Neurorehabilitation research

In the field of rehabilitation, neurological disorders (traumatic brain injury, stroke, spinal cord injury, polyneuropathies and other neurological pathologies) are those requiring the greatest number of interventions and, moreover, of an intensive type (according to a recent survey in the USA, they account for 80% of admissions for rehabilitation treatment). Due to the urgent need to respond to the growing demand for care, in recent years rehabilitation medicine has begun to place great emphasis on the development of translational research, focusing on evidence-based medicine.

In recent years, different strategies have been developed in the area of cell transplantation that have opened up new possibilities for exploring in depth the mechanisms of recovery from Central Nervous System (CNS) lesions. Spinal cord injury, as one of the most serious events that a person can suffer throughout his or her life in an abrupt and unannounced manner, represents a good model for analyzing the possible mechanisms of neuronal recovery. The three fundamental problems associated with spinal cord injury are secondary neuronal death, the formation in the area of injury of an environment inhibitory to axonal regeneration, and the formation of a glial scar. Currently, several reparative strategies are being tested with the aim of reducing the damage caused by the 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 the last two decades, different preclinical tests on cell transplantation in the spinal cord injury model have been performed. Various types of cells have been tested according to their myelin formation potential, how to promote axonal growth, or how to create bridges that overcome the focus of injury. It has also 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 medulla. What is clear is that the possible beneficial effects of cell therapies will be multifactorial and cannot be attributed to a single mechanism.

We have reviewed in the literature the different trials published with cell transplants, both at a basic level, with experimental animals, and in humans, which present great variability and limitations, since, at present, 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 of a small quantity of cells in suspension through multiple injections at the site of the lesion or close to it. Other forms of administration that have been tried are the introduction of these same cells through the intrathecal or systemic route, with very questionable results, however. 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 have been few investigations in chronic models, due to the difficulty of keeping the animals alive after causing a severe spinal cord injury. In contrast to 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.

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With cell transplants, we see that the most commonly 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 will be needed to obtain good or acceptable results. In relation to Schwann cells, they are probably the most studied.

They are myelin-forming cells of the peripheral nervous system and have been shown not only to be able to remyelinate axons after transplantation into the spinal cord, but also to form a substrate that allows some axonal regeneration. The beneficial effects after transplantation in experimental animals are well known; the first investigations date back to 1981 with the work of Duncan. From then until now, most research has been carried out in adult mice and the possibility of using them in combination with neuroprotective drugs or growth factors has been postulated.

The clinical translation of this work to humans is still difficult and many more preclinical trials are needed to demonstrate the potential benefits of the technique before it can be tested in humans. Olfactory bulb ensheathing glia cells have represented a promising avenue of research, although it is known that, depending on their origin, nerve or mucosa, the results have been very different, as well as depending on the culture conditions. The published results, at the level of basic experimentation, have been very interesting; however, their replication in humans has been highly questioned.

In relation to this avenue of research, it is worth mentioning the work published by the Lima group, in Portugal, with neurological improvements in 11 of 20 chronic patients (with more than 18 months of evolution). The criticisms that this work has received from groups of independent experts, together with the different results published in the literature at a basic level, mean that this type of cells, although they represent a good avenue for research, their transfer to humans is viewed with certain caution, given the discrepancies in the results and the difficulty in repeating the neurological improvements achieved by some authors. As we can see, only one study has been published with olfactory bulb ensheathing glia cells in patients with chronic spinal cord injury, and more are needed to be able to demonstrate whether they are safe and effective.

Another very interesting avenue is the use of progenitor cells, which have shown a relevant capacity to integrate into the spinal cord and achieve, in most studies in rodents and in larger animals, functional improvements that make them a good model for transplantation. The fear in these cell lines is the risk of generating the formation of teratomas, tumors. In this regard, the FDA (Food and Drug Administration) authorized for the first time, in May 2008, the American laboratory GERON, a Phase I trial in 8 patients with acute spinal cord injury, of embryonic cells derived from oligodendrocyte precursors. The first cell transplantation in a patient with acute spinal cord injury using this type of embryonic cell was performed in October 2010. Unfortunately, the research was suspended last November due to lack of funding, although it is to be hoped that, in the near future, some other research group will recover this avenue of work. Of the four patients who received these cells, none of them presented serious adverse effects, but none of them experienced any neurological change.

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Finally, we would like to comment on the transplantation or use of mesenchymal cells in patients with severe neurological lesions. Stromal cells, isolated from bone marrow after separation of the hematopoietic fraction, have great properties to survive, integrate and differentiate into neural cells in models of spinal cord injury. This type of transplantation, due to its low side effects, has been tested in different types of injury, cranioencephalic trauma, stroke and spinal cord injury. In the literature, there are many studies in basic research, both in rodents, pigs and primates, where favorable results are presented in many of them.

In relation to their translational perspectives, transplants with mesenchymal cells, due to their high safety, have been tested in humans, although the studies are in cohorts of few cases, using uncharacterized mixtures and, in most cases, uncontrolled trials. In short, these are grafts with a type of cells that has been widely studied, but the integration of the cells at the site of the spinal cord injury is scarce, the differentiation into neural cells is not convincing and, many times, the cultures that we implant contain a large number of subpopulations of mesenchymal cells.

Regenerative medicine, today, is one of the most fascinating lines for researchers, as it represents a great potential to create possible bridges across the site of neurological injury and, in turn, to promote axonal regeneration. The growing interest in the efficacy of stem cell transplantation in all parts of the world is a reality. Clinicians and patients are calling for more rapid development of transnational medicine. Announcements such as the FDA’s approval of the use of embryonic stem cells in the acute phase of spinal cord injury created great excitement, although, as always in these cases, one must be extremely cautious and weigh the advantages and disadvantages of using these techniques.

Do these transplants survive, do they integrate at the site of the lesion 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 its usefulness in changing the functional prognosis of a patient with a central nervous system injury, and taking into account the many attempts being made in different parts of the world in recent decades to find an effective solution, and in the face of the growing demand of the affected group that often finds supposed “miraculous” solutions far from scientific rigor, often encouraged by inaccurate and self-serving information, the role we have to offer as expert clinicians in neurorehabilitation is to provide an answer to the question of what can be done to change the functional prognosis of a patient with a central nervous system injury, The role we must offer as expert clinicians in neurorehabilitation is to provide a response based on scientific rigor and an 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.

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Finally, the role of neurorehabilitation in research (clinical specialty dedicated to restoring, minimizing and/or compensating the functional alterations that appear after an injury or disease of the nervous system) should be mentioned. 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 (the capacity of neurons to adapt their activity and even their morphology to alterations in the environment and the pathways they use after CNS injury); spontaneous functional recovery and neuronal repair (interventions carried out on neuronal circuits with the aim of restoring 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 neuroprostheses to replace functions lost after CNS injury or disease.

If we analyze publications in journals indexed in medicine, the terms “rehabilitation” and “evidence-based medicine” do not appear in articles until 1994. From then until 2003, their overlap increased by 25.5 times. The term “neurorehabilitation” only appeared in an average of 10 articles per year until 1994; from that date until 2003, the annual number of articles indexed in Medlinea increased 9.4 times. During the same period, the number of articles on “neuroplasticity” or “regeneration” and “physical rehabilitation” increased 7.6 times. At the same time, 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 rehabilitation model that is patient-centered, personalized (that adapts procedures to the characteristics and needs of each patient), ubiquitous (that integrates rehabilitation services into the patient’s daily life), objective (with technologies and services that help in decision-making), evidence-based (that combines clinical experience with basic and clinical systematic research findings), open to learning (that facilitates the generation of knowledge), effective (that allows treatment to be maintained with sufficient intensity and intensity, and that allows treatment to be maintained at a sufficiently high level of intensity and with a high degree of efficiency, evidence-based (combining clinical experience with the findings of basic and clinical systematic research), open to learning (facilitating the generation of knowledge), effective (allowing treatment to be maintained with sufficient intensity and for the necessary period of time), with greater scope (increasing the number of patients who can benefit from the system), and sustainable (balancing cost and quality of life). of the service and the available resources).