Rats walk again after breakthrough spinal cord repair with 3D printed organoid scaffolds

Good news!

"... researchers developed a 3D-printed scaffold that directs stem cells to grow into functioning nerve cells, successfully restoring movement in rats with severed spinal cords. This promising technique could transform future treatment for spinal cord injuries. ..."

From the abstract:

"The transplantation of regionally specific spinal neural progenitor cells (sNPCs) has shown promise for functional restoration after spinal cord injury (SCI) by forming connections with host neural circuits.

Here, 3D-printed organoid scaffolds for transplantation using clinically relevant human induced pluripotent stem cell-derived regionally specific sNPCs is developed.

Scaffolds with microscale channels are printed, and sNPCs are subsequently printed within these channels. The scaffolds direct axonal projections along the channels and guide the cells to simulate in vivo-like conditions, leading to more effective cell maturation and the development of neuronal networks crucial for restoring function after SCI.

The scaffolds, with organoids assembled along their lengths, are transplanted into the transected spinal cords of rats. This significantly promotes the functional recovery of the rats.

At 12 weeks post-transplantation, the majority of the cells in the scaffolds differentiate into neurons and integrate into the host spinal cord tissue.

These results demonstrate their potential to create a relay system along the spinal cord and form synapses in both the rostral and caudal directions relative to the scaffold. It is envisioned that combining sNPCs, organoid assembly, and 3D printing strategies can ultimately lead to a transformative treatment approach for SCI."

Rats walk again after breakthrough spinal cord repair with 3D printing | ScienceDaily "Scientists have pioneered a new way to help repair spinal cord injuries by combining 3D printing, stem cell technology, and lab-grown tissues."

Breakthrough in 3D-printed scaffolds offers hope for spinal cord injury recovery (original news release) "Currently, there is no proven way to completely reverse spinal cord injuries"

3D-Printed Scaffolds Promote Enhanced Spinal Organoid Formation for Use in Spinal Cord Injury (open access)

Fig. 1 Schematic of experiments.

Could electrical stimulation and robot-assisted exercise reverse paralysis? New results are a resounding 'yes!'

Good news! Amazing stuff! They also discovered a new group of neurons involved in recovery and developed a new molecular way to map neurons.

"A group of Swiss researchers is showing that even chronic spine injuries can be treated to restore a patient’s walking ability using a mix of electrical stimulation and intense physical therapy. ...
The current study identified the exact nerve groups that are stimulated by such treatment, filling in an important gap in our scientific understanding of spinal function. ...
Each participant went through five months of stimulation and rehabilitation, with four to five sessions per week. By the end of the trial period, all of the participants were able to take steps on their own, without the aid of the walker. ...
Subsequent experiments using mice showed that a single population of previously unknown neurons can learn to take over walking after a lumbar spinal injury. This group of cells is found within the Laminae of the lumbar cord and is made up of cells called SCVsx2::Hoxa10 neurons. Normally, these are not needed for walking, but they play an essential role in recovering after spinal injuries ..."

"Neuroscientists have identified the nerve cells responsible for helping paralysed people to walk again, opening up the possibility of targeted therapies that could benefit a wider range of people with spinal-cord injuries ...
team has now extended the work, showing that the system works in people who have lost all sensation in their legs. The group reports in Nature today that nine participants in the same trial — three of whom had complete paralysis and no sensation in their legs — regained the ability to walk after training paired with EES delivered by devices implanted in their spines. Five months into the trial, all participants could bear their own weight and take steps, using a walker for stability. ..."

From the abstract:

"A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord applied during neurorehabilitation (EESREHAB) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EESREHAB in mice. We applied single-nucleus RNA sequencing, and spatial transcriptomics to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EESREHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours."

Could electrical stimulation and robot-assisted exercise reverse paralysis? New results are a resounding 'yes!' We're learning more and more about how our bodies can recover from spinal cord injuries.

Electrical stimulation helps paralysed people walk again — and now we know why Detailed gene-activity map could pave way for more precise treatments for many more people with spinal-cord injuries.

The neurons that restore walking after paralysis (open access)

Fig. 1: EESREHAB remodels the spinal cord of humans and mice

Drug Spurs Neuron Growth in Mice with Chronic Spinal Cord Injury

Good news, but progress is slow! I guess, we have to wait for the next breakthrough!

However, this study shows that neuron growth can be stimulated even long after the injury occurred.

"A weekly drug treatment strengthens neural connections and enhances neuron regeneration in mice with chronic spinal cord injuries ...
The new study finds that activating the CREB-binding protein (CBP) and a related protein called p300 can promote axon regeneration at the lesion site long after the initial injury. CBP/p300 are histone acetyltransferases, meaning they can modify histones and unwind DNA, promoting the transcription of a number of genes, including growth-associated ones, by making them more physically accessible to cellular machinery. But the study, which involved treating mice with a drug that activates CBP/p300, did not find that the proteins’ effects led to any improvements in the mice’s ability to move or walk. ...
this is the first study to show that epigenetic activation can boost neural growth in a near-complete spinal lesion long after the initial injury. ..."

From the abstract:

"The interruption of spinal circuitry following spinal cord injury (SCI) disrupts neural activity and is followed by a failure to mount an effective regenerative response resulting in permanent neurological disability. ... Here, we have investigated whether the epigenetic stimulation of the regenerative gene expression program can overcome the current inability to promote neurological recovery in chronic SCI with severe disability. We delivered the CBP/p300 activator CSP-TTK21 or vehicle CSP weekly between week 12 and 22 following a transection model of SCI in mice housed in an enriched environment. Data analysis showed that CSP-TTK21 enhanced classical regenerative signalling in dorsal root ganglia sensory but not cortical motor neurons, stimulated motor and sensory axon growth, sprouting, and synaptic plasticity, but failed to promote neurological sensorimotor recovery. This work provides direct evidence that clinically suitable pharmacological CBP/p300 activation can promote the expression of regeneration-associated genes and axonal growth in a chronic SCI with severe neurological disability."

Drug Spurs Neuron Growth in Mice with Chronic Spinal Cord Injury | The Scientist Magazine® A protein duo increases transcription of growth-related genes to enhance axon regeneration and boost plasticity, a study finds—but fails to improve mobility.

CBP/p300 activation promotes axon growth, sprouting, and synaptic plasticity in chronic experimental spinal cord injury with severe disability (open access)

Fig 3. Axonal growth and synaptic plasticity in CSP-TTK21-treated mice in a chronic SCI.

In world-first, Tel Aviv University researchers engineer human spinal cord implants for treating paralysis

Good news!

"For the first time in the world, researchers from Sagol Center for Regenerative Biotechnology at Tel Aviv University have engineered 3D human spinal cord tissues and implanted them in lab model with long-term chronic paralysis. The results were highly encouraging: an approximately 80% success rate in restoring walking abilities. Now the researchers are preparing for the next stage of the study: clinical trials in human patients. They hope that within a few years the engineered tissues will be implanted in paralyzed individuals enabling them to stand up and walk again. ...

 "Our technology is based on taking a small biopsy of belly fat tissue from the patient. This tissue, like all tissues in our body, consists of cells together with an extracellular matrix (comprising substances like collagens and sugars). After separating the cells from the extracellular matrix we used genetic engineering to reprogram the cells, reverting them to a state that resembles embryonic stem cells – namely cells capable of becoming any type of cell in the body. From the extracellular matrix we produced a personalized hydrogel, that would evoke no immune response or rejection after implantation. We then encapsulated the stem cells in the hydrogel and in a process that mimics the embryonic development of the spinal cord we turned the cells into 3D implants of neuronal networks containing motor neurons."

The human spinal cord implants were then implanted in lab models, divided into two groups: those who had only recently been paralyzed (the acute model) and those who had been paralyzed for a long time – equivalent to a year in human terms (the chronic model). Following the implantation, 100% of the lab models with acute paralysis and 80% of those with chronic paralysis regained their ability to walk. ..."

From the abstract:

"Cell therapy using induced pluripotent stem cell-derived neurons is considered a promising approach to regenerate the injured spinal cord (SC). However, the scar formed at the chronic phase is not a permissive microenvironment for cell or biomaterial engraftment or for tissue assembly. Engineering of a functional human neuronal network is now reported by mimicking the embryonic development of the SC in a 3D dynamic biomaterial-based microenvironment. Throughout the in vitro cultivation stage, the system's components have a synergistic effect, providing appropriate cues for SC neurogenesis. While the initial biomaterial supported efficient cell differentiation in 3D, the cells remodeled it to provide an inductive microenvironment for the assembly of functional SC implants. The engineered tissues are characterized for morphology and function, and their therapeutic potential is investigated, revealing improved structural and functional outcomes after acute and chronic SC injuries. Such technology is envisioned to be translated to the clinic to rewire human injured SC."

In world-first, Tel Aviv University researche | EurekAlert!

Regenerating the Injured Spinal Cord at the Chronic Phase by Engineered iPSCs-Derived 3D Neuronal Networks (open access)