International Guidelines on Diabetic Foot .
He is participant in the Eurodiale network that includes the leading centers for the cure of diabetic foot in Europe.
He has written more than 100 articles on peer reviewed scientific journals.





These lectures were performed during NEVELIA LIVE WEBINAR of 15th of October 2020.


[1] MACROPHAGE ACTIVATION AND M2 POLARIZATION IN WOUND BED OF DIABETIC PATIENTS TREATED BY DERMAL/EPIDERMAL SUBSTITUTE NEVELIA. The international journal of lower extremity wounds. 2020 aug 20. Manuela Montanaro, Marco Meloni, Lucia Anemona, Laura Giurato, Manuel Scimeca, Valentina Izzo, Francesca Servadei, Artem Smirnov, Eleonora Candi, Alessandro Mauriello, Luigi Uccioli, 2020
Available at
[2] International Diabetes Federation. IDF Diabetes Atlas, 9th edn. Brussels, Belgium: 2019.
Available at
[3] FORTUNE BUSINESS INSIGHT Market research report Aug 20.
Available at