After single injection, paralyzed animals regained ability to walk within four weeks.
Northwestern University researchers have developed a new injectable therapy that harnesses “dancing molecules” to reverse paralysis and repair tissue after severe spinal cord injuries.
In a new study, researchers administered a single injection to tissues surrounding the spinal cords of paralyzed mice. Just four weeks later, the animals regained the ability to walk.
The research will be published in the November 12, 2021, issue of the journal Science.
By sending bioactive signals to trigger cells to repair and regenerate, the breakthrough therapy dramatically improved severely injured spinal cords in five key ways: (1) The severed extensions of neurons, called axons, regenerated; (2) scar tissue, which can create a physical barrier to regeneration and repair, significantly diminished; (3) myelin, the insulating layer of axons that is important in transmitting electrical signals efficiently, reformed around cells; (4) functional blood vessels formed to deliver nutrients to cells at the injury site; and (5) more motor neurons survived.
After the therapy performs its function, the materials biodegrade into nutrients for the cells within 12 weeks and then completely disappear from the body without noticeable side effects. This is the first study in which researchers controlled the collective motion of molecules through changes in chemical structure to increase a therapeutic’s efficacy.
A simple animation shows how a single injection restores connections in the nervous system below the site of a severe spinal cord injury. Credit: Samuel I. Stupp Laboratory/Mark Seniw/Northwestern University
“Our research aims to find a therapy that can prevent individuals from becoming paralyzed after major trauma or disease,” said Northwestern’s Samuel I. Stupp, who led the study. “For decades, this has remained a major challenge for scientists because our body’s central nervous system, which includes the brain and spinal cord, does not have any significant capacity to repair itself after injury or after the onset of a degenerative disease. We are going straight to the FDA to start the process of getting this new therapy approved for use in human patients, who currently have very few treatment options.”
Stupp is Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he is founding director of the Simpson Querrey Institute for BioNanotechnology (SQI) and its affiliated research center, the Center for Regenerative Nanomedicine. He has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences, and Feinberg School of Medicine.
A paralyzed mouse (left) drags its hind legs, compared to a paralyzed mouse that has regained its ability to move its legs after receiving Northwestern’s injectable therapy. Credit: Samuel I. Stupp Laboratory/Northwestern University
Life expectancy has not improved since the 1980s
According to the National Spinal Cord Injury Statistical Center, nearly 300,000 people are currently living with a spinal cord injury in the United States. Life for these patients can be extraordinarily difficult. Less than 3% of people with complete injury ever recover basic physical functions. And approximately 30% are re-hospitalized at least once during any given year after the initial injury, costing millions of dollars in average lifetime health care costs per patient. Life expectancy for people with spinal cord injuries is significantly lower than people without spinal cord injuries and has not improved since the 1980s.
“I wanted to make a difference on the outcomes of spinal cord injury and to tackle this problem, given the tremendous impact it could have on the lives of patients.”
— Samuel I. Stupp, materials scientist
“Currently, there are no therapeutics that trigger spinal cord regeneration,” said Stupp, an expert in regenerative medicine. “I wanted to make a difference on the outcomes of spinal cord injury and to tackle this problem, given the tremendous impact it could have on the lives of patients. Also, new science to address spinal cord injury could have impact on strategies for neurodegenerative diseases and stroke.”
‘Dancing molecules’ hit moving targets
The secret behind Stupp’s new breakthrough therapeutic is tuning the motion of molecules, so they can find and properly engage constantly moving cellular receptors. Injected as a liquid, the therapy immediately gels into a complex network of nanofibers that mimic the extracellular matrix of the spinal cord. By matching the matrix’s structure, mimicking the motion of biological molecules and incorporating signals for receptors, the synthetic materials are able to communicate with cells.
“Receptors in neurons and other cells constantly move around,” Stupp said. “The key innovation in our research, which has never been done before, is to control the collective motion of more than 100,000 molecules within our nanofibers. By making the molecules move, ‘dance’ or even leap temporarily out of these structures, known as supramolecular polymers, they are able to connect more effectively with receptors.”
Nanofibers containing molecules that bear two different bioactive signals (green and orange) more effectively engage cell receptors (yellow and blue) as a result of the molecules’ fast motion. Credit: Samuel I. Stupp Laboratory/Mark Seniw/Northwestern University
Stupp and his team found that fine-tuning the molecules’ motion within the nanofiber network to make them more agile resulted in greater therapeutic efficacy in paralyzed mice. They also confirmed that formulations of their therapy with enhanced molecular motion performed better during in vitro tests with human cells, indicating increased bioactivity and cellular signaling.
“Given that cells themselves and their receptors are in constant motion, you can imagine that molecules moving more rapidly would encounter these receptors more often,” Stupp said. “If the molecules are sluggish and not as ‘social,’ they may never come into contact with the cells.”
One injection, two signals
Once connected to the receptors, the moving molecules trigger two cascading signals, both of which are critical to spinal cord repair. One signal prompts the long tails of neurons in the spinal cord, called axons, to regenerate. Similar to electrical cables, axons send signals between the brain and the rest of the body. Severing or damaging axons can result in the loss of feeling in the body or even paralysis. Repairing axons, on the other hand, increases communication between the body and brain.
The second signal helps neurons survive after injury because it causes other cell types to proliferate, promoting the regrowth of lost blood vessels that feed neurons and critical cells for tissue repair. The therapy also induces myelin to rebuild around axons and reduces glial scarring, which acts as a physical barrier that prevents the spinal cord from healing.
“The signals used in the study mimic the natural proteins that are needed to induce the desired biological responses. However, proteins have extremely short half-lives and are expensive to produce,” said Zaida Álvarez, the study’s first author. “Our synthetic signals are short, modified peptides that — when bonded together by the thousands — will survive for weeks to deliver bioactivity. The end result is a therapy that is less expensive to produce and lasts much longer.”
A former research assistant professor in Stupp’s laboratory, Álvarez is now a visiting scholar at SQI and a researcher at the Institute for Bioengineering of Catalona in Spain.
While the new therapy could be used to prevent paralysis after major trauma (automobile accidents, falls, sports accidents and gunshot wounds) as well as from diseases, Stupp believes the underlying discovery — that “supramolecular motion” is a key factor in bioactivity — can be applied to other therapies and targets.
“The central nervous system tissues we have successfully regenerated in the injured spinal cord are similar to those in the brain affected by stroke and neurodegenerative diseases, such as ALS, Parkinson’s disease and Alzheimer’s disease,” Stupp said. “Beyond that, our fundamental discovery about controlling the motion of molecular assemblies to enhance cell signaling could be applied universally across biomedical targets.”
Reference: “Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury” by Z. Álvarez, A. N. Kolberg-Edelbrock, I. R. Sasselli, J. A. Ortega, R. Qiu, Z. Syrgiannis, P. A. Mirau, F. Chen, S. M. Chin, S. Weigand, E. Kiskinis and S. I. Stupp, 11 November 2021, Science.
Other Northwestern study authors include Evangelos Kiskinis, assistant professor of neurology and neuroscience in Feinberg; research technician Feng Chen; postdoctoral researchers Ivan Sasselli, Alberto Ortega and Zois Syrgiannis; and graduate students Alexandra Kolberg-Edelbrock, Ruomeng Qiu and Stacey Chin. Peter Mirau of the Air Force Research Laboratories and Steven Weigand of Argonne National Laboratory also are co-authors.
The study, “Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury,” was supported by the Louis A. Simpson and Kimberly K. Querrey Center for Regenerative Nanomedicine at the Simpson Querrey Institute for BioNanotechnology, the Air Force Research Laboratory (award number FA8650-15-2-5518), National Institute of Neurological Disorders and Stroke and the National Institute on Aging (award numbers R01NS104219, R21NS107761 and R21NS107761-01A1), the Les Turner ALS Foundation, the New York Stem Cell Foundation, the Paralyzed Veterans of America Research Foundation (award number PVA17RF0008), the National Science Foundation and the French Muscular Dystrophy Association.
I’m hopeful for uses for people who are NOT paralyzed. People like me who have degenerative disk disease and the spine is literally falling apart. Also I have significant scar tissue. This sounds great!
What I need to know is if this would be effective on individuals with old injuries, like 20 years old. Please answer. Thank you.
I was wondering the same thing???
Would this also help people with MS?
Wow, I am a retired Special Agent, who was shot in 1971, damaging, but not severing the spinal cord at L1-2. I have been using long leg braces and crutches for mobility for the last 50 years and continue to do so to date. Should a need for volunteer patients ever exist, I would be happy to volunteer. Any improvement would be a gift.
Would this help people with Stiff Person syndrome?
I’m a speech Pathologist who works with the elderly, many who have spinal chord issues from a variety of reasons. This application holds such promise.
What about conditions like spina bifida? Are these individuals able to volunteer for trials and how do they sign up for trials?
Thats great. Glad to hear spinal injurys may soon have a treatment available. I wonder if the same type of treatment could be used on diminished and crushed disk as my father lives in constant back pain.
I would to see my mother walk again or maybe with just a walker she deserves it she was a hard worker never in trouble and took good care of her family
I was in an auto accident and my break is to my T12-L1 with spinal chord injury. Paralyzed below break. I live in constant nerve pain in both legs and feet. The pain level never goes below a 6/u and I have frequent days of 9/10 level pain. I go to a pain clinic but get no relief. Currently I am takong percocet 10mg and Lyrica 200mg three time daily. I usually have to go to ER at least once weekly for relief which is short lived. I am a 31 year old male and I really am desperate for some relief.
I had a Retroperitoneal groin injury from a blood clot from a PICC line which has left my left leg severely damaged and I would love to be a volunteer test subject!
Iam interested to learn if is a potential cure for neuropathy!
wow this sounds exactly like the repair nanotech in Travelers and the nanomachines in the Metal Gear series. it’s god tier science.
I to would like to know if help me can’t get doctors do anything after drunk driver almost killed me 21 years ago.still to this day I have excruciating pain in back numbness n tingling through out body I need help I was 39 at time,
Would this work if they took out part of spine an replace with rod an screws.? An about MS patient with nerve damage and not able to use limbs?
My wife broke her neck 5 years ago in a horse accident. She is now walking with a numb leg. Both of her legs a numb fro the knee down and both hands from the elbow to the fingers. She has severe nerve pain. Do you think this could help her.
My husband has transverse myolitis and has problems because his left leg is effected and drags. Would this help him?
Can this be used for the Cauda Equina Syndrome? I have this and know many others who do as well, world wide. I am literally crying from reading this discovery, to even think there’s a glimmer of hope! After 15 years of this nightmare, it’d be BEYOND a blessing, to be rid of the paralysis in the bowels and bladder areas.
I was involved in a motorcycle accident. So far I have had 2 neck surgeries and 2 back surgeries. I continue to have peripheral neuropathy on my left leg due to nerve damage (foot drop).I would be very interested in getting an injection to possibly repair my nerve(s),
I’ll sign up for the testing
I would do anything to try this! I hope the FDA gives them the green light to get this into clinical trials. This brings so much hope to us spinal cord patients looking for some kind of answer.
I have cerrabellar ataxia. Will this help me and how long? My neurologist is Dr Ralph Pagano, a graduate of NW.
Second request. I have cerrabellar ataxia diagnosed 15 yrs ago. In excellent health. Would this procedure help me. My neurologist is interested in your answer. I live in Sun City AZ. Please advise.
I am from India waiting for this treatment soon in India for my 23yr daughter who is spinal cord injury patient. Want to see her walking LIKE before.. praying for green signal from FDA
My brother is in a similar situation with injury in L2. He is paralyzed for last 30 years. It will be perfect if he can walk again. Looking forward.
Third request. Would this help cerrabellar ataxia. I was diagnosed 15 yrs ago by Mayo Clinic Scottsdale AZ.
I WILL VOLUNTER FOR THE CLINICAL TESTS. i AM IN MEMPHIS, TN. i HOPE WE CAN FAST TRACK THIS PROCESS. PLEASE CONTACT ME
I would love to know when this is approved for I have used Stem cells w/ Umbilical cord w/ Bone Marrow to repair my hip joint of Acetabular ball and socket.
The procedure was went well however; the right side New Hip is nerves were damaged have numbness.
Notable: Have had Fusion C-5 and have Degenerative Disc disease and still able to exercise on my bike.
Very frustrating with Degenerative Disc and have been exercising All my life on daily bases!
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