Silky feeling – Silks may restore nerve function
Peripheral nerves carry information between the central nervous system (CNS) and parts of the body. The effect of damage to the system depends on the particular nerves affected, but all types of injury interrupt the body’s communication with the CNS. Nerve damage can lead to muscle paralysis or weakness, and loss of both sensation and control of bodily functions. Fortunately in many cases such loss is only temporary because peripheral nerves can be repaired.
All in the cell
Nerve cells have a cell body that contains all the machinery to maintain its function, and a long process – the axon – which carries the nerve signal. Peripheral nerves contain many thousands of axons in bundles called fascicles. A typical nerve will comprise both motor and sensory axons and contain several fascicles (see image below, right). Each fascicle is surrounded by a membrane, the perineurium, and is bound together by an outer membrane – the epineurium. The nerve also contains blood vessels and supporting cells, including fibroblasts and Schwann cells.
If a nerve is damaged and the axon becomes fragmented, any part separated from the cell body will die. This broken off piece of the axon is referred to as the distal portion. The part of the axon that remains connected to the cell body – the proximal axon – will survive and regenerate. Regeneration is supported by the Schwann cells and is a slow process – at approximately one millimetre a day, but eventually functionality will return.
The success of regeneration depends on the extent of nerve injury. If the axon is physically damaged but the surrounding membranes are intact, regrowth is normally successful. But, if the membranes are also damaged and there is a physical gap in the nerve, surgical repair is required. If possible, the surgeon will directly connect the proximal and distal portions of the nerve by suturing the perineurium and/or epineurium. But if direct repair places the nerve under tension, then something is required to bridge the gap and support the regeneration of axons.
Grafts and biomaterial conduits
The current method for bridging a nerve gap is to remove a portion of healthy nerve from another part of the body and graft it into the gap. The sural nerve, which provides skin sensation to the lower leg, is often used for this purpose. Spaces of as long as 20cm can be repaired in this way.
But autologous grafts have serious disadvantages. They require a second operation to retrieve the donor nerve, which loses its function. Complications can arise, such as chronic pain at the donor site, and recovery of function in the repaired nerve is only partial.
Published studies report that graft repair of the median and ulnar nerves in the hand gives satisfactory motor recovery in only 47% of cases, and satisfactory sensory recovery in 40%. Due to these limitations there has been interest in developing an artificial nerve conduit or tube.
Alternative tissue grafts, such as muscle and veins, support some degree of axonal regeneration. However, their cellular and gross structure cannot be manipulated and does not match the polyfascicular organisation of a peripheral nerve. Recent studies have therefore focused on artificial conduits, based on natural materials such as collagen, laminin and hyaluronic acid or on synthetic materials such as silicon, polyglycolic acid and poly-3-hydroxybutyrate.
These materials can be fabricated into tubes of different dimensions with sophisticated substructures such as a porous outer sheath and luminal fibres or channels embedded in a growth-supporting matrix. The ideal biomaterial conduit would match the fascicular structure of the damaged nerve and provide a scaffold that both supports and guides axonal growth.
Preclinical studies have established the feasibility of such a technique and three conduits have been approved by the American Federal Drug Agency for clinical use. But these are all simple tubes, without any luminal components, and are only able to support growth across relatively small gaps. Therefore, the use of a novel material for nerve repair is being investigated.
Neurotex conduits consist of a sheath made from a silk tube which contains luminal fibres embedded in a hyaluronic acid matrix. The luminal fibres are inset at each end to allow insertion of proximal and distal nerve ends. Manufactured by Oxford Biomaterials, UK, the sheath is made from reconstituted silk proteins cast into a hollow tube.
The sheath is designed to integrate into the surrounding tissue and fit snugly over the damaged nerve, allowing the surgeon to insert the severed nerve ends close to the luminal fibres. These fibres, which guide the regenerating axons through the conduit, are formed from a proprietary silk biomaterial called Spidrex. This shares many similarities in protein sequence with silk produced by spiders.
One of the key features of Spidrex is the presence of numerous copies of the three amino acid repeat – arginine-glycine-aspartic acid (RGD) – in the protein sequence. This is the target of a family of cell surface proteins called the integrins. By binding to RGD sequences, integrins help the cell to stick to materials. By providing numerous targets on the surface of the nerve cells, the fibres may help to guide the regenerating axons through the Neurotex conduit. Once the conduit has restored nerve function, it will slowly be broken down and the amino constituents will be naturally absorbed, leaving only the repaired nerve.
Initial tissue culture studies in preclinical tests established that the fibres support nerve growth and Schwann cell migration, and therefore are a promising material for a nerve repair conduit. This has been confirmed in rodent nerve injury models, which show that the conduits support extensive axonal growth. Schwann cells migrate into the conduit from the proximal nerve. Axons grow between the longitudinally aligned luminal fibres and axons continue to regenerate out of the conduit and into the fascicles and branches of the distal nerve. Axon growth through the conduit is comparable to that obtained with an autologous graft, and neurological assessments indicate that the regenerating axons are able to restore nerve function.
Further preclinical studies are needed before the Neurotex conduits are ready for clinical assessment, but current results look promising. Studies are also under way to determine whether silk conduits can help regeneration and bridge tracts after spinal cord injury. This is a far more ambitious goal, as CNS axons do not normally regenerate. It is therefore likely that additional factors, such as growth factors and regeneration supporting cells, will need to be incorporated.
Co-authored by W L Huang, Q Yang, R Begum, V R King, R Skipper, T Gheysens, D Knight, and N Skaer. With thanks to BBSRC, UK, Keith Pell and Mick Willis.
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