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 Nov. 12 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.
“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.
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.
“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
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.”
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.
Through silver staining neurons, Ramon y Cajal discovered that peripheral nervous system (PNS) neurons regenerate after injury, contrasting the minor regenerative response of central spinal cord neurons (Ramon y Cajal, 1928). This then prompted the question: Do central nervous system (CNS) neurons lack the intrinsic capability of regeneration or are there extrinsic factors that influence this dichotomous observation?
In actuality, both of these factors come into play when spinal cord neurons are tasked with regenerating after axotomy. Several families of molecules present in the extracellular matrix (ECM) prevent axon growth including chondroitin sulphate proteoglycans (CSPGs), myelin‐associated molecules, ephrins and semaphorins (Miranda et al, 1999; Chen et al, 2000; Willson et al, 2002; Silver & Miller, 2004; Geoffroy & Zheng, 2014; Worzfeld & Offermanns, 2014).
Yet even when provided with a growth‐permissive environment, central neurons regenerate feebly compared to their peripheral or immature CNS counterparts, indicating that they also have intrinsic growth limiting factors (Hilton & Bradke, 2017). On the brighter side and nearly 100 years on from Cajal’s statement that “in adult centres, the nerve paths are something fixed, ended, immutable; everything may die, nothing may be regenerated” (Ramon‐Cueto et al, 1998), we now know this statement to be not entirely true.
Many research groups have reported axon regeneration and functional recovery after experimental spinal cord injury (SCI) following a variety of treatments (Thuret et al, 2006). While this is certainly a feat, many of the experimental approaches are problematic for clinical translation.
For those that are, it is also becoming increasingly apparent that addressing singular aspects of the problem won’t facilitate successful and functional regeneration after SCI in humans. Conversely, it will likely require the combination of various treatment strategies that address the variety of problems that result after SCI.
Many attempts have been made, to varying degrees of success, that combine tissue replacement, removal of inhibitory molecules, supplying neurotrophic factors, manipulation of pro‐regenerative neuronal signalling pathways and neurorehabilitation. This review will provide an update to the many therapeutic interventions after SCI and then will focus on the attempted combinatory approaches, how they could be improved and the road to their clinical translation.
SCI induces complex processes. SCI first leads to death of cells in the CNS, including neurons, astrocytes, microglia, oligodendrocytes and endothelial cells. In particular, the damage to long axonal projections leads to interruption of descending and ascending pathways that transmit information between the brain and the rest of the body.
Secondary damage from vascular changes, acute injury signalling, neuroinflammation, excitotoxicity, demyelination, degeneration, astrogliosis and ECM remodelling exacerbates the initial pathology (Hilton et al, 2017; Bradbury & Burnside, 2019). This unfolds as a temporal cascade of complex biological processes that can last months to years after the injury (Buss et al, 2004; Norenberg et al, 2004; Donnelly & Popovich, 2008). Some degree of spontaneous recovery is observed in experimental animal models and to a lesser extent in humans (Curt et al, 2008; Hilton et al, 2016). However, endogenous repair mechanisms are minor and recovery remains incomplete (Fawcett et al, 2007; Courtine et al, 2008). Based on the pathologies that result from SCI, researchers have identified several targets for the development of potential therapeutic interventions. These can be referred to as the “7 R’s” (Fig 1).
Figure 1 The seven targets for therapeutic interventions following spinal cord injury
A horizontal plane view through a region of thoracic spinal cord injury depicting some of the features of the pathology. SCI leads to immediate and continued death of neural alongside disruption of descending and ascending fibres. Seven therapeutic targets are present which can improve functional recovery after SCI: neuroprotective strategies to limit ongoing secondary damage resulting in spared tissue; tissue and cellular transplants to replace lost cells and may provide trophic or growth‐permissive environments; removal of inhibitory factors such as CSPGs to allow for enhanced axonal growth; targeting neuron‐intrinsic mechanisms to enhance intrinsic regenerative response which could then be directed through the resupply of trophic support; and remyelination of demyelinated axons may improve axonal conduction. Finally, rehabilitation to function in circuit remodelling and strengthens beneficial connections.
- 1Reduction of secondary damage (neuroprotection).
- 2Replacement of cells lost to primary and secondary damage.
- 3Removal of inhibitory molecules.
- 4Regeneration to enhance the spontaneous reparative and regenerative responses.
- 5Resupply of neurotrophic support to improve neuronal survival and direct axonal growth.
- 6Remyelination of regenerated, replaced or spared (demyelinated) axons.
- 7Rehabilitation strategies to induce neuroplasticity and/or to shape neuronal connections.
We will discuss these targets and their respective interventions in the following sections.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059014/
Original Research: Closed access.
“Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury” by Samuel Stupp et al. Science