**2. Tissue repair and regeneration**

pace because reprogramming raises serious concerns about safety because of their genetic

PRP, an autologous plasma fraction of peripheral blood, is the simplest regenerative medicine intervention that is rapidly extending to multiple medical fields mainly due to the easy use and biosafety that facilitates translation in humans. In fact, regulatory requirements for cell therapy involve multiple preclinical experiments to demonstrate their safety and nonteratogen effects in addition to GLP compliance in the preparation, and the use of adequate expensive installations [3]. In contrast, PRP therapies involve minimal manipulation, and in general, regulatory requirements are easy to comply thereby facilitating the widespread clinical use and commercial success of PRP kits and devices. In fact, PRP can be prepared by using any of the commercial systems available. PRPs can also be prepared by in house

While regenerative medicine with cells is directed to inherent non-healing problems and a wide range of pathological conditions, PRP embrace normal healing conditions such as tissue repair during surgical invasion or traumatic injuries seeking to enhance and accelerate physiological repair. Alternatively, PRPs as occurs with cell therapies, seek to direct nonhealing conditions, e.g. chronic conditions such as osteoarthritis (OA) or tendinopathy,

Due to the biosafety of these products, i.e. advantageous balance risk-benefit, clinical appli‐ cations have preceded the basic research. Actually, in its very beginnings PRPs have been used with a vague idea of the biological mechanisms they were influencing. Thereafter, most studies were directed to examining clinical outcomes rather than identifying the precise biochemical mechanisms underlying PRP effects, which remain to be elucidated in the most part. In fact, PRP widespread use was not driven by the principles of the scientific methods instead patient demand has been boosted by sports news and propaganda reporting that outstanding elite athletes had been successfully treated with PRP. The need is clear, to investigate and describe main PRP targets and action mechanisms underlying their clinical effects. In fact, translational medicine addresses both, the biological and the clinical aspect of the novel biotechnologies.

In this book chapter, first, we will discuss recent progress on understanding the tissue regeneration process with a particular focus on the healing stages, and the role of PRP released signaling proteins in targeting different cells and inducing paracrine actions. Current biolog‐ ical interventions aiming tissue regeneration stem from two concepts, namely cells responsible for tissue homeostasis, and the signaling cytokines that control cell fate. Several cell pheno‐ types are involved in tissue repair and some processes such as inflammation and angiogenesis are commonly involved in the repair process in several conditions. Hence, several notions of tissue repair mechanisms are compatible with the biological hallmarks of regeneration in different tissues. Common mechanisms involved in healing can be modulated using PRP. This

Second, from a practical point of view on PRP biotechnology we will discuss the main formulations, and summarize commercial systems to prepare PRP. Regulatory requirements

procedures, providing that basic rules of quality are implemented.

towards healing and restoration of tissue homeostasis.

is the basic knowledge to drive clinical applications.

will be briefly exposed.

instability and potential to form tumors.

2 Biotechnology

Despite growing knowledge on tissue regeneration mechanisms currently we are incapable to fully regenerate human tissues. The only approximation to tissue regeneration in the human body is the so-called "compensatory regeneration" in the liver. In fact, after lobe removal the liver compensates the loss and recovers its former size by balanced proliferation of all the existing cell types, including hepatocytes, kupffer macrophages, endothelial cells, duct cells, and fat storing cells. Moreover, these cells retain their functional identity and are able to produce all the liver-specific enzymes necessary for liver function [4].

In contrast to the lack of regenerative mechanisms in humans where there is no return to the embryonic state and no recapitulation of differentiating mechanisms, some amphibians as the salamander, after amputation replace their body parts by recapitulating embryological events. In these amphibians regeneration involves reactivation of developmental mechanisms in the post-natal life to restore wounded tissues identically as they were before injury.

Research in this area of experimental biology has provided useful information to the field of Regenerative Medicine. For example, the study of amphibians offers important insights into the mechanisms involved in the regeneration of complex structures. Indeed, after limb amputation in the salamander, a mass of undifferentiated cells called blastema is formed, and the blastema is capable of growing into different body parts [5].

Nevertheless, dramatic differences between frogs and salamanders in tissue repair/regenera‐ tion exist. Indeed adult frogs, despite being amphibians, cannot recapitulate embryologic mechanisms in their adult life. These differences are mainly attributed to at least three broad dissimilarities, first in their immune systems, secondly in cell differentiation mechanisms, and lastly in their potential for nerve regeneration [6].

Therefore these three notions derived from studies on experimental biology will drive our exposition of potential layers of PRP control in healing mechanisms. We will focus firstly, on immune-modulatory mechanisms i.e. the pattern of leukocyte infiltration (PMNs, monocytes, lymphocytes), and macrophage polarization, second the importance of stem/progenitor cell activation, and adequate differentiation, and third the requirement of nerve participation, as regeneration is dependent on the presence of nerves. In fact a minimum number of nerve fibers is necessary for regeneration to take place. We will emphasize the importance of an adequate crosstalk between immune cells, progenitor cells as well as local differentiated cells and the paracrine actions.

All these regenerative events constitute different layers of biological control that can be influenced by PRP administration.

**Figure 1.** Potential layers for PRP influence in tissue regeneration
