IT USED to be so easy to tell humans and computers apart鈥攈umans are
carbon-based life forms, computers are silicon-based machines. But then came the
idea of 鈥淒NA computers鈥� which hold the promise of performing trillions of
calculations simultaneously using the blueprint of life. Now the distinction is
being blurred still further鈥攖his time by the possibility of using silicon,
the stuff of computer chips, to build artificial body parts. And tiny silicon
capsules could even monitor and adjust the balance of chemicals in our bodies,
delivering drugs or hormones to keep us in tip-top health.
Until now, silicon has not been considered a promising material for
biological applications because it is not compatible with our bodies, meaning
that bony deposits and living cells refuse to grow on it. The good news is that
materials researchers have potentially found a way to wire up your body to
silicon-based medical devices, melding the living with the artificial. The trick
is to pepper the silicon with tiny holes. Unlike 鈥渂ulk鈥� silicon, this porous
silicon could be tolerated by living organisms鈥攊t could be
biocompatible.
The pores in PS are very narrow, with diameters as small as between 1 and 2
nanometres, but several micrometres long. Because they can be packed quite
closely together, the resulting piece of silicon has a sieve-like surface. PS is
made by etching a silicon wafer with hydrofluoric acid in an electrochemical
cell, with the wafer acting as the positive electrode. Etching the wafer riddles
the surface with nanometre-size pits. Once these have formed, etching continues
at the bottom of the pits but leaves the pristine silicon surface alone, making
the pits grow deeper rather than wider.
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This occurs because electrical resistance is lowest at the bottom of the pits
and so current, and hence etching, is greater at these points. Continued etching
creates a forest of branched silicon 鈥渘anowires鈥� or 鈥渘anocolumns鈥�, the precise
dimensions of which can be controlled by altering the current and the strength
of the acid. This fine structure is thought to be responsible for some of the
material鈥檚 remarkable properties.
Throughout the 1990s, PS has been billed as 鈥渢he next big thing鈥� in
optoelectronics, because of its photovoltaic and photoluminescent properties. It
can be made to produce an electric current or glow simply by illuminating it
with certain wavelengths of light, and it will also light up if a voltage is
applied (鈥淎 glowing future for silicon鈥�, 快猫短视频, 10 April 1993,
p 23).
But PS has been slow to fulfil its promise鈥攊t was not until November
last year that a team managed to combine microelectronic circuitry with
light-emitting PS on a single chip. And while attention has focused on PS in
optoelectronics, nearly everyone seems to have overlooked the enormous potential
of a biocompatible material into which electronics engineers can carve intricate
circuits and sensor devices.
PS only becomes biocompatible after removal from the cell at the end of
etching. A thin layer of hydrogen atoms, built up during the etching process
from the acid, is gradually replaced by oxygen, transforming the surface into
silicon oxide. PS then behaves like a passive substrate on which it is possible
to grow cells, and it also seems to actively encourage hydroxyapatite, the main
form of calcium phosphate found in human bone, to deposit on it. The secrets of
these two abilities are likely to be very different.
In the case of cell growth, the answer may be straightforward. 鈥淭he oxide is
inert and doesn鈥檛 poison the cells,鈥� says Sue Bayliss, whose research group at
De Montfort University in Leicester has been studying PS. 鈥淚鈥檓 convinced that
has got a lot to do with it.鈥�
It is less clear why PS encourages hydroxyapatite to grow. When calcium
phosphate and other biological salts are deposited on it, 鈥渋t鈥檚 acting as an
active substrate,鈥� says Bayliss, encouraging the salts to form. 鈥淭he salts start
up at certain sites on the nanostructured surface and then the
hydroxyapatite-like material grows from those.鈥� She believes that defects of the
right shape in the surface of PS could be the sites where seeds of
hydroxyapatite are sown, but stresses that no one really knows what happens.
Leigh Canham, from the Defence Research Agency in Malvern, Worcestershire,
heads a group looking at the potential of microstructured silicon as an active
biomaterial. He has tested various silicon surfaces by leaving them for several
days in simulated body fluid鈥攁 solution of salts designed to mimic those
found in blood plasma. Rather than behaving like materials such as bulk silicon
oxide, aluminium oxide and titanium, which are bioinert鈥攖hey are ignored
by the body鈥擟anham has found that PS attracts a layer of hydroxyapatite in
a similar way to more established 鈥渁ctive鈥� biomaterials, such as Bioglass or
Ceravital.
Corrosion cells
鈥淚n the case of PS, the mechanisms aren鈥檛 understood by anyone,鈥� he says.
鈥淏ut we know PS provides a more chemically active surface than bulk silicon
oxide.鈥� Canham suspects that minute 鈥渃orrosion cells鈥� are set up on the surface
where atoms are lost, perhaps containing trapped electrons to give a negative
charge. These could attract the positively charged calcium ions needed to get
hydroxyapatite deposition started.
Canham鈥檚 recent experiments support his idea that such electrochemistry is
the key. He found that the rate of hydroxyapatite deposition can be altered by
giving the PS an electrical charge. With a negative charge, a coating of calcium
phosphate was created in a few hours鈥攎uch faster than the natural rate of
bone-building鈥攚hile a positive charge slowed the process compared to
uncharged PS.
Whatever gets them going, the structure of the hydroxyapatite deposits that
accumulate on PS bears a close resemblance to natural bone. According to
Bayliss, this could make PS an ideal material for coating orthopaedic implants.
鈥淣atural hydroxyapatite is disordered, but [synthetic versions are] highly
crystalline, and not very like what you get in the body,鈥� she says. 鈥淭he
material you get on the PS surface is much more like the substance in the
产辞诲测.鈥�
Synthetic hydroxyapatite coatings are already applied to many artificial
joints such as hips and knees to encourage the patients鈥� bone to bond with the
implants. Such a bond ensures that the implant does not come loose from the bone
it is supposed to be reinforcing.
Coating an implant with PS might provide an even better bond. By applying a
negative electrical charge to the surface of the implant, doctors might be able
to promote bonding between the PS and the living bone, rather than simply
providing a passive substrate for tissue growth such as artificial
hydroxyapatite, which can鈥檛 easily be electrically charged.
PS scientists are relative newcomers to the field of biocompatible materials,
however, and established researchers are sceptical about the potential benefits
of the new material. Larry Hench of Imperial College, London, has been studying
the mechanisms behind mineralisation for over thirty years, and does not see the
PS work as anything new. 鈥淭he field of electrical stimulation of bone is pretty
advanced [already],鈥� he says.
Blocked signals
Ironically, Hench thinks that the tendency of PS to accumulate a bony
covering could hamper attempts to exploit its electronic properties inside the
body in small efficient electrical devices. For example, if you wanted to
develop a PS-coated chip implant to electrically stimulate nerve cells,
hydroxyapatite deposits might form over the electrical connection sites,
blocking signals. 鈥淗ow could you get signals to and from the chip?鈥� asks
Hench.
But Canham has already established that applying different electrical
potentials to PS affects the rate at which hydroxyapatite deposits. And as it is
already possible to create very fine patterns on the surface of silicon, he
thinks it should be possible to build chips that have tightly controlled regions
of electrical potential across their surface. These would only accumulate
hydroxyapatite where necessary, and leave certain areas free to make electrical
connections. 鈥淚t should be possible to, say, keep a sensor surface clear, or
perhaps keep hydroxyapatite formation to one small area in order to fix the chip
in place,鈥� says Canham.
An alternative method of creating pores could be used to etch patterns of the
required precision. It involves making nanoscale protrusions on the surface of
silicon鈥攃reating pores from the bottom up rather than from the top down.
The De Montfort team is using the interference pattern generated by two lasers
to control the deposition of a stream of silicon atoms on a silicon base. In
this way, the researchers build up a regular nanostructure of bumps. 鈥淭he atoms
only land close to the minima in the [lasers鈥� interference] pattern,鈥� says
Bayliss. She believes such a tightly controlled technique could be useful in
creating material similar to PS on a complex chip. The equipment is more
expensive than that for electrochemical etching, but once it was up and running,
the technique would be relatively cheap.
Whichever way it is made, given its biocompatibility and its potential for
intricate electrical manipulation, PS could make a big impact in a variety of
applications. In today鈥檚 smart implants, such as pacemakers or cochlear
implants鈥攚hich are used to improve the hearing of profoundly deaf
people鈥攁ny electronic components have to be kept away from direct contact
with body fluids. They are often encased in boxes made of titanium alloy. By
using established chipmaking techniques, PS itself could act as the packaging
material, incorporated on the same chip as the electronics, leading to a much
smaller device.
Once again Hench injects a note of caution. 鈥淚t still doesn鈥檛 get over the
problem of how to get signals safely to interface with the body,鈥� he says. He
points out that pacemakers and cochlear implants already function successfully
in patients, delivering signals to the nerves via standard electrodes. 鈥淣o one
has yet come up with a superior way of stimulating nerve tissues,鈥� he argues.
But none of the PS researchers is suggesting that these smart, miniaturised
implants are short-term prospects, although the potential for future
applications is clear.
It鈥檚 not only better versions of today鈥檚 implants that might one day be
available. For example, researchers from MIT and the Harvard Medical School have
begun work on an artificial retina chip that would sit at the back of the eye
(鈥淪ight for sore eyes鈥�, 快猫短视频, 19 August 1995, p 38) This is
exactly the kind of device that could exploit PS as a signal-carrying
biocompatible substrate linked to the retina.
As well as biocompatibility, PS has another crucial property鈥攁 massive
surface area of up to 800 square metres per gram. Bayliss and other researchers
are hoping to take advantage of this property to make a range of chemical
sensors, for industrial monitoring applications and for implants to monitor
chemicals in the bloodstream. These could be incredibly sensitive if the whole
of the available surface was coated with enzymes or other molecules able to
鈥渞ecognise鈥� a specific target. The pores would have to be made large enough to
accommodate these molecules, however, which would reduce the total surface area
per gram of material.
A team from the University of Lund in Sweden has built just such a sensor
implant coated with the enzyme glucose oxidase to detect glucose in the blood of
a diabetic. When an enzyme molecule encounters a glucose molecule, a reaction
occurs and an electron is released at the surface of the sensor. This can travel
back through the underlying PS to an electronic monitor. The bigger the coated
surface area, the more electrons are likely to be released for a given
concentration of glucose molecules, and the larger the current that will be sent
back to the monitor. The current detected will give a measurement of the
concentration of glucose molecules.
A major advantage of this technique is its adaptability鈥攑ick a
different enzyme to coat the surface and you have got a completely different
sensor. By coating different areas of a chip with different enzymes and
separating their electrical responses, a single implant could monitor several
important chemicals at once.
Permanent sensor implants are some way off, however. The main obstacle is the
stability of the enzyme coatings, which can break down after only a few hours.
Initially, such implants are far more likely to be used as short-term,
disposable sensors for monitoring patients during operations. For example,
levels of blood gases could be monitored by a set of chips designed to last 5-6
hours鈥攍ong enough for most operations.
Living conditions
In industrial applications, PS sensors could take off much faster. The De
Montfort team is looking at ways of monitoring the conditions under which cells
are grown in the biotechnology industry鈥攖hese have to be carefully
controlled to prevent the cells from dying. Cells attached to the surface of PS
could act as monitors, checking that conditions for the growth of other cells
are just right. Bayliss and her team have successfully grown chinese hamster
ovary cells on PS. 鈥淐HO cells are surface-growing cells that don鈥檛 grow on
silicon but do grow on silicon oxide,鈥� she says.
CHO cells are widely used in biotechnology because they can be engineered to
produce important pharmaceutical compounds, such as the anticancer drug
interferon and factor 8, the blood clotting agent that haemophiliacs lack. At
the moment, measurements in the reaction vessels in which the cells are grown,
for example the concentration of glucose or the pH of the growing
medium, have to be taken periodically. Continuous monitoring of the electrical
activity of CHO cells growing on a PS chip would provide more precise feedback
on conditions. If reactor conditions become less than ideal, then the electrical
activity of the CHO cells would drop, alerting staff to the problem.
Back in the human body, cells attached to a PS substrate inside a PS 鈥渃age鈥�
could be used as sophisticated drug delivery implants. According to Canham, the
pore size of a PS capsule could be tightly controlled so that it acts as a
filter, allowing only certain molecules in and out. In theory, at least, this
might enable biological molecules to be trapped in a PS implant and used to
produce drugs for delivery directly into the bloodstream through the pores.
Similarly, nutrients for the cells would be small enough to enter the implant,
but antibodies and immune cells would be too large to get in. 鈥淚 haven鈥檛 really
considered specific applications at this stage,鈥� says Canham, 鈥渂ut I don鈥檛 see
why biologically complex things couldn鈥檛 be contained within a chip, provided
that the pore size can be engineered, and over different [pore] lengths.鈥�
So by combining a complex PS monitor with several drug or hormone-producing
implants, our bodies might one day play host to a silicon pharmacy
which would maintain levels of vital chemicals in our bodies if our natural
systems have broken down. The marriage of carbon-based life and silicon-based
machine would have begun in earnest.
