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Interactions of cytokines, growth factors, and proteases in acute and chronic wounds
Abstract
A healing wound represents a complex series of interactions between cells, soluble mediators, and extracellular matrix. Within this multifaceted environment, there are multiple regulatory points which control the ordered series of events that lead to normal tissue repair. An alteration in this physiologic network can lead to the development of a chronic wound. This article presents an update on the numerous mediators that exist within the wound environment in both acute normal healing and chronic nonhealing wounds. We also present a hypothesis which may provide a conceptual pathophysiologic mechanism with which to understand all chronic wounds.
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“Elevated levels of IL-1β have been found in wounds of diabetic humans and mice (12,15,19,20)”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [19]
In the citing paper
“Chronic wounds are typically associated with a persistent inflammatory response that involves accumulation of Mp (19,26–28)”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [19]
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Self-citationPreclinical promise of becaplermin (rhPDGF-BB) in wound healing
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“However, if the wound is exposed to a high level of TNF-α for a long time, procollagen mRNAs and protein synthesis decrease, which reduces the tensile strength of the wound and thus the wound is affected negatively [34] TNF-α is of importance in the activation of endothelial cells and angiogenesis [40] and plays a rol…”
InfluentialLow-Intensity Vibration Improves Angiogenesis and Wound Healing in Diabetic Mice
Weinheimer-Haus, E. M., Judex, S., Ennis, W., & Koh, T. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091355 · Cited by 99
“However, there are similarities between the healing responses in db/db mice and diabetic humans, including prolonged accumulation of monocytes/macrophages and pro-inflammatory cytokines and proteases, reduced levels of various growth factors, delayed closure, and reduced angiogenesis and matrix deposition [2,21,22,27,…”
BackgroundThe role of stem cells in the treatment of diabetic foot ulcers
Blumberg, S. N., Berger, A. J., Hwang, L. A., Pastar, I., Warren, S. M., & Chen, W. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.10.032 · Cited by 97
“Continual influx of inflammatory cells and sustained production of their inflammatory mediators cause imbalances in wound proteases and their inhibitors, preventing ECM synthesis and remodeling that are essential for normal wound healing [8–12].”
BackgroundGene therapy in wound healing: present status and future directions
Branski, L. K., Pereira, C. T., Herndon, D. N., & Jeschke, M. G. (2006) · Gene Therapy · doi:10.1038/sj.gt.3302837 · Cited by 97
Biological processes and factors involved in soft and hard tissue healing
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“In addition, elevated levels of IL-1β have been found in wounds from diabetic humans and mice, which exhibit a persistent inflammatory response and impaired healing [9,10,19,20].”
BackgroundNguyen, K. T., Seth, A. K., Hong, S. J., Geringer, M. R., Xie, P., Leung, K. P., Mustoe, T. A., & Galiano, R. D. (2013) · Wound Repair and Regeneration · doi:10.1111/wrr.12109 · Cited by 93
“It has been hypothesized that excessive inflammation resulting from metabolic derangements and vascular disease can cause soft tissue injury and ulceration.(5,19,21,22) However, in clinical situations, biofilm formation in wounds is also common and can contribute to wound chronicity.”
Human acellular dermal wound matrix: evidence and experience
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“In chronic wounds, the ECM is often dysfunctional, not only due to the inflammatory and proteolytic environment of chronic wounds, which breaks down ECM but also due to the relative deficiency in protease inhibitors, which normally regulate proteases (6,7).”
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“It initiates the inflammatory phase by promoting the recruitment of inflammatory leukocytes into the wound tissues.(2) During the inflammatory phase, major cellular sources of TNF-a are shifted into the infiltrating neutrophils and macrophages, creating a positive amplification circuit for extending the inflammatory r…”
BackgroundInfluentialHaque, S. T., Saha, S. K., Haque, M. E., & Biswas, N. (2021) · Biomaterials Science · doi:10.1039/d1bm01211h · Cited by 87
pH Influence on Antibacterial Efficacy of Common Antiseptic Substances
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“ance in the ratios of MMPs and TIMPs has been associated with chronic wounds, including chronic pressure ulcers.(2,3,12,14,15,21) MMPs are important throughout the healing process, including the remodeling phase (which can take sev-”
BackgroundSelf-citationChronic Wounds: Innovations in Diagnostics and Therapeutics
Haalboom, M. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867324666170710120556 · Cited by 88
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Current research on fungi in chronic wounds
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“Thus, an altered accumulation of ECM might be induced either by paracrine signals from activated lymphocytes and macrophages or by autocrine factors secreted by fibroblasts [2,9,21-26].”
BackgroundPorous Silicon Resonant Microcavity Biosensor for Matrix Metalloproteinase Detection
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“ROS cause the breaking down of proteins, which are vital to healing.(3) For this paper, biofilms are referred to as microorganisms that are attached to each other (aggregated or co-aggregated) or to a surface and are encased within an extracellular matrix, referred to as extracellular polymeric substance (EPS).”
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Gauthier‐Kemper, A., Fisch, A., Seuwen, K., Baumgarten, B. U., Ruffner, H., Aebi, A., Rausch, M., Kiessling, F. M., Bartneck, M., Weiskirchen, R., et al. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.04.006 · Cited by 80
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“15 high protease activity, decreased levels of natural metalloproteinase inhibitors, and diminished growth factor activity [26-28].”
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Antioxidative and antiinflammatory activities of quercetin-loaded silica nanoparticles
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Wound healing in animals: a review of physiology and clinical evaluation
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“This alteration is characterized by increased destruction and degradation of ECM components, with concomitant lack of synthesis of these elements (19).”
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“the levels of IL-8 were similar in CWF and acute wound fluid (Mast and Schultz, 1996).”
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“They are produced by macrophages and other cell types and participate in the stimulation of inflammatory cells or the activation of proteases ( Mast and Schultz 1996; Schultz and Mast 1998; Trengrove et al. 1999; Barrick et al. 1999).”
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“High and consistent secretion of proinflammatory mediators has been shown to contribute to creation of chronic wounds and retarded healing.(22) In agreement with these findings, we observed a general retardation of in vitro wound closure.”
IL‐17A promotes neutrophilic inflammation and disturbs acute wound healing in skin
Takagi, N., Kawakami, K., Kanno, E., Tanno, H., Takeda, A., Ishii, K., Imai, Y., Iwakura, Y., & Tachi, M. (2017) · Experimental Dermatology · doi:10.1111/exd.13115 · Cited by 79
Recent advances in bacterial cellulose-based antibacterial composites for infected wound therapy
Meng, S., Wu, H., Xiao, D., Lan, S., & Dong, A. (2023) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2023.121082 · Cited by 81
Pressure Ulcers in Individuals Receiving Palliative Care
Langemo, D. K., & Black, J. M. (2010) · Advances in Skin & Wound Care · doi:10.1097/01.asw.0000363502.84737.c8 · Cited by 75
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Intelligent Nanoparticle-Based Dressings for Bacterial Wound Infections
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Progress in copper‐based materials for wound healing
Diao, W., Li, P., Jiang, X., Zhou, J., & Yang, S. (2023) · Wound Repair and Regeneration · doi:10.1111/wrr.13122 · Cited by 75
StarPEG‐Heparin Hydrogels to Protect and Sustainably Deliver IL‐4
Schirmer, L., Atallah, P., Werner, C., & Freudenberg, U. (2016) · Advanced Healthcare Materials · doi:10.1002/adhm.201600797 · Cited by 72
Current and emerging therapies in the management of diabetic foot ulcers
Karri, V. V. S. R., Kuppusamy, G., Talluri, S. V., Yamjala, K., Mannemala, S. S., & Malayandi, R. (2015) · Current Medical Research and Opinion · doi:10.1185/03007995.2015.1128888 · Cited by 74
The effect of topical tripeptide-copper complex on healing of ischemic open wounds
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“Induction of ASC pyroptosome, and subsequent activation of Casp-1 are in agreement with previous findings of increased levels of activated IL-1β in DFU (48-51), suggesting that high levels of this pro-inflammatory cytokine in DFU may be the result of increased pyroptosis.”
ResultBest Practice Recommendations for the Prevention and Treatment of Pressure Ulcers
Keast, D. H., Parslow, N. E., Houghton, P. E., Norton, L., & Fraser, C. (2007) · Advances in Skin & Wound Care · doi:10.1097/01.asw.0000284922.69932.c5 · Cited by 70
Topical application of quercetin improves wound repair and regeneration in diabetic rats
Kant, V., Jangir, B. L., Sharma, M., Kumar, V., & Joshi, V. G. (2021) · Immunopharmacology and Immunotoxicology · doi:10.1080/08923973.2021.1950758 · Cited by 69
“It might be concluded from the present study that once daily topical application of quercetin on diabetic wounds for 21days resulted in increased expressions of IL-10, VEGF and TGF-b1, and decreased the expressions of TNF-a, IL-1b, MMP-9 in comparison to wounds of diabetic control group.”
BackgroundInfluentialMota, F. A. R., Passos, M. L. C., Santos, J. L. M., & Saraiva, M. L. M. F. S. (2024) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2024.116095 · Cited by 76
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Cellular Senescence and Matrix Metalloproteinase Activity in Chronic Wounds
Mulder, G., & Berg, J. S. V. (2002) · Journal of the American Podiatric Medical Association · doi:10.7547/87507315-92-1-34 · Cited by 69
Swab Versus Biopsy for the Diagnosis of Chronic Infected Wounds
Rondas, A., Schols, J. M. G. A., Halfens, R. J. G., & Stobberingh, E. E. (2013) · Advances in Skin & Wound Care · doi:10.1097/01.asw.0000428984.58483.aa · Cited by 68
Long-term outcome study of growth factor-treated pressure ulcers
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“Mast and Schultz [5] and Tarnuzzer et al [6] have postulated that this deficiency is due to the fact that in chronic wounds, repeated trauma, ischemia, and infection increase the level of proinflammatory cytokines, increase the level of matrix metalloproteinases (MMPs), decrease the presence of tissue inhibitors of me…”
BackgroundCorrelation of Procalcitonin and Cytokine Expression with Dehiscence of Wartime Extremity Wounds
Forsberg, J. A., Elster, E. A., Andersen, R. C., et al. (2008) · Journal of Bone and Joint Surgery · doi:10.2106/jbjs.g.00265 · Cited by 66
The effect of amelogenins (Xelma™) on hard‐to‐heal venous leg ulcers
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Retention of Endogenous Viable Cells Enhances the Anti-Inflammatory Activity of Cryopreserved Amnion
Duan-Arnold, Y., Gyurdieva, A. V., Johnson, A., Uveges, T. E., Jacobstein, D. A., & Danilkovitch, A. (2015) · Advances in Wound Care · doi:10.1089/wound.2015.0636 · Cited by 66
“However, elevated and prolonged expression of inflammatory cytokines and proteases leads to the degradation of extracellular matrix (ECM) and growth factors, which prevents wounds from progressing into the proliferative and remodeling phases and inhibits healing.(1) Therefore, wound-care modalities that adYi Duan-Arno…”
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“Several studies on cytokine levels in wound fluids from CVLUs have been conducted, but results are inconclusive and more studies are warranted [3,12–16].”
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“Once the excessive inflammation is controlled by aggressive wound care, then the proliferative and remodeling phases begin; however, the resulting scar is often excessive and fibrotic.(56) These chronic nonhealing ulcers are examples of”
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Recent Advances in Functional Wound Dressings
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“7,9,37 Hence, the impregnation of these GFs on dressing materials might compensate for their insufficiency in promoting chronic wound healing.”
Macrophage Depletion Impairs Corneal Wound Healing after Autologous Transplantation in Mice
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“Wounds normally heal in an orderly manner through the inflammatory phase, proliferation phase and remodeling phase, which are overlapping and involve many cell types, such as neutrophils, macrophages, fibroblasts and endothelial cells [1].”
BackgroundPDGF-BB Does Not Accelerate Healing in Diabetic Mice with Splinted Skin Wounds
Park, S. A., Raghunathan, V. K., Shah, N. M., Teixeira, L. B. C., Motta, M. J., Covert, J. C., Dubielzig, R. R., Schurr, M. J., Isseroff, R. R., Abbott, N. L., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104447 · Cited by 60
“We also recognize that the expression and activities of matrix metalloproteinases and other proteases are altered during diabetes and may contribute to accelerated degradation of growth factors [43–46] present inherently in the wound site or those topically administered.”
BackgroundPain mediators and wound healing—Establishing the connection
Widgerow, A. D., & Kalaria, S. S. (2012) · Burns · doi:10.1016/j.burns.2012.05.024 · Cited by 60
“Include interleukins, interferons, tumor necrosis factors, growth factors and chemokines Mainly pro-inflammatory in excess—also increase activation of complement, neutrophil chemotactic factors, fibrinopeptides, all inducing proinflammatory responses [34] b u r n s 3 8 ( 2 0 1 2 ) 9 5 1 – 9 5 9 953”
BackgroundInfluentialCytokine manipulation of the wound
Robson, M. C. (2003) · Clinics in Plastic Surgery · doi:10.1016/s0094-1298(02)00073-1 · Cited by 59
“Despite preclinical studies suggesting that exogenous IL-1B might shift the wound trajectory to the left, the attempt in pressure ulcers was possibly ill conceived because increased levels of proinflammatory cytokines are thought to be part of the pathobiology of wound chronicity [4,8].”
BackgroundWound Exudate—The Good, the Bad, and the Ugly
Spear, M. E. (2012) · Plastic and Aesthetic Nursing · doi:10.1097/psn.0b013e318256d638 · Cited by 59
Rondas, A., Schols, J. M. G. A., Stobberingh, E. E., & Halfens, R. J. G. (2013) · International Wound Journal · doi:10.1111/iwj.12172 · Cited by 58
“Wound care nurse for chronic wounds 7 (11) Discussion of patients within multidisciplinary meetings 4 (7) Implementation of a protocol/guideline 8 (13) Cause of chronic wound is mentioned in the patient record 1 (2) Preventive measures are mentioned in the patient record 20 (33) Information brochure on chronic wounds…”
BackgroundHeberprot-P: a novel product for treating advanced diabetic foot ulcer
Berlanga, J., Fernández, J. I., López, E., López, P. A., del Río, A., Valenzuela, C., Baldomero, J., Muzio, V., Raı́ces, M., Silva, R. P., et al. (2013) · MEDICC Review · doi:10.1590/s1555-79602013000100004 · Cited by 58
“[21] This was somewhat surprising as other studies had already established proteolysis affecting growth factors and their receptors in chronic circumstances.[22,23] It is worth noting that previous studies had also documented the need for prolonged interaction between EGF and its receptor to achieve a significant gran…”
Tanno, H., Kawakami, K., Kanno, E., Suzuki, A., Takagi, N., Yamamoto, H., Ishii, K., Imai, Y., Maruyama, R., & Tachi, M. (2017) · Wound Repair and Regeneration · doi:10.1111/wrr.12588 · Cited by 60
“In chronic wounds, such as a pressure ulcer and a diabetic foot ulcer, these normal wound healing processes are impaired.(6) Persistent neutrophil accumulation is observed at chronic wound sites, and this leads to chronic inflammation, which results in delayed wound healing.”
BackgroundHow Signaling Molecules Regulate Tumor Microenvironment: Parallels to Wound Repair
Gál, P., Varinská, L., Fáber, L., Novak, S., Szabó, P., Mitrengová, P., Miroššay, A., Mučaji, P., & Smetana, K. (2017) · Molecules · doi:10.3390/molecules22111818 · Cited by 60
“Firstly, proteases activated at the injury site are able to degrade both endogenous and exogenous growth factors and other signaling molecules [101].”
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Berlanga‐Acosta, J. (2011) · International Wound Journal · doi:10.1111/j.1742-481x.2011.00840.x · Cited by 59
Uric Acid and Xanthine Oxidoreductase in Wound Healing
Fernandez, M. L., Upton, Z., & Shooter, G. K. (2013) · Current Rheumatology Reports · doi:10.1007/s11926-013-0396-1 · Cited by 55
“Interestingly, previous studies have revealed elevated levels of IL-1β in wound fluid from patients with chronic wounds [38–40].”
BackgroundTambella, A. M., Attili, A., Dini, F., Piccionello, A. P., Vullo, C., Serri, E., Scrollavezza, P., & Dupré, G. (2014) · Veterinary Surgery · doi:10.1111/j.1532-950x.2014.12148.x · Cited by 55
“Elevated pro‐inflammatory cytokines, high protease activity, and diminished GFs activity is often identified in fluids collected from chronic wounds compared with acute wounds.(4) Platelets play an important role in healing.”
BackgroundMolecular Wound Assessments: Matrix Metalloproteinases
Gibson, D. J., & Schultz, G. S. (2013) · Advances in Wound Care · doi:10.1089/wound.2011.0359 · Cited by 55
“In both cases, excessive proteinases are responsible for destroying endogenous pro-healing growth factors, co-factors, receptors, and the underlying extracellular matrix.(8,9) While effective pro-healing biological therapies, such as recombinant growth factors, acellular matrices, and grafts, have been shown to effect…”
BackgroundSelf-citationThe Role of Collagen-Based Biomaterials in Chronic Wound Healing and Sports Medicine Applications
Yeung, D. A., & Kelly, N. H. (2021) · Bioengineering · doi:10.3390/bioengineering8010008 · Cited by 56
“Elevated and prolonged expression of inflammatory cytokines and proteases leads to the degradation of extracellular matrix and growth factors, which prevents wounds and injuries from progressing to the proliferative and remodeling phases, thus inhibiting healing [83].”
BackgroundNanotheranostics: A Possible Solution for Drug-Resistant Staphylococcus aureus and their Biofilms?
Mosselhy, D. A., Assad, M. A., Sironen, T. A., & Elbahri, M. (2021) · Nanomaterials · doi:10.3390/nano11010082 · Cited by 56
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Sonoporation of the Minicircle-VEGF165 for Wound Healing of Diabetic Mice
Yoon, C. S., Jung, H. S., Kwon, M. J., Lee, S. Y., Kim, C. W., Kim, M.-K., Lee, M., & Park, J. H. (2008) · Pharmaceutical Research · doi:10.1007/s11095-008-9778-x · Cited by 52
“In the high blood glucose level, the wound tissue showed decreased growth factor levels (VEGF, EGF, TGF-β and PDGF) via Western blot analyses which is concurrent with the impaired wound healing of diabetes (data not shown) (34,35).”
BackgroundMannello, F., Ligi, D., Canale, M., & Raffetto, J. D. (2014) · Expert Review of Molecular Diagnostics · doi:10.1586/14737159.2014.927312 · Cited by 52
“Previous published research has demonstrated an upregulation of several cytokines and growth factors in varicose vein tissues [37,38] (e.g., IL-12 and VEGF) compared with normal veins [28,39–41], in particular, the following molecules may have important roles in CVeD that include TGF-b, MCP-1, IL-8, IP-10, RANTES, MIP…”
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Arresting cell cycles and the effect on wound healing
Berg, J. S. V., & Robson, M. C. (2003) · Surgical Clinics of North America · doi:10.1016/s0039-6109(02)00195-0 · Cited by 51
“Mast and Schultz [29] attribute chronicity in wounds to repeated trauma, ischemia, or bacterial contamination, which in excess promotes increased production of metalloproteinases.”
BackgroundRole of Nitric Oxide in Wound Healing
Childress, B. B., & Stechmiller, J. K. (2002) · Biological Research For Nursing · doi:10.1177/1099800402004001002 · Cited by 52
Fernandez, M. L., Broadbent, J. A., Shooter, G. K., Malda, J., & Upton, Z. (2007) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2007.08362.x · Cited by 51
Wang, Q., Liu, C., An, J., Liu, J., Wang, Y., & Cai, Y. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1657928 · Cited by 69
Baker, E. A., El‐Gaddal, S., Williams, L., et al. (2006) · Wound Repair and Regeneration · doi:10.1111/j.1743-6109.2006.00163.x · Cited by 49
Identifying and treating foot ulcers in patients with diabetes: saving feet, legs and lives
Ousey, K. J., Chadwick, P., Jawień, A., Tariq, G., Nair, H. K. R., Lázaro‐Martínez, J. L., Sandy‐Hodgetts, K., Alves, P. J. P., Wu, S., & Moore, Z. E. H. (2018) · Journal of Wound Care · doi:10.12968/jowc.2018.27.sup5.s1 · Cited by 48
Polymer‐based Biomaterials as Dressings for Chronic Stagnating Wounds
Wiegand, C., & Hipler, U. (2010) · Macromolecular Symposia · doi:10.1002/masy.200900028 · Cited by 47
Coacervate delivery of HB‐EGF accelerates healing of type 2 diabetic wounds
Johnson, N. R., & Wang, Y. (2015) · Wound Repair and Regeneration · doi:10.1111/wrr.12319 · Cited by 47
“The half-lives of GFs exogenously applied in the body are very short and are likely to be even shorter in a wound environment that has high proteolytic activity.(6) Consequently, numerous delivery systems have been developed for protection and sustained release of EGF family proteins and tested in animal models of dia…”
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The therapeutic potential of MSC-EVs as a bioactive material for wound healing
Hou, Y., Li, J., Guan, S., & Witte, F. (2021) · Engineered Regeneration · doi:10.1016/j.engreg.2021.11.003 · Cited by 46
Smart biomaterial-based systems for intrinsic stimuli-responsive chronic wound management
Alves, P. M., Barrias, C. C., Gomes, P. A. C., & Martins, M. C. L. (2021) · Materials Today Chemistry · doi:10.1016/j.mtchem.2021.100623 · Cited by 48
Topical therapies for diabetic foot ulcers: standard treatments
White, R. J., & McIntosh, C. D. (2008) · Journal of Wound Care · doi:10.12968/jowc.2008.17.10.31305 · Cited by 43
Zhang, Y., Zheng, Z., Zhu, S., Xu, L., Zhang, Q., Gao, J., Ye, M., Shen, S., Xing, J., Wu, M., et al. (2025) · Advanced Science · doi:10.1002/advs.202416267 · Cited by 47
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Wound swab and wound biopsy yield similar culture results
Haalboom, M., Blokhuis‐Arkes, M. H. E., Beuk, R. J., Klont, R., Guebitz, G. M., Heinzle, A., & van der Palen, J. A. M. (2018) · Wound Repair and Regeneration · doi:10.1111/wrr.12629 · Cited by 42
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Metadata
- Authors
- Mast, B. A., & Schultz, G. S.
- Affiliations
- University of Florida Health (US)
- University of Florida (US)
- Corresponding author
- Mast, Bruce A.
- Venue
- Wound Repair and Regeneration
- Publisher
- Wiley
- Published
- 1996-10
- Volume
- 4
- Issue
- 4
- Pages
- 411-420
- ISSN
- 1067-1927 (ISSN-L)
- 1524-475X
- OpenAlex
- W1970955409
- Cited by
- 598
- References
- 0
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 26 · 2023: 23 · 2022: 23 · 2021: 37 · 2020: 32 · 2019: 31 · 2018: 39 · 2017: 24 · 2016: 25 · 2015: 24 · 2014: 24 · 2013: 33 · 2012: 30
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Wound Repair and Regeneration (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- chronic wounds, acute wound healing, cytokines, growth factors, proteolytic enzymes, extracellular matrix, tissue repair
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