Swift Downregulation of Gelatinases (MMP-2, MMP-9) in Neuropathic Diabetic Foot Ulcers Treated With Total Contact Cast

SLR - September 2019 - Du H. Jun

Reference: Alvarez  OM, Markowitz L, Onumah N, Wendelken M. Swift Downregulation of Gelatinases (MMP-2, MMP-9) in Neuropathic Diabetic Foot Ulcers Treated With Total Contact Cast. Wounds 2019 May;31(5):E39-E41..

Scientific Literature Review

Reviewed By: Du H. Jun, DPM
Residency Program: North Colorado Medical Center Podiatric Medicine and Surgery – Greeley, CO

Podiatric Relevance: It has been well hypothesized that diabetic foot wounds have a prolonged inflammatory phase likely due to the imbalance of matrix metalloproteases (MMP) and the metalloproteinases that inhibit MMP’s (e.g. TIMP, tissue inhibitor matrix metalloproteinase). MMP’s are significantly higher and TIMP’s lower in non-infected diabetic foot wounds compared to wounds in patients without diabetes. Total contact casting has been the gold standard for treatments of diabetic foot wounds, however little is known about the role TCC plays in affecting MMP and TIMP in diabetic foot wounds. The aim of this study was to evaluate how treatment with TCC affects the balance of proteases in DFUs as they heal.

Methods: Twenty-two patients total were treated with TCC with weekly follow ups and reapplications. Wound tissues were obtained at time zero, week three, six and 12 and analyzed for MMP2 (made constitutively), MMP9 (produced by inflammatory cells), TIMP1, and TIMP2. Wound measurements were obtained with healing rates calculated with digital planimetry software. Inclusion criteria consisted of patients who were diagnosed with DM I or II with a plantar foot wound with a grade of 1A under the University of Texas scoring system. Patients also had to have adequate arterial flow with cutoffs for ABI >0.75, TBI  >0.65, or toe systolic pressure >50 mmHg. Patients were excluded if the DFU was not a grade 1A, signs of osteomyelitis, non-diabetic etiology of wound, cancer history or those who have previously received wound therapies within the past 30 days. Multiple regression analyses and Spearman’s rank correlation coefficient tests were performed to detect percentage decreases in wound area and changes to MMP/TIMP levels.

Results: Baseline MMP were measured and after treatment with TCC for three weeks, a 20 percent decrease in MMP2 and 40 percent decrease in MMP9 were observed. By week six these levels have been reduced by 37 percent and 55 percent respectively. TIMP 1 and 2 levels were noted to slightly increase by the week three point, however by week six their levels had significantly increased by 45 percent and 44 percent respectively.

Conclusions: The rapid drop of MMP and Increase in TIMP levels strongly suggest a decline in the inflammatory phase of diabetic wounds and the initiation of the proliferation phase. The levels of MMP that were observed prior to TCC treatment is in accordance with the findings in the literature that suggest that excess of metalloproteinases is harmful to diabetic foot ulcer healing. Limitations to this study is that it would have been beneficial to measure inflammatory cytokine markers together with the MMP as they both together play a role in the destruction of the provisional matrix.