Northwestern University researchers developed an injectable therapy that uses "dancing molecules", which can reverse paralysis or repair damaged tissue following severe spinal cord injuries.
Researchers administered one injection to the tissues surrounding paralyzed mice's spinal cords in a new study. The animals were able to walk again four weeks later.
Science will publish the research in its Nov. 12 issue.
This breakthrough therapy uses bioactive signals to stimulate cells to heal and regenerate. It dramatically improves severely injured spinal cords in five ways. (1) The axons were regenerated. (2) Scar tissue, which can be a barrier to healing and repair, was significantly reduced. (3) Myelin, an insulating layer that aids in transmitting electrical signals efficiently, was reformed around the cells. (4) Functional blood vessels were formed to supply nutrients to the injured cells. (5) More motor neurons survived.
The therapy works by converting the materials into nutrients that are used in the cells. After 12 weeks, they completely disappear from the body. Researchers have controlled the collective motions of molecules using changes in the chemical structure to improve therapeutic efficacy. This is the first time this has been done.
Northwestern's Samuel I. Stupp led the research. He stated, "Our research aims at finding a therapy to prevent individuals becoming paralyzed following major trauma or disease." This has been a problem for scientists for decades. Our central nervous system (brain and spinal cord) is not able to heal itself from injury or the onset degenerative diseases. This new therapy will be approved by the FDA for human use. Human patients have limited treatment options.
Stupp is Board of Trustees Professor of Materials Science and Engineering and Chemistry, Medicine and Biomedical Engineering. He is also the founding director of the Simpson Querrey Institute for BioNanotechnology, (SQI), and its associated research center, The Center for Regenerative Nanomedicine. He holds appointments at the McCormick School of Engineering and Weinberg College of Arts and Sciences, as well as the Feinberg School of Medicine.
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Since the 1980s, life expectancy has not increased.
The National Spinal Cord Injury Statistical Center estimates that nearly 300,000. Americans are living with a spinal injury. These patients face a difficult life. Only 3% of those with severe injuries ever regain basic bodily functions. A staggering 30% of patients with complete injuries are hospitalized again within a year. This adds up to millions in lifetime healthcare costs. The life expectancy of people with spinal cord injuries has been significantly lower than that of people without them, and it has not improved since 1980.
"Currently, there is no therapy that triggers spinal cord regeneration," stated Stupp, a specialist in regenerative medicine. "I wanted to make an impact on spinal cord injury and tackle this issue, considering the huge impact it could have on patients' lives. New science could help to treat spinal cord injury and improve strategies for stroke prevention and neurodegenerative diseases.
"Dancing molecules" hit moving targets
Stupp's breakthrough therapeutic involves tuning the motions of molecules so that they can properly engage constantly moving cell receptors. The therapy is injected as a liquid and immediately gels into complex networks of nanofibers, which mimic the extracellular matrix in the spinal cord. The synthetic materials can communicate with cells by matching the structure of the matrix, mimicking biological molecules' motions and incorporating signals for receptors.
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Stupp stated that receptors in neurons and other cells are constantly moving around. Our research is unique in that we control the collective motions of over 100,000 molecules within our nanofibers. They can connect with receptors more effectively by making molecules move, dance, or leap temporarily from these structures (also known as supramolecular polmers).
Stupp and his colleagues found that fine-tuning molecules' motions within the nanofiber network, to make them more agile, resulted in greater therapeutic efficacy for paralyzed mice. In vitro testing with human cells confirmed that their therapy formulations with enhanced molecular movement performed better, which indicates increased bioactivity.
"Given the fact that cells and their receptors are constantly in motion, it is easy to imagine that molecules moving faster would encounter these receptors more often," Stupp stated. "If molecules are slow and not as social, they might never come in contact with cells."
One injection, two signals
The moving molecules are connected to the receptors and trigger two cascading signaling events, which are both crucial for spinal cord repair. The other signal causes the long tails (or axons) of spinal cord neurons to regenerate. Axons transmit signals to the brain, much like electrical cables. Axon damage or severing can lead to paralysis or loss of sensation. Restoring axons can increase communication between the brain and body.
This second signal is important for neurons to survive injury. It causes other cell types and cells to proliferate, which promotes the regrowth blood vessels that supply neurons and vital cells for tissue repair. Therapy also causes myelin to build around axons, and decreases glial scarring. This acts as a physical barrier to prevent the spinal cord's healing.
"The signals used in this study mimic natural proteins needed to trigger the desired biological reactions." Zaida Alvarez (the study's first author, and former research assistant professor at Stupp's lab) said that proteins are very expensive to make and have short half-lives. "Our synthetic signals, which are modified peptides with short chains that can be bonded together in thousands to provide bioactivity, will last for several weeks. This therapy is cheaper to make and lasts longer.
Universal applicability
The new therapy can be used to prevent paralysis from major trauma (automobile accidents/falls, sports accidents or gunshot wounds), as well as diseases. However, Stupp believes that the fundamental discovery of "supramolecular movement" as a key factor for bioactivity, can be applied to other therapies.
"The injured spinal cord tissues of the central nervous system that we successfully regenerated are very similar to the brains affected by stroke, neurodegenerative diseases and such as ALS, Parkinson’s disease, and Alzheimer's," Stupp stated. "Our fundamental discovery regarding controlling cell signaling by molecular assemblies could be used to improve cell signaling across all biomedical targets.
Evangelos Kiskinis (assistant professor of neurology in Feinberg); Feng Chen, research technician; postdoctoral scientists Ivan Sasselli and Alberto Ortega; and Stacey Chin, graduate student Alexandra Kolberg–Edelbrock and Ruomeng Qiu are also Northwestern study authors. Steven Weigand from Argonne National Laboratories and Peter Mirau from the Air Force Research Laboratories are also co-authors.
The study was funded by the Louis A. Simpson and Kimberly K. Querrey Center for Regenerative Nanomedicine at Simpson Querrey Institute for BioNanotechnology.
Video of severe spinal cord injuries repaired: https://www.youtube.com/watch?v=Q_xvCE904YU
