Locally Delivered Umbilical Cord Mesenchymal Stromal Cells Reduce Chronic Inflammation in Long-Term Nonhealing Wounds: A Randomized Study

Abstract

Inflammation is part of a complex biological response to injury that mediates a rapid mobilization of cells and triggers the restoration of tissue homeostasis. The systemic diseases of the connective tissues, repetitive strain injuries, neuropathy, and vascular impairment lead to the development of a chronic inflammatory state. In such cases, a forced intervention is required to trigger tissue regeneration. Mesenchymal stromal cells (MSCs) have been considered a perspective tool for regenerative medicine because of their ability to change the expression and secretory profile under the influence of signals from the microenvironment to perform a regulatory function at the site of tissue damage. In this study, MSCs were isolated from the human umbilical cord (UCMSCs). The ability of UCMSCs to regulate chronic inflammation was investigated in a randomized placebo-controlled pilot study to assess the efficacy and safety of UCMSC therapy in patients with nonhealing wounds. A total of 108 patients with chronic wounds of different etiologies were randomly divided into two groups according to the criteria of inclusion and exclusion. The group (n = 59) that was treated with a single local subcutaneous infusion of UCMSCs around the wound periphery showed a pronounced growth of granulation tissue, improved blood microcirculation, and reduction in wound size compared to the placebo group (n = 49). No prominent adverse events were detected in patients from the UCMSC group during the 1-year follow-up period. This research has demonstrated that locally delivered allogeneic UCMSCs can contribute to chronic wound repair and provide an additional support toward new therapeutic strategies. Registration certificate №FS2006/341 was issued by the Federal Service for Surveillance in Healthcare.

Figure 1

Pathophysiological variants of case scenario in tissue repair after injury. The best case scenario for wound healing is tissue regeneration—the complete repair of structure and function. Adults usually experience wound healing with various degrees of scar formation. Tissue repair does not occur if chronic inflammation develops. The strategy to control the inflammatory response is a shift in the balance from chronic inflammation toward tissue regeneration.

Figure 2

The dynamics of granulation tissue formation in chronic wounds. (a) The qualitative characteristics of granulation tissue in patients of the placebo and UCMSC groups before and 14 days after treatment (χ² test; ^∗reliability of the differences at p < 0.05). (b) representative images of wounds of the UCMSC group before and 14 days after cell therapy.

Figure 3

The dynamics of changes in wound sizes. (a) Wound area on the 1st, 14th, and 28th days of the study in the placebo and UCMSC groups. Data are presented as the median, 25% and 75% quartiles, and minimum and maximum (U test; ^∗reliability of the differences at p < 0.05; “°” symbol indicates an outlier from the data set). (b) Reepithelialization of the wound in a patient from the UCMSC group 14 days after cell therapy. (c) Wound contraction in a patient from the UCMSC group 14 days after cell therapy.

Figure 4

The quantitative analysis of microvascular hemodynamic parameters of periwound tissues. (a) Transcutaneous oxygen pressure (TcPO₂) in patients of the placebo and UCMSC groups before and 14 days after treatment. (b) Average blood perfusion in patients of the placebo and UCMSC groups before and 14 days after treatment (t-test; ^∗reliability of the differences at p < 0.05).