Nanolayered siRNA delivery platforms for local silencing of CTGF reduce cutaneous scar contraction in third-degree burns.
Wound healing is an incredibly complex biological process that often results in thickened collagen-enriched healed tissue called scar. Cutaneous scars lack many functional structures of the skin such as hair follicles, sweat glands, and papillae. The absence of these structures contributes to a number of the long-term morbidities of wound healing, including loss of function for tissues, increased risk of re-injury, and aesthetic complications. Scar formation is a pervasive factor in our daily lives; however, in the case of serious traumatic injury, scars can create long-lasting complications due to contraction and poor tissue remodeling. Within this report we target the expression of connective tissue growth factor (CTGF), a key mediator of TGFβ pro-fibrotic response in cutaneous wound healing, with controlled local delivery of RNA interference. Through this work we describe both a thorough in vitro analysis of nanolayer coated sutures for the controlled delivery of siRNA and its application to improve scar outcomes in a third-degree burn induced scar model in rats. We demonstrate that the knockdown of CTGF significantly altered the local expression of αSMA, TIMP1, and Col1a1, which are known to play roles in scar formation. The knockdown of CTGF within the healing burn wounds resulted in improved tissue remodeling, reduced scar contraction, and the regeneration of papillary structures within the healing tissue. This work adds support to a number of previous reports that indicate CTGF as a potential therapeutic target for fibrosis. Additionally, we believe that the controlled local delivery of siRNA from ultrathin polymer coatings described within this work is a promising approach in RNA interference that could be applied in developing improved cancer therapies, regenerative medicine, and fundamental scientific research.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, 02139, USA.
Steven A
SA
Castleberry
Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, and the Shriners Burns Hospital, Boston, MA, 02114, USA; Porter School of Environmental Studies, Tel Aviv University, Ramat-Aviv, Tel Aviv, Israel.
Alexander
A
Golberg
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Malak Abu
MA
Sharkh
Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Saiqa
S
Khan
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Benjamin D
BD
Almquist
Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
William G
WG
Austen
Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, and the Shriners Burns Hospital, Boston, MA, 02114, USA; Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, 08901, USA.
Martin L
ML
Yarmush
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. Electronic address: hammond@mit.edu.
Paula T
PT
Hammond
D000818:Animals; D002056:Burns / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D002921:Cicatrix / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D016503:Drug Delivery Systems; D005355:Fibrosis / Q000473:pathology / Q000628:therapy; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D049329:Nanostructures / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D012867:Skin / Q000187:drug effects; D013537:Sutures; D016212:Transforming Growth Factor beta / Q000378:metabolism
D011108:Polymers; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor
CTGF; Controlled release; Layer-by-layer; Scar formation; Wound healing; siRNA delivery