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Pathophysiology/Complications
Systematic review and meta-analysis of mouse models of diabetes-associated ulcers
  1. Pacific Huynh1,
  2. James Phie1,
  3. Smriti Murali Krishna1,
  4. Jonathan Golledge1,2
  1. 1Queensland Research Centre for Peripheral Vascular Disease, James Cook University, Townsville, Queensland, Australia
  2. 2Department of Vascular and Endovascular Surgery, Townsville University Hospital, Townsville, Queensland, Australia
  1. Correspondence to Professor Jonathan Golledge; jonathan.golledge{at}jcu.edu.au

Abstract

Mouse models are frequently used to study diabetes-associated ulcers, however, whether these models accurately simulate impaired wound healing has not been thoroughly investigated. This systematic review aimed to determine whether wound healing is impaired in mouse models of diabetes and assess the quality of the past research. A systematic literature search was performed of publicly available databases to identify original articles examining wound healing in mouse models of diabetes. A meta-analysis was performed to examine the effect of diabetes on wound healing rate using random effect models. A meta-regression was performed to examine the effect of diabetes duration on wound healing impairment. The quality of the included studies was also assessed using two newly developed tools. 77 studies using eight different models of diabetes within 678 non-diabetic and 720 diabetic mice were included. Meta-analysis showed that wound healing was impaired in all eight models. Meta-regression suggested that longer duration of diabetes prior to wound induction was correlated with greater degree of wound healing impairment. Pairwise comparisons suggested that non-obese diabetic mice exhibited more severe wound healing impairment compared with db/db mice, streptozotocin-induced diabetic mice or high-fat fed mice at an intermediate stage of wound healing (p<0.01). Quality assessment suggested that the prior research frequently lacked incorporation of key clinically relevant characteristics. This systematic review suggested that impaired wound healing can be simulated in many different mouse models of diabetes but these require further refinement to become more clinically relevant.

  • transgenic and knockout mice
  • meta-analysis
  • ulcer(s)
  • laboratory research in diabetes
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjdrc-2019-000982

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    Introduction

    Diabetes-related foot disease (DFD) is a leading cause of impaired health-related quality of life, amputation, hospitalization and healthcare costs.1–6 The most common presentation of DFD is a foot ulcer which is estimated to develop in 10–20 million people worldwide annually.1 The lifetime incidence of foot ulceration in people with diabetes has been estimated as up to 30%.1 4 The mortality of patients with diabetes-related foot ulcers has been estimated to be 50% over 5 years and more than double that of people with diabetes but no foot ulcer.1 7 8 The development of improved understanding of diabetes-related ulcer pathogenesis and the discovery of novel treatments are therefore global priorities.

    Animal models of human disease are commonly used to identify new treatments. There are many methods of inducing diabetes that have been used to study atherosclerosis, nephropathy and neuropathy in mice.9–11 There has, however, been limited focus on modeling DFD in mice. There is no current consensus on the most appropriate mouse model of diabetes-associated ulceration. A key requirement of a model of diabetes-associated ulceration is impaired wound healing. This has been attributed to several pathological processes stimulated by chronic hyperglycemia, including atherosclerosis and microvascular disease that lead to leg ischemia and peripheral neuropathy.12 13 It is not currently clear which of the different methods of inducing diabetes in mice are associated with wound healing impairment. In order to inform the appropriate choice of animal model, this review aimed to systematically examine the healing rates of wounds in mouse models of diabetes. The review also examined the quality and clinical relevance of this past research.

    Methods

    Search strategy, inclusion and exclusion criteria

    This review was performed according to the 2015 Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols statement (online supplementary table 1).14 The protocol was registered in the PROSPERO database (Registration Number: CRD42018116224). Searches of the literature were conducted between 16 August 2018 and 24 January 2019 by one author (PH) on three separate occasions. The databases Medline, PubMed, Scopus, ScienceDirect and Web of Science were searched to identify preclinical studies examining the effects of diabetes on wound healing in mice. The full search strategy consisted of the terms (‘diabetic wound’ OR ‘diabetic foot ulcer’) AND (mouse OR mice OR murine) AND (nondiabetic OR non-diabetic OR normoglycemi* OR normoglycaemi*) using both Medical Subject Headings and keyword searches. The resultant articles were filtered in two stages, automatically using the database filters and manually by one author (PH) to only include original journal articles written in English. For inclusion, studies had to examine wound healing in mouse models of diabetes compared with age-matched controls and report wound area as a ratio or percentage of the initial wound area monitored over time for both groups.

    Supplemental material

    Data extraction and quality assessment of included studies

    Full-text publications of included studies were independently assessed by two investigators (PH and JP). Data extracted included sex, age and strain of mice, model of diabetes, diagnostic criteria for diabetes, whether diabetes was confirmed prior to wound generation, the size and location of the initial wound, method and period of monitoring, and wound closure percentage defined as detailed below. ImageJ V.1.48 (National Institutes of Health, USA) was used to extrapolate data from figures if required. Extracted data were discussed in a consensus meeting.

    The quality of the included studies was assessed using two tools specifically developed for this systematic review (online supplementary tables 2 and 3). One tool assessed the study design and reporting quality of the studies and was based on a prior tool,15 and the Animal Research: Reporting of In Vivo Experiments guidelines (online supplementary table 2). The second tool assessed the design of the mouse model experiment in relation to recognized characteristic features of human diabetes-associated ulcers (online supplementary table 3). Each checklist item was weighted equally and graded 0, 0.5 or 1 for no, unclear or yes, respectively. Each study was scored as a percentage of the total possible score for each tool.

    Data analysis

    The primary outcome of this systematic review and meta-analysis was percentage (%) wound closure which was calculated from extracted data using the following formula:

    % Wound ClosureEmbedded Image

    To gauge the effect of diabetes on wound closure over time, extracted data were sorted for analysis to early (2–5 days), intermediate (6–10 days) and late stages (11–20 days) of wound healing. In the event that a single article contained multiple independent animal studies, wound closure data were extracted from each of these studies and treated as independent data. If an article appeared to have multiple animal studies using the same mice in their experimental groups, sample sizes were evenly divided among them for meta-analysis to minimize duplication of data. For example, if primary outcome data were available for two different sets of diabetic mice but the authors used the same mice as controls for both, the sample size of the control group was evenly divided between the two diabetic groups for analysis. Corresponding authors of studies were contacted for key missing data. When necessary, SEMs were converted to SDs using GraphPad Prism V.7 (San Diego, California, USA). Meta-analyses were performed to assess the effect of diabetes on wound closure using Review Manager V.5.3.5 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014), while meta-regression analyses were performed using Open Meta-Analyst.16 Since heterogeneity between studies was expected, random effects models were used. Data were reported as standardized mean difference (SMD) with 95% CIs. Subgroup analyses were performed to examine whether the extent of wound healing impairment was different between the models of diabetes included. These pairwise comparisons were corrected for multiple testing using Bonferroni’s correction. Leave-one-out sensitivity analyses were also performed. The I2 index was used to assess the degree of heterogeneity between studies, with I2>50% accepted to denote statistical heterogeneity. Funnel plots of the effect size versus the SEM of the log-transformed effect were constructed to assess potential publication bias. A p value <0.05 was considered to be statistically significant.

    Results

    Study selection

    After a systematic search, a total of 77 studies were included in this systematic review and meta-analysis (online supplementary figure 1).17–93

    Characteristics of the included studies

    The characteristics of the 77 included studies are shown in online supplementary table 4. There were a total of eight different mouse models of diabetes used (with three studies using multiple models).62 68 89 These included streptozotocin (STZ) injection (n=41; 20 single dose; 21 multiple doses), leptin receptor defective db/db mice (n=27), alloxan injection (n=4; 3 single dose; 1 multiple doses), high-fat fed mice (n=4), leptin-deficient ob/ob mice (n=2) and non-obese diabetic (NOD) mice (n=2). The majority of studies reported including male mice only (49/77). Eleven investigations included female mice only, two included mice of both sexes and the remaining studies did not report the sex of the mice included (15/77).

    Only three studies examined wounds created in the hindlimb.37 51 61 The other studies investigated wounds created on the torso of mice (74 in total; 71 on the back, 3 on the flank). The initial wound size differed greatly between studies (online supplementary table 4). Ten studies used splints to prevent the closure of wounds via contraction and promote wound healing through re-epithelialization since this has been suggested to be more typical of humans.94 95

    Quality of design and reporting of the included studies

    The mean study design quality assessment score was 55.1% (range 19.2%–80.8%) (online supplementary table 5). Most studies (n=73) provided an ethics statement.23 Only nine studies reported that examination of wound closure was performed by an assessor blinded to group allocation. Only two studies indicated that investigators were blinded to the experimental groups of mice.17 72 Only three studies reported that power calculations were performed to determine appropriate sample sizes,32 37 47 while an additional two justified their sample sizes based on previous experiments.63 72

    Forty-one studies did not report full information about the strain of mice used. Twelve studies did not indicate the start date of their studies,20 40–44 48 54 55 57 80 84 with an additional 27 only reporting the age of mice as ranges.17–19 21 23 24 26 28 29 36 39 49–53 60 62 73 78 79 81 87–90 93 Eighteen studies which investigated STZ-induced diabetes did not indicate whether non-diabetic mice were injected with vehicle.25 27 30 38 51 54 55 58 60–62 68 71 73 74 78 79 83 In studies which used genetic models of diabetes, 14 used homozygote mice of the background strain or non-diabetic littermates, as controls mice,19–21 23 24 29 45 46 50 52 70 81 82 89 while two studies did not indicate the use of littermate controls.40 56 Two studies described the wound closure measurements in the methods but represented their data in another way.70 85

    Relevance of the reported mouse models to human diabetes-associated ulceration

    The mean clinical relevance quality assessment score was 44.9% (range 26.9%–65.4%) (online supplementary table 6). Most studies (n=46) reported a clear diagnostic criterion for diabetes. This was mainly based on blood glucose concentrations. One study reported the confirmation of diabetes by the presence of glycosuria.20 Despite the Diabetic Complications Consortium recommendations for the appropriate confirmation of diabetes in animal models, only 15 of the 46 studies reported blood glucose measurements were performed in fasted mice18 25 33 35 38 65–69 72 76 77 81 91 and only three reported monitoring additional diabetes-associated metabolic parameters, with glycosuria being the common parameter measured.25 58 61 Furthermore, only 16 studies extensively reported blood glucose levels of included mice.33 35 38 42 49 59 60 63–65 69 74 77 81 87 91 Only nine studies reported the time required for complete wound healing.18 38 40 52 62 63 80 88 91 Four studies reported measures of wound blood supply,49 69 71 87 with an additional study only reporting perfusion in a subset of mice.29 No investigation reported signs of neuropathy.

    The effect of diabetes on wound closure

    Meta-analyses included data extracted to assess the effect of diabetes on wound closure at early (n=1346), intermediate (n=1398) and late (n=870) stages of wound healing. Diabetes led to impairment of wound closure at all stages (SMD 1.25 (95% CI 1.01 to 1.48, p<0.001), 2.28 (95% CI 1.94 to 2.62, p<0.001) and 3.12 (95% CI 2.66 to 3.59, p<0.001) at early, intermediate and late stages, respectively (figures 1–3 and online supplementary tables 7–9)). There was substantial statistical heterogeneity between studies (I2=70%–80%, figures 1–3 and online supplementary tables 7–9).

    Figure 1
    Figure 1

    Forest plots showing the effect of diabetes on the early stages of wound closure in different mouse models of diabetes. Forest plots were generated from Review Manager V.5.3 to represent early (2–5 days) stages of wound closure. Comparisons were made using standard mean differences and random effects models.

    Figure 2
    Figure 2

    Forest plots showing the effect of diabetes on the intermediate stages of wound closure in different mouse models of diabetes. Forest plots were generated from Review Manager V.5.3 to represent intermediate (6–10 days) stages of wound closure. Comparisons were made using standard mean differences and random effects models.

    Figure 3
    Figure 3

    Forest plots showing the effect of diabetes on the late stages of wound closure in different mouse models of diabetes. Forest plots were generated from Review Manager V.5.3 to represent late (11–20 days) stages of wound closure. Comparisons were made using standard mean differences and random effects models.

    Subgroup analyses suggested that wound closure was significantly impaired when compared with non-diabetic mice at all stages of wound healing in all models of diabetes (figures 1–3 and online supplementary tables 7-9) except in the high-fat fed mice and ob/ob mice at the early stage of wound healing (SMD –0.17 (95% CI −0.89 to 1.23), and SMD 3.55 (95% CI −0.07 to 7.18), respectively) (figure 1 and online supplementary table 7). Pairwise comparisons suggested significant differences in the degree of wound healing impairment in the different diabetes models (online supplementary table 10). db/db mice had greater wound healing impairment than found in the multiple-dose STZ-induced and high-fat fed models at intermediate and late stages of wound healing (online supplementary table 10). The single-dose STZ-induced diabetes model had more severe wound healing impairment than the multiple-dose STZ-induced diabetes model at late stages of wound healing (online supplementary table 10).

    Meta-regression suggested that a longer duration of diabetes prior to wound generation was associated with greater impairment of wound healing (online supplementary figure 2c, p=0.021 at late stages after removal of statistical outliers). Leave-one-out sensitivity analyses suggested that all studies contributed towards the main findings in the meta-analysis (online supplementary figure 3). Funnel plots suggested potential publication bias (online supplementary figure 4).

    Discussion

    This systematic review suggests that mouse models of diabetes consistently have impaired wound healing. The wound healing impairment was clearer as the time after wound induction increased. The severity of wound healing impairment varied between the different mouse models. The meta-regression suggested a tendency towards greater wound healing impairment with longer duration of hyperglycemia. There was substantial statistical heterogeneity and limited reporting of important information in the included studies. Furthermore, very few studies modeled some of the common characteristics of human diabetes-associated ulcers, such as location in the periphery of the limb and concurrent ischemia and neuropathy (online supplementary table 11). These findings highlight the need for more clinically relevant models of diabetes-associated ulceration.

    Eight different methods of modeling diabetes were used in the studies included in this systematic review (summarized in table 1, sorted from most to least severe wound healing impairment). Meta-analysis of data reported early after wound induction suggested that the multiple-dose alloxan-induced diabetes model had the most severe wound healing impairment. Meta-analyses of data reported at intermediate and late stages after wound induction suggested that NOD mice had the most severe impairment of wound healing. These findings, however, should be interpreted cautiously given the small and uneven number of studies which reported the use of these models. Indeed, only a total of three studies reported the use of the multiple-dose alloxan-induced diabetes and NOD models. The infrequent use of these models is likely due to a number of factors. First, both models simulate type 1 rather than type 2 diabetes, which is the less common form of diabetes in people.96 Second, these models have disadvantages compared with the more commonly used mouse models of diabetes. For example, alloxan is generally considered less favorable as a diabetogenic agent to STZ due to greater organ toxicity and lower effectiveness,97 while NOD mice have variable onset of diabetes.98 Nonetheless, these models do appear to simulate diabetes-associated wound healing impairment. High-fat feeding is an approach used to simulate type 2 diabetes. This review suggested that this model had the least severe wound healing impairment of all the models examined, possibly due to its milder metabolic derangement. Meta-analyses of data obtained late after wound induction also suggested that impairment of wound healing was more severe in the single-dose STZ-induced diabetes model compared with the multiple-dose STZ-induced diabetes model. It should be noted though that there were substantial methodological differences between the included studies. These comparisons between models should therefore be interpreted very cautiously.

    View this table:
    Table 1

    Mouse models of diabetes-associated ulceration ordered in relation to the severity of wound healing impairment

    It was surprising to find limited reporting of relevant metabolic parameters and data to confirm the diagnosis of diabetes within the included studies. Susceptibility towards diabetes-associated complications in mice is dependent on a number of different factors, such as age, strain and sex.99–102 Furthermore, studies focusing on other diabetic complications, such as atherosclerosis and neuropathy, typically require an extended duration of diabetes, as well as genetic manipulation, to simulate these complications.9–11 103 104 In the meta-regression, there was a trend towards greater wound healing impairment with longer duration of hyperglycemia before wound induction (online supplementary figure 2). Many of the studies with a relatively long duration of diabetes (>6 weeks) used genetic models which may have influenced the findings of the meta-regression. Nonetheless, investigators should take into consideration the severity and duration of diabetes required to simulate the clinical presentation.

    While limbs are the main site of diabetes-associated ulcers in patients, all but three studies included in this systematic review examined wounds generated on the torso of mice. The greater area on the torso allows multiple wounds to be studied but it is unlikely such ulcers simulate the clinical situation. Peripheral artery disease and neuropathy are key causes of ulcers in people. Only four of the included studies examined blood flow within the mice.49 69 71 87 None of the included studies artificially induced artery disease or neuropathy within the mice. Artificial generation of peripheral ischemia or neuropathy is likely required to simulate the clinical presentation since mice are very resistant to development of diabetes-associated microvascular complications.105 Use of genetically modified mice may also be used to simulate other clinically relevant risk factors, such as dyslipidemia which accelerates diabetes-associated atherosclerosis and neuropathy.106 107 Table 2 presents suggested criteria for future diabetes-associated ulcer studies in rodents aimed to improve the clinical relevance of the research.

    View this table:
    Table 2

    Proposed reporting standards for mouse models of diabetes-associated ulceration

    Limitations and strengths

    To the best of our knowledge, this is the first systematic review and meta-analysis examining wound healing impairment in different mouse models of diabetes. The current study used a range of analysis methods and quality assessment methods in order to rigorously assess past research. The included studies had many quality weaknesses such as small sample sizes. There was also absence of key study design and reporting features, like blinding of outcome assessors and inclusion of sample size calculations. Many of the included studies did not report parameters relevant to diabetes or determined the severity of diabetes. Therefore, it was not possible to systematically assess the correlation between glucose control and wound healing impairment. There was also statistical and methodological heterogeneity between studies. Due to the heterogeneous and intermittent reporting of outcomes, it was not possible to systematically examine the molecular mechanisms involved in wound healing impairment. Nonetheless, the findings from this study provide important insight into the strengths and weaknesses of current mice models of diabetes-associated ulcers.

    Conclusion

    In conclusion, this systematic review suggests that, regardless of diabetes induction method, hyperglycemia impairs wound healing in mice. Incorporation of clinically relevant aspects, such as limb ischemia and prolonged diabetes duration, may improve the translation of findings from the mouse models.

    Acknowledgments

    We thank Emeritus Professor Rhondda Jones for her statistical advice.

    References

    1. ↵
      1. Armstrong DG,
      2. Boulton AJM,
      3. Bus SA
      . Diabetic foot ulcers and their recurrence. N Engl J Med 2017;376:2367–75.doi:10.1056/NEJMra1615439pmid:http://www.ncbi.nlm.nih.gov/pubmed/28614678
      OpenUrlCrossRefPubMed
    2. ↵
      1. Boulton AJM,
      2. Vileikyte L,
      3. Ragnarson-Tennvall G, et al
      . The global burden of diabetic foot disease. Lancet 2005;366:1719–24.doi:10.1016/S0140-6736(05)67698-2pmid:http://www.ncbi.nlm.nih.gov/pubmed/16291066
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Lazzarini PA,
      2. Hurn SE,
      3. Fernando ME, et al
      . Prevalence of foot disease and risk factors in general inpatient populations: a systematic review and meta-analysis. BMJ Open 2015;5:e008544.doi:10.1136/bmjopen-2015-008544pmid:http://www.ncbi.nlm.nih.gov/pubmed/26597864
      OpenUrlAbstract/FREE Full Text
    4. ↵
      1. Boulton AJM,
      2. Kirsner RS,
      3. Vileikyte L
      . Neuropathic diabetic foot ulcers. N Engl J Med Overseas Ed 2004;351:48–55.doi:10.1056/NEJMcp032966
      OpenUrl
    5. ↵
      1. Baker IDI Heart and Diabetes Institute
      . National evidence-based guideline on prevention, identification and management of foot complications in diabetes. Melbourne Australia, 2011.
    6. ↵
      1. Lazzarini PA,
      2. Pacella RE,
      3. Armstrong DG, et al
      . Diabetes-Related lower-extremity complications are a leading cause of the global burden of disability. Diabet Med 2018. doi:doi:10.1111/dme.13680. [Epub ahead of print: 23 May 2018].pmid:http://www.ncbi.nlm.nih.gov/pubmed/29791033
    7. ↵
      1. Walsh JW,
      2. Hoffstad OJ,
      3. Sullivan MO, et al
      . Association of diabetic foot ulcer and death in a population-based cohort from the United Kingdom. Diabet Med 2016;33:1493–8.doi:10.1111/dme.13054pmid:http://www.ncbi.nlm.nih.gov/pubmed/26666583
      OpenUrlPubMed
    8. ↵
      1. Iversen MM,
      2. Tell GS,
      3. Riise T, et al
      . History of foot ulcer increases mortality among individuals with diabetes: ten-year follow-up of the Nord-Trøndelag health study, Norway. Diabetes Care 2009;32:2193–9.doi:10.2337/dc09-0651pmid:http://www.ncbi.nlm.nih.gov/pubmed/19729524
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Kleinert M,
      2. Clemmensen C,
      3. Hofmann SM, et al
      . Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol 2018;14:140–62.doi:10.1038/nrendo.2017.161pmid:http://www.ncbi.nlm.nih.gov/pubmed/29348476
      OpenUrlCrossRefPubMed
    10. ↵
      1. Jolivalt CG,
      2. Frizzi KE,
      3. Guernsey L, et al
      . Peripheral neuropathy in mouse models of diabetes. Curr Protoc Mouse Biol 2016;6:223–55.doi:10.1002/cpmo.11pmid:http://www.ncbi.nlm.nih.gov/pubmed/27584552
      OpenUrlPubMed
    11. ↵
      1. Azushima K,
      2. Gurley SB,
      3. Coffman TM
      . Modelling diabetic nephropathy in mice. Nat Rev Nephrol 2018;14:48–56.doi:10.1038/nrneph.2017.142pmid:http://www.ncbi.nlm.nih.gov/pubmed/29062142
      OpenUrlPubMed
    12. ↵
      1. Davis FM,
      2. Kimball A,
      3. Boniakowski A, et al
      . Dysfunctional wound healing in diabetic foot ulcers: new crossroads. Curr Diab Rep 2018;18:2.doi:10.1007/s11892-018-0970-zpmid:http://www.ncbi.nlm.nih.gov/pubmed/29362914
      OpenUrlPubMed
    13. ↵
      1. Nativel M,
      2. Potier L,
      3. Alexandre L, et al
      . Lower extremity arterial disease in patients with diabetes: a contemporary narrative review. Cardiovasc Diabetol 2018;17:138.doi:10.1186/s12933-018-0781-1pmid:http://www.ncbi.nlm.nih.gov/pubmed/30352589
      OpenUrlPubMed
    14. ↵
      1. Moher D,
      2. Shamseer L,
      3. Clarke M, et al
      . Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1.doi:10.1186/2046-4053-4-1pmid:http://www.ncbi.nlm.nih.gov/pubmed/25554246
      OpenUrlCrossRefPubMed
    15. ↵
      1. Phie J,
      2. Krishna SM,
      3. Moxon JV, et al
      . Flavonols reduce aortic atherosclerosis lesion area in apolipoprotein E deficient mice: a systematic review and meta-analysis. PLoS One 2017;12:e0181832.doi:10.1371/journal.pone.0181832pmid:http://www.ncbi.nlm.nih.gov/pubmed/28742839
      OpenUrlPubMed
    16. ↵
      1. Wallace BC,
      2. Dahabreh IJ,
      3. Trikalinos TA, et al
      . Closing the Gap between Methodologists and End-Users: R as a Computational Back-End. J Stat Softw 2012;49:15.doi:10.18637/jss.v049.i05
    17. ↵
      1. Brown RL,
      2. Breeden MP,
      3. Greenhalgh DG
      . Pdgf and TGF-alpha act synergistically to improve wound healing in the genetically diabetic mouse. J Surg Res 1994;56:562–70.doi:10.1006/jsre.1994.1090pmid:http://www.ncbi.nlm.nih.gov/pubmed/8015312
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. Matuszewska B,
      2. Keogan M,
      3. Fisher DM, et al
      . Acidic fibroblast growth factor: evaluation of topical formulations in a diabetic mouse wound healing model. Pharm Res 1994;11:65–71.doi:10.1023/A:1018993610801pmid:http://www.ncbi.nlm.nih.gov/pubmed/7511240
      OpenUrlCrossRefPubMed
    19. ↵
      1. Brown DL,
      2. Kao WW,
      3. Greenhalgh DG
      . Apoptosis down-regulates inflammation under the advancing epithelial wound edge: delayed patterns in diabetes and improvement with topical growth factors. Surgery 1997;121:372–80.doi:10.1016/S0039-6060(97)90306-8pmid:http://www.ncbi.nlm.nih.gov/pubmed/9122866
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Darby IA,
      2. Bisucci T,
      3. Hewitson TD, et al
      . Apoptosis is increased in a model of diabetes-impaired wound healing in genetically diabetic mice. Int J Biochem Cell Biol 1997;29:191–200.doi:10.1016/S1357-2725(96)00131-8pmid:http://www.ncbi.nlm.nih.gov/pubmed/9076954
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Crowe MJ,
      2. McNeill RB,
      3. Schlemm DJ, et al
      . Topical application of yeast extract accelerates the wound healing of diabetic mice. J Burn Care Rehabil 1999;20:155–62.doi:10.1097/00004630-199903000-00032pmid:http://www.ncbi.nlm.nih.gov/pubmed/10188114
      OpenUrlPubMed
    22. ↵
      1. Hart J,
      2. Silcock D,
      3. Gunnigle S, et al
      . The role of oxidised regenerated cellulose/collagen in wound repair: effects in vitro on fibroblast biology and in vivo in a model of compromised healing. Int J Biochem Cell Biol 2002;34:1557–70.doi:10.1016/S1357-2725(02)00062-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/12379278
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Wall SJ,
      2. Bevan D,
      3. Thomas DW, et al
      . Differential expression of matrix metalloproteinases during impaired wound healing of the diabetes mouse. J Invest Dermatol 2002;119:91–8.doi:10.1046/j.1523-1747.2002.01779.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/12164930
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Kirchner LM,
      2. Meerbaum SO,
      3. Gruber BS, et al
      . Effects of vascular endothelial growth factor on wound closure rates in the genetically diabetic mouse model. Wound Repair Regen 2003;11:127–31.doi:10.1046/j.1524-475X.2003.11208.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/12631300
      OpenUrlCrossRefPubMedWeb of Science
    25. ↵
      1. Graiani G,
      2. Emanueli C,
      3. Desortes E, et al
      . Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of type 1 diabetic mice. Diabetologia 2004;47:1047–54.doi:10.1007/s00125-004-1414-7pmid:http://www.ncbi.nlm.nih.gov/pubmed/15164170
      OpenUrlPubMedWeb of Science
    26. ↵
      1. Chen J,
      2. Kasper M,
      3. Heck T, et al
      . Tissue factor as a link between wounding and tissue repair. Diabetes 2005;54:2143–54.doi:10.2337/diabetes.54.7.2143pmid:http://www.ncbi.nlm.nih.gov/pubmed/15983216
      OpenUrlAbstract/FREE Full Text
    27. ↵
      1. Cianfarani F,
      2. Zambruno G,
      3. Brogelli L, et al
      . Placenta growth factor in diabetic wound healing: altered expression and therapeutic potential. Am J Pathol 2006;169:1167–82.doi:10.2353/ajpath.2006.051314pmid:http://www.ncbi.nlm.nih.gov/pubmed/17003476
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Mace KA,
      2. Yu DH,
      3. Paydar KZ, et al
      . Sustained expression of HIF-1alpha in the diabetic environment promotes angiogenesis and cutaneous wound repair. Wound Repair Regen 2007;15:636–45.doi:10.1111/j.1524-475X.2007.00278.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/17971009
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Callaghan MJ,
      2. Chang EI,
      3. Seiser N, et al
      . Pulsed electromagnetic fields accelerate normal and diabetic wound healing by increasing endogenous FGF-2 release. Plast Reconstr Surg 2008;121:130–41.doi:10.1097/01.prs.0000293761.27219.84pmid:http://www.ncbi.nlm.nih.gov/pubmed/18176216
      OpenUrlCrossRefPubMed
    30. ↵
      1. Straino S,
      2. Di Carlo A,
      3. Mangoni A, et al
      . High-Mobility group box 1 protein in human and murine skin: involvement in wound healing. J Invest Dermatol 2008;128:1545–53.doi:10.1038/sj.jid.5701212pmid:http://www.ncbi.nlm.nih.gov/pubmed/18239618
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      1. Pietramaggiori G,
      2. Scherer SS,
      3. Alperovich M, et al
      . Improved cutaneous healing in diabetic mice exposed to healthy peripheral circulation. J Invest Dermatol 2009;129:2265–74.doi:10.1038/jid.2009.60pmid:http://www.ncbi.nlm.nih.gov/pubmed/19295612
      OpenUrlCrossRefPubMedWeb of Science
    32. ↵
      1. Trousdale RK,
      2. Jacobs Sharone',
      3. Simhaee DA, et al
      . Wound closure and metabolic parameter variability in a db/db mouse model for diabetic ulcers. J Surg Res 2009;151:100–7.doi:10.1016/j.jss.2008.01.023pmid:http://www.ncbi.nlm.nih.gov/pubmed/18619614
      OpenUrlCrossRefPubMed
    33. ↵
      1. Abu-Al-Basal MA
      . Healing potential of Rosmarinus officinalis L. on full-thickness excision cutaneous wounds in alloxan-induced-diabetic BALB/c mice. J Ethnopharmacol 2010;131:443–50.doi:10.1016/j.jep.2010.07.007pmid:http://www.ncbi.nlm.nih.gov/pubmed/20633625
      OpenUrlPubMed
    34. ↵
      1. Fang Y,
      2. Shen J,
      3. Yao M, et al
      . Granulocyte-Macrophage colony-stimulating factor enhances wound healing in diabetes via upregulation of proinflammatory cytokines. Br J Dermatol 2010;162:478–86.doi:10.1111/j.1365-2133.2009.09528.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/19799605
      OpenUrlCrossRefPubMed
    35. ↵
      1. Jacobsen JN,
      2. Steffensen B,
      3. Häkkinen L, et al
      . Skin wound healing in diabetic β6 integrin-deficient mice. APMIS 2010;118:753–64.doi:10.1111/j.1600-0463.2010.02654.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/20854469
      OpenUrlCrossRefPubMed
    36. ↵
      1. Marrotte EJ,
      2. Chen D-D,
      3. Hakim JS, et al
      . Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice. J Clin Invest 2010;120:4207–19.doi:10.1172/JCI36858pmid:http://www.ncbi.nlm.nih.gov/pubmed/21060152
      OpenUrlCrossRefPubMedWeb of Science
    37. ↵
      1. Albiero M,
      2. Menegazzo L,
      3. Boscaro E, et al
      . Defective recruitment, survival and proliferation of bone marrow-derived progenitor cells at sites of delayed diabetic wound healing in mice. Diabetologia 2011;54:945–53.doi:10.1007/s00125-010-2007-2pmid:http://www.ncbi.nlm.nih.gov/pubmed/21165593
      OpenUrlCrossRefPubMed
    38. ↵
      1. Hegde VN,
      2. Prabhu V,
      3. Rao SBS, et al
      . Effect of laser dose and treatment schedule on excision wound healing in diabetic mice. Photochem Photobiol 2011;87:1433–41.doi:10.1111/j.1751-1097.2011.00991.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/21883243
      OpenUrlPubMed
    39. ↵
      1. Mirza R,
      2. Koh TJ
      . Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice. Cytokine 2011;56:256–64.doi:10.1016/j.cyto.2011.06.016pmid:http://www.ncbi.nlm.nih.gov/pubmed/21803601
      OpenUrlCrossRefPubMedWeb of Science
    40. ↵
      1. Wetterau M,
      2. George F,
      3. Weinstein A, et al
      . Topical prolyl hydroxylase domain-2 silencing improves diabetic murine wound closure. Wound Repair Regen 2011;19:481–6.doi:10.1111/j.1524-475X.2011.00697.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/21627711
      OpenUrlCrossRefPubMed
    41. ↵
      1. Badr G
      . Supplementation with undenatured whey protein during diabetes mellitus improves the healing and closure of diabetic wounds through the rescue of functional long-lived wound macrophages. Cell Physiol Biochem 2012;29:571–82.doi:10.1159/000338511pmid:http://www.ncbi.nlm.nih.gov/pubmed/22508064
      OpenUrlCrossRefPubMed
    42. ↵
      1. Badr G,
      2. Badr BM,
      3. Mahmoud MH, et al
      . Treatment of diabetic mice with undenatured whey protein accelerates the wound healing process by enhancing the expression of MIP-1α, MIP-2, KC, CX3CL1 and TGF-β in wounded tissue. BMC Immunol 2012;13:32.doi:10.1186/1471-2172-13-32pmid:http://www.ncbi.nlm.nih.gov/pubmed/22708778
      OpenUrlPubMed
    43. ↵
      1. Loyd CM,
      2. Diaconu D,
      3. Fu W, et al
      . Transgenic overexpression of keratinocyte-specific VEGF and Ang1 in combination promotes wound healing under nondiabetic but not diabetic conditions. Int J Clin Exp Pathol 2012;5:1–11.pmid:http://www.ncbi.nlm.nih.gov/pubmed/22295141
      OpenUrlPubMed
    44. ↵
      1. Mohany M,
      2. Badr BM,
      3. Mahmoud M, et al
      . Un-denatured whey protein expedites wound healing in diabetic mice model by enhancing the expression of β-defensin 2, 3 and vascular endothelial growth factor (VEGF) in the wounded tissue. Afr J Microbiol Res 2012;6:2137–44.doi:10.5897/AJMR11.1501
      OpenUrl
    45. ↵
      1. Shin L,
      2. Peterson DA
      . Impaired therapeutic capacity of autologous stem cells in a model of type 2 diabetes. Stem Cells Transl Med 2012;1:125–35.doi:10.5966/sctm.2012-0031pmid:http://www.ncbi.nlm.nih.gov/pubmed/23197759
      OpenUrlCrossRefPubMed
    46. ↵
      1. Steinstraesser L,
      2. Hirsch T,
      3. Schulte M, et al
      . Innate defense regulator peptide 1018 in wound healing and wound infection. PLoS One 2012;7:e39373.doi:10.1371/journal.pone.0039373pmid:http://www.ncbi.nlm.nih.gov/pubmed/22879874
      OpenUrlCrossRefPubMed
    47. ↵
      1. Wagner IJ,
      2. Szpalski C,
      3. Allen RJ, et al
      . Obesity impairs wound closure through a vasculogenic mechanism. Wound Repair Regen 2012;20:n/a–22.doi:10.1111/j.1524-475X.2012.00803.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/22672117
      OpenUrlPubMed
    48. ↵
      1. Badr G
      . Camel whey protein enhances diabetic wound healing in a streptozotocin-induced diabetic mouse model: the critical role of β-Defensin-1, -2 and -3. Lipids Health Dis 2013;12:46.doi:10.1186/1476-511X-12-46pmid:http://www.ncbi.nlm.nih.gov/pubmed/23547923
      OpenUrlCrossRefPubMed
    49. ↵
      1. Tie L,
      2. An Y,
      3. Han J, et al
      . Genistein accelerates refractory wound healing by suppressing superoxide and FoxO1/iNOS pathway in type 1 diabetes. J Nutr Biochem 2013;24:88–96.doi:10.1016/j.jnutbio.2012.02.011pmid:http://www.ncbi.nlm.nih.gov/pubmed/22819564
      OpenUrlPubMed
    50. ↵
      1. Dhall S,
      2. Do DC,
      3. Garcia M, et al
      . Generating and reversing chronic wounds in diabetic mice by manipulating wound redox parameters. J Diabetes Res 2014;2014:562625doi:10.1155/2014/562625pmid:25587545
      OpenUrlCrossRefPubMed
    51. ↵
      1. Fadini GP,
      2. Albiero M,
      3. Millioni R, et al
      . The molecular signature of impaired diabetic wound healing identifies serpinB3 as a healing biomarker. Diabetologia 2014;57:1947–56.doi:10.1007/s00125-014-3300-2pmid:http://www.ncbi.nlm.nih.gov/pubmed/24962668
      OpenUrlCrossRefPubMed
    52. ↵
      1. Gooyit M,
      2. Peng Z,
      3. Wolter WR, et al
      . A chemical biological strategy to facilitate diabetic wound healing. ACS Chem Biol 2014;9:105–10.doi:10.1021/cb4005468pmid:http://www.ncbi.nlm.nih.gov/pubmed/24053680
      OpenUrlCrossRefPubMed
    53. ↵
      1. Liu F,
      2. Chen D-D,
      3. Sun X, et al
      . Hydrogen sulfide improves wound healing via restoration of endothelial progenitor cell functions and activation of angiopoietin-1 in type 2 diabetes. Diabetes 2014;63:1763–78.doi:10.2337/db13-0483pmid:http://www.ncbi.nlm.nih.gov/pubmed/24487028
      OpenUrlAbstract/FREE Full Text
    54. ↵
      1. Moura LIF,
      2. Dias AMA,
      3. Leal EC, et al
      . Chitosan-based dressings loaded with neurotensin--an efficient strategy to improve early diabetic wound healing. Acta Biomater 2014;10:843–57.doi:10.1016/j.actbio.2013.09.040pmid:http://www.ncbi.nlm.nih.gov/pubmed/24121197
      OpenUrlCrossRefPubMed
    55. ↵
      1. Moura LIF,
      2. Dias AMA,
      3. Suesca E, et al
      . Neurotensin-loaded collagen dressings reduce inflammation and improve wound healing in diabetic mice. Biochim Biophys Acta 2014;1842:32–43.doi:10.1016/j.bbadis.2013.10.009pmid:http://www.ncbi.nlm.nih.gov/pubmed/24161538
      OpenUrlPubMed
    56. ↵
      1. Steinstraesser L,
      2. Lam MC,
      3. Jacobsen F, et al
      . Skin electroporation of a plasmid encoding hCAP-18/LL-37 host defense peptide promotes wound healing. Mol Ther 2014;22:734–42.doi:10.1038/mt.2013.258pmid:http://www.ncbi.nlm.nih.gov/pubmed/24394186
      OpenUrlPubMed
    57. ↵
      1. Wang X-Q,
      2. Lee S,
      3. Wilson H, et al
      . Ganglioside GM3 depletion reverses impaired wound healing in diabetic mice by activating IGF-1 and insulin receptors. J Invest Dermatol 2014;134:1446–55.doi:10.1038/jid.2013.532pmid:http://www.ncbi.nlm.nih.gov/pubmed/24326453
      OpenUrlCrossRefPubMedWeb of Science
    58. ↵
      1. Avitabile S,
      2. Odorisio T,
      3. Madonna S, et al
      . Interleukin-22 promotes wound repair in diabetes by improving keratinocyte pro-healing functions. J Invest Dermatol 2015;135:2862–70.doi:10.1038/jid.2015.278pmid:http://www.ncbi.nlm.nih.gov/pubmed/26168231
      OpenUrlCrossRefPubMed
    59. ↵
      1. Hozzein WN,
      2. Badr G,
      3. Al Ghamdi AA, et al
      . Topical application of propolis enhances cutaneous wound healing by promoting TGF-beta/Smad-mediated collagen production in a streptozotocin-induced type I diabetic mouse model. Cell Physiol Biochem 2015;37:940–54.doi:10.1159/000430221pmid:http://www.ncbi.nlm.nih.gov/pubmed/26381245
      OpenUrlCrossRefPubMed
    60. ↵
      1. Leal EC,
      2. Carvalho E,
      3. Tellechea A, et al
      . Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am J Pathol 2015;185:1638–48.doi:10.1016/j.ajpath.2015.02.011pmid:http://www.ncbi.nlm.nih.gov/pubmed/25871534
      OpenUrlCrossRefPubMed
    61. ↵
      1. Lim Y-C,
      2. Bhatt MP,
      3. Kwon M-H, et al
      . Proinsulin C-peptide prevents impaired wound healing by activating angiogenesis in diabetes. J Invest Dermatol 2015;135:269–78.doi:10.1038/jid.2014.285pmid:http://www.ncbi.nlm.nih.gov/pubmed/25007043
      OpenUrlCrossRefPubMed
    62. ↵
      1. Rebalka IA,
      2. Raleigh MJ,
      3. D'Souza DM, et al
      . Inhibition of PAI-1 via PAI-039 improves dermal wound closure in diabetes. Diabetes 2015;64:2593–602.doi:10.2337/db14-1174pmid:http://www.ncbi.nlm.nih.gov/pubmed/25754958
      OpenUrlAbstract/FREE Full Text
    63. ↵
      1. Wong SL,
      2. Demers M,
      3. Martinod K, et al
      . Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med 2015;21:815–9.doi:10.1038/nm.3887pmid:http://www.ncbi.nlm.nih.gov/pubmed/26076037
      OpenUrlCrossRefPubMed
    64. ↵
      1. Badr G,
      2. Hozzein WN,
      3. Badr BM, et al
      . Bee Venom Accelerates Wound Healing in Diabetic Mice by Suppressing Activating Transcription Factor-3 (ATF-3) and Inducible Nitric Oxide Synthase (iNOS)-Mediated Oxidative Stress and Recruiting Bone Marrow-Derived Endothelial Progenitor Cells. J Cell Physiol 2016;231:2159–71.doi:10.1002/jcp.25328pmid:http://www.ncbi.nlm.nih.gov/pubmed/26825453
      OpenUrlCrossRefPubMed
    65. ↵
      1. Desposito D,
      2. Chollet C,
      3. Taveau C, et al
      . Improvement of skin wound healing in diabetic mice by kinin B2 receptor blockade. Clin Sci 2016;130:45–56.doi:10.1042/CS20150295pmid:http://www.ncbi.nlm.nih.gov/pubmed/26443866
      OpenUrlPubMed
    66. ↵
      1. Dong M-W,
      2. Li M,
      3. Chen J, et al
      . Activation of α7nAChR promotes diabetic wound healing by suppressing age-induced TNF-α production. Inflammation 2016;39:687–99.doi:10.1007/s10753-015-0295-xpmid:http://www.ncbi.nlm.nih.gov/pubmed/26650489
      OpenUrlPubMed
    67. ↵
      1. Eo H,
      2. Lee H-J,
      3. Lim Y
      . Ameliorative effect of dietary genistein on diabetes induced hyper-inflammation and oxidative stress during early stage of wound healing in alloxan induced diabetic mice. Biochem Biophys Res Commun 2016;478:1021–7.doi:10.1016/j.bbrc.2016.07.039pmid:http://www.ncbi.nlm.nih.gov/pubmed/27431618
      OpenUrlPubMed
    68. ↵
      1. Katagiri S,
      2. Park K,
      3. Maeda Y, et al
      . Overexpressing IRS1 in endothelial cells enhances angioblast differentiation and wound healing in diabetes and insulin resistance. Diabetes 2016;65:2760–71.doi:10.2337/db15-1721pmid:http://www.ncbi.nlm.nih.gov/pubmed/27217486
      OpenUrlAbstract/FREE Full Text
    69. ↵
      1. Long M,
      2. Rojo de la Vega M,
      3. Wen Q, et al
      . An essential role of Nrf2 in diabetic wound healing. Diabetes 2016;65:780–93.doi:10.2337/db15-0564pmid:http://www.ncbi.nlm.nih.gov/pubmed/26718502
      OpenUrlAbstract/FREE Full Text
    70. ↵
      1. Soares MA,
      2. Cohen OD,
      3. Low YC, et al
      . Restoration of Nrf2 signaling normalizes the regenerative niche. Diabetes 2016;65:633–46.doi:10.2337/db15-0453pmid:http://www.ncbi.nlm.nih.gov/pubmed/26647385
      OpenUrlAbstract/FREE Full Text
    71. ↵
      1. Tan JTM,
      2. Prosser HCG,
      3. Dunn LL, et al
      . High-Density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor class B type I. Diabetes 2016;65:3091–103.doi:10.2337/db15-1668pmid:http://www.ncbi.nlm.nih.gov/pubmed/27284113
      OpenUrlAbstract/FREE Full Text
    72. ↵
      1. Tellechea A,
      2. Leal EC,
      3. Kafanas A, et al
      . Mast cells regulate wound healing in diabetes. Diabetes 2016;65:2006–19.doi:10.2337/db15-0340pmid:http://www.ncbi.nlm.nih.gov/pubmed/27207516
      OpenUrlAbstract/FREE Full Text
    73. ↵
      1. Wu Y,
      2. Quan Y,
      3. Liu Y, et al
      . Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes. Nat Commun 2016;7:13393.doi:10.1038/ncomms13393pmid:http://www.ncbi.nlm.nih.gov/pubmed/27830702
      OpenUrlPubMed
    74. ↵
      1. Yu J-W,
      2. Deng Y-P,
      3. Han X, et al
      . Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice. Cardiovasc Diabetol 2016;15:88.doi:10.1186/s12933-016-0408-3pmid:http://www.ncbi.nlm.nih.gov/pubmed/27316923
      OpenUrlPubMed
    75. ↵
      1. Agostinho Hunt AM,
      2. Gibson JA,
      3. Larrivee CL, et al
      . A bioluminescent Pseudomonas aeruginosa wound model reveals increased mortality of type 1 diabetic mice to biofilm infection. J Wound Care 2017;26:S24–33.doi:10.12968/jowc.2017.26.Sup7.S24pmid:http://www.ncbi.nlm.nih.gov/pubmed/28704171
      OpenUrlPubMed
    76. ↵
      1. Nishikai-Yan Shen T,
      2. Kanazawa S,
      3. Kado M, et al
      . Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice. PLoS One 2017;12:e0178232.doi:10.1371/journal.pone.0178232pmid:http://www.ncbi.nlm.nih.gov/pubmed/28542434
      OpenUrlPubMed
    77. ↵
      1. Shin J,
      2. Yang SJ,
      3. Lim Y
      . Gamma-Tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice. Exp Biol Med 2017;242:505–15.doi:10.1177/1535370216683836pmid:http://www.ncbi.nlm.nih.gov/pubmed/28211759
      OpenUrlPubMed
    78. ↵
      1. Singla R,
      2. Soni S,
      3. Patial V, et al
      . In vivo diabetic wound healing potential of nanobiocomposites containing bamboo cellulose nanocrystals impregnated with silver nanoparticles. Int J Biol Macromol 2017;105:45–55.doi:10.1016/j.ijbiomac.2017.06.109pmid:http://www.ncbi.nlm.nih.gov/pubmed/28669805
      OpenUrlPubMed
    79. ↵
      1. Wang Y,
      2. Bai Y,
      3. Li Y, et al
      . Il-15 enhances activation and IGF-1 production of dendritic epidermal T cells to promote wound healing in diabetic mice. Front Immunol 2017;8:1557.doi:10.3389/fimmu.2017.01557pmid:http://www.ncbi.nlm.nih.gov/pubmed/29225596
      OpenUrlPubMed
    80. ↵
      1. Xu C,
      2. Bentinger M,
      3. Savu O, et al
      . Mono-epoxy-tocotrienol-α enhances wound healing in diabetic mice and stimulates in vitro angiogenesis and cell migration. J Diabetes Complications 2017;31:4–12.doi:10.1016/j.jdiacomp.2016.10.010pmid:http://www.ncbi.nlm.nih.gov/pubmed/27839658
      OpenUrlPubMed
    81. ↵
      1. Zhao H,
      2. Chen J,
      3. Chai J, et al
      . Cytochrome P450 (CYP) epoxygenases as potential targets in the management of impaired diabetic wound healing. Lab Invest 2017;97:782–91.doi:10.1038/labinvest.2017.21pmid:http://www.ncbi.nlm.nih.gov/pubmed/28319086
      OpenUrlCrossRefPubMed
    82. ↵
      1. Zhao H,
      2. Lu S,
      3. Chai J, et al
      . Hydrogen sulfide improves diabetic wound healing in ob/ob mice via attenuating inflammation. J Diabetes Complications 2017;31:1363–9.doi:10.1016/j.jdiacomp.2017.06.011pmid:http://www.ncbi.nlm.nih.gov/pubmed/28720320
      OpenUrlPubMed
    83. ↵
      1. Botusan IR,
      2. Zheng X,
      3. Narayanan S, et al
      . Deficiency of liver-derived insulin-like growth factor-I (IGF-I) does not interfere with the skin wound healing rate. PLoS One 2018;13:e0193084.doi:10.1371/journal.pone.0193084pmid:http://www.ncbi.nlm.nih.gov/pubmed/29534073
      OpenUrlPubMed
    84. ↵
      1. Cardoso SH,
      2. de Oliveira CR,
      3. Guimarães AS, et al
      . Synthesis of newly functionalized 1,4-naphthoquinone derivatives and their effects on wound healing in alloxan-induced diabetic mice. Chem Biol Interact 2018;291:55–64.doi:10.1016/j.cbi.2018.06.007pmid:http://www.ncbi.nlm.nih.gov/pubmed/29902415
      OpenUrlPubMed
    85. ↵
      1. Hozzein WN,
      2. Badr G,
      3. Badr BM, et al
      . Bee venom improves diabetic wound healing by protecting functional macrophages from apoptosis and enhancing Nrf2, Ang-1 and Tie-2 signaling. Mol Immunol 2018;103:322–35.doi:10.1016/j.molimm.2018.10.016pmid:http://www.ncbi.nlm.nih.gov/pubmed/30366166
      OpenUrlPubMed
    86. ↵
      1. Jiménez-Jiménez C,
      2. Lara-Chica M,
      3. Palomares B, et al
      . Effect of N-acyl-dopamines on beta cell differentiation and wound healing in diabetic mice. Biochim Biophys Acta Mol Cell Res 2018;1865:1539–51.doi:10.1016/j.bbamcr.2018.08.008pmid:http://www.ncbi.nlm.nih.gov/pubmed/30327197
      OpenUrlPubMed
    87. ↵
      1. Shi Y,
      2. Fan S,
      3. Wang D, et al
      . Foxo1 inhibition potentiates endothelial angiogenic functions in diabetes via suppression of ROCK1/Drp1-mediated mitochondrial fission. Biochim Biophys Acta Mol Basis Dis 2018;1864:2481–94.doi:10.1016/j.bbadis.2018.04.005pmid:http://www.ncbi.nlm.nih.gov/pubmed/29654945
      OpenUrlPubMed
    88. ↵
      1. Wang F,
      2. Liu B,
      3. Yu Z, et al
      . Effects of CD100 promote wound healing in diabetic mice. J Mol Histol 2018;49:277–87.doi:10.1007/s10735-018-9767-2pmid:http://www.ncbi.nlm.nih.gov/pubmed/29637382
      OpenUrlPubMed
    89. ↵
      1. Yan J,
      2. Tie G,
      3. Wang S, et al
      . Diabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages. Nat Commun 2018;9:33.doi:10.1038/s41467-017-02425-zpmid:http://www.ncbi.nlm.nih.gov/pubmed/29295997
      OpenUrlPubMed
    90. ↵
      1. Yu B,
      2. Alboslemy T,
      3. Safadi F, et al
      . Glycoprotein nonmelanoma clone B regulates the crosstalk between macrophages and mesenchymal stem cells toward wound repair. J Invest Dermatol 2018;138:219–27.doi:10.1016/j.jid.2017.08.034pmid:http://www.ncbi.nlm.nih.gov/pubmed/28899684
      OpenUrlPubMed
    91. ↵
      1. Yuan Y,
      2. Das SK,
      3. Li M
      . Vitamin D ameliorates impaired wound healing in streptozotocin-induced diabetic mice by suppressing NF-κB-mediated inflammatory genes. Biosci Rep 2018;38. doi:doi:10.1042/BSR20171294. [Epub ahead of print: 27 Apr 2018].pmid:29330224
      OpenUrlAbstract/FREE Full Text
    92. ↵
      1. Li X,
      2. Wu G,
      3. Han F, et al
      . Sirt1 activation promotes angiogenesis in diabetic wounds by protecting endothelial cells against oxidative stress. Arch Biochem Biophys 2019;661:117–24.doi:10.1016/j.abb.2018.11.016pmid:http://www.ncbi.nlm.nih.gov/pubmed/30458128
      OpenUrlPubMed
    93. ↵
      1. Yang C-T,
      2. Chen L,
      3. Chen W-L, et al
      . Hydrogen sulfide primes diabetic wound to close through inhibition of NETosis. Mol Cell Endocrinol 2019;480:74–82.doi:10.1016/j.mce.2018.10.013pmid:http://www.ncbi.nlm.nih.gov/pubmed/30339820
      OpenUrlPubMed
    94. ↵
      1. Galiano RD,
      2. Michaels J,
      3. Dobryansky M, et al
      . Quantitative and reproducible murine model of excisional wound healing. Wound Repair Regen 2004;12:485–92.doi:10.1111/j.1067-1927.2004.12404.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/15260814
      OpenUrlCrossRefPubMedWeb of Science
    95. ↵
      1. Davidson JM,
      2. Yu F,
      3. Opalenik SR
      . Splinting strategies to overcome confounding wound contraction in experimental animal models. Adv Wound Care 2013;2:142–8.doi:10.1089/wound.2012.0424
      OpenUrl
    96. ↵
      1. American Diabetes Association
      . Diagnosis and classification of diabetes mellitus. Diabetes Care 2009;32 Suppl 1:S62–7.doi:10.2337/dc09-S062pmid:http://www.ncbi.nlm.nih.gov/pubmed/19118289
      OpenUrlPubMed
    97. ↵
      1. Lenzen S
      . The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 2008;51:216–26.doi:10.1007/s00125-007-0886-7pmid:http://www.ncbi.nlm.nih.gov/pubmed/18087688
      OpenUrlCrossRefPubMedWeb of Science
    98. ↵
      1. Breyer MD,
      2. Böttinger E,
      3. Brosius FC, et al
      . Mouse models of diabetic nephropathy. J Am Soc Nephrol 2005;16:27–45.doi:10.1681/ASN.2004080648pmid:http://www.ncbi.nlm.nih.gov/pubmed/15563560
      OpenUrlAbstract/FREE Full Text
    99. ↵
      1. Furman BL
      . Streptozotocin-Induced diabetic models in mice and rats. Curr Protoc Pharmacol 2015;70:1–20.doi:10.1002/0471141755.ph0547s70pmid:http://www.ncbi.nlm.nih.gov/pubmed/26331889
      OpenUrlCrossRefPubMed
    100. ↵
      1. Gurley SB,
      2. Clare SE,
      3. Snow KP, et al
      . Impact of genetic background on nephropathy in diabetic mice. Am J Physiol Renal Physiol 2006;290:F214–22.doi:10.1152/ajprenal.00204.2005pmid:http://www.ncbi.nlm.nih.gov/pubmed/16118394
      OpenUrlCrossRefPubMed
    101. ↵
      1. Allen TJ,
      2. Cooper ME,
      3. Lan HY
      . Use of genetic mouse models in the study of diabetic nephropathy. Curr Atheroscler Rep 2004;6:197–202.doi:10.1007/s11883-004-0032-7pmid:http://www.ncbi.nlm.nih.gov/pubmed/15068744
      OpenUrlCrossRefPubMed
    102. ↵
      1. Coleman DL
      . Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 1978;14:141–8.doi:10.1007/BF00429772pmid:http://www.ncbi.nlm.nih.gov/pubmed/350680
      OpenUrlCrossRefPubMedWeb of Science
    103. ↵
      1. Lee YT,
      2. Lin HY,
      3. Chan YWF, et al
      . Mouse models of atherosclerosis: a historical perspective and recent advances. Lipids Health Dis 2017;16:12.doi:10.1186/s12944-016-0402-5pmid:http://www.ncbi.nlm.nih.gov/pubmed/28095860
      OpenUrlCrossRefPubMed
    104. ↵
      1. O'Brien PD,
      2. Sakowski SA,
      3. Feldman EL
      . Mouse models of diabetic neuropathy. Ilar J 2014;54:259–72.doi:10.1093/ilar/ilt052pmid:http://www.ncbi.nlm.nih.gov/pubmed/24615439
      OpenUrlCrossRefPubMed
    105. ↵
      1. Krishna SM,
      2. Omer SM,
      3. Golledge J
      . Evaluation of the clinical relevance and limitations of current pre-clinical models of peripheral artery disease. Clin Sci 2016;130:127–50.doi:10.1042/CS20150435pmid:http://www.ncbi.nlm.nih.gov/pubmed/26678170
      OpenUrlPubMed
    106. ↵
      1. Sullivan KA,
      2. Hayes JM,
      3. Wiggin TD, et al
      . Mouse models of diabetic neuropathy. Neurobiol Dis 2007;28:276–85.doi:10.1016/j.nbd.2007.07.022pmid:http://www.ncbi.nlm.nih.gov/pubmed/17804249
      OpenUrlCrossRefPubMedWeb of Science
    107. ↵
      1. Wu KK,
      2. Huan Y
      . Diabetic atherosclerosis mouse models. Atherosclerosis 2007;191:241–9.doi:10.1016/j.atherosclerosis.2006.08.030pmid:http://www.ncbi.nlm.nih.gov/pubmed/16979174
      OpenUrlCrossRefPubMedWeb of Science

    Footnotes

    • Contributors PH, JP, SMK and JG were responsible for the conceptualization of the review, with data curation and analysis performed by PH and JP. The writing of this manuscript was performed by PH and JG.

    • Funding This work was supported by James Cook University’s Strategic Research Intent Fund. JG holds a National Health and Medical Research Council (NHMRC) Practitioner Fellowship (1117061) and Queensland Government Senior Clinical Research Fellowship (SCRF).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.