Israeli researchers try to find a solution when peripheral nerves fail and significant, long-term disability results

Israeli researchers try to find a solution when peripheral nerves fail and significant, long-term disability results

Each year, hundreds of thousands of people worldwide suffer from peripheral nerve injuries, which often leave them with long-term disabilities. Peripheral nerves send messages from your brain and spinal cord to the rest of your body, helping you to sense that your feet are cold and allowing you to move your muscles so that you can walk. Made of fibers called axons that are insulated by surrounding tissues, peripheral nerves are fragile and easily damaged.

The peripheral nervous system is analogous to the circulatory system – a network of vessels that reaches all parts of the body – but instead of blood flowing through vessels, electrical signals send data through the axons, which are engulfed within nerve trunks. If one of the nerve trunks is damaged or torn, a patient can experience pain, paralysis and even a life-long disability.

A nerve injury can affect your brain’s ability to communicate with your muscles and organs. Damage to the peripheral nerves is called peripheral neuropathy. It’s vital to get medical care for a peripheral nerve injury as soon as possible. Early diagnosis and treatment may prevent complications and permanent damage.

With a peripheral nerve injury, you may suffer from symptoms ranging from mild to those that seriously limit your daily activities. The degree of suffering depends on which nerve fibers are affected. Motor nerves regulate all the muscles under your conscious control such as walking, talking, and holding objects. Damage to these nerves is typically associated with muscle weakness, painful cramps and uncontrollable muscle twitching.

Because sensory nerves relay information about touch, temperature and pain, someone with damage to these peripheral nerves may experience a variety of symptoms including numbness or tingling in your hands or feet. You may have trouble sensing pain or changes in temperature, walking, keeping your balance with your eyes closed or fastening buttons.

Autonomic nerves regulate activities that are not controlled consciously, such as breathing, heart and thyroid function and digesting food. Symptoms of damage to these nerves may include excessive sweating, changes in blood pressure, the inability to tolerate heat and gastrointestinal symptoms.

Peripheral nerves can be damaged in an accident, a fall or sports, causing stretching, compression, crushing or cut nerves. Medical conditions such as diabetes, Guillain-Barre syndrome and carpal tunnel syndrome and autoimmune diseases including lupus, rheumatoid arthritis and Sjogren’s syndrome can also harm peripheral nerves. Other causes include narrowing of the arteries, hormonal imbalances and tumors.

In such situations, surgical intervention is necessary to repair the damaged nerve. The standard treatments are direct suturing of detached nerves or, in cases where the gap formed in the nerve trunk is large, surgeons transfer an intact nerve trunk from the patient’s leg and implant it at the site of the injury, thus creating damage in another area (i.e., the leg). Today, there are methods to rejoin nerve trunks to allow the axons to regrow and restore motor and sensory function. One such method is by implanting a synthetic hollow nerve conduit aimed at bridging the gap and allowing the nerve to heal without secondary damage to the patient.

One of the main problems preventing optimal regeneration is that axons within severed nerves have difficulty regenerating and reaching their target. This may be due in part to misguided axons that sprout in multiple directions, decreasing probability to reach their target organs. “They need orienting cues to help them,” explains Prof. Orit Shefi of the Faculty of Engineering and the Institute for Nanotechnology and Advanced Materials and the Gonda (Goldschmied) Multidisciplinary Brain Research Center at Bar-Ilan University (BIU) in Ramat Gan (near Tel Aviv). Dr. Merav Antman-Passig, a researcher in her lab, added: “These guiding instructions need to remain in the body for an extended time, since axons grow fairly slowly.”

A technique developed by the research team of Prof. Shefi’s laboratory, led by Dr. Antman-Passig and Dr. Jonathan Giron, is used to fill a nerve conduit with gel containing a number of physical and chemical components that promote and align axon regrowth. Their technique was recently published in Advanced Functional Materials under the title “Magnetic Assembly of a Multifunctional Guidance Conduit for Peripheral Nerve Repair.”

The researchers filled hollow nerve conduits with engineered aligned collagen gels. In the body, aligned collagen fibers help axon pathfinding, but, in the hollow nerve guides available today, the aligned collagen fibers are absent. The aligned collagen gel acts as a scaffold for axons and directs their growth. In addition, the conduits contain a substance called NGF (nerve growth factor) which, as its name implies, is essential for the growth of the nervous system. 

Imagine that we implanted guiding cues in the gel, which are the aligned collagen fibers, and that these guiding cues also have a treat for the growing axons,” suggested Antman-Passig, “like bait neatly scattered for the growing axons.” 

“An axon that reaches the gel follows these cues and finds the right direction more easily. In fact, the novel system combines several techniques for nerve regeneration,” Shefi added. “Axons like to grow toward these markers that can be left for them, like collagen scaffolding and NGF. The novelty of our method is in the engineering of an organized tissue-like gel that contains components that help restore the nerves and especially in extending the duration of activity of the gel in the body. If collagen and NGF are simply added in hollow nerve conduits, just like real bait, different cells consume them and actually break them do”

After a short time, the growing axons do not have these road signs. “In the method we developed, we extended the time that these factors are accessible to axons during regeneration. We did this by incorporating NGF-coated magnetic particles that we arranged into the correct structure via a magnetic alignment strategy. This also creates an arrangement of the particles and collagen,” Shefi continued.

After characterizing the gel components, the researchers implanted them in nerve conduits and examined the direction of their growth and the platform’s efficacy. The researchers measured the direction of the cell growth and found that with the help of the gel combining aligned collagen and NGF- coated particles, they were able to direct and enhance their growth. Subsequently, they examined the efficacy of the conduit in the rehabilitation of rats with peripheral nerve injury at the sciatic nerve, which prevented them from walking properly. 

The number of axons that penetrated the innovative gel-filled tube and successfully crossed the injured area was greater compared to the empty tube, and accordingly, the restoration of nerve tissue was the highest. The researchers showed that with the implantation of the tubes and the use of the engineered collagen gel, the functional motor restoration was highest, in comparison to the use of other types of conduits and compared to conduits with gel that was not enriched.

The researchers are now exploring the possibility of commercialization and hope that will lead to helping patients regain functions and accelerate nerve repair following injury.