The actor in the Hollywood movie before I Met You was a top business acquisition expert and adventure sports expert, but a traffic accident caused a severe spinal cord injury, leaving him paralyzed from the head down, confined to a wheelchair, and a pneumonia could easily have killed him. He tried suicide, was rescued and then went to Switzerland for euthanasia, even though he fell in love with the woman who cared for him.
Diseases like spinal cord injury can cause great pain and despair.
Spinal cord injury is the most serious complication of spinal cord injury, which can be caused by trauma (e.g. car accidents, falls), disease or degeneration (e.g. arthritis, cancer). Due to the integrity and continuity of the spinal cord is damaged, send and receive signals between the brain and other parts of the body’s cells and nerve damage, and the feeling of patients were below the injured area, motion, force and will be temporary or permanent changes in body function, so many tetraplegia or paraplegia patients may want to spend the rest of your life in a wheelchair, They were also two to five times more likely to die prematurely than those without spinal cord injury.
According to the World Health Organization, between 250,000 and 500,000 people worldwide suffer spinal cord injuries each year. With the current medical technology, there is no effective treatment to reverse the neurological damage of patients with spinal cord injury, and the prevention, treatment and rehabilitation of such diseases are still difficult problems in the medical field.
But that may change in the near future. Earlier this month, a team at the Sagol Center for Regenerative Biotechnology at Tel Aviv University in Israel published a study in The scientific journal Advanced Materials in which they artificially synthesized 3D human spinal cord tissue from human cells and Materials and implanted it into paralyzed mice.
This is the first time in the world to transplant spinal cord tissue from human cells, and achieved good results: the recovery success rate of acute experimental model (short-term or short-term paralyzed mice) is 100%, and the recovery success rate of chronic experimental model (long-term paralyzed mice) is 80%.
The difficulty of spinal cord injury treatment lies in the limited ability of nerve self-repair. When spinal cord injury first occurs, the primary trauma that causes the injury results in cell death, a breakdown of the blood barrier, and degradation of the extracellular matrix (ECM), a network of macromolecules that affect cell metabolism, proliferation, and differentiation and provide a place for cells to survive and function.
This process can lead to secondary damage, which can lead to tissue damage and gelatinous scarring. Around the damaged area of healthy nervous tissue has the possibility to promote tissue repair, but due to the lack of scar allows the microenvironment of cell growth, cell inner growth potential is poorer, so once nerve is replaced by scar tissue damage, neurons lose regeneration and a chance to reconnect, may become permanent neurological dysfunction.
At present, the representative research directions for spinal cord injury treatment include neuroprotection, repair and regeneration, cell therapy and assistive technology. The idea of these studies may be to reduce the occurrence of further spinal cord damage, or promote the regeneration of neurons in the spinal cord and train the patient’s central nervous system. Among them, cell-based therapy, which can replace damaged cells according to cell type and state by utilizing the self-replication ability of cells, has become a representative strategy for the treatment of spinal cord injury.
Spinal cord injury can be treated in a variety of ways. These implanted cells are usually derived from allogeneic cells, autologous primary cells, or xenogeneic cells.
The isolation of cells from allogeneic or heterogeneic donors is influenced by factors such as donor age, genetics, donor deficiency, and depends on the patient’s immune response to achieve long-term results of transplantation. In addition, the method also faces problems of unsuccessful cell isolation and implantation due to immune rejection.
Primitive cells in order to overcome the risk of rejection, the self as an option, it is derived from the patient’s own immune response is small, but because of the need for patients before transplantation surgery and in vitro amplification, cost is higher, usually from self and central nervous system tissue cells, there may be separate and proliferation in vitro differentiation is difficult problem.
Tel aviv university’s latest research adopted induced pluripotent stem cells (iPSC), it takes advantage of gene editing techniques, also from the patients with autologous available, but is not limited the central nervous system tissue, but allowed to obtain from other organizations, these cells can be programmed to pluripotent cells, and then differentiated cells spectrum is required for patients.
“Our technique is a patient-specific treatment, and the idea is that it’s completely autogenous, using cells and materials from the patient’s own tissue, so it minimizes the risk of rejection.” “Lior Wertheim, a researcher at Sagol Regenerative Biotechnology Center and lead author of the study, told China Business News.
They first took biopsy tissue from the patient’s abdominal adipocytes, which are made up of cells and extracellular matrix. After isolating cells from the extracellular matrix, the researchers used genetic engineering to reprogram the cells back into a state similar to embryonic stem cells, which can “become” any cell in the body (iPSCs), or a more pluripotent state.
The iPSCs were then encapsulated in hydrogels (hydrophilic polymers) and differentiated effectively in a 3D-approved microbial environment, mimicking embryonic development of spinal cord tissue. After 30 days, the iPSCs were successfully transformed into 3D implants containing spinal cord motor neuron networks.
In theory, a hydrogel could be made by taking omental tissue cells — the “protective membrane” that covers the outside of human organs — from a patient and separating them from the extracellular matrix. However, due to the limited availability of human omentum, porcine omentum based hydrogel was used in this experiment. According to Professor Tal Dvir, head of the Sagol Center for Regenerative Biotechnology and lead researcher on the study, the ability to produce human omentum based hydrogels is now available and will soon be used in trials.
All the mice received spinal cord cell implants from three people. Six weeks of paralysis in mice is the equivalent of six months to a year of paralysis in humans. The breakthrough was to include chronically paralyzed mice.
Previous stem-cell-related research has been more limited to short-term paralysis – short-term models are generally easier to use but fail to provide effective treatment for more patients because they do not focus on long-term, permanent mechanisms of damage. “In patients with chronic paralysis, where the glial scar is fully developed at the site of injury, surgery is more complex, and patients are paralysed for longer periods of time, which can lead to tissue degeneration and longer recovery times, so long-term models are a better representation of the time frame in which treatment can be applied.” Wertheim says.
According to him, though the experiment has not been found to restore the exact mechanism of cells in mice, but in mice after transplant, from network of astrocytes and microglia injury on the lower expression of can see the obvious inflammation, the organization formed a more favorable environment, the number of neurons also increased significantly. “These manifestations ultimately translated into higher levels of behavioral function recovery in mice.”
Because the implants in the mice were derived from human cells, it also meant that the researchers did not have to go back to square one in preparation for clinical trials in humans. “This treatment is ultimately for humans, and it makes more sense to develop treatments using human cells. Using human cells eliminates the xenoimmune response in mice, and the potential for autologous transplantation in humans is greater.” Wertheim says,
With the development of exoskeleton robots, there are now exoskeleton-assisted robots for patients with paralysis, which detect the user’s intention through sensors and then drive the affected limb to move and carry out auxiliary training. Its main role is to take patients to move first to stimulate neural plasticity and other ways to start the rehabilitation process.
The exoskeleton robot can also continue to help patients with restraint training, using programmed movements to gradually increase the range of movements and the length of each training session. After the patient has recovered enough, the exoskeleton robot can further aid resistance training by exerting resistance in the opposite direction to build strength in the affected limb.
However, this does not mean that patients will eventually be able to live a normal life without the robot. The optimal outcome of such an approach would still be robot assisted movement, rather than a complete return to the life before paralysis.
The ultimate goal of the Tal Dvir team is to help spinal cord injury patients regain their ability to stand and even walk again.
In 2019, Dvir and a partner co-founded a company called Matricelf to conduct further experiments and possible commercialization of the study. Currently, ipSC-based therapies have not yet reached the commercial stage where biologics licensing applications (BLAs) have been submitted for market approval. “The company is currently in pre-clinical trials and hopefully will be in clinical trials within two to three years.” Dvir told China Business News magazine.
Dvir’s team is optimistic about the future of the technology. Although the research is still in its early stages, they believe that there are many more possibilities to explore. The technology could be used not only for spinal cord injuries, but also for diseases such as Parkinson’s disease, brain injury and myocardial infarction.
In the movie Before I Met You, the hero’s final farewell message to the heroine reads, “It’s a luxury to know you still have a chance.” Cutting-edge research, such as 3D spinal cord printing, is trying to make luxury “everyday”.
For human, regeneration of not only spinal cord, but also many organs and tissues is a difficult problem. Stem cells play an important role in tissue regeneration and become the foothold for many scientists to explore human tissue regeneration. The combination of cell therapy and genetic engineering, biomaterials and artificial intelligence will also make tissue regeneration more possible.
