Scientists has created a biodegradable – synthetic conduit that repairs large gaps in injured nerves

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A team of scientists has created a biodegradable, synthetic conduit that repairs large gaps in injured nerves, which supported recovery and accelerated neuronal healing in a macaque model.

The synthetic nerve conduits could offer a viable alternative to autografts – the current gold standard treatment – for supporting the regeneration of nerves in patients who have experienced trauma and severe injuries.

Traumas or surgical procedures can damage the body’s peripheral nerves, resulting in gaps between the nerves that impair movement and daily life. Peripheral nerves do have the ability to slowly regenerate across small gaps with some assistance, but larger gaps from more severe injuries are more challenging to heal.

Clinicians treat large nerve gaps by transplanting nerve tissue from elsewhere in the body – called an autograft – but this approach doesn’t work for all types of injuries and can cause pain or a loss of sensation.

Building on previous work in rats, Neil Fadia and colleagues tested a synthetic conduit that can bridge large nerve gaps by guiding the regrowth of neurons.

Their device is a small, tube-shaped object made of a biodegradable polyester with microspheres that release GDNF – a protein that supports the survival of neurons – embedded in the wall of the tube.

This shows microspheres with neural growth factor

Microspheres containing a neural growth factor adhering to the nerve conduit during the manufacturing process. Image is credited to N.B. Fadia et al., Science Translational Medicine (2019).

When implanted into macaques with large nerve defects in their arms, the nerve guide boosted nerve regeneration and the nerves’ ability to conduct signals over the course of a year.

The animals that received the conduits recovered their motor skills as well as those treated with autografts and showed superior recruitment of cells that sheathe neurons in myelin, an important protein that insulates nerves.


Insights of neuronal injury and repair date back to early periods, specifically to Galen in the second century AD (Nawabi et al., 2006). The research on this topic has been rising continuously and several nerve repair techniques have progressed with time. Despite this fact, the status of peripheral nerve injuries (PNIs) and peripheral nerve regeneration (PNR) has always been in the shadow of the neurosurgery field.

It is regarded has less significant when compared to areas such as central nervous system (CNS) disorders, which are seen as more prominent, tougher and therefore perceived as a more distinguished and notable field. In fact, it has been estimated that ~2–3% of all patients admitted to a Level I trauma centers suffer from PNIs (Noble et al., 1998) while cervical spine injury occurs in up to 3–6% of all patients with trauma (Ghafoor et al., 2005).

This means that the CNS injuries are almost doubled when compared to the peripheral ones, which also carries higher costs. The main reason appointed to this is based on the word “peripheral” itself, as it suggests lesser relevance and difficulty. Furthermore, to increase this fallacy, several forged ideas increase the devaluation of this field, such as the idea that PNIs are irreversible, that peripheral nerves do not have any capacity to regenerate, and the results of peripheral nerve surgery are insignificant to the patient (Rasulić, 2018).

However, although peripheral nerve repair is not a life-saving surgery, it has been proved that it is a life-changing surgery, with significant benefits in the patient’s quality of life. Also, since most patients with PNIs fit in the working-age population, peripheral nerve repair also has substantial socioeconomic implications (Wojtkiewicz et al., 2015). After decades of investigation, it is becoming progressively clear that peripheral nerve repair is not a “peripheral” area and the full attention by the part of clinicians and scientists is needed to overcome this public-health concern.

Peripheral nerves provide the path for all types of axons that compose the peripheral nervous system (PNS), (e.g., motor (afferent), sensory (efferent) axons). Injuries to these nerves are common conditions, due to their scarce physical protection (unlike the CNS, which is protected by bone and layers of meninges) and superficial position throughout the human body. Depending on the injury, an extensive array of symptoms and outcomes are possible. They will be contingent on the severity, type of trauma, age, and type of nerves involved (Siemionow and Brzezicki, 2009).

Although much awareness and information already exist on the natural mechanisms of injury and regeneration, effective regenerative treatments that ensure complete functional and sensory recovery are rare (Grinsell and Keating, 2014; He et al., 2014).

To deep understand the phenomena of nerve injury and repair, the basic anatomy of peripheral nerves must be known (Figure 1). After the injury, the process of Wallerian degeneration starts immediately (Rotshenker, 2011).

In brief, nerve stumps distal to the injury site will experience cellular variations despite the fact that the cells themselves were not injured in the first place. Axons starts to collapse, Schwann cells discard their ensheathing myelin and macrophages are recruited. The later are employed to remove degenerated axons and myelin debris, along with Schwann cells (Deumens et al., 2010).

Furthermore, after a few days, Schwann cells de-differentiate owing to their lost connection with axons, starting a vigorous proliferation. Galectin-3 is known to play a key role in activating myelin phagocytosis. In this process, macrophages and Schwann cells are promoted to degrade myelin, thus having a major importance in the degeneration process (Pesheva et al., 2002).

Both types of Schwann cells, the pre-existent and the recently produced Schwann cells, align together to form the bands of Bungner, which are highly aligned fibers formed by the basal lamina of the Schwan cells. These bands are key topographical cues responsible for guiding the axon and their growth cones, from the proximal to the distal site, across the gap. In optimal conditions, the growth cones can extend at a rate of 1–3 mm a day (Griffin et al., 2013).

Overall, Schwann cells affect PNR in three distinct manners: (i) proliferation, (ii) development of bands of Bungner, and (iii) secretion of adequate growth factors (GF) (Jessen et al., 2015). Figure 2 depicts the process of injury and regeneration of peripheral nerves.

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Basic anatomy of a peripheral nerve. A connective tissue layer, endoneurium, involves the individual axons. An arrangement of axons, designed fascicles, is surrounded by the perineurium, and groups of fascicles are separated by the epineurium. External to this layer is the blood supply derived from major arteries and the latter is involved by the mesoneurium. Reproduced with permission from Pedrosa et al. (2016).
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Schematic representation of injury and regenerative process involved in peripheral nerves. (A) Represents the intact nerve, with myelin enwrapping healthy axons; (B) The moment where an injury occurs, instantaneous tissue damage happens at the injury site. After a few hours, macrophages gather at the lesion; (C) The normal Wallerian degeneration process starts roughly 1 day after the initial trauma and axons start to disintegrate; Growth factors are released by Schwann cells in the distal end. (D) Enrolment of Galectin-3 macrophages, which contribute to myelin degradation and removal of myelin debris. Growth factors are retrogradely transported to the proximal end, toward the cell body; and (E) The typical degradation of the distal nerve end happens with the participation of the Galectin-3 macrophages and Schwann cells. These cellular components scavenge deteriorated myelin and axonal matter. After the clearance of the debris, Schwann cells proliferate and align, forming the Bunger bands, for future guiding of the regenerating axons. Reproduced with the permission from Rotshenker (2011).

Herein, we aim to summarize the necessary concepts to fully understand the phenomena of PNIs and regeneration, which pose complex and demanding challenges in tissue engineering and regenerative medicine (TERM).


Source:
AAAS

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