# The Application of Mesenchymal Stem Cells on Wound Repair and Regeneration
## 5 Phases and Complications of the Wound-Healing Process  
Wounds have diverse causes, namely injuries, pathologic conditions or even surgeries. There are four phases that characterize wound healing: hemostasis, inflammation, granulation/proliferation and tissue reconstruction/remodeling (Figure 2). If these steps do not occur in a consecutive order and at the appropriate moment, the healing process is compromised and will fail or be abnormal. In addition, there can be complications such as the development of chronic wounds, infections and even keloids or hypertrophic scars derived from an excessive wound-healing process [28, 31, 33]. The main causes of chronic wounds are diabetic disease or other metabolic pathologies, inappropriate keratinocytes proliferation, some medications (chemotherapeutic drugs, glucocorticoid steroids, non-steroidal anti-inflammatory drugs), impaired angiogenesis, severe wounds extended into the dermis or even deeper layers, and lack of appropriate coverage. All these conditions contribute with a moist environment for the wound bed that provides protection [28]. Promptly after the skin injury, a blood clot and a platelet plug seals the wound temporarily, and this mechanism prevents blood loss and initiates the molecular cascade [31]. Therefore, in the first phase, hemostasis and inflammatory response occur, and the damaged epithelial and the blood clot release chemotactic factors to recruit immune cells that have a major role in the inflammation. This phase is important to prevent infections and remove necrotic and apoptotic cells from the lesion site. The feedback to the inflammatory cues is the appearance of neutrophils, followed by circulating monocytes that differentiate into mature tissue macrophages and mast cells afterwards [28, 31]. In the second phase, these cells secrete chemokines and other molecules (IL-1\(\alpha\), IL-33), such as growth factors (TGF-8), that help in the development of granulation tissue and migration/proliferation of fibroblasts and keratinocytes. These cells also secrete some toxic mediators such as reactive oxygen species and proteases that can be destructive to the surrounding tissues [31]. Therefore, the excess of these cells infiltration (especially macrophages and neutrophils) and the delayed inflammation might restrain rather than enhance the process of healing. Therefore, this can be a cause of chronic wound situation and the constant tissue-destroying natureof this type of wound [28, 31]. In the third phase, a re-epithelialization occurs, as well as wound contraction, important to the next phases of tissue remodeling [34, 35]. The tissue remodeling phase is defined by declined cellularity and matrix remodeling. Consequently, originally disordered collagen fibers are cross-linked and rearranged [31]. There are several techniques to target the healing phases using different materials and bioactive molecules. Antibiotic drugs can be used to prevent and clear bacterial colonization in early phases. Moreover, growth factors like epidermal growth factor (EGF), platelet-derived growth factor (PDGF) or basic fibroblast growth factor can stimulate growth and proliferation in a middle stage of the healing process [20, 34]. Another example is the use of immunomodulatory molecules (IL-4) to modulate macrophages function to achieve wound repair. Therefore, a lot of techniques and strategies can be used to help regenerate skin tissue and accelerate the healing process [34, 36]. However, when the process is disordered, chronic wounds are created, exhibiting persistent inflammation, biofilm development, microorganism recruitment and release of platelet-derived factors. Therefore, growth factors are truly important since they are the focal regulatory points of repair. In normal wounds when the dermal defect is closed, and the epithelization complete there are signals to stop the repair process. However, when these signals are inefficient, the process of repair may continue and form an excessive scar [30, 37].