CONTENTS

Chronic leg ulcers (CLU) are a common and complicated disease to treat, and result in high morbidity and significantly reduced quality of life. Normal wound healing consists of four overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Most ulcers heal when the cause is eliminated and the ulcer is treated with standard wound care. Some ulcers, however, are for various reasons locked in the inflammatory stage and do not heal. Regarding CLUs, most of the ulcers are caused by venous insufficiency or arterial ischemia, often secondary to diabetes, but some CLUs do not have an apparent underlying condition.

CLUs are a challenge for the physician, a significant physical and psychological setback for the patient, and a heavy burden on the healthcare systems. Thus, an American study reported an average cost of treating chronic venous leg ulcers of $9685 per patient per year. This reflects that these patients are difficult to treat, as the available treatment options are limited, leaving patients with a chronic condition severely affecting their quality of life. CLUs result in substantial use of the resources of healthcare systems regarding materials, hospital appointments, reduced working capability for the patients, and impairment of the patient in general.

Treatment with stem cells might be a new treatment option for these patients. Stem cells have the potential to differentiate into numerous types of cells . Over the last decade, stem cell therapy has shown great potential in the treatment of a variety of different conditions, such as orthopedic disorders, inflammatory diseases, hepatic failure, and autoimmune disorders . At the time of writing, adverse events have not been reported; therefore, stem cell treatment is currently regarded as safe. A review including more than 1400 patients found a favorable safety profile of adipose-derived stem cells (ADSC), but also highlighted the poor quality of most studies in regard to registering adverse events.

Adipose tissue is an excellent source of autologous ADSC and can be harvested easily compared with bone marrow-derived stem cells (BMSC) . Adipose tissue has in recent years surpassed bone marrow as the preferred source of mesenchymal stem cells. Besides being abundant, far easier to harvest, and with a lower risk of complications for the patient, adipose tissue additionally contains about 40 times more stem cells than bone marrow . A simple liposuction of the abdomen or inner thigh performed under local or general anesthesia is sufficient to harvest the required number of ADSC without any significant risk of complications . ADSC can be either freshly isolated or cultured. The culturing takes several days or weeks, and cannot be performed as a same-day procedure.

Stem cells are a heterogeneous pool of cells with numerous capabilities . They possess anti-inflammatory and neoangiogenic effects, secrete numerous growth factors, and can differentiate into various cells types. Many of these are known to be involved in the complex healing of wounds, although the exact capabilities and mechanisms of action of stem cells in wound healing are not yet fully understood. Research suggests that stem cells work though two mechanisms of action: firstly they attenuate the general inflammatory response and, secondly, they transform into cells involved in wound healing such as fibroblasts, myofibroblasts, antigen presenting cells, endothelial progenitor cells, and so forth.

Freshly isolated ADSC are far more heterogeneous compared with the quite homogeneous cells harvested from cultured ADSC. The greater variety of cell types in the freshly isolated ADSC could have a significant advantage in wound healing, compared with the far more limited number of different cells in cultured ADSC. In ADSC, endothelial, hematopoietic, and pericytic lineages represent 10–20%, 25–45%, and 3–5%, respectively, of the total nucleated cells.

Several methods of isolating ADSC have been reported . The most common is enzymatic isolation. Some techniques use simple centrifugation and vibration to isolate a stem cell pellet. Others are more complex and involve, for example, enzymatic (collagenase) dissolving of the adipose tissue. Fully automatic systems also exist. The different methods have advantages and disadvantages regarding the time required for the procedure, the need for advanced equipment/specially trained personnel, and financial cost. Data describing the efficacy of various methods are not available; therefore, no standardized method exists. In addition, the optimal method of application of ADSC is still undecided.

Various animal studies have documented the positive effect of ADSC in accelerating healing of chronic ulcers. The clinical translation is ongoing, with several clinical studies already published. The aim of this review is to describe the available data on the treatment of CLU with autologous ADSC by identifying published human studies and ongoing/registered clinical trials on the matter.