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

Abstract

Healing mechanisms are disrupted in complex wounds. Proteases may persist longer in nonhealing wounds. We sought to investigate whether protease activity, protease inhibitor activity, or their combinations are independent prognostic factors for healing of complex wounds. We searched MEDLINE, EMBASE, CINAHL, and The Cochrane Library to March 2019. Study selection comprised longitudinal studies assessing the independent effect of proteases, their inhibitors or ratios of the two, on healing of complex wounds, while controlling for confounding factors. Two reviewers independently extracted data and assessed risk of bias. We conducted meta‐analyses separately for proteases, inhibitors, and ratios. We graded the evidence certainty (quality). We identified eight eligible studies in 10 cohorts involving 343 participants. Risk of bias was moderate or high. Elevated protease activity may be associated with less wound healing (standardized mean difference [SMD]: −0.41, 95% CI −0.72 to −0.11; nine cohorts); and elevated protease inhibitor activity with more healing (SMD: 0.37, 95% CI 0.06‐0.68; five cohorts), this is low certainty evidence. Increased protease: inhibitor ratios may be associated with less healing (SMD −0.47, 95% CI −0.94 to −0.01; four cohorts), but this evidence is of very low certainty. Heterogeneity in protease activity was unexplained by prespecified subgroup analyses for wound type or protease activity status, but partially explained by protease class. Posthoc analysis suggested elevated levels of a particular protease, MMP‐1, may be associated with more healing and other proteases with less healing. This is low/very low certainty evidence. Limitations were small included studies at moderate or high risk of bias, and the use of posthoc analyses. Elevated protease activity and protease: inhibitor ratios may be associated with less healing, and elevated inhibitor levels with more healing. There may be important differences between MMP‐1 and other proteases. High quality research is needed to explore these new findings further.

Biomarkers of Skin Graft Healing in Venous Leg Ulcers

“…In addition, the proteolytic activity of MMPs is tightly regulated by tissue inhibitor of metalloproteinases (TIMPs). Increased levels of MMPs have been associated with delayed healing and have been suggested as predictive biomarkers ( 16 ). The serine proteinase, human neutrophil elastase (HNE), is secreted by polymorphonuclear neutrophils (PMNs), and its activity is an indicator of PMN tissue infiltration ( 17 ).…”

Adipose-Derived Stromal Cells for Chronic Wounds: Scientific Evidence and Roadmap Toward Clinical Practice

“…Exploited through the use of a conditioned media, 12-14 purified exosomes, 15 or cell therapy, 11 the ASC secretome contains ECM proteins (collagens, laminin, fibronectin), 16 and many MMPs that are key players in the healing process. 17 In wounds, excessive levels of some MMPs have been correlated with chronicity, 18 probably altering the equilibrium between ECM production and degradation. It is still not clear whether the concomitant production of ECM and MMPs by therapeutic ASC contributes to their therapeutic effect on chronic wounds where a disequilibrium in remodelling is observed.…”

A pH/Enzyme Dual Responsive PMB Spatiotemporal Release Hydrogel Promoting Chronic Wound Repair

“…Persistent bacterial infection will lead to everlasting chronic in ammation and infection, further disrupting the repairing cascade of in ammation resolution and reepithelialization in complex wounds (such as typical chronic wounds: diabetic wounds) [3]. Diabetic infected wounds have a typical microenvironment such as low pH [4], and high proteases for long periods of time in persistently non-healing wounds [5]. Infection is a chief factor that brings such a complex microenvironment [6].…”