Nano-Neurobiology and Axon Regeneration
Nano-Neurobiology and Axon Regeneration
Nanotechnology deals with the study of nanostructures, or assemblies of bonded atoms with dimensions in the range of 1 to 100 nanometers (1). Due to their incredibly small size and diverse functional capabilities, these structures are the subject of extensive research by solid-state physicists, materials scientists and electrical engineers. This initial research led to a plethora of synthetic and analytical technologies as well as the development of nanomaterial fabrication, microelectronics and microfluidics (2).
In the field of biology, nanostructures are commonplace as well. From proteins to viruses to cellular organelles, many biological structures have dimensions in the nanoscale. Currently, biologists employ the concept of molecular self-assembly, where molecules under equilibrium conditions spontaneously associate into stable, structurally well-defined aggregates, to synthesize nanostructures with biomedical applications (2). To this end, nanotechnology and molecular self-assembly present a novel and attractive method to repair injured nerves and axons. Before one can understand the nanotechnological approach to axon repair, however, it is important to address the pathology of nerve damage.
If you cut the electrical chord connecting a television to an outlet, the television ceases to function. Like a television, the human nervous system communicates and directs our bodies through electrical chords. These chords, or nerves, propagate electrical signals from the central nervous system (CNS) through the peripheral nervous system to control effector cells, “which carry out the physiological responses ‘requested’ by the brain” (3). Nerves are bundles of axons, the long structures that extend outward from the neuron cell body. These axons carry electrical signals away from the neuron cell body, towards the distal tips of the axon and thereby communicate with effector cells, such as motor neurons, to induce a response (3). When nerves, or individual axons, are damaged, the signal between the neuron cell body and effectors cells is interrupted. When a nerve’s axons are damaged, these interruptions can result in permanent neurobiological damage, producing lifelong and debilitating symptoms (4).Damage to nerves and axons occur primarily through trauma and disease. Traumatic brain injury (TBI) impairs the nervous system through the compression or severance of nerves and axons. The causes of TBI are diverse, and in the United States, the top three causes are motor vehicle accidents, firearms and severe falls (4). This condition manifests itself through a variety of symptoms including seizures, physical impairments (such as paralysis, spasticity, chronic pain, sleep disorders, and etc), social and emotional changes. Moreover, TBI also impacts a patient’s cognitive ability, speech, language, and sensory perception. This condition is common in the United States and according to the Center for Disease Control and Prevention (CDC), there are approximately 1.5 million people in the U.S. who suffer from a traumatic brain injury each year (4).
Several types of diseases lead to axon degradation and nerve impairment. Multiple sclerosis, diabetes, spina bifide, and polio have all been shown to cause nerve damage (3). For instance, multiple sclerosis causes the breakdown of the insulating myelin in surrounding axons. Degenerative neurological disorders, such as Alzheimer’s and Parkinson’s disease, also cause nerve damage. In the case of Alzheimer’s, degeneration of hippocampal neurons leads to a progressive loss of memory and cognitive ability (5). Over five million people live with Alzheimer’s and Parkinson’s disease in the US and it is estimated that this country alone will see a 50% annual increase in the prevalence of these neurological conditions by the year 2025 (6). Due to the varying pathology of these neurological diseases and the dire necessity to develop more effective treatments to aid the growing number of people suffering from these illnesses, axon regeneration has become an attractive field for the application of biomedical nanotechnology.
Current research by Zhang and co-workers is geared towards the design and synthesis of self-assembling peptide nanofiber scaffolds (SAPNSs). These scaffolds are formed through the assembly of ionic self-complementary peptides and are designed by using alternating positive and negative L-amino acids that form hydrated scaffolds in physiological conditions. Therefore, these scaffold are highly biocompatible in physiological conditions, where the nanofibers are broken down into natural L-amino acids, allowing the majority of the material to be excreted in the urine. The SAPNSs also facilitate axon reinnervation since the scaffold forms a network of nanofibers that are similar in scale to the native extracellular matrix and therefore, “provides an “in vivo” environment for cell growth, migration, and differentiation” (2). Lastly, these scaffolds appear to be immunologically inert and so, they are unlikely to lead to neural tissue rejection. These attributes enhance axon reinnervation, as illustrated by in vivo studies.
After severing the optic nerve in a hamster midbrain, SAPNS injection induced axon regeneration and restored the hamster’s sight. To completely severe the optic nerve, Zhang and co-workers created a tissue gap in the optic tract in the hamster midbrain. Next, scaffold peptide was injected into this cavity and after 60 days, behavioral testing of the animals found that 75% had regained functional vision. “Although the animals’ turning responses to the [visual] stimulus was 29% slower than the responses by normal animals,” these results indicate that SAPNS injection allowed for the reconnection of brain tissue in animals that sustained an acute injury (2). In other words, these scaffolds create a “permissive environment” for axons not only to regenerate at the site of an acute injury but also facilities the reconnection of brain tissue.
Essentially, the group designed a self-assembling peptide that spontaneously forms nanofibers, creating a scaffold-like tissue-bridging structure that provides a framework for the reinnervation of axons in the optic nerve. These nanoscale peptide fibers create a direct interaction between the peptide scaffold, the extracellular matric, and the neural tissue on both sides of the lesion. These structures connect the two faces of the lesion, allowing movement of cells into the scaffold, which allowed for axonal growth while preventing the formation of scar tissue that results after CNS injury.
What about our brains? Clinical trials are the next step. If the results of the animal trials are confirmed in controlled patient studies, one can envision a wide variety of applications for this scaffold peptide. Used in neurosurgery, it could prevent the formation of scare tissue and ensure graft retention. Moreover, SAPNS could serve as the next therapy for neurological disorders and TBI. In conclusion, nanobiomedical technology provides a novel, more efficient route to treating brain trauma.