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Continuous NPWT Regulates Fibrosis in Murine Diabetic Wound Healing

ORCID
0000-0003-2646-3372
Affiliation
Department of Plastic Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
Wu, Mengfan;
ORCID
0000-0001-7108-0413
Affiliation
Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Matar, Dany Y.;
ORCID
0000-0003-3456-3584
Affiliation
Shenzhen Key Ophthalmic Laboratory, Department of Ophthalmology, Shenzhen Eye Hospital, Jinan University, Shenzhen 518040, China
Yu, Zhen;
Affiliation
Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Chen, Ziyu;
ORCID
0000-0001-5798-8003
Affiliation
Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Knoedler, Samuel;
Affiliation
Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Ng, Brian;
Affiliation
Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Darwish, Oliver A.;
Affiliation
Division of Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Sohrabi, Sadaf;
ORCID
0000-0002-4047-7896
Affiliation
Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Friedman, Leigh;
ORCID
0000-0002-2964-979X
Affiliation
Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Haug, Valentin;
Affiliation
Division of Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Murphy, George F.;
Affiliation
School of Medicine, Helmholtz Zentrum München, Institute of Regenerative Biology and Medicine, 81377 Munich, Germany
Rinkevich, Yuval;
Affiliation
Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Orgill, Dennis P.;
Affiliation
Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Panayi, Adriana C.

Scarring is associated with significant morbidity. The mechanical signaling factor yes-associated protein (YAP) has been linked to Engrailed-1 (En1)-lineage positive fibroblasts (EPFs), a pro-scarring fibroblast lineage, establishing a connection between mechanotransduction and fibrosis. In this study, we investigate the impact of micromechanical forces exerted through negative pressure wound therapy (NPWT) on the pathophysiology of fibrosis. Full-thickness excisional dorsal skin wounds were created on diabetic (db/db) mice which were treated with occlusive covering (control) or NPWT (continuous, −125 mmHg, 7 days; NPWT). Analysis was performed on tissue harvested 10 days after wounding. NPWT was associated with increased YAP ( p = 0.04) but decreased En1 ( p = 0.0001) and CD26 ( p < 0.0001). The pro-fibrotic factors Vimentin ( p = 0.04), α-SMA ( p = 0.04) and HSP47 ( p = 0.0008) were decreased with NPWT. Fibronectin was higher ( p = 0.01) and collagen deposition lower in the NPWT group ( p = 0.02). NPWT increased cellular proliferation ( p = 0.002) and decreased apoptosis ( p = 0.03). Western blotting demonstrated increased YAP ( p = 0.02) and RhoA ( p = 0.03) and decreased Caspase-3 ( p = 0.03) with NPWT. NPWT uncouples YAP from EPF activation, through downregulation of Caspace-3, a pro-apoptotic factor linked to keloid formation. Mechanotransduction decreases multiple pro-fibrotic factors. Through this multifactorial process, NPWT significantly decreases fibrosis and offers promising potential as a mode to improve scar appearance.

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