Between the hope of immortality and the inevitability of mortality, humans have always sought to counter the aging and defect of functional parts of their bodies.
AThe myth of Prometheus shows that the ancient Greeks were already aware of the potential of certain body parts to repair themselves. This God, who was tied to a rock for having given fire to men, saw every day his liver partly devoured by an eagle. Whose liver regenerated itself the next day so that the litany of punishment would be fulfilled. If the elders chose the liver rather than other organs to illustrate the myth, it was because they knew the liver was capable of regenerating itself to a large extent.
More recently, the symbolism of witches has often been associated with the salamander, capable of regenerating its limbs. Humans and higher vertebrates do not have the same capacity as the salamander, zebrafish or axolotl, let alone the capacity for total plant regeneration. But recent studies show that this capacity could exist, or at least be locally stimulated.
Stem cells: the key to regeneration?
The capacity for regeneration is mainly carried by cells in the body that will reprogram themselves to replace the damaged tissue or organ. Some of these so-called "strains" are generated by the bone marrow and can circulate throughout the body. Other stem cells are generated by the tissues themselves, such as those stem cells in the skin bulbs, which are responsible for the growth of hair and body hair throughout life.
Whatever their origin, these cells have the potential to transform themselves to repair and grow all kinds of tissues. This potential to become different, known as cell differentiation, has raised many hopes, especially since they have also been identified in the central nervous system (the brain) and peripheral nervous system (bone marrow and nerves).
If the phenomenon of regeneration is not very obvious in humans, there is a mechanism that everyone knows. It is the Healing. It's all in the word, it's a repair that leaves a scar. The regeneration is therefore only partial and does not allow an identical reproduction. Just look at the regenerated skin of serious burns, whose cardboard appearance is only a pale reproduction of the beautiful elasticity of the original skin tissue. It is therefore necessary to understand the reason for this deficiency, even if it is well understood that healing is essential, even vital.
The actors of body repair
The actors working for the regeneration of the body are at the crossroads of many intrinsic mechanisms of the living, which includes in the first line biologists and the medical profession, of course, but also physicists and mathematicians engineers or theoreticians, chemists, engineers, psychologists and many actors in the human and social sciences.
These actors of human regeneration can direct their work towards the regeneration of a function, by seeking to replace this deficient function, for example the knee, the skin or the heart, or by encouraging the body itself to participate in this regeneration, for example by driving the regrowth of damaged nerve ducts. The current option is certainly a mix of both approaches, through inclusive and incentive-based body engineering. Thus, new generation prostheses replace and respect the function to be recreated, by reproducing the damaged organ in a personalized way, and at the same time, they must be biocompatible, by integrating into the body without generating defense or rejection mechanisms.
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The Holy Grail of this research is to consider the inserted element as the starting point for regeneration, encouraging and guiding the body's own mechanisms of repair and regeneration. It is then a question of creating a niche so that the mechanisms of this regeneration are duly encouraged to move towards a complete dynamic of reconstitution, and not only of healing.
In other words, researchers, engineers and physicians view the repair/regeneration site as a coherent ecosystem. It must be connected or must be able to connect itself, i.e. be vascularized and innervated. It must retain the circulating stem cells and inform the resident stem cells with the necessary information to direct them towards differentiated growth. It must provide a precise mechanical environment, as the cells are so sensitive to the mechanical properties of the surrounding tissues; this is illustrated by the healing of the skin which takes place in the plastic environment formed by rigidified meshes of collagen which no longer has anything to do with the elasticity of the young skin used as a reference for the discourse of cosmetics.
After the 3D printer, here comes 4D printing!
These theoretical considerations are those of modern tissue engineering, which is part of a global approach in which materials chemistry, cellular pharmacology, embryology and biomechanics, among others, combine to provide injured tissues with cellular and tissue niches, both functional prosthesis and regenerative matrix. In this context, the time factor is an essential element.
It is well known to the surgeon who follows the evolutions/involutions directly on the body of the people being treated. It becomes a complex element for researchers to take into account. Time adds a fourth dimension to the modeling of prostheses and orthoses, whether they are classically synthesized with a single material or by the orchestrated addition of several materials sequentially added under the control of software during three-dimensional printing. This "4D printing" (3D printing and the time factor) is certainly a key to optimizing the personalization of prostheses and orthotics and promoting hybridization with the body. Its potential is the basis for engineering these niches that are conducive to the regeneration of tissues, and even organs in the long term.
The systematic introduction of time introduces a final concept that is at the forefront of our knowledge. This is the fate of regenerated tissue. We can see that the fate of healed tissues is often not optimal, in view of their initial function, even if the body has duly done its emergency work. Tissue growth must be rapid, otherwise other mechanisms (inflammation, infection) will take place. Tissue growth must be objectified: a nerve must give back a nerve. Growth must be limited: cells must die or stop growing at the wound front, often by invoking this programmed death mechanism called apoptosis. Growth must be evolutionary: the initial information transmitted to the cells must either evolve or be interpreted differently by the cells. This is where epigenetic mechanisms will come into play. The aim is to ensure that the piece of tissue or organ under construction evolves into a complete and functional whole.
If the initial niche information provided is translated by the genes into an initial program of cell growth and differentiation, the evolution of the environment will regulate this action over time. This epigenetics, around genetics, involves mechanisms that are far from being understood and are the subject of exciting research. An important driver of epigenetic regulation is the mechanical environment of tissues. The softness of a liver has nothing to do with the elasticity of blood vessels and skin or the hardness of a ligament or bone. This biomechanical factor has become essential in the modelling of prostheses, orthoses and even environmental niches favourable to regeneration.
In summary, partial regeneration of the body is the subject of numerous studies that are already being translated clinically. However, there is much to be done, as there is so much hope, such as that of regenerating the nerves in the quadriplegic patient. But what was unthinkable a few decades ago is becoming a realistic goal. Only time will tell if it is achievable. The liver could lose its regenerative singularity inscribed in the myth of Prometheus. As for the regeneration of the whole human being, not even the salamander is capable of it. For the time being.
Pascal SommerBiologist at the Institute of Movement Sciences (CNRS/Aix-Marseille University), National Centre for Scientific Research (CNRS)