Regenerating Tissues Essay, Research Paper

The ability to regenerate the tissues of the human central nervous system

(CNS) is one of the greatest projects undertaken by biomedical engineers

today. With this eventual technology, permanent paralysis and blindness

due to CNS injury will be a thing of the past. Central nervous system

injuries will be repairable, an idea that was, until recently, just a

fanciful dream, something out of a science fiction novel.

In the last few years, however, giant strides have been made to make the

idea of CNS regeneration a reality within the grasp of engineers and

doctors alike. This technology has advanced to the point where successful

tests are being performed on lower level adult mammals. If all continues

to go well, human implementation may soon follow.

The axons of the central nervous system in adult mammals do not regenerate

spontaneously after injury, mainly because of the presence of

oligodendrocytes that inhibit axonal growth. These glial cells block the

growth of the axons in the central nervous system, preventing any kind of

regeneration within the CNS.

What was discovered, through experimentation, was that lower non-mammalian

vertebrates could regenerate their central nervous system after injury.

Regeneration of the optic nerve occurs spontaneously in fish. This

phenomenon has been correlated to the presence of factors that are toxic

to oligodendrocytes. This substance is closely related to interleukin-2.

Lower level mammals, on the other hand, are, like humans, unable to

regenerate their CNS. The same experiment performed on the fish above

yielded completely different results when done on adult mammals. Severing

of the optic nerve near the eye is followed by a loss of retinal ganglion

cells combined with a failure of axons to regrow into the brain.

Further experimentation found that by manipulating the environment around

the injured retinal ganglion cells, increases the survival rate of

neurons, and make lengthy axonal regeneration, that restores nerve

function to the injured area, possible. This discovery suggested that

that injured nerve cells in the mature mammal CNS are influenced by

interactions with their immediate environment. In certain conditions,

injured central nervous system neurons can resemble normally developing

neurons, and return to a functioning state.

The restoration of connections in the injured CNS of adult mammals is

aided by a guided channeling of the injured axons along a transplanted

segment of peripheral nerve. These neurons recover their capacity to form

synapses along their former channel. These peripheral nerve grafts

increase the survival rate of severed neurons in adult rats twenty

percent. Some of these neurons returned to a fully functional form,

making complete synaptic connections with other neurons.

To explore further the capacity of damaged CNS neurons to initiate and

sustain fiber growth, PN grafts were first applied to the spine of adult

rats. After six to forty two weeks, the range in which the CNS and PN

grafts have been known to integrate, the rats’ spines were crushed.

Investigated four to eleven weeks later, it was shown that these grafts

had significantly helped the regeneration of the spinal cord. The number

and distribution of neurons in the crushed areas of the rats’ spines was

found to be similar to that of the uncrushed regions. This suggests that

central neurons whose axons are grafted with peripheral nerve cells are

capable of renewed growth after injury. Under these experimental

conditions, CNS neurons respond to injury in a similar manner to

peripheral nerve cells.

Another hypothesis was made, that suggested that axons could only

regenerate when their growing tips are surrounded by extracellular fluid

containing proteins from the blood. An experiment was done on fetal rat

explants to test the hypothesis. The explants were cultured in serum

medium for ten days, followed by an eight day period in a serum free

medium. It was found that all explants cultured in serum medium for ten

days showed a greater than seventy seven percent viability. The explants

that were kept in the serum for eight more days retained their viability

rate, while the viability rate for the explants that were placed in the

serum free environment dropped to seven and a half percent. Electron

microscope analysis, showed that tissue viability was above seventy five

percent in all explants, indicating that serum is important only to axon

growth and not neuron survival . This data strengthened the hypothesis

that blood derived proteins were needed for prolonged regen!

eration.

There are certain cells, found in the peripheral nervous system, that

undertake a broad field of tasks in the peripheral nervous system. Called

Schwann cells, they regulate ensheathment and myelination, they are

involved in extracellular matrix production, and they are also

instrumental in the promotion of peripheral nervous system regeneration by

remyelating axons and restoring electrophysiological conduction. Along

with astrocytes, which provide nutritional proteins for the regeneration

of axons, these two cells are primarily responsible for peripheral nervous

system regeneration.

The conjecture that was made next was that these Schwann cells were the

reason that the peripheral graft experiments went so well. The Schwann

cells and astrocytes were helping to rebuild not only the peripheral

nerves that had been crushed, but the CNS neurons as well.

Another experiment was done on rats to determine whether or not the

Schwann cells were responsible for the regeneration in the peripheral

nervous system. Semipermeable nerve guidance channels were prepared,

inserted to connect to ends of a severed peripheral nerve, and the seeded

with astrocytes, Schwann cells, or a mixture of the two. The astrocytes

alone, impeded regeneration, while the Schwann cells increased the amount

of growth. The combination of the two worked as well, provided that the

Schwann cells out numbered the astrocytes.

Taking this into account, the latest move has been to attempt to create

nerve guidance channels for the central nervous system. Using the all the

previous research in the field, biomedical engineers have designed and

created a device that is being tested in animals right now. Using a nerve

guidance channel filled with agarose hydrogel, a gel-like medium ideal for

nerve regeneration and excellent at conducting electricity, this channel

is inserted into the body at the site of CNS injury. Each separated end

of the nerve is enclosed in the guidance channel, and then the channel is

seeded with Schwann cells, astrocytes, proteins to nourish the growing

nerve, and interleukin-2, to destroy the inhibiting Oligodendrocytes.

If this works, we may soon be able to cure paralysis and some types of

blindness. Mankind will make another great stride forward in the field of

medicine, curing another seemingly incurable affliction. This technology

will be an achievement of utmost magnitude and importance, and we will all

benefit from the realization of something that, until recently was just a

pipe dream.

List of Works

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Aguayo AJ, et al. Synaptic Connections Made by Axons Regenerating in the

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Bray GM, et al. The Use of Peripheral Nerve Grafts to Enhance Neuronal

Survival, Promote Growth and Permit Terminal Reconnections in the Central

Nervous System of Adult Rats. Journal of Experimental Biology. 132:5-19,

1987 September.

Bunge RP. The Role of the Schwann Cell in Trophic Support and

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December.

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Guenard V, Aebischer P, Bunge RP. The Astrocyte Inhibition of Peripheral

Nerve Regeneration is Reversed by Schwann Cells. Experimental Neurology.

126(1):44-60, 1994 March.

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