Efficacy of human living skin equivalent in the treatment of inherited epidermolysis bullosa

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Abstract

Background. Inherited epidermolysis bullosa is a group of genetic skin disorders caused by mutations in genes encoding structural proteins of epidermis and dermo-epidermal junction. Clinical manifestations are characterized by spontaneous or trauma-induced skin and/or mucosal blistering, and extensive wounds. The use of tissue-engineered skin substitutes composed of allogeneic human skin cells is considered to be a perspective therapeutic approach in improving wound healing process.

Aims. To assess safety and efficacy of human skin equivalent in the treatment of inherited epidermolysis bullosa patients

Methods. 7 patients (5 female and 2 male subjects) from the age of 20 to 55 with inherited epidermolysis bullosa with different clinical subtypes were enrolled in the study: 3 patients with intermediate recessive dystrophic epidermolysis bullosa, 2 patients with severe recessive dystrophic epidermolysis bullosa, 1 patient with dominant dystrophic epidermolysis bullosa and 1 patient with junctional epidermolysis bullosa. Transplantation of composite allogeneic living skin equivalent comprising allogeneic keratinocytes and fibroblasts in low concentration (5 mg/ml) embedded within a type I collagen gel matrix was performed. The living skin equivalent was developed at N.K. Koltsov Institute of Developmental Biology. 19 erosions and ulcers with a surface area between 0.4 and 120 cm2 were evaluated. At day 14 clinical assessment was performed. To assess level of expression immunofluorescence antigen mapping was used.

Results. At day 14 complete erosion closure was achieved in 10 (53%) erosions. 4 (21%) erosions reduced in size > 75%. Size reduction between 25 and 75% was shown in a single (5%) case, no clinical efficacy was demonstrated in 4 (21%) cases. Collagen VII expression increased comparing to baseline level and accompanied clinical improvement.

Conclusions. The obtained data showed clinical efficacy of topical treatment with living skin equivalent, although no statistically significant difference was seen between living skin equivalent and atraumatic non-adhesive dressings.

About the authors

Arfenya E. Karamova

State Research Center of Dermatovenereology and Cosmetology

Author for correspondence.
Email: karamova@cnikvi.ru
ORCID iD: 0000-0003-3805-8489
SPIN-code: 3604-6491

MD, Cand. Sci. (Med.), Assistant Professor

Russian Federation, 3 bldg 6 Korolenko street, 107076 Moscow

Alexey A. Kubanov

State Research Center of Dermatovenereology and Cosmetology

Email: alex@cnikvi.ru
ORCID iD: 0000-0002-7625-0503
SPIN-code: 8771-4990

MD, Dr. Sci. (Med.), Professor, Academician of the Russian Academy of Sciences

Russian Federation, 3 bldg 6 Korolenko street, 107076 Moscow

Ekaterina A. Vorotelyak

N.K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences

Email: vorotelyak@yandex.ru
ORCID iD: 0000-0001-5405-0212
SPIN-code: 2310-9118

Dr. Sci. (Biol.), Corresponding Member of the Russian Academy of Sciences

Russian Federation, Moscow

Olga S. Rogovaya

N.K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences

Email: rogovaya26f@gmail.com
ORCID iD: 0000-0003-4251-9372
SPIN-code: 1441-8532

Cand. Sci. (Biol.)

Russian Federation, Moscow

Vadim V. Chikin

State Research Center of Dermatovenereology and Cosmetology

Email: chikin@cnikvi.ru
ORCID iD: 0000-0002-9688-2727
SPIN-code: 3385-4723

MD, Dr. Sci. (Med.), Senior Researcher

Russian Federation, 3 bldg 6 Korolenko street, 107076 Moscow

Mariya A. Nefedova

State Research Center of Dermatovenereology and Cosmetology

Email: nefedova.maria.arb@gmail.com
ORCID iD: 0000-0003-1141-9352

Junior Research Associate

Russian Federation, 3 bldg 6 Korolenko street, 107076 Moscow

Ekaterina S. Monchakovskaya

State Research Center of Dermatovenereology and Cosmetology

Email: monchakovskaya@cnikvi.ru
ORCID iD: 0000-0002-6402-0962
SPIN-code: 9859-1912

Junior Research Associate

Russian Federation, 3 bldg 6 Korolenko street, 107076 Moscow

References

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  2. Hou PC, Wang HT, Abhee S, Tu WT, McGrath JA, Hsu CK. Investigational treatments for epidermolysis bullosa. Am J Clin Dermatol. 2021;22(6):801–817. doi: 10.1007/s40257-021-00626-3
  3. Fine JD, Eady RA, Bauer EA, Bauer JW, Bruckner-Tuderman L, Heagerty A, et al. The classification of in- herited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on DIAGNOSIS and classification of EB. J Am Acad Dermatol. 2008;58(6):931–950. doi: 10.1016/j.jaad.2008.02.004
  4. Bardhan A, Bruckner-Tuderman L, Chapple ILC, Fine JD, HarperN, Has C, et al. Epidermolysis bullosa. Nat Rev Dis Primers. 2020;6(1):78. doi: 10.1038/ s41572-020-0210-0
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  6. Alex du Rand A, Hunt JMT, Feisst V, Sheppard HM. Epidermolysis bullosa: a review of the tissue-engineered skin substitutes used to treat wounds. Mol Diagn Ther. 2022;26(6):627–643. doi: 10.1007/s40291-022-00613-2
  7. Hasegawa T, Suga Y, Mizoguchi M, Ikeda S, Ogawa H, Kubo K, et al. Clinical trial of allogeneic cultured dermal substitute for the treatment of intractable skin ulcers in 3 patients with recessive dystrophic epidermolysis bullosa. J Am Acad Dermatol. 2004;50(5):803–804. doi: 10.1016/j.jaad.2003.08.013
  8. Supp DM, Hahn JM, Combs KA, McFarland KL, Powell HM. Isolation and feeder-free primary culture of four cell types from a single human skin sample. STAR Protoc. 2022;3(1):101172. doi: 10.1016/j.xpro.2022.101172
  9. Falabella AF, Valencia IC, Eaglstein WH, Schachner LA. Tissue-engineered skin (Apligraf) in the healing of patients with epidermolysis bullosa wounds. Arch Dermatol. 2000;136(10):1225–1230. doi: 10.1001/archderm.136.10.1225
  10. Falabella AF, Schachner LA, Valencia IC, Eaglstein WH. The use of tissue-engineered skin (Apligraf) to treat a newborn with epidermolysis bullosa. Arch Dermatol. 1999;135(10):1219–1222. doi: 10.1001/archderm.135.10.1219
  11. Ozerdem OR, Wolfe SA, Marshall D. Use of skin substitutes in pediatric patients. J Craniofac Surg. 2003;14(4):517–520. doi: 10.1097/00001665-200307000-00023

Supplementary files

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2. Fig. 1. Multiple erosions in the area of atrophic scarring on the trunk of a 20-year-old patient with recessive dystrophic epidermolysis bullosa

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3. Fig. 2. Reduction in erosion size in patients with epidermolysis bullosa at day 14 after human living skin equivalent transplantation, n (%)

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4. Fig. 3. Reduction in erosion size in patients with epidermolysis bullosa at day 14 after treatment with atraumatic non-adhesive dressings, n (%)

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5. Fig. 4. Type 7 collagen expression in skin specimen at day 14 after human living skin equivalent transplantation, n (%)

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6. Fig. 5. Expression of type VII collagen in skin biopsy material from 20-years-old patient with severe recessive dystrophic bullous epidermolysis before and in 14 days after living skin equivalent transplantation: а — before the treatment the fluorescence of anti-collagen VII antibodies is detected along the borderline between cutaneous appendages and dermal stroma and looks like broken line and single dots (magnification ×600); б — in 14 days after living skin equivalent transplantation the fluorescence of anti-collagen VII antibodies in the biopsy sample from the same person looks like forming solid line along dermal-epidermal junction (magnification ×200)

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Copyright (c) 2024 Karamova A.E., Kubanov A.A., Vorotelyak E.A., Rogovaya O.S., Chikin V.V., Nefedova M.A., Monchakovskaya E.S.

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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