Evaluating STZ-Induced Impaired Wound Healing in Rats

Ansell, David M.; Marsh, Charlotte; Walker, Liam; Hardman, Matthew J.; Holden, Kirsty

doi:10.1016/j.jid.2017.10.020

Cited by 14 publications

(16 citation statements)

References 15 publications

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“…Staphylococcus aureus-specific biofilms into splinted excisional wounds delays epithelialization and wound closure in db/db mice (Nguyen et al, 2013), whereas wounds in aged db/ db mice heal with reduced stiffness and breaking load, along with reduced deposition of granulation tissue that is independent of glycemia (Brem et al, 2007). Ansell et al (2018) discuss the lack of experimental details reported in the literature when the STZ model is used, particularly with regard to the impact of duration of diabetes on healing outcome. They examine this model more closely by evaluating Figure 1.…”

Section: Discussionmentioning

confidence: 98%

“…Assessment of gross wound size, planimetry, presence of the scab, re-epithelialization by histology, tensile/breaking strength, tensile stiffness, fibrosis, cellular infiltrate, microbial composition, inflammation, granulation tissue formation, and transcutaneous water loss are among the methods used to evaluate wound healing. Even if one chooses to ignore the obvious structural differences between human and mouse skin ( Figure 1) and does not take into account additional biological variables (age, sex, microbiome, location), it becomes clear that reproducibility and extrapolation of data, as well as comparison among published studies, is very challenging, especially when details of experimental design are missing (Ansell et al, 2018). As an example, recombinant human platelet-derived growth factor-BB, which has received U.S. Food and Drug Administration approval for treatment of diabetic foot ulcers, shows variable efficacy in preclinical murine models, ranging from improved wound closure of 1.5-cm excisional diabetic mouse wounds (Greenhalgh et al, 1990), to significant increase of granulation tissue without improvement in the time to wound closure (and only in the 1.5-cm but not in 0.6-to 1.0-cmediameter excisional wounds) (Chan et al, 2006), to no effect on reepithelialization in a murine splinted diabetic wound model (Park et al, 2014).…”

Section: Murine Models Of Wound Healingmentioning

confidence: 99%

“…A model that is very useful for studying mechanisms is not automatically appropriate for preclinical testing. Ansell et al (2018) show an approach to testing important biological variables, sex differences, and duration of diabetes, underscoring the necessity of validating and characterizing the wound healing phenotype in the model of choice before proceeding with preclinical testing.…”

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confidence: 99%

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A Modeling Conundrum: Murine Models for Cutaneous Wound Healing

Elliot

Wikramanayake

Jozic

et al. 2018

Journal of Investigative Dermatology

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The complexity of the cutaneous wound healing process and its impairment in disease states, combined with the urgent clinical need for new therapies demand well-defined preclinical models that facilitate translation of research findings to clinical use. Many murine wound models are well suited for studying mechanisms of various aspects of wound healing, but they have shown limited utility for translating research findings to human conditions, thereby impeding therapeutic developments. Ansell et al. underscore the need for standardization of preclinical murine models by showing the impact of duration of diabetes, animal sex, and assessment methods on healing outcomes in the streptozotocin-induced diabetes mellitus rat model. Recognizing and understanding the limitations and advantages of preclinical murine wound models will facilitate more effective translation of experimental results to improved treatment of human chronic wounds.

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Section: Discussionmentioning

confidence: 98%

Section: Murine Models Of Wound Healingmentioning

confidence: 99%

mentioning

confidence: 99%

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A Modeling Conundrum: Murine Models for Cutaneous Wound Healing

Elliot

Wikramanayake

Jozic

et al. 2018

Journal of Investigative Dermatology

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“…Although wound re‐epithelialization was delayed in R‐Ras KO at day 2, we show no difference in all other time points during wound healing process between WT and R‐Ras KO mice, indicating that R‐Ras does not play a significant role in skin wound healing. Despite employing both excision and splint wound models, one needs to acknowledge that rodent wound models do not perfectly recapitulate human wound healing . Thus, certain limitations are warranted for the interpretation of our results.…”

Section: Discussionmentioning

confidence: 99%

R‐Ras regulates vascular permeability, but not overall healing in skin wounds

Ketomäki

Vähätupa

May

et al. 2018

Experimental Dermatology

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Wounds close by keratinocytes migrating from the edge of the wound and re‐epithelializing the epidermis. It has been proposed that the major stimuli for wound closure are blood‐derived growth factors, chemokines and cytokines. The small GTPase R‐Ras, a known integrin activator, also regulates vascular permeability during angiogenesis, and blood vessels lacking R‐Ras leak plasma proteins constantly. We explored whether the access to blood‐derived proteins influences skin wound healing in R‐Ras knockout (KO) mice. In skin wounds, R‐Ras expression was mostly restricted to the vasculature in the granulation tissue. Angiogenic blood vessels in the R‐Ras KO mice were significantly more permeable than in wild‐type (WT) controls. Although the distances between epidermal tongues, and the panniculus carnosus muscles, were significantly longer in R‐Ras KO than WT controls before the granulation tissue formation took place, there were no differences in the wound closure or re‐epithelialization rates or granulation tissue formation. These findings were also corroborated in a special splint excision wound model. Our study shows that although R‐Ras does not influence the skin wound healing itself, the blood vessels lacking R‐Ras are leaky and thus could facilitate the access of blood‐derived proteins to the wound.

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“…Finally, the studies on animal models haven’t historically taken into account additional important variables such as animal age, sex, microbiome, diabetes, or length of underlying condition into their study design [26–29]. These factors have been shown to impact healing in the models, and may contribute to the poor translation of preclinical animal trials to human trials [26, 29, 27]. …”

Section: Introductionmentioning

confidence: 99%

Healing Chronic Wounds: Current Challenges and Potential Solutions

Darwin

Tomic‐Canic

2018

Curr Derm Rep

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Purpose of Review: The purpose of this review is to raise awareness, examine the challenges faced by wound care researchers and explore opportunities for potential improvements. Recent findings: Chronic wounds are associated with significant morbidity and mortality, and they represent a major medical and financial burden. Despite this, no new therapy has received FDA efficacy approval for the treatment of chronic wounds since 1997. Previous preclinical studies using animal models did not translate to human wounds due to inherent limitations of experimental models, variability in assessment methods and overall experimental design. Clinical trials continued to be challenged by the balance of the inclusion and exclusion criteria, the high cost and time expenditure of the trials, and the constraint of a single FDA-acceptable outcome of complete wound closure. Summary: Wound research faces multiple challenges in both pre-clinical and clinical research that slowed progress and development of efficacious therapies. Solutions to such challenges will provide new opportunities for improved study design in the future.

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Evaluating STZ-Induced Impaired Wound Healing in Rats

Cited by 14 publications

References 15 publications

A Modeling Conundrum: Murine Models for Cutaneous Wound Healing

A Modeling Conundrum: Murine Models for Cutaneous Wound Healing

R‐Ras regulates vascular permeability, but not overall healing in skin wounds

Healing Chronic Wounds: Current Challenges and Potential Solutions

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