An MMP/TIMP ratio scoring system as a potential predictive marker of diabetic foot ulcer healing

Abstract

Objectives: The mechanism of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in diabetic foot ulcers (DFUs) is unclear. The purpose of this study was to describe changes in MMP-1, MMP-9, and TIMP-1 levels during DFU healing, and to search for any correlation in the changes in MMP levels with wound healing, in order to find possible predictors of healing. Methods: Patients with a DFU were recruited and placed into two groups, according to the degree of wound healing: ‘good healers’ and ‘poor healers’. Levels of MMP-1, MMP-9, and TIMP-1 were analysed by ELISA (enzyme-linked immunosorbent assay). Results: A total of 22 patients participated in the study. The MMP-1 level was significantly higher at weeks zero (W0) and 12 (W12) in ‘good healers’ than in ‘poor healers’ (p=0.045 and 0.008, respectively). In contrast, the MMP-9 level was significantly lower in ‘good healers’ than in ‘poor healers’ at W0, W4, and W12 (p=0.001, 0.001 and 0.028, respectively). Receiver operator curve (ROC) analysis of the MMP-9 level, MMP-1/TIMP-1 ratio, and MMP-9/TIMP-1 ratio at W0 provided cut-off levels of 0.38, 0.056, and 9.06, respectively, which were best predictive of a reduction in wound area at W4 (‘good healers’ versus ‘poor healers’; thereby predicting wound healing condition at W12) with a sensitivity of 81.8%, 81.8%, and 90.9%, and a specificity of 64.6%, 55%, and 64.6%, respectively. Conclusion: A ‘poor healing scoring system’ is therefore proposed that could be determined on patient admission, which has the potential to be used clinically as a predictor of healing, thus allowing an appropriate treatment plan to be developed.

Protease activity as a prognostic factor for wound healing in complex wounds

“…Eight studies, with 343 participants, met the inclusion criteria for the review. [31][32][33][34][35][36][37][38] One study split the participants into two cohorts; 32 (a) a "discovery" set formed from people with "rapidly healing" wounds (healed after 6 months) and an age and sex-matched set of people with nonhealing (deteriorating) wounds, and (b) a "validation" set formed from the remaining participants. One RCT combined the results for two randomized arms (protease modulating matrix and placebo) 35 and another reported results separately for each randomized group (doxycycline and placebo) 37 , giving a total of 10 cohorts.…”

“…Six cohorts (five studies) took account of at least half the prespecified confounding factors either in the study design or analysis [31][32][33][34]36 and four cohorts (three studies) considered less than half of the key confounding factors. 35,37,38 Three studies conducted a multivariable analysis.…”

“…Seven studies (eight cohorts) measured wound protease levels; some examining more than one protease: MMP-1; 31,33,35 MMP-2; 31,34 MMP-8; 31 MMP-9; 31,[33][34][35]37,38 the serine protease, HNE; 35,36 and a combination of proteases, MMP-9 plus HNE. 35 Five cohorts (four studies) investigated protease inhibitors: TIMP-1 31,33,34 and the serine protease inhibitor, Serpin B3. 32 Four cohorts (four studies) investigated ratios of proteases with protease inhibitors: MMP-1:…”

“…TIMP-1, 31,33 MMP-2:TIMP-1, 34 MMP-9:TIMP-1, [33][34][35] giving a total of 27 cohort-protease combinations.…”

“…Four cohorts 31,[33][34][35] reported results separately for the active form of at least some proteases (MMP-9, 31,33 HNE, 35 MMP-2, and MMP-9 34 ) and the remainder reported total levels of proteases or used ELISA analysis, which we assumed measured the total level unless stated otherwise. See Table A1 for more detail.…”