Time course study of delayed wound healing in a biofilm-challenged diabetic mouse model
Open accessAbstract
Bacterial biofilm has been shown to play a role in delaying wound healing of chronic wounds, a major medical problem that results in significant health care burden. A reproducible animal model could be very valuable for studying the mechanism and management of chronic wounds. Our previous work showed that P seudomonas aeruginosa (PAO 1) biofilm challenge on wounds in diabetic (db/db) mice significantly delayed wound healing. In this wound time course study, we further characterize the bacterial burden, delayed wound healing, and certain aspects of the host inflammatory response in the PAO 1 biofilm‐challenged db/db mouse model. PAO 1 biofilms were transferred onto 2‐day‐old wounds created on the dorsal surface of db/db mice. Control wounds without biofilm challenge healed by 4 weeks, consistent with previous studies; none of the biofilm‐challenged wounds healed by 4 weeks. Of the biofilm‐challenged wounds, 64% healed by 6 weeks, and all of the biofilm‐challenged wounds healed by 8 weeks. During the wound‐healing process, P. aeruginosa was gradually cleared from the wounds while the presence of S taphylococcus aureus (part of the normal mouse skin flora) increased. Scabs from all unhealed wounds contained 10 7 P. aeruginosa, which was 100‐fold higher than the counts isolated from wound beds (i.e., 99% of the P. aeruginosa was in the scab). Histology and genetic analysis showed proliferative epidermis, deficient vascularization, and increased inflammatory cytokines. Hypoxia inducible factor expression increased threefold in 4‐week wounds. In summary, our study shows that biofilm‐challenged wounds typically heal in approximately 6 weeks, at least 2 weeks longer than nonbiofilm‐challenged normal wounds. These data suggest that this delayed wound healing model enables the in vivo study of bacterial biofilm responses to host defenses and the effects of biofilms on host wound healing pathways. It may also be used to test antibiofilm strategies for treating chronic wounds.
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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 [37]
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 [37]
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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-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-citationComprehensive transposon mutant library of Pseudomonas aeruginosa
Jacobs, M. A., Alwood, A., Thaipisuttikul, I., Spencer, D. H., Haugen, E., Ernst, S., Will, O., Kaul, R., Raymond, C. K., Levy, R., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2036282100 · Cited by 1,129 · see citing works
Anderl, 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-citationWhy chronic wounds will not heal: a novel hypothesis
Bjarnsholt, T., Kirketerp‐Møller, K., Jensen, P. Ø., Madsen, K. G., Phipps, R. K., Krogfelt, K. A., Høiby, N., & Givskov, M. (2007) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2007.00283.x · Cited by 886 · 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
Multiple 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
Dowd, S. E., Wolcott, R. D., Sun, Y., McKeehan, T., Smith, E., & Rhoads, D. D. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003326 · Cited by 562 · see citing works
Distribution, Organization, and Ecology of Bacteria in Chronic Wounds
Kirketerp‐Møller, K., Jensen, P. Ø., Fazli, M., Madsen, K. G., Pedersen, J., Moser, C. E., Tolker‐Nielsen, T., Høiby, N., Givskov, M., & Bjarnsholt, T. (2008) · Journal of Clinical Microbiology · doi:10.1128/jcm.00501-08 · Cited by 547 · see citing works
Nonrandom Distribution of Pseudomonas aeruginosa and Staphylococcus aureus in Chronic Wounds
Fazli, M., Bjarnsholt, T., Kirketerp‐Møller, K., Jørgensen, B., Andersen, A. S., Krogfelt, K. A., Givskov, M., & Tolker‐Nielsen, T. (2009) · Journal of Clinical Microbiology · doi:10.1128/jcm.01395-09 · Cited by 496 · see citing works
Chronic Wound Care: A Clinical Source Book for Healthcare Professionals
Krasner, D. L., & Kane, D. P. (1990) · Medical Entomology and Zoology · Cited by 442 · see citing works
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. (2010) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2010.00608.x · Cited by 275 · see citing works
Self-citationUsui, 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-citationBiswas, S., Roy, S., Banerjee, J., Hussain, S.-R. A., Khanna, S., Meenakshisundaram, G., Kuppusamy, P., Friedman, A., & Sen, C. K. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001653107 · Cited by 272 · see citing works
Price, L. B., Liu, C. M., Melendez, J. H., Frankel, Y. M., Engelthaler, D., Aziz, M., Bowers, J., Rattray, R., Ravel, J., Kingsley, C., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006462 · Cited by 237 · see citing works
The microbiology of infected and noninfected leg ulcers
Bowler, P. G., & Davies, B. J. (1999) · International Journal of Dermatology · doi:10.1046/j.1365-4362.1999.00738.x · Cited by 233 · see citing works
Longitudinal shift in diabetic wound microbiota correlates with prolonged skin defense response
Grice, E. A., Snitkin, E. S., Yockey, L. J., Bermudez, D. M., Program, N. C. S., Liechty, K. W., Segre, J. A., Mullikin, J., Blakesley, R., Young, A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004204107 · Cited by 227 · 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-citationHansson, C., Hoborn, J., Möller, A., & Swanbeck, G. (1995) · Acta Dermato Venereologica · doi:10.2340/00015555752430 · Cited by 197 · see citing works
Gurjala, A. N., Geringer, M. R., Seth, A. K., Hong, S. J., Smeltzer, M. S., Galiano, R. D., Leung, K. P., & Mustoe, T. A. (2011) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2011.00690.x · Cited by 183 · 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
The bacteriology of chronic venous leg ulcer examined by culture-independent molecular methods
Thomsen, T. R., Aasholm, M. S., Rudkjøbing, V. B., Saunders, A. M., Bjarnsholt, T., Givskov, M., Kirketerp‐Møller, K., & Nielsen, P. H. (2010) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2009.00561.x · Cited by 141 · see citing works
Singh, A., Halder, S., Chumber, S., et al. (2004) · Asian Journal of Surgery · doi:10.1016/s1015-9584(09)60061-0 · Cited by 112 · 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-citationClinical experience with wound biofilm and management: a case series.
Hurlow, J., & Bowler, P. G. (2009) · PubMed · Cited by 102 · see citing works
The Clinical Significance of Bacterial Growth in Venous Leg Ulcers
Eriksson, G., Eklund, A.-E., & Kallings, L. O. (1984) · Scandinavian Journal of Infectious Diseases · doi:10.3109/00365548409087138 · Cited by 99 · see citing works
Scortegagna, M., Martin, R. J., Kladney, R. D., Neumann, R. G., & Arbeit, J. M. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3643 · Cited by 64 · see citing works
Fukano, 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-citationMathieu, D., & Mani, R. (2007) · The International Journal of Lower Extremity Wounds · doi:10.1177/1534734607310299 · Cited by 53 · see citing works
The Epidermis in Wound Healing
Rovee, D. T., & Maibach, H. I. (2003) · CRC Press eBooks · doi:10.1201/b14246 · Cited by 51 · 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
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
Resident bacterial flora in the skin of C57BL/6 mice housed under SPF conditions.
(2010) · PubMed Central · Cited by 33 · 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
Ousey, K. J. (2009) · University of Huddersfield Repository (University of Huddersfield) · Cited by 15 · see citing works
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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
- Authors
- Zhao, G., 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
- 2012-05
- Volume
- 20
- Issue
- 3
- Pages
- 342-352
- ISSN
- 1067-1927 (ISSN-L)
- 1524-475X
- PMC
- PMC3349451
- OpenAlex
- W1503714410
- Cited by
- 127
- References
- 38
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 9 · 2023: 12 · 2022: 14 · 2021: 8 · 2020: 12 · 2019: 9 · 2018: 5 · 2017: 7 · 2016: 11 · 2015: 8 · 2014: 6 · 2013: 10
- FWCI
- 8.12
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- 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 Heart, Lung, and Blood Institute (K24HL102246)
- 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, bacterial biofilms, Pseudomonas aeruginosa, diabetic wound healing, db/db mice, Staphylococcus aureus, wound inflammation, hypoxia-inducible factor, vascularization, antibiofilm strategies
- MeSH terms
- Animals, Diabetes Mellitus, Experimental, Male, Pseudomonas aeruginosa, Pseudomonas Infections, Time Factors, Wound Healing, Mice, Inbred NOD, Biofilms, Mice
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