Background: The success of antimicrobial therapy has been impaired by the emergence of resistant bacterial strains. Antimicrobial peptides are ubiquitous proteins that are part of the innate immune system and are successful against such antibiotic-resistant microorganisms. The authors have previously demonstrated the feasibility of protein delivery via microvascular free flap gene therapy and here they examine this approach for recalcitrant infections.
Methods: The authors investigated the production of the human cathelicidin antimicrobial peptide-LL37, delivered by ex vivo transduction of the rodent superficial inferior epigastric free flap with Ad/CMV-LL37. The vascular permeabilizing agent vascular endothelial growth factor (VEGF) was co-administered during ex vivo transduction with adenoviral vectors in an attempt to augment transduction efficiency. A rodent model of chronic wound/foreign body infection seeded with bioluminescent Staphylococcus aureus was used to assess the biological efficacy of delivering therapeutic antimicrobial genes using this technology.
Results: The authors were successful in demonstrating significant LL37 expression, which persisted for 14 days after ex vivo transduction with Ad/CMV-LL37. Transduction efficiency was significantly improved with the co-administration of 5 μg of VEGF during transduction without significantly increasing systemic dissemination of adenovirus or systemic toxicity. They were able to demonstrate in the rodent model of chronic wound/foreign body infections a significant reduction in bacterial loads from infected catheters following transduction with Ad/CMV-LL37 and increased bacterial clearance.
Conclusion: This study demonstrates for the first time that microbicidal gene therapy via microvascular free flaps is able to clear chronic infections such as occurs with osteomyelitis resulting from trauma or an infected foreign body.
Stanford and San Diego, Calif.; and London, United Kingdom
From the Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, the Department of Plastic and Reconstructive Surgery, Royal Free Hospital, and the Division of Dermatology, University of California, San Diego.
Received for publication May 26, 2008; accepted October 27, 2008.
This work received the 2007 Plastic Surgery Research Council Clifford C. Snyder award.
Disclosure: None of the authors has any commercial associations or financial relationships that may create a conflict of interest with the work presented in this article.
Geoffrey C. Gurtner, M.D., Stanford University, PSRL, GK-201, 257 Campus Drive, Stanford, Calif. 94305-5148, firstname.lastname@example.org
Treating Chronic Wound Infections with Genetically Modified Free Flaps
The last name of the sixth author was misspelled when this article was published in the April 2009 issue of Plastic and Reconstructive Surgery. The author's name should have appeared as Shahram Aarabi. This erratum is published in the August 2009 issue.