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A dual-action peptide-containing hydrogel targets wound infection and inflammation

Puthia, Manoj LU ; Butrym, Marta LU ; Petrlova, Jitka LU ; Strömdahl, Ann Charlotte LU ; Andersson, Madelene ; Kjellström, Sven LU and Schmidtchen, Artur LU (2020) In Science Translational Medicine 12(524).
Abstract

There is a clinical need for improved wound treatments that prevent both infection and excessive inflammation. TCP-25, a thrombin-derived peptide, is antibacterial and scavenges pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, thereby preventing CD14 interaction and Toll-like receptor dimerization, leading to reduced downstream immune activation. Here, we describe the development of a hydrogel formulation that was functionalized with TCP-25 to target bacteria and associated PAMP-induced inflammation. In vitro studies determined the polymer prerequisites for such TCP-25-mediated dual action, favoring the use of noncharged hydrophilic hydrogels, which enabled peptide conformational changes and LPS binding. The... (More)

There is a clinical need for improved wound treatments that prevent both infection and excessive inflammation. TCP-25, a thrombin-derived peptide, is antibacterial and scavenges pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, thereby preventing CD14 interaction and Toll-like receptor dimerization, leading to reduced downstream immune activation. Here, we describe the development of a hydrogel formulation that was functionalized with TCP-25 to target bacteria and associated PAMP-induced inflammation. In vitro studies determined the polymer prerequisites for such TCP-25-mediated dual action, favoring the use of noncharged hydrophilic hydrogels, which enabled peptide conformational changes and LPS binding. The TCP-25-functionalized hydrogels killed Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa bacteria in vitro, as well as in experimental mouse models of subcutaneous infection. The TCP-25 hydrogel also mediated reduction of LPS-induced local inflammatory responses, as demonstrated by analysis of local cytokine production and in vivo bioimaging using nuclear factor κB (NF-κB) reporter mice. In porcine partial thickness wound models, TCP-25 prevented infection with S. aureus and reduced concentrations of proinflammatory cytokines. Proteolytic fragmentation of TCP-25 in vitro yielded a series of bioactive TCP fragments that were identical or similar to those present in wounds in vivo. Together, the results demonstrate the therapeutic potential of TCP-25 hydrogel, a wound treatment based on the body's peptide defense, for prevention of both bacterial infection and the accompanying inflammation.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Translational Medicine
volume
12
issue
524
article number
eaax6601
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85077381224
  • pmid:31894104
ISSN
1946-6242
DOI
10.1126/scitranslmed.aax6601
language
English
LU publication?
yes
id
a0f85c35-9cc4-40a0-b404-2d6c0ef6c50b
date added to LUP
2020-01-21 16:16:08
date last changed
2024-06-13 09:59:28
@article{a0f85c35-9cc4-40a0-b404-2d6c0ef6c50b,
  abstract     = {{<p>There is a clinical need for improved wound treatments that prevent both infection and excessive inflammation. TCP-25, a thrombin-derived peptide, is antibacterial and scavenges pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, thereby preventing CD14 interaction and Toll-like receptor dimerization, leading to reduced downstream immune activation. Here, we describe the development of a hydrogel formulation that was functionalized with TCP-25 to target bacteria and associated PAMP-induced inflammation. In vitro studies determined the polymer prerequisites for such TCP-25-mediated dual action, favoring the use of noncharged hydrophilic hydrogels, which enabled peptide conformational changes and LPS binding. The TCP-25-functionalized hydrogels killed Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa bacteria in vitro, as well as in experimental mouse models of subcutaneous infection. The TCP-25 hydrogel also mediated reduction of LPS-induced local inflammatory responses, as demonstrated by analysis of local cytokine production and in vivo bioimaging using nuclear factor κB (NF-κB) reporter mice. In porcine partial thickness wound models, TCP-25 prevented infection with S. aureus and reduced concentrations of proinflammatory cytokines. Proteolytic fragmentation of TCP-25 in vitro yielded a series of bioactive TCP fragments that were identical or similar to those present in wounds in vivo. Together, the results demonstrate the therapeutic potential of TCP-25 hydrogel, a wound treatment based on the body's peptide defense, for prevention of both bacterial infection and the accompanying inflammation.</p>}},
  author       = {{Puthia, Manoj and Butrym, Marta and Petrlova, Jitka and Strömdahl, Ann Charlotte and Andersson, Madelene and Kjellström, Sven and Schmidtchen, Artur}},
  issn         = {{1946-6242}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{524}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Translational Medicine}},
  title        = {{A dual-action peptide-containing hydrogel targets wound infection and inflammation}},
  url          = {{http://dx.doi.org/10.1126/scitranslmed.aax6601}},
  doi          = {{10.1126/scitranslmed.aax6601}},
  volume       = {{12}},
  year         = {{2020}},
}