Sheets AR, Demidova-Rice TN, Shi L, Ronfard V, Grover KV, Herman IM, et al.
PloS one. Date of publication 2016 Jul 26;volume 11(7):e0159598.
1. PLoS One. 2016 Jul 26;11(7):e0159598. doi: 10.1371/journal.pone.0159598.
eCollection 2016.
Identification and Characterization of Novel Matrix-Derived Bioactive Peptides: A
Role for Collagenase from Santyl® Ointment in Post-Debridement Wound Healing?
Sheets AR(1)(2)(3), Demidova-Rice TN(3), Shi L(4), Ronfard V(5), Grover KV(4),
Herman IM(1)(6)(2)(3).
Author information:
(1)Graduate Program in Cellular & Molecular Physiology, The Sackler School of
Graduate Biomedical Sciences, Tufts University, 136 Harrison Ave, Boston, MA,
02111, United States of America.
(2)Department of Developmental, Molecular and Chemical Biology, School of
Medicine, Tufts University, 136 Harrison Ave, Boston, MA, 02111, United States of
America.
(3)The Center for Innovations in Wound Healing Research, School of Medicine,
Tufts University, 136 Harrison Ave, Boston, MA, 02111, United States of America.
(4)Smith & Nephew PLC, 3909 Hulen St., Fort Worth, TX, 76107, United States of
America.
(5)University of North Texas Health Science Center, College of Pharmacy, 3500
Camp Bowie Blvd., Fort Worth, TX, 76107, United States of America.
(6)Graduate Program in Cell, Molecular and Developmental Biology, The Sackler
School of Graduate Biomedical Sciences, Tufts University, 136 Harrison Ave,
Boston, MA, 02111, United States of America.
Debridement, the removal of diseased, nonviable tissue, is critical for
clinicians to readily assess wound status and prepare the wound bed for advanced
therapeutics or downstream active healing. Removing necrotic slough and eschar
through surgical or mechanical methods is less specific and may be painful for
patients. Enzymatic debridement agents, such as Clostridial collagenase,
selectively and painlessly degrade devitalized tissue. In addition to its
debriding activities, highly-purified Clostridial collagenase actively promotes
healing, and our past studies reveal that extracellular matrices digested with
this enzyme yield peptides that activate cellular migratory, proliferative and
angiogenic responses to injury in vitro, and promote wound closure in vivo.
Intriguingly, while collagenase Santyl® ointment, a sterile preparation
containing Clostridial collagenases and other non-specific proteases, is a
well-accepted enzymatic debridement agent, its role as an active healing entity
has never been established. Based on our previous studies of pure Clostridial
collagenase, we now ask whether the mixture of enzymes contained within Santyl®
produces matrix-derived peptides that promote cellular injury responses in vitro
and stimulate wound closure in vivo. Here, we identify novel collagen fragments,
along with collagen-associated peptides derived from thrombospondin-1,
multimerin-1, fibronectin, TGFβ-induced protein ig-h3 and tenascin-C, generated
from Santyl® collagenase-digested human dermal capillary endothelial and
fibroblastic matrices, which increase cell proliferation and angiogenic
remodeling in vitro by 50-100% over controls. Using an established model of
impaired healing, we further demonstrate a specific dose of collagenase from
Santyl® ointment, as well as the newly-identified and chemically-synthesized
ECM-derived peptides significantly increase wound re-epithelialization by 60-100%
over saline-treated controls. These results not only confirm and extend our
earlier studies using purified collagenase- and matrix-derived peptides to
stimulate healing in vitro and in vivo, but these Santyl®-generated,
matrix-derived peptides may also represent exciting new opportunities for
creating advanced wound healing therapies that are enabled by enzymatic
debridement and potentially go beyond debridement.
DOI: 10.1371/journal.pone.0159598
PMCID: PMC4961374
PMID: 27459729 [Indexed for MEDLINE]
