Liquid-type non-thermal atmospheric plasma ameliorates vocal fold scarring by modulating vocal fold fibroblast

Abstract

Injection laryngoplasty is a widely used therapeutic option for drug delivery into vocal folds (VFs). Efficient injectable materials are urgently needed for treating intractable VF disease. Liquid-type non-thermal atmospheric plasma (LTP) has been found to be useful for various biological applications, including in regenerative medicine. We evaluated the effects of LTP on VF regeneration. Migration and matrix metalloproteinase-2 expression of lipopolysaccharide (LPS)-treated human vocal fold-derived mesenchymal stem cells (VF-MSCs) were enhanced by LTP treatment. LTP treatment not only ameliorated nuclear factor-κB and interleukin-6 activation, induced by LPS treatment, but also the increased manifestation of α-smooth muscle actin and fibronectin, induced by transforming growth factor-ß. In a rabbit VF scarring animal model, histological analyses showed increased hyaluronic acid deposition and decreased collagen accumulation after LTP injection. Videokymographic analysis showed more improved vibrations in LTP-treated VF mucosa compared to those in non-treated group. In conclusion, LTP treatment enhanced the recruitment and activation of VF-MSCs. Regulated extracellular matrix (ECM) synthesis and eventual functional improvement of scarred VFs were observed upon LTP treatment. The results of this study suggest that LTP injection can enhance wound healing and improve functional remodeling following VF injury.

Impact statement

Voice disorder has a significant impact on life quality, and one of the major causes of this voice disorder is vocal fold scarring. Therefore, various approaches have been tried to treat for voice disorder. However, no method has satisfied all requirements until now. Plasma medicine, which involves the medical application of plasma, is a rapidly developing field. We have confirmed that liquid-type plasma improved vocal fold scarring by mobilizing and activating vocal fold fibroblast. In conclusion, liquid-type plasma is a potential therapeutic agent for promoting vocal fold scarring through simple injection and it may be an alternative therapeutic agent for the current situation to treat voice disorder.

Keywords

Extracellular matrix lipopolysaccharide mesenchymal stem cell vocal fold fibroblast wound healing

Get full access to this article

View all access options for this article.

References

Hirano

Bless

Heisey

Ford

CN.

Effect of growth factors on hyaluronan production by canine vocal fold fibroblasts. Ann Otol Rhinol Laryngol 2003; 112:617–24

Hiwatashi

Bing

Kraja

Branski

RC.

Mesenchymal stem cells have antifibrotic effects on transforming growth factor-beta1-stimulated vocal fold fibroblasts. Laryngoscope 2017; 127:E35–E41

Hirano

Kishimoto

Suehiro

Kanemaru

Ito

Regeneration of aged vocal fold: first human case treated with fibroblast growth factor. Laryngoscope 2009; 119:197–202

Wang

JH.

Fibroblasts and myofibroblasts in wound healing: force generation and measurement. J Tissue Viability 2011; 20:108–20

Jette

Hayer

Thibeault

SL.

Characterization of human vocal fold fibroblasts derived from chronic scar. Laryngoscope 2013; 123:738–45

Ying

Wray

Nichols

Batlle-Morera

Doble

Woodgett

Cohen

Smith

The ground state of embryonic stem cell self-renewal. Nature 2008; 453:519–23

Uccelli

Moretta

Pistoia

Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008; 8:726–36

Haertel

von Woedtke

Weltmann

Lindequist

Non-thermal atmospheric-pressure plasma possible application in wound healing. Biomol Ther (Seoul) 2014; 22:477–90

Choi

Kang

Kim

Park

Yang

Kim

Lee

Kim

CH.

Novel therapeutic effects of non-thermal atmospheric pressure plasma for muscle regeneration and differentiation. Sci Rep 2016; 6:28829

10.

Kang

Choi

Chang

Kim

Park

Kim

Lee

Yang

Kim

CH.

N2 non-thermal atmospheric pressure plasma promotes wound healing in vitro and in vivo: potential modulation of adhesion molecules and matrix metalloproteinase-9. Exp Dermatol 2017; 26:163–70

11.

Kalghatgi

Dobrynin

Sensenig

Cerchar

Podolsky

Dulaimi

Paff

Wasko

Arjunan

Garcia

Fridman

Balasubramanian

Ownbey

Barbee

Fridman

Friedman

Joshi

Brooks

AD.

Porcine intact and wounded skin responses to atmospheric nonthermal plasma. J Surg Res 2013; 179:e1–e12

12.

Thibeault

Bartley

A method for identification of vocal fold lamina propria fibroblasts in culture. Otolaryngol Head Neck Surg 2008; 139:816–22

13.

Choi

Park

Chang

Kim

Shin

Kim

CH.

Small intestine submucosa and mesenchymal stem cells composite gel for scarless vocal fold regeneration. Biomaterials 2014; 35:4911–8

14.

King

Berchtold

Thibeault

SL.

Lipopolysaccharide responsiveness in vocal fold fibroblasts. J Inflamm (Lond) 2014; 11:42

15.

Ghosh

May

Kopp

EB.

NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998; 16:225–60

16.

Wang

Zhang

JL.

Farrerol inhibits IL-6 and IL-8 production in LPS-stimulated human gingival fibroblasts by suppressing PI3K/AKT/NF-kappaB signaling pathway. Arch Oral Biol 2016; 62:28–32

17.

Lim

Tateya

Munoz-Del-Rio

Bless

DM.

Immediate inflammatory response and scar formation in wounded vocal folds. Ann Otol Rhinol Laryngol 2006; 115:921–9

18.

Singer

Caplan

AI.

Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol 2011; 6:457–78

19.

Dominici

Le Blanc

Mueller

Slaper-Cortenbach

Marini

Krause

Deans

Keating

Prockop

Horwitz

Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8:315–7

20.

Horwitz

Le Blanc

Dominici

Mueller

Slaper-Cortenbach

Marini

Deans

Krause

Keating

, International Society For Cellular Therapy. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 2005; 7:393–5

21.

Caplan

AI.

Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue Eng 2005; 11:1198–211

22.

Caplan

AI.

Mesenchymal stem cells. J Orthop Res 1991; 9:641–50

23.

Caplan

AI.

Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 2007; 213:341–7

24.

Trivedi

Hematti

Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells. Exp Hematol 2008; 36:350–9

25.

Hanson

Kim

Johnson

Bradley

Breunig

Hematti

Thibeault

SL.

Characterization of mesenchymal stem cells from human vocal fold fibroblasts. Laryngoscope 2010; 120:546–51

26.

Chhetri

Head

Revazova

Hart

Bhuta

Berke

GS.

Lamina propria replacement therapy with cultured autologous fibroblasts for vocal fold scars. Otolaryngol Head Neck Surg 2004; 131:864–70

27.

Fishman

Long

Gugatschka

De Coppi

Hirano

Hertegard

Thibeault

Birchall

MA.

Stem cell approaches for vocal fold regeneration. Laryngoscope 2016; 126:1865–70

28.

Isakson

de Blacam

Whelan

McArdle

Clover

AJ.

Mesenchymal stem cells and cutaneous wound healing: current evidence and future potential. Stem Cells Int 2015; 2015:831095

29.

Ravanti

Kahari

VM.

Matrix metalloproteinases in wound repair (review). Int J Mol Med 2000; 6:391–407

30.

Caley

Martins

O'Toole

EA.

Metalloproteinases and wound healing. Adv Wound Care (New Rochelle) 2015; 4:225–34

31.

Desmouliere

Factors influencing myofibroblast differentiation during wound healing and fibrosis. Cell Biol Int 1995; 19:471–6

32.

Border

Noble

NA.

Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331:1286–92

33.

Yamashita

Hirano

Kanemaru

Tsuji

Suehiro

Ito

Side population cells in the human vocal fold. Ann Otol Rhinol Laryngol 2007; 116:847–52

34.

Gugatschka

Kojima

Ohno

Kanemaru

Hirano

Recruitment patterns of side population cells during wound healing in rat vocal folds. Laryngoscope 2011; 121:1662–7