Combination therapy of autologous adipose mesenchymal stem cell-enriched, high-density lipoaspirate and topical timolol for healing chronic wounds

Abstract

Chronic venous leg ulcers are profoundly debilitating and result in billions in health care expenditure. Thus, there is a quest for engineered and innovative approaches. Herein we present a 63-year-old patient with a 30 year history of venous stasis and left lower extremity ulcers, which have been refractory to standard of care, anticoagulation and venous stripping. The medial ulcer was treated with transplantation of autologous adipose mesenchymal stem cell (AMSC)-enriched, high-density lipoaspirate (HDL) on OASIS wound matrix and compression therapy. The lateral ulcer was treated as a control with standard debridement and compression therapy. Four weeks later, both ulcers received daily topical timolol. Three months later, the test ulcer was completely epithelized and remains healed for over 15 months. However, the control showed minimal signs of improvement. In companion studies in our laboratory, human AMSC were cultured in Minimum Essential Medium Eagle Alpha Modifications (MEMα) with fetal bovine serum (FBS). Timolol was administered to AMSC prior to treatment with epinephrine and 104 bacteria/ml heat-killed Staphylococcus aureus. The MEMα with FBS devoid of AMSC served as a background control. After 24 h, cell culture supernatants and protein lysates were collected to determine cytokine production. There was a statistical significant decrease in pro-inflammatory interleukin-6 and -8 induced by the bacteria (to model the wound environment) in AMSC in the presence of timolol compared with control (p < 0.5). This is the first case of a successful combination of autologous AMSC-enriched, HDL with topical timolol for the healing of chronic venous leg ulcers. Copyright © 2016 John Wiley & Sons, Ltd.

The role of β‐blockers in dermatological treatment: a review

“…[64][65][66][67] Numerous case studies have also reported success in treating chronic, recalcitrant wounds with non-selective topical b-blockers such as timolol and propranolol. [68][69][70][71][72][73][74] Furthermore, two randomized controlled trials including 79 and 69 burn patients found that oral propranolol administration markedly decreases the time needed to receive skin graft and the area needed to be grafted. 75,76 Pyoderma gangrenosum Pyoderma gangrenosum is a rare, ulcerative inflammatory skin disorder with unknown aetiology.…”

Evolution of ASC Immunophenotypical Subsets During Expansion In Vitro

“…ASCs have been recognized to be highly biologically active, with regenerative roles in tissue formation, homeostasis, and immune regulation [3][4][5]. These unique properties render ASCs attractive in scenarios where the traditional approaches fall short of the desired therapeutic outcome, such as for chronic wounds, diabetic ulcers, osteoarthritis, ischemic heart disease, or type 1 diabetes, just to mention a few important areas [6][7][8][9][10]. Many ASC-based regimens have already progressed into clinical testing, and in the United States alone, more than 20 phase I and II clinical trials are currently being conducted (clinicaltrials.gov).…”

Tunable hydrogels for mesenchymal stem cell delivery: Integrin-induced transcriptome alterations and hydrogel optimization for human wound healing

“…Prior research has focused mainly on the ability of extracellular matrix (ECM)‐encapsulated stem cells to improve wound healing . However, fibrin may be suboptimal for such applications: it degrades quickly, requiring multiple treatment sessions; lacks intrinsic antimicrobial properties, which are needed to promote wound healing; and has limited ability to hold moisture.…”

“…Prior research has focused mainly on the ability of extracellular matrix (ECM)-encapsulated stem cells to improve wound healing. [7][8][9][10][11] However, fibrin may be suboptimal for such applications: it degrades quickly, requiring multiple treatment sessions 7 ; lacks intrinsic antimicrobial properties, which are needed to promote wound healing 12,13 ; and has limited ability to hold moisture. In contrast, well-defined synthetic hydrogels have emerged as promising vehicles for stem cell delivery because their 3D structure and high water content is ideal to support stem cell growth.…”