Delayed wound healing in diabetic (db/db) mice with Pseudomonas aeruginosa biofilm challenge: a model for the study of chronic wounds: A biofilm-challenged chronic wound model
Open accessAbstract
Chronic wounds are a major clinical problem that lead to considerable morbidity and mortality. We hypothesized that an important factor in the failure of chronic wounds to heal was the presence of microbial biofilm resistant to antibiotics and protected from host defenses. A major difficulty in studying chronic wounds is the absence of suitable animal models. The goal of this study was to create a reproducible chronic wound model in diabetic mice by the application of bacterial biofilm. Six-millimeter punch biopsy wounds were created on the dorsal surface of diabetic (db/db) mice, subsequently challenged with Pseudomonas aeruginosa (PAO1) biofilms 2 days postwounding, and covered with semiocclusive dressings for 2 weeks. Most of the control wounds were epithelialized by 28 days postwounding. In contrast, none of biofilm-challenged wounds were closed. Histological analysis showed extensive inflammatory cell infiltration, tissue necrosis, and epidermal hyperplasia adjacent to challenged wounds-all indicators of an inflammatory nonhealing wound. Quantitative cultures and transmission electron microscopy demonstrated that the majority of bacteria were in the scab above the wound bed rather than in the wound tissue. The model was reproducible, allowed localized cutaneous wound infections without high mortality, and demonstrated delayed wound healing following a biofilm challenge. This model may provide an approach to study the role of microbial biofilms in chronic wounds as well as the effect of specific biofilm therapy on wound healing.
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Infection with either S. aureus or P. aeruginosa has been shown to delay wound closure in mouse and rabbit wound healing models.
“infection with either S. aureus or P. aeruginosa has been shown to delay wound closure in mouse and rabbit wound healing models [31], [37], [39], [40], [41].”
From Interactions of Methicillin Resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in Polymicrobial Wound Infection (2013) · cites this paper as [31]
Both QS systems (LasI-LasR and RhlI-RhlR) contribute to the pathology of cutaneous wound infections.
“Both QS systems contribute to the pathology of cutaneous wound infections [31], [32]”
From Interactions of Methicillin Resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in Polymicrobial Wound Infection (2013) · cites this paper as [31]
Wounds infected with Pseudomonas are slower to heal.
“wounds infected with Pseudomonas are slower to heal [31], [37], [38]”
From Interactions of Methicillin Resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in Polymicrobial Wound Infection (2013) · cites this paper as [31]
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Cites
Bacterial Biofilms: A Common Cause of Persistent Infections
Costerton, J. W., Stewart, P. S., & Greenberg, E. P. (1999) · Science · doi:10.1126/science.284.5418.1318 · Cited by 12,167 · see citing works
Self-citationBiofilms: Survival Mechanisms of Clinically Relevant Microorganisms
Donlan, R. M., & Costerton, J. W. (2002) · Clinical Microbiology Reviews · doi:10.1128/cmr.15.2.167-193.2002 · Cited by 6,644 · see citing works
Cellular and molecular basis of wound healing in diabetes
Brem, H., & Tomic‐Canic, M. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32169 · Cited by 1,816 · see citing works
Survival strategies of infectious biofilms
Fux, C. A., Costerton, J. W., Stewart, P. S., & Stoodley, P. (2004) · Trends in Microbiology · doi:10.1016/j.tim.2004.11.010 · Cited by 1,812 · see citing works
Self-citationBacterial Biofilms: An Emerging Link to Disease Pathogenesis
Parsek, M. R., & Singh, P. K. (2003) · Annual Review of Microbiology · doi:10.1146/annurev.micro.57.030502.090720 · Cited by 1,563 · see citing works
Self-citationJames, G. A., Swogger, E., Wolcott, R., Pulcini, E. D., Secor, P., Sestrich, J., Costerton, J. W., & Stewart, P. S. (2008) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2007.00321.x · Cited by 1,543 · see citing works
Self-citationGene expression in Pseudomonas aeruginosa biofilms
Whiteley, M., Bangera, M. G., Bumgarner, R. E., Parsek, M. R., Teitzel, G. M., Lory, S. J., & Greenberg, E. P. (2001) · Nature · doi:10.1038/35101627 · Cited by 1,186 · see citing works
Evolving concepts in biofilm infections
Hall‐Stoodley, L., & Stoodley, P. (2009) · Cellular Microbiology · doi:10.1111/j.1462-5822.2009.01323.x · Cited by 1,138 · see citing works
Walters, M. C., Roe, F., Bugnicourt, A., Franklin, M. J., & Stewart, P. S. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.1.317-323.2003 · Cited by 1,005 · see citing works
Self-citationAnderl, J. N., Franklin, M. J., & Stewart, P. S. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.7.1818-1824.2000 · Cited by 958 · see citing works
Self-citationInvolvement of Nitric Oxide in Biofilm Dispersal of Pseudomonas aeruginosa
Barraud, N., Hassett, D. J., Hwang, S.-H., Rice, S. A., Kjelleberg, S. J., & Webb, J. S. (2006) · Journal of Bacteriology · doi:10.1128/jb.00779-06 · Cited by 785 · see citing works
Dowd, S. E., Sun, Y., Secor, P. R., Rhoads, D. D., Wolcott, B. M., James, G. A., & Wolcott, R. D. (2008) · BMC Microbiology · doi:10.1186/1471-2180-8-43 · Cited by 783 · see citing works
Self-citationPDGF and FGF stimulate wound healing in the genetically diabetic mouse.
Greenhalgh, D. G., Sprugel, K. H., Murray, M. J., & Ross, R. (1990) · Europe PMC (PubMed Central) · Cited by 681 · see citing works
Fonder, M. A., Lazarus, G. S., Cowan, D. A., Aronson-Cook, B., Kohli, A. R., & Mamelak, A. J. (2008) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2007.08.048 · Cited by 665 · see citing works
Kaneko, Y., Thoendel, M., Olakanmi, O., Britigan, B. E., & Singh, P. K. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30783 · Cited by 663 · see citing works
Self-citationMultiple bacterial species reside in chronic wounds: a longitudinal study
Gjødsbøl, K., Christensen, J. J., Karlsmark, T., Jørgensen, B., Klein, B. M., & Krogfelt, K. A. (2006) · International Wound Journal · doi:10.1111/j.1742-481x.2006.00159.x · Cited by 623 · see citing works
Microscopic and physiologic evidence for biofilm-associated wound colonization in vivo
Davis, S. C., Ricotti, C., Cazzaniga, A., Welsh, E., Eaglstein, W. H., & Mertz, P. M. (2008) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2007.00303.x · Cited by 393 · see citing works
Ryan, M. C., Lee, K., Miyashita, Y., & Carter, W. G. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.145.6.1309 · Cited by 315 · see citing works
Animal models for wound repair
Davidson, J. M. (1998) · Archives of Dermatological Research · doi:10.1007/pl00007448 · Cited by 282 · see citing works
Baltimore, R. S., Christie, C. D. C., & Smith, G. J. (1989) · American Review of Respiratory Disease · doi:10.1164/ajrccm/140.6.1650 · Cited by 277 · see citing works
Usui, M. L., Mansbridge, J. N., Carter, W. G., Fujita, M., & Olerud, J. E. (2008) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.2008.951194 · Cited by 272 · see citing works
Self-citationWound Healing Alterations Caused by Infection
Robson, M. C., Stenberg, B. D., & Heggers, J. P. (1990) · Clinics in Plastic Surgery · doi:10.1016/s0094-1298(20)30623-4 · Cited by 266 · see citing works
Gibran, N. S., Jang, Y., Isik, F. F., Greenhalgh, D. G., Muffley, L. A., Underwood, R. A., Usui, M. L., Larsen, J. A., Smith, D. G., Bunnett, N. W., et al. (2002) · Journal of Surgical Research · doi:10.1006/jsre.2002.6525 · Cited by 199 · see citing works
Self-citationBurns, biofilm and a new appraisal of burn wound sepsis
Kennedy, P. J., Brammah, S., & Wills, E. J. (2009) · Burns · doi:10.1016/j.burns.2009.02.017 · Cited by 172 · see citing works
Effects of Ischemia on Ulcer Wound Healing: A New Model in the Rabbit Ear
Ahn, S. T., & Mustoe, T. A. (1990) · Annals of Plastic Surgery · doi:10.1097/00000637-199001000-00004 · Cited by 161 · see citing works
Giacometti, A., Cirioni, O., Gov, Y., Ghiselli, R., Prete, M. S. D., Mocchegiani, F., Saba, V., Orlando, F., Scalise, G., Balaban, N., et al. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.6.1979-1983.2003 · Cited by 120 · see citing works
Kirker, K. R., Secor, P. R., James, G. A., Fleckman, P. H., Olerud, J. E., & Stewart, P. S. (2009) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2009.00523.x · Cited by 110 · see citing works
Self-citationStewart, P. S., Wattanakaroon, W., Goodrum, L., et al. (1999) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.43.2.292 · Cited by 95 · see citing works
Self-citationValidation of a Model for the Study of Multiple Wounds in the Diabetic Mouse (db/db)
Sullivan, S. R., Underwood, R. A., Gibran, N. S., et al. (2004) · Plastic & Reconstructive Surgery · doi:10.1097/01.prs.0000105044.03230.f4 · Cited by 82 · see citing works
Self-citationFukano, Y., Knowles, N. G., Usui, M. L., Underwood, R. A., Hauch, K. D., Marshall, A. J., Ratner, B. D., Giachelli, C. M., Carter, W. G., Fleckman, P. H., et al. (2006) · Wound Repair and Regeneration · doi:10.1111/j.1743-6109.2006.00138.x · Cited by 62 · see citing works
Self-citationEpidermal proliferation is not impaired in chronic venous ulcers.
Andriessen, M. P. M., van Bergen, B. H., Spruijt, K. I. J., et al. (1995) · Acta Dermato Venereologica · doi:10.2340/0001555575459462 · Cited by 50 · see citing works
Gu, Q., Wang, D., Gao, Y., et al. (2002) · Journal of Environmental Pathology Toxicology and Oncology · doi:10.1615/jenvironpatholtoxicoloncol.v21.i1.70 · Cited by 46 · see citing works
Kelly, N. M., Kluftinger, J. L., Pasloske, B. L., et al. (1989) · Infection and Immunity · doi:10.1128/iai.57.12.3841-3845.1989 · Cited by 40 · see citing works
Terasaki, K., Kanzaki, T., Aoki, T., Iwata, K., & Saiki, I. (2003) · The Journal of Dermatology · doi:10.1111/j.1346-8138.2003.tb00367.x · Cited by 35 · see citing works
Mixture of sugar and povidone-iodine stimulates healing of MRSA-infected skin ulcers on db/db mice
Shi, C., Nakao, H., Yamazaki, M., et al. (2007) · Archives of Dermatological Research · doi:10.1007/s00403-007-0776-3 · Cited by 34 · see citing works
The Epidermis in Wound Healing
Scheinfeld, N. S. (2005) · SKINmed Dermatology for the Clinician · doi:10.1111/j.1540-9740.2005.03895.x · Cited by 32 · see citing works
Holder, I. A., Brown, R. L., & Greenhalgh, D. G. (1997) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.1997.50213.x · Cited by 30 · see citing works
Senter, L. H., LeGrand, E. K., Laemmerhirt, K. E., et al. (1995) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.1995.30316.x · Cited by 17 · see citing works
Development of a chronic wound in a diabetic (db/db) mouse by infection with biofilm
Zhao, G., Hochwalt, P. C., Usui, M. L., Underwood, R. A., Singh, P. K., James, G. A., Stewart, P. S., Fleckman, P. H., & Olerud, J. E. (2008) · Montana State University ScholarWorks (Montana State University) · Cited by 1 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [20]Dorland's illustrated medical dictionary 2007 Saunders Philadelphia, PA
Cited by
Sorted by citations
Biofilms and Inflammation in Chronic Wounds
Zhao, G., Usui, M. L., Lippman, S. I., James, G. A., Stewart, P. S., Fleckman, P., & Olerud, J. E. (2013) · Advances in Wound Care · doi:10.1089/wound.2012.0381 · Cited by 448 · see citing works
Self-citationPastar, I., Nusbaum, A. G., Gil, J., Patel, S. B., Chen, J., Valdes, J., Stojadinovic, O., Plano, L. R., Tomic-Canic, M., & Davis, S. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056846 · Cited by 391 · see citing works
Mixed‐species biofilm compromises wound healing by disrupting epidermal barrier function
Roy, S., Elgharably, H., Sinha, M., Ganesh, K., Chaney, S., Mann, E., Miller, C., Khanna, S., Bergdall, V. K., Powell, H. M., et al. (2014) · The Journal of Pathology · doi:10.1002/path.4360 · Cited by 208 · see citing works
Time course study of delayed wound healing in a biofilm-challenged diabetic mouse model
Zhao, G., Usui, M. L., Underwood, R. A., Singh, P. K., James, G. A., Stewart, P. S., Fleckman, P., & Olerud, J. E. (2012) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2012.00793.x · Cited by 127 · see citing works
Self-citationSeth, A. K., Geringer, M. R., Galiano, R. D., Leung, K. P., Mustoe, T. A., & Hong, S. J. (2012) · Journal of the American College of Surgeons · doi:10.1016/j.jamcollsurg.2012.05.028 · Cited by 65 · see citing works
Roche, E. D., Renick, P. J., Tetens, S. P., Ramsay, S. J., Daniels, E. Q., & Carson, D. L. (2012) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2012.00808.x · Cited by 56 · see citing works
Levinson, H. (2013) · Advances in Wound Care · doi:10.1089/wound.2012.0389 · Cited by 30 · see citing works
- Authors
- Zhao, G., Hochwalt, P. C., Usui, M. L., Underwood, R. A., Singh, P. K., James, G. A., Stewart, P. S., Fleckman, P., & Olerud, J. E.
- Affiliations
- University of Washington (US)
- Montana State University (US)
- Corresponding author
- Zhao, Ge
- Venue
- Wound Repair and Regeneration
- Publisher
- Wiley
- Published
- 2010-08-19
- Volume
- 18
- Issue
- 5
- Pages
- 467-477
- ISSN
- 1067-1927 (ISSN-L)
- PMC
- PMC2939909
- OpenAlex
- W1577305427
- Cited by
- 275
- References
- 39
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 24 · 2023: 28 · 2022: 22 · 2021: 18 · 2020: 23 · 2019: 20 · 2018: 16 · 2017: 12 · 2016: 20 · 2015: 13 · 2014: 14 · 2013: 20 · 2012: 14
- FWCI
- 12.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Wound Repair and Regeneration (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Montana State University ScholarWorks (Montana State University) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (P20GM078445)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetic Foot Ulcer Assessment and Management
- Keywords
- chronic wounds, delayed wound healing, Pseudomonas aeruginosa biofilm, diabetic wound healing
- MeSH terms
- Animals, Chronic Disease, Diabetes Mellitus, Experimental, Female, Follow-Up Studies, Pilot Projects, Pseudomonas aeruginosa, Pseudomonas Infections, Time Factors, Wound Healing, Wound Infection, Biofilms, Mice
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