The research in neurorehabilitation

In the field of rehabilitation, neurological disorders (traumatic brain injury, stroke, spinal cord injury, polyneuropathies and other neurological diseases), are those that require more interventions and, in addition, intensive (according to a survey recent in the United States, represent 80% of the income for rehabilitation treatment). Due to the urgent need to respond to the growing demand for care, in recent years, rehabilitation medicine has begun to give great emphasis to the development of translational research, focusing on evidence-based medicine.

In recent years, different approaches have been developed in the cellular transplants section that have opened new possibilities to deepen the mechanisms of recovery of lesions of the Central Nervous System (CNS).. Spinal cord injury, as one of the most serious events that a person can suffer throughout his life in an abrupt and unannounced way, represents a good model for analyzing the possible mechanisms of neuronal recovery. The three fundamental problems associated with spinal cord injuries are the secondary neuronal death, formation in the injury zone of an inhibitory environment of axonal regeneration and the formation of a glial scar. Currently, various repair strategies are being tested in order to reduce the damage caused by secondary injury (neuroprotection) or to enhance the regenerative capacity of the injured central neurons, trying to partially restore the functions abolished after the injury.

During these last two decades, different preclinical examinations have been carried out on cellular transplants in the model of spinal cord injury. Several types of cells have been tested based on their potential for myelin formation, how to promote axonal growth, or how to create bridges that overcome the focus of injury. Likewise, it has been seen that many of the applied cells have the capacity to secrete trophic factors, with neuroprotective effects, capable of promoting neuroplasticity phenomena in the injured patient.. What is clear is that the possible beneficial effects of cell therapies will be multifactorial and that they can not be attributed solely to a single mechanism.

The different published trials with cellular transplants have been reviewed in the literature, both at the basic level, with experimental animals, and in humans, which present great variability and limitations, since, today, there is still no consensus among the different research groups on the methodology to be used, the type of cells, the profile of the subjects to be transplanted, the benefits and risks of the technique, etc.

Most of the transplants used are based on the direct application at the site of the injury or close to it of a small amount of cells in suspension through multiple injections. Other forms of administration that have been tried are the introduction of these same cells through the intrathecal or systemic route, with results, however, very questionable. With few exceptions, in the model of spinal cord injury in small animals, such as experimental mice, they have been transplanted in the acute phases, during the first or second week after the injury, and there are few investigations in chronic models, because to the difficulty of keeping the animals alive after provoking a serious spinal injury. Unlike what happens in humans, where the studies carried out in phases I and II, are trials in chronic patients with more than one year of evolution and, therefore, the possible benefits of these techniques are more difficult to observe.

With cellular transplants, we see that the most used types are: Schwann cells, olfactory bulb cells, progenitor cells (adult or embryonic) and mesenchymal cells.. The advantages and disadvantages of each implant are known and it is likely that, in the end, a mixture of different cell lines is needed to obtain good or acceptable results. In relation to Schwann cells, they are probably the most studied.

These are cells of the peripheral nervous system, forming myelin, and it has been seen that not only are they capable of remyelinating axons after a transplant inside the spinal cord, but they form a substrate that allows some axonal regeneration. The beneficial effects after transplantation in experimental animals are well known; the first investigations are dated in 1981 with the works of Duncan. From then until now, most research has been conducted in adult mice and the possibility of using them in combination with neuroprotective drugs or with growth factors has been postulated.

The clinical translation to humans of these works is still difficult and many more preclinical trials are needed to demonstrate the possible benefits of the technique, before testing them in humans.. Olfactory bulb enveloping glia cells have represented a promising avenue of research, although it is known that, depending on the origin of the nerve or mucosa, the results have been very different, as well as depending on the conditions of the culture.. The published results, at the level of basic experimentation, have been very interesting; however, its replication in humans has been very questioned.

In relation to this research, highlight the work published by the group from Lima, in Portugal, with neurological improvements presented in 11 of 20 chronic injuries (more than 18 months of evolution). The criticisms that this work has received from independent groups of experts, together with the different results published in the literature at the basic level, make this type of cells, although they represent a good research channel, with a certain prudence. transfer to humans, considering the discrepancies in the results and the difficulty in repeating the neurological improvements achieved by some authors. As we can see, only one work with olfactory bulb envelope glia cells has been published in patients with chronic spinal cord injury and more is needed to really show if they are safe and effective.

Another very interesting way is the use of progenitor cells, which have demonstrated a relevant ability to integrate into the spinal cord and achieve, in the majority of studies in rodents and larger animals, functional improvements that make these a good model of transplantation. The fear in these cell lines is the risk of generating the formation of teratomas, tumors. In this regard, comment that, for the first time, the FDA (Food and Drug Administration) authorized, in May 2008, the American laboratoryGERON, an assay in 8 patients with an acute spinal cord injury, in Phase I, of embryonic cells derived from precursors of oligodendrocytes. The first cellular transplant in a patient with an acute spinal cord injury with this type of embryonic cells was carried out in October 2010. Unfortunately, the investigation was suspended last November due to lack of funding, although it is expected that, in the near future, another research group will recover this way of working.. Of the four patients who received these cells, none of them had serious adverse effects, but none of them experienced any neurological changes either.

Finally, comment on transplants or the use of mesenchymal cells in patients with severe neurological injuries. Stromal cells, isolated from the bone marrow after separating the hematopoietic fraction, have great properties of surviving, integrating and differentiating into neural cells in models of spinal cord injury. This type of transplants, due to its few side effects, has been tried in different types of injury, head trauma, stroke and spinal cord injury. In the literature, there are many works in basic research, both in rodents, pigs and primates, where they are presented, in many of them, favorable results.

In relation to their translational perspectives, transplants with mesenchymal cells, due to their high safety, have been tested in humans, although the works are in a few cases cohorts, using uncharacterized mixtures and, in most cases, uncontrolled trials.. In short, these are grafts with a cell type widely studied, but the integration of the cells in the place of spinal cord injury is scarce, does not convince the differentiation in neural cells and, often, the cultures that we implant contain large number of sub-populations of mesenchymal cells.

Regenerative medicine, today, is one of the most fascinating lines for researchers, since it represents a great potential to create possible bridges that cross the site of neurological injury and that favor, in turn, axonal regeneration. The growing interest in the effectiveness of stem cell transplants in all parts of the world is a reality. Clinicians and patients advocate for a more rapid development of transnational medicine. Announcements such as the authorization by the FDA of the use of embryonic stem cells in the acute phase of spinal cord injuries created a great expectation, although, as always in these cases, we must be extremely cautious and value the advantages and disadvantages represented by the use of these techniques.

Do these transplants survive? Do they integrate at the site of the injury or migrate to other parts? How do they influence the cellular environment surrounding the lesion? In the absence of any proven strategy in the field of regenerative medicine that has proven useful for changing the functional prognosis of a patient with a central nervous system lesion, and taking into account the many attempts that are being made in different places of the world, in these last decades, to find an effective solution, and in front of the increasing demand, of the affected group that, often, finds supposed "miraculous" solutions far from the scientific rigor, often encouraged by an information imprecise and interested, the role we must offer as clinical experts in neurorehabilitation is to provide an answer based on scientific rigor and active commitment to promote the translation of new advances in cellular engineering applied to the treatment of spinal cord injury and Acquired brain damage, as soon as possible.

Finally, comment on the role of neurorehabilitation in research (clinical specialty that is dedicated to restore, minimize and / or compensate for the functional alterations that appear after an injury or disease of the nervous system). This discipline has intensified research in two areas of basic science accepted by the entire scientific community as essential elements in the understanding of functional recovery: neuroplasticity (ability of neurons to adapt their activity and even their morphology to alterations of the environment and the routes used after an injury to the CNS); spontaneous functional recovery and neuronal repair (interventions performed on neuronal circuits in order to restore them, non-spontaneous functional recovery).

Neurorehabilitation has a basic role in the investigation of the possible mechanisms involved in neuroplasticity, through neuroimaging technology, neurophysiological studies with electrical and magnetic potentials, non-invasive brain stimulation, etc.. In the field of neural repair, neurorehabilitation includes all therapies related to axonal regeneration, cell and tissue transplants to replace lost neurons, as well as the use of neuroprosthetics to replace functions lost after injury or CNS disease.

If we analyze publications in journals indexed in medicine, the terms "rehabilitation" and "evidence-based medicine" do not appear in articles until 1994. Since then and until 2003, their coincidence increased by 25.5 times. The term "neurorehabilitation" only appeared in an average of 10 articles per year until 1994; from this date until 2003, the annual number of articles indexed in Medline increased 9,4 times. During that same period, the number of articles on "neuroplasticity" or "regeneration" and "physical rehabilitation" increased 7.6 times. In parallel, during the last few years, the technology industry has shown great interest in occupying the "emerging market" of neurorehabilitation, with an exponential increase in patents, without reaching, for the moment, the effect observed in other fields of medicine such as cardiology, nephrology, oncology, traumatology or medical imaging.

Technological advances, complemented by regenerative medicine, will play a fundamental role in the necessary evolution of rehabilitation towards a patient-centered, personalized rehabilitation model (that adapts the procedures to the characteristics and needs of each patient), ubiquitous ( that integrates rehabilitation services into the daily life of the patient), objective (with technologies and services that help decision-making), based on scientific evidence (that combines clinical experience with the findings of basic and clinical systematic research ), open to learning (that facilitates the generation of knowledge), effective (that allows to maintain the treatment with sufficient intensity and during the necessary period of time), with greater scope (that allows to increase the number of patients who can benefit from the system) and sustainable (that there is a balance between the cost of the service and the available resources). is). MR