Normal Tissue healing is a complex and dynamic series of events involving the coordinated interaction of cells, proteins, proteases, growth factors, and extracellular matrix (ECM) components. The tissue healing process can be divided into three phases: (1) inflammatory phase; (2) proliferative phase; and (3) remodeling phase [Sinno and Prakash, 2013]. Although different growth factors and predominant cell types have been shown to be essential during each step at different times, a considerable overlap can occur. After an injury, immediately starts coagulation and the inflammatory phase, that is characterized by hemostasis and inflammation. Platelets secrete several chemokines that help to stabilize the wound through clot formation and also attract and activate macrophages and fibroblasts [Heldin and Westermark, 1996]. The proliferative phase is marked by epithelialization, angiogenesis, granulation tissue formation, and collagen deposition. Epithelialization [Heldin and Westermark 1996, Folkman and D’Amore, 1996; Iruela-Arispe and Dvorak, 1997] starts within hours after injury. Neovascularization, regulateded by many humoral factors, is needed to deliver nutrients and maintain the granulation tissue bed. Granulation tissue begins to invade the wound space about four days after injury. Meanwhile, macrophages continue to supply growth factors stimulating further angiogenesis and fibroplasia. The secreted platelet-derived growth factor [Heldin and Westermark, 1996] and transforming growth factor β [Roberts, 1995] along with the extracellular matrix (ECM) molecules [Xu and Clarck, 1996] stimulate fibroblast differentiation to produce new ECM through the synthesis of collagen, fibronectin, laminin and metalloproteases. Fibroblasts are the key players in the synthesis, deposition, and remodeling of the ECM, providing strength and substance to the wound. The third and final phase is the remodeling phase, characterized by the transition from granulation tissue to scar formation. During repair, the ECM is continuously remodeled by the synergistic action of different cell types (endothelial, fibroblasts, etc..). The wound becomes a transitory structure that can be utilized by endothelial cells to drive the formation of new blood vessels [Tettamanti et al., 2004]. In the case of healing by second intention, wound contraction due to myofibroblasts occurs.
Monitoring Tissue Healing
The recent progress in monitoring the different phases of the tissue regeneration process by objective, quantitative devices allowed for a better treatment of wounds from both the diagnostic and healing point of view. At present, it is possible to find commercial devices capable of monitoring the most important parameters, like skin thickness, wound morphology, tissue elasticity, and skin barriers [Kassal, 2015; Zhou, 2011; Kayleigh, 2013] elasticity for a quantitative assessment of the healing process. Quantitative monitoring represents an important improvement in a field that has been traditionally linked by qualitative assessment (visual, tactile) of experienced medical doctors. However, sophisticated techniques are suitable only for research purposes and the devices actually at the commercial stage are quite expensive, often require the support of medical infrastructure and/or qualified professionals and even when non-invasive, they could create significant discomfort in usage by common people. To tackle these issues, the recent trend is to create monitoring devices that should be wearable -i.e. intimately connected to the tissue under investigation, cost-effective, possibly disposable and easy to use while keeping a good precision, accuracy, sensitivity and stability [Sharp, 2008; Sridhar 2009]. Moreover, they should monitor multiple parameters contemporarily and be energetically friendly [Whelan, 2002; Amay, 2014]. The main challenge comes from the design and fabrication of the monitoring and medical devices, usually micro/nano sensors and smart actuators opportunely arranged in a biocompatible packaging, a sensor platform [Prakash, 2013]. As a matter of fact, although basic and applied research is continuously progressing, there is still a knowledge gap to be filled at the interface between the system biology and the sensing/medical devices.