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Double defense
Wound infections can increase risk of systemic complications, such as sepsis, and can be difficult to treat due to growing antimicrobial resistance. Puthia et al. developed a hydrogel containing a thrombin-derived peptide, TCP-25, that kills bacteria and reduces inflammation. The hydrogel was effective against Staphylococcus aureus, Pseudomonas aeruginosa, and clinical bacterial isolates in vitro, and treated murine models of subcutaneous infections and porcine partial thickness wound infections. Bioactive cleavage fragments of the peptide were similar to those found in human wound fluid. Results suggest that this dual-action anti-inflammatory and antibacterial peptide-functionalized hydrogel is a promising approach for wound healing.
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 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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