J Transl Med. 2015 Jul 24;13:242.

Riordan NH, George BA, Chandler TB, McKenna RW.


Wound healing is a complex process whereby multiple cell types, growth factors, and extra-cellular proteins interact to repair a disruption in the dermal and epidermal layers of the skin. In some cases, the mechanism behind said repair fails to restore the integrity of the injured tissue in a timely manner, delaying the progression of inflammatory, proliferative, and remodeling phases of healing [1]. The resulting chronic, non-healing wound is vulnerable to infection, may cause pain, reduce quality of life, and become a burden on the healthcare system [2]. Non-healing wounds, frequently seen in older patients [3], are associated with certain conditions such as diabetes, obesity, and rheumatoid arthritis, but may also occur following acute trauma or surgical intervention [45]. It is estimated that 1–2% of patients in developed countries will experience non-healing wounds in their lifetime [6], and certain types of chronic wounds are estimated to account for billions of dollars of treatment costs in the United States [3].

An adequate progression of wound healing [178] begins with the secretion of growth factors such as Transforming Growth Factor beta (TGF-β) [9], as well as Fibroblast (FGF), Endothelial (EGF), Platelet Derived (PDGF) and Vascular Endothelial (VEGF) Growth Factors [10]. Neutrophils attracted by PDGF signals clear excess bacteria at the site with the aid of monocytes—later transformed to macrophages. Macrophages regulate the production of TGF-β, which in turn stimulates migration and proliferation of fibroblasts as well as epithelialization [11]. Extracellular matrix and granulation tissue begin forming as fibroblasts secrete fibronectin and collagen precursors concurrently with VEGF-stimulated angiogenesis which carries oxygen and nutrients to the injured site [12]. Finally, the collagen structure in the wound area matures and reassembles into a tighter structure with greater tensile strength. An interruption or delay at any stage of this complex process results in a non-healing wound [21314].

Treatments for non-healing wounds include compression therapy, negative pressure wound devices [15], skin grafts [1617] and tissue bioengineering [181920], as well as cell therapy [21] particularly using mesenchymal stem cells (MSC). These cells, known to enhance wound healing, have been broadly studied in clinical trials. Contrary to the early paradigm of cell replacement and differentiation as a therapeutic mechanism of action, evidence is mounting that the secretions of the MSC are responsible for their therapeutic effects [22]. These secretions include molecules and extracellular vesicles that yield both local and distant effects. The most important factors present in a conditioned medium of MSC can also be considered protagonists of MSC physiological effects including HGF, TGF-b, VEGF, TSG-6, PGE2 and galectins 1, and 9 [22]. It is important to note that fresh amniotic membranes contain live MSCs while dehydrated amniotic membranes do not. Rather, dehydrated amniotic membranes (as in the case of the AlphaPatch) function as a biologic scaffold to facilitate and enhance tissue regeneration and rehabilitation by way of the said molecules in addition to PGE2, WNT4, and GDF-11 [22].

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