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Nanotechnology for Medicine and Healthcare

The application of nanotechnologies to the medical sector is referred to as nanomedicine. Specify, this area of application uses nanometre-scale materials and nano-enabled techniques to diagnose, monitor, treat and prevent diseases. These include cardiovascular diseases, cancer, musculoskeletal and inflammatory conditions, neurodegenerative and psychiatric diseases, diabetes and infectious diseases (bacterial and viral infections, such as HIV), and more. The potential contribution of nanotechnologies in the medical sector is extremely broad and includes new diagnostic tools; imaging agents and methods; drug delivery systems and pharmaceuticals; therapies; implants and tissue-engineered constructs.

Why nanotechnologies? Nanomaterials are defined as materials at the nanoscale level, which, in nanomedicine, often goes beyond 100 nm and up to about 500 nm. This is the size range of biomolecules (e.g. proteins, enzymes, DNA) and molecular complexes such as the ion pump. These natural nanomaterials are the constituents of larger hierarchical structures that regulate the function of the cell. Bacteria and viruses are larger (a  few micrometers), but their functions (including toxicity   to healthy cells) derive from the interactions between the biomolecules that  compose them and  the surrounding media

(including surrounding cells). Basically, nanotechnologies make it possible to create engineering materials (such as drug delivery systems, disease imaging probes, or even tissue-engineered constructs) that have dimensions on the scale of biomolecules which, in turn, is the scale that regulates the functions of cells. Nanotechnologies have the potential to improve the whole care process that starts for a patient once a disease is suspected, from diagnosis to therapy and follow-up monitoring. The aim is the development of new materials and methods to detect and treat diseases in a targeted, precise, effective and lasting way, with the ultimate goal of making medical practice safer, less intrusive and more personalised. The timescale from the invention of a medical device or drug to release for clinical use is extremely long. In a few cases (such as drug delivery devices), nanotechnology is already in use for improving patient care but, in most of the areas to be discussed, the applications are still some years from being useable products.

Diagnosis

Diagnosis of a suspected disease is one of the most critical steps in healthcare and medicine. Diag- noses are wanted quickly, but must also be reliable, specific and accurate, and with the minimum risk of ‘false positives’. Nanomedicine has the potential to greatly improve the entire diagnostic process. Instead of collecting a blood sample in a vial and sending this to a specialized laboratory for testing (which can take days), doctors will be able to use miniaturised in vitro diagnostic devices in their surgeries. These are small but highly integrated devices capable of carrying out many tests quickly at the same time using very small quantities of sample to perform the analysis. Some miniaturised in vitro diagnostic devices already exist such as the breathalyzers that the police carry for alcohol screening or the portable glucose test devices used by diabetics. These devices can measure ions, small molecules or proteins, or can test for specific DNA sequences that are diagnostic for a particular disease or medical condition. In the last years, there has been a trend to make these devices even smaller, able to perform hundreds of tests at the same time and be easier to use.  Nanotechnologies have an important role in this development: nanomaterials, such as nanoparticles or nanotubes, can be integrated into the device. Scientists can engineer nanomaterials to be very specific, so their use will make the device even more accurate and capable of carrying out even more tests simultaneously. Nanomaterials have the characteristic of exhibiting some peculiar quantum effects that can be used to amplify the signal arising from the detection. Thus, the use of nanomaterials in miniaturised in vitro diagnostic devices will make it possible to improve the specificity of the analysis, its throughput (the number of tests that can be done simultaneously) and its read-out. In the future, these types of devices will make it possible to perform ‘point-of-care diagnostics’: it will be possible to make a diagnostic test anywhere, not just in the doctor’s surgery or hospital. The nature of the sample to be tested will probably change, and become saliva rather than blood, which is much more convenient and safer to handle. This will allow large numbers of patients to be tested, for example in the event of an epidemic, or large numbers of diseases, or the many parameters needed for one specific disease to be considered for the diagnosis of complex medical conditions.

Miniaturised diagnostic devices include biosensors, microarrays and ‘lab-on-a-chip’ (LOC) devices, also called miniaturised total analysis systems (µTAS). The first two are based on a parallel processing technique, whereas LOC devices are based on a serial processing technique.

Biosensors

Generally speaking, a sensor is a device capable of recognising a specific chemical species and ‘signaling’ the presence, activity or concentration of that species in solution through some chemical change.   A ‘transducer’ converts the chemical signal (such as a catalytic activity of a specific biomolecule) into a quantifiable signal (such as a change in color or intensity) with a defined sensitivity. When the sensing is based on biomolecular recognition, it is called a biosensor. There are various types of biosensors, such as those based on antibodies/antigens, nucleic acids and enzymes. Furthermore, depending on the technique used in signal transduction, biosensors are classified as optical detection biosensors (as in the example above), electrochemical biosensors, mass-sensitive biosensors or thermal biosensors.

There are numerous nanoparticles that can be used as biosensor components. These work as probes recognising an analyte or differentiating between analytes of interest. In such applications, some biological molecular species are attached to the surface of  the nanoparticles to recognise the target of interest through a  lock-and-key mechanism. The probes then signal the presence of the target by a change in colour, mass or other physical change. Nanoparticles used as elements for biosensors include quantum dots, metallic nanoparticles, silica nanoparticles, magnetic beads and fullerenes, which are hollow cages of carbon atoms, shaped like footballs.

Other biosensors use nanostructured particles as nano-sieves through which charged molecules are transported in an electric field. In this case, particles with engineered nanopores are used.

Carbon nanotubes and nanowires are also employed for sensing. The latter can be fabricated out of semiconductor material and their size tuned to have a specific conducting property. This, together with the ability to bind a specific analyte on their surface, yields a direct, label-free electrical read-out. These nanowire biosensors allow the detection of a wide range of chemical and biological species, including low concentrations of protein and viruses, and their application ranges from the medical to the environmental sector. Figures 1 and 2 illustrate a silicon nanowire biosensor based on biorecognition.

Nanoscale biosensors have the potential to greatly aid in the diagnosis of diseases and the monitoring of therapies. A large number of approaches have been developed in recent years while relatively few have so far been converted into clinical diagnostic tools — their wide application inpatient care is foreseen in the next 5–10 years.

Cantilever biosensor

A cantilever biosensor is a biosensor made of numerous ‘arms’ (called cantilevers) which are tens of micrometers long but very thin (a few micrometers). These devices are fabricated through lithography and etching. The surface of the cantilever is functionalized with a nanometre-thick layer of coating which ensures anchorage of the probe material (which can be a DNA strand or a protein, for example). Each cantilever is different and can probe for a different target, as schematized in Figure 3. In this type of sensor, the adsorption of the analyte to the specific targets on a cantilever causes surface stress and bends the cantilever. The most common read-out is optical where the angular disturbance of a laser beam is measured following the bending of the cantilever. Although common, this method suffers from the limitation that measurements are difficult in opaque liquids, such as blood, because of the absorption of the laser light. An alternative to this method is the piezoresistive read-out, where a piezoresistor is integrated into the cantilever. Upon detection of  the analyte, the stress applied to the resister changes, which is reflected in a change of its resistance, which in turn is measured as an electrical signal. This approach offers the advantage of allowing the detection in opaque media, the possibility of miniaturising the sensor and incorporating it in portable devices for point-of-use sensing.

Plasmonic biosensors

The optical properties of noble metal nanoparticles have received significant research attention in recent years for their potential as components in many applications, including chemical/biochemical sensors. The optical properties of noble metal nanoparticles are dominated by an effect called localized surface plasmon resonance (LSPR), which was described in Module 1, Chapter 4: Fundamental ‘nano-effects’. One of the consequences of the LSPR effect in metal nanoparticles is that they have very strong visible absorption due to the resonant coherent oscillation of the plasmons. As a result, colloids of metal nanoparticles such as gold or silver can display colours that are not found in their bulk form, such as red, purple or orange, depending on the shape, size and surrounding media of the nanoparticles. The energy of LSPR is sensitive to the dielectric function of the material and the surroundings and to the shape and size of the nanoparticle. This means that if a ligand such as a protein attaches to the surface of the metal nanoparticle, its LSPR energy changes. Similarly,  the LSPR effect is sensitive to other variations such as the distance between the nanoparticles, which can be changed by the presence of surfactants or ions. The fact that the LSPR depends on the dielectric environment means that the refractive index can be used as the sensing parameter: changes in the local dielectric environment, induced by the sensing process, are used to detecting the binding of molecules in the particle nano-environment.

In a plasmonic biosensor, the nanoparticles can be dispersed in a medium (in which case the biosensor is a colloidal plasmonic biosensor) or supported on a surface (surface plasmonic biosensor). Both types of sensors exploit the fact that the sensing event changes the LSPR of the metal nanoparticles, but use different read-out report strategies.

In a colloidal plasmonic biosensor (e.g. made of gold nanoparticles), the sensing event results in a change of aggregation among the nanoparticles that form the colloid (Figure 4), which can determine a colour change of the colloid. Absorption spectroscopy is used to quantify the biosensing event. In the case of gold colloid, which is normally red, the sensing event can result in the colloid becoming blue. Thus, metal colloids can be used as plasmonic colorimetric biosensors. In nanomedicine, this effect is used, for example, in genetic screening, where scientists look for a specific gene sequence in a sample which can be indicative of a specific disease. How is this done? First, the sequence of bases in the target DNA is identified. Then, two sets of gold particles are prepared — one has DNA attached that binds to one end of the target DNA, and the second set carries DNA that binds to the other end. The nanoparticles are dispersed in water. When the target DNA is added, it binds both types of nanoparticle together, linking them to form an aggregate. The formation of this aggregate causes a shift in the light-scattering spectrum from the solution (i.e. a colour change in the solution which can easily be detected). An example is illustrated in Figure 5.

In a surface plasmonic sensor, metal nanoparticles are immobilised on a surface as illustrated in Figure 6(a). The metal nanoparticles are attached to the surface by means of chemical linkers or prepared by nanolithography (b) and are then modified with the sensor moiety (c). The analyte (the target) attaches from solution specifically on to the recognition function adsorbed on to the particles (d), causing a change in the refractive index around the particle, resulting in an LSPR shift. The LSPR shift is measured through a technique called extinction spectroscopy (e).

Artificial nose biosensor

An artificial nose biosensor is a device that mimics the ability of some mammals, such as dogs, to detect explosives and drugs through their olfactory system. Recent research has shown that this fine capacity in dogs may also be used to detect molecules that, if present, are early indicators of various diseases such as cancer. Numerous research programs are under way around the world to create an artificial nose: one such is the European project BOND. The application of such types of biosensor ranges from medicine (early disease detection) and security (explosives detection) to the food industry (to measure whether food has gone off). This type of biosensor is an electrochemical sensor that mimics the natural mammal olfactory system. The nose-biosensor, like our own noses, is composed of three main parts,    a biomolecule receptor, an electrode, and a transducer. When the detector finds the target, a chemical reaction occurs between the detector and the receptor biomolecules for odour. The chemical reaction between the receptor and the substance we smell emits a chemical signal. The electrode translates this chemical signal into electrical signals and transports them to the brain or, in the case of the nose biosensor, they are transported to a transducer. In mammals, the equivalent of the electrodes would be neurons. The transducer (the brain in mammals) receives the electrical signal and translates it into analytical information. In the nose-biosensor, the transducer would give information on a screen.

Microarrays

These devices are used for diagnostic purposes such as DNA analysis (DNA microarray), protein detection (protein microarrays) as well as whole-cell analysis. Microarrays are platforms made of hundreds of detection sites that have micron-sized dimensions and allow the specific detection of a (bio)chemical within a mixture or the simultaneous detection of many (bio)chemicals. The detection is related to the chemical functionality on the micron-sized spots in the array and it leads to a single chemical ‘yes/no’ reaction per spot. Microarrays are used as screening tools, not only for diagnostic purposes but also for screening new drugs. Nanotechnology can impact microarray technology by creating densely packed, smaller, nano-sized arrays (nanoarrays) that could allow faster screening of a larger number of (bio) chemicals. There are,  however,  some problems associated with the handling of ultra-small quantities of liquid so nanotechnologies offer the most promising advantages in sample detection on arrays. The conventional method used for detecting the ‘yes/no’ reaction at each spot is fluorescence. This technique uses fluorescent probes made of organic molecules attached to the species to be detected (e.g. a protein or a fragment of DNA): when a reaction occurs, this is attached to the detection spot, which becomes fluorescent in a ‘colour’ corresponding to the emission of the fluorescent probe. Fluorescent staining suffers from some disadvantages, mainly fast bleaching of the fluorescent molecules (that is,  loss of ‘brightness’ of the colour in time during imaging); limited numbers of dye molecules that have distinct ‘colors’ and that can be can be simultaneously imaged; and limited sensitivity. Nanoparticles in the form of quantum dots (QD) can be used as an alternative to conventional organic dyes, being more stable, sensitive and monochromatic. A substantial (tenfold) enhancement in sensitivity compared to common fluorescent markers has been accomplished through the use of gold and silver particles of uniform dimensions in the range 40 to 120 nm. Signal amplification is also obtained using metal nanoparticle labels, such as DNA-modified gold nanoparticles. These nano-sized probes have molecules attached to their surface that ensure the selectivity of the detection, while the nano-properties of the probe are responsible for enhancing the signal. The overall effect is an improvement in the sensitivity and selectivity of microarray technology.

Nanobarcodes

The unique properties of nanoparticles, such as the relationship between particle size and colour, can also be used to create multiplexed detection systems in the form of nano

barcodes, for example using quantum dots to create different color-based codes. Alternatively, fragments of DNA on nanospheres can be used to create a ‘bio-barcode’, for example for protein detection. A bio-barcode has been used to detect small levels of the cancer marker prostate-specific antigen (PSA) in serum. The results showed an increased sensitivity to the PSA protein compared to conventional protein assays, demonstrating the potential of such approaches for detecting cancers at an earlier stage.

Lab-on-a-chip

These devices are ‘miniaturised integrated laboratories’ that allow the separation and analysis of biological samples (e.g. blood) in a single device. They are made of microfluidic systems, including micro-pumps and micro-valves, integrated with microelectronic components. The devices can also integrate one or more sensors. As with microarray technology, the impact of nanotechnologies in this area is in further miniaturisation of these devices, although the handing of ultra-small volumes of samples would pose a problem. Presently, nanotechnologies are making an impact in improving specific components and functions of lab-on-a-chip devices. For example, analysis is commonly done by dielectrophoresis, where non-uniform alternating electrical fields are used to separate and guide small objects through field gradients: this manipulation requires high electrical field strengths that can be obtained using nano-sized electrodes. Another example is nanopore-based separation systems that can be integrated into the membranes used in lab-on-a-chip devices — for example, nanopore-membranes are proposed for DNA sequencing.

Imaging

The second step in the diagnosis of the disease involves in vivo imaging, which searches for the symptoms of the disease within the live tissue suspected of being infected without the need to perform surgery. Nanotechnologies are having a very important impact in this area, particularly by developing molecular imaging agents. The latest improvements in the area of imaging deal with the capability of tracking changes at the cellular and molecular level through the analysis of some specific biological markers (a technique called ‘targeted molecular imaging’ or ‘nano-imaging’). A biomarker is an indicator of a biological process or state, such as a disease, or the response to a therapeutic intervention. This can be an altered gene, or a change in protein production, or even a physical feature of a cell. The aim is to detect biomarkers of disease and diagnose illnesses before, or at the onset of, the first symptoms,  in this way making in vivo imaging a tool for the early detection of disease. Effective early detection is crucial for planning a therapy with less severe and costly therapeutic demands, especially in diseases such as cancers, where timing is vital for the success of the treatment. Biomarkers could also be used as early indicators of the success of a treatment, thus reducing treatment time and cost. Targeted molecular imaging is important not only for diagnostic purposes, and for monitoring the progress of therapy, but also for research in controlled drug release, in assessing the distribution of a drug within the patient’s body, and for the early detection of unexpected and potentially toxic drug accumulations. The ability to trace the distribution of a drug leads to the possibility of activating it only when and where needed, thus reducing potential drug toxicity.

Diagnostic imaging

Techniques such as X-ray, computer tomography (CT), ultrasound (US), magnetic resonance imaging (MRI) and nuclear medicine (NM) are well-established imaging techniques, widely used in both medicine and biochemical research. Originally, imaging techniques could only detect changes in the appearance of a tissue when the symptoms of the disease were relatively advanced. Later, targeting and contrast agents were introduced to mark the disease site at the tissue level, increasing imaging specificity and resolution. It is in this specific area that nanotechnologies are making their greatest contribution by developing better contrast agents for nearly all imaging techniques. The physiochemical characteristics of the nanoparticles (particle size, surface charge, surface coating and stability) allow the redirection and concentration of the marker at the site of interest. An example of nanoparticles used in research for imaging is perfluorocarbon nanoparticles employed as contrast agents for nuclear imaging, magnetic resonance imaging and ultrasound, with applications in the imaging of blood clots, angiogenesis, cancer metastases and other pathogenic changes in blood vessels. Gadolinium complexes have been incorporated into emulsion nanoparticles for the molecular imaging of thrombi, resulting in a dramatic enhancement of the signal compared to conventional MRI contrast agents. Fullerenes are also used in magnetic resonance imaging research, filled with smaller molecules that act as contrast-enhancement agents. Metals and silicon nanoparticles are also used to enhance MRI. Silicon particles fabricated into different shapes and coated with conductive layers can have enhanced magnetic resonance interactions with an imaging field.

In X-ray imaging, to enhance the signal, an agent must deliver a detectable number of heavy atoms into targeted tissue without toxic effects. Nanoparticles of heavy metals have the highest density of surface atoms but they must be inert and stable. Nanoparticles of inert metals like silver and gold are too expensive and would render the technique not cost-effective. A solution has been proposed by General Electric in the form of nanoparticles made of heavy metal compounds encapsulated in gold shells. The added advantage is that organic compounds with sulfide (-S-H) groups (thiols) can easily be attached to the gold surface through the thiol end (forming an S-Au bond). The thiol molecule can be functionalised at the other end with groups that act as receptors for specific binding of antigens, antibodies or even target compounds on the surface of the cell. By targeting receptors unique to a certain type of cancer cell, gold nanoparticles can enhance an X-ray image of suspected cancer tissue by many orders of magnitude.

Gold nanoshells are a promising material for the optical imaging of cancer. Optical technologies could provide high resolution, non-invasive functional imaging of tissue at competitive costs. However, at present, these technologies are limited by the inherently weak optical signals which come from the endogenous chromophores and the small spectral differences between normal and diseased tissue. Gold nanoshells are made of a dielectric core (silica) covered in a thin metallic (gold) shield. Gold nanoshells possess physical properties similar to gold colloid (as described previously), in particular, a strong optical absorption due to the collective electronic response of the metal to light (the LSPR effect). By changing the relative dimensions of the core and shell, the optical resonance of the nanoparticles can be precisely and systematically varied over a broad region ranging from the near-UV to the mid-infrared (Figure 7). This range includes the near-infrared (NIR) wavelength region where tissue transmissivity is higher. Researchers are using these gold nanoshells cells as contrast agents for Optical Coherence Tomography (OCT) (9) of cancer cells. As discussed later, gold nanoshells are also capable of treating cancer cells through the overheating of the cells. This is discussed in the next section.

In situ diagnostic devices

In recent years, in situ diagnostic devices have been developed, such as wireless capsule endoscopy cameras. These devices are swallowed by the patient and make it possible to closely monitor and locate the site of bleeding and other intestinal problems. Currently, many of these devices, such as the CamPill® produced and sold by Given Imaging Ltd, can only imagine the problem. In the future, these devices could also incorporate sensors for the detection of specific chemicals, pH, bacteria, viruses, etc. Micro and nanotechnologies now allow the creation of extremely small sensors and research is being conducted on integrating them into swallowable capsules. This will widen their applicability and utility. In the future, they could also be drug-loaded for targeted drug delivery.

Therapy

The same disease, such as cancer, can express itself in many different forms: for example, there are at least 14 different types of breast cancer. Thus, in an ideal world, therapy should be specific, in order to remove only the ‘bad’ cells, and effective, both in terms of action and time.

A therapy normally involves a pharmaceutical route (drugs)  to treat the disease from the inside of the body, or, when a pharmaceutical therapy is not possible or not effective, other routes to fight the disease from the ‘outside’  of the body,  such as radiative therapies. In some circumstances, surgery is required, and an organ-substitute is inserted into the body in the form of an implant or a donated organ. In all these approaches, which are often used in combination, the aim is always the same: to eliminate selectively the source of the disease in a  long-lasting way.  Nanotechnologies are making a tremendous impact in this field, with new drugs and new types of treatments under development, some of which have already proven clinically effective and have entered the market.

Drug development and targeted drug delivery

Advances in the field of pharmacology stem from two main concepts: the development of new biologically active drugs (drug discovery) and the development of new drug delivery systems able to reach the specific site of the disease. Drug delivery systems (DDS) are not a new concept: research in this field started in the mid-1960s and resulted in the type of drugs used today (i.e. medicines where the active ingredient is encapsulated and released inside the body by gradual dissolution, osmotic effects, or other mechanisms). Drug delivery systems are in the same form as the ‘pills’ that are frequently taken and that release their active component gradually in time (slow-release drugs) or that dissolve based on some physiological conditions (e.g. acidity of the environment). Drug delivery systems also exist in the form of implants, inserts or other drug-releasing systems.

Drug design and screening

The structure of biological macromolecules defines a three-dimensional nano-environment that mediates specific functions in the cell. The design of new drugs requires a very detailed understanding of this nano-environment. Therefore, gaining insight into the structure of macromolecules on the nanoscale through electron microscopy, nuclear magnetic resonance spectroscopy (NMR) and X-ray crystallography is of fundamental importance to understanding biological processes and for the development of new medicines.

One of the bottlenecks in drug discovery is the necessity to screen thousands of candidate drugs for their efficacy in fighting targeted macromolecules in a disease state. Micro and, now, nanotechnologies have enabled the development of microarray platforms and new detection methods (including label-free) to investigate the effects of candidate drugs against disease macromolecules with unprecedented speed.

Targeted drug delivery

Pharmaceutical drugs developed using conventional synthesis routes are limited by problems such as low efficacy, low solubility in water and lack of selectivity. In addition, physiological barriers often prevent the drug from reaching and acting at the target site — a phenomenon called drug resistance. The low solubility and limited bioavailability of conventional drugs is responsible for their limited effectiveness: the body often clears away the drug before its action is complete. The efficacy of drugs is also dependent on the dose used, but dose-dependent side effects often limit their acceptable usage. The lack of selectivity is especially detrimental, for example, in cancer therapies, since anti-cancer drugs, usually distributed in large volumes, are toxic to both normal and cancer cells.

A recognised need exists to improve drug composition, delivery, release and action, and thus to develop new drugs that can act at the specific site of the disease, maximising the drug’s therapeutic action while minimising side effects. For drugs to be able to do this, the delivery systems need to be miniaturised to much smaller than the target, and specific in composition to elicit a certain response. With the use of nanotechnologies, targeted drugs (in terms of composition and delivery system) are becoming a reality. In the future, this could lead to targeted therapies and personalised medicine. The aim is to design and deliver drugs in such a way that they can recognise the ‘bad’ cells at a molecular level, penetrate the cell membrane, and act inside the infected cell. This is often crucial for the efficacy of a drug since most virus replication and other disease conditions take place across the cell membrane and inside the cell. This way, the treatment will be delivered where it is needed and will be specific, eliminating the problem of the drug killing healthy cells. An example of this approach is siRNA drug delivery.

Targeted drugs and targeted DDS could allow the creation of drug formulations with optimal loading, which deliver to the body only the necessary amount of the drugs and reduce side effects for the patients. Together with the possibility of having nano-DDS that are biodegradable inside the body, this will help to reduce drug toxicity. Drug safety can be further enhanced by the possibility of introducing inside the drug formulation a label that changes colour when the drug reaches its expiry date or is no longer functioning. This will allow for the improvement of drug shelflife and better monitoring of drug safety.

siRNA drug delivery

RNA interference is a natural, fundamental mechanism in gene regulation that occurs in both plants and animals, humans included. Genes carry the genetic material of an individual, the DNA, and are contained in the nucleus of a cell. When genes are express (i.e. activated), the genetic information is copied from DNA to messenger molecules, called messenger RNA (mRNA), which then orchestrate the formation of proteins outside the nucleus of the cell. In 1998, Andrew Fire and Craig Mello discovered that double-stranded RNA (dsRNA) can interfere with and break down the mRNA for a specific gene, thus stopping the production of a specific protein. The gene is, therefore, ‘silenced’ and the production of the protein is turned off. Fire and Mello found that this RNA interference mechanism is specific and can be obtained with a few molecules of dsRNA and that the effect of dsRNA could spread from cell to cell and from tissue to tissue, and even passed on to offspring. The discovery won the scientists the Nobel Prize in Medicine in 2006. Now researchers know that RNA interference plays an important role in switching off genes during an organism’s development and controlling cellular functions. But the discovery of RNA interference not only enables scientists to better understand the fundamentals of gene regulation: it also opens new possibilities for genetic engineering in biological and medical research. In the laboratory, scientists can now tailor RNA molecules — silencing RNAs — that activate the breakdown of endogenous mRNAs (i.e. RNA that belongs to that specific cell). When silencing RNA (siRNA) molecules enter the cell, they activate RNA interference and endogenous mRNA molecules that bind to the added siRNA are destroyed. Researchers are now hoping to use RNA interference to treat diseases such as viral infections, cardiovascular diseases, cancer and metabolic disorders. So far, many experiments with RNA interference have yielded promising results, but in order to maximise the therapeutic efficacy of the technique, some fundamental difficulties must be overcome. These include the low stability of siRNA in biological fluids and low specificity of action due to gene off-target effects caused by the similarity in behavior of synthetic siRNA to natural microRNA produced by the cell. Therefore, there is the need to develop delivery methods capable of overcoming the extracellular and intracellular barriers and getting the siRNA molecules into the right type of cell (targeted delivery) whilst maintaining the stability of siRNA.

Researchers at iNANO (Aarhus University) and other institutions worldwide are developing nanocarriers for the targeted delivery of siRNA. For example, they are studying a novel chitosan-based siRNA nanoparticle delivery system for RNA interference in vitro and in vivo. Chitosan is a naturally occurring cationic polysaccharide that has been widely used in drug delivery systems. It contains positively charged amine groups that can interact with the negatively charged backbone of siRNA and form polyplexes in the form of nanoparticles about 200 nm in size. The protonated amino groups allow transport across cellular membranes and subsequent endocytosis into cells. It has been shown that a chitosan/siRNA nanoparticle delivery system silences genes both in vivo and in vitro (Figure 8). Moreover, this delivery system has been shown to be biocompatible, non-toxic and biodegradable. Another requirement in targeted siRNA delivery is the capability of the carrier to reach a specific cellular compartment and release the cargo (the siRNA) inside that cell. Synthetic vectors based on polycations such as poly-L-lysine have been widely used but have several drawbacks such as high cellular toxicity, sequestration in subcellular compartments and lack of intracellular targeting. In contrast, bioresponsive polypeptides containing reducible disulfide bridges that respond to intracellular acidity conditions have proven advantageous in delivering nucleic acids into cells. These systems exploit the redox potential gradient existing between the extracellular and the intracellular environment so that the disulfide bridges are broken (and the cargo released) only in one compartment of the cell (in this case, the nucleus). For these reasons, research is being conducted in developing nano-carriers rich in histidine groups.

Stimuli-activated drug delivery

In this area of research, the idea is to incorporate some specific properties into the delivery system so that the drug can be activated only on reaching the target, and the active component released at a controlled rate. This is called stimuli-activated drug delivery. Controlled activation could be linked to some environmental property, such as pH, or ‘lock-and-key’ molecular recognition mechanisms. One example is stimuli-activated gene delivery.

In gene therapy, one of the biggest challenges is the targeted delivery of the nucleic acid load to the target (e.g. plasmid-DNA or siRNA) either to silence  (RNA silencing) or to activate the expression of a protein as a way to treat a number of diseases. In the previous section, how nanocarrier delivery systems formed by electrostatic interactions between cation polymers and DNA or RNA have been developed to overcome extracellular and intracellular barriers to maximise the delivery of the nucleic acids in the cell was discussed. One way to control the spatial and temporal activity of nucleic acids is to use polymers that change properties in response to stimuli such as temperature and redox potential gradients. This approach to targeted delivery is being investigated at iNANO and is schematically illustrated in Figure 9. The idea is to utilise a nanocarrier that passively accumulates in the diseased tissues (e.g. tumors), followed by stimuli-induced activation at the required site (inside or outside the cell). In the case of thermoresponsive systems, the application of heat in precise locations of the tissue can induce the deposition of the nanocarrier in the extracellular target region.

Researchers are studying, for example, the use of a thermoresponsive polymer to form a polyplex with plasmid DNA and using AFM to visualize the resulting nanoparticles. They found that the size of the polyplex nanoparticles from around 50 to more than 200 nm could be changed by heating the particles. The AFM images revealed that smaller particles merged to form larger particles during the temperature treatment. Since the ability of polyplexes to cross vasculature endothelial barriers and enter/exit tissues depends on particle size, a term stimulus could be used to control migration inside tissues. The idea is to apply a term stimulus in the diseased tissue so as to induce a size increase in the nanoparticles and prevent these from re-entering the bloodstream (Figure 9). This general approach could be used for nanocarriers containing drugs or imaging agents for therapeutic and diagnostic applications.

Current and future nano-drug carriers 

Nano-sized drug carriers currently under development include either materials that self-assemble or conjugated multicomponent systems, for instance a drug linked to a protein and a polymer (called a polymer-drug conjugate, Figure 10). Numerous nanosystems are now being investigated and include micelles, nanoemulsions, nanotubes, nanofibres, liposomes, dendrimers, polymer therapeutics, nanoparticles, nanocapsules, nanospheres and hydrogels. Some of these nano-sized drug carriers are established in the field of drug delivery, such as liposomes: others have made their way to the market in recent years, such as polymer-protein conjugates (polymer pharmaceutics).

Many are now used for treating some forms of cancer, hepatitis, and leukemia. An example is an anti-cancer drug called DOXIL (Sequus Pharmaceuticals, Inc.).

The future of nano-DDS enabled by nanotechnologies could be miniaturised implantable chips loaded with different drugs that can be released by external stimuli. This could free patients, such as diabetics, from having to administer drugs repeatedly during the day. Research in this area is very active but still requires years for commercial realisation.

Externally activated therapies that use nanoparticles

One of the distinguishing properties of nano-sized drug carriers is their ability to accumulate passively in cancerous solid tumor tissue due to an effect called enhanced permeability and retention (EPR). This passive mechanism has been attributed to the ‘leaky’ nature of tumor vessels. The blood vessels that supply tumors with nutrients have tiny gaps in them that allow nano-DDS (60–400 nm in size)     to enter the tumor region and accumulate there. This further enhances the targeted approach to treating infected cells. Moreover, this allows the accumulation of therapeutic agents inside the tumor region with activation by an external source. Based on this concept, some new anti-cancer therapies have been developed and have entered advanced clinical trial stages. In these therapies, nanoparticles are delivered to the tumour site, where they accumulate. An external source is then used to specifically activate the nanoparticles and overheat the tumour region (the therapy is called hyperthermia). Due to the EPR effect, the nanoparticles accumulate only in the tumour region, so the treatment is extremely localised and healthy tissue is not affected. Overheating the tumour site can be achieved, for example, by activating magnetic nanoparticles with an alternating magnetic field so that they start vibrating and thus generate heat. This is the principle on which a new anti-cancer therapy, MagForce®, has been developed: this therapy entered Phase II clinical trials in 2007 for the treatment of prostate cancer. Another approach uses gold nanoshells (as described previously) designed to absorb light in the near-infrared (NIR) region. This is the region where light penetration through tissue is optimal (800–1 300 nm). The nanoshells absorb NIR light, delivered with a laser, converting light into heat. In animal model studies, the nanoshell treatment has been shown to induce complete resorption of a tumour in 10 days, with all the animals remaining healthy and tumor-free for more than three months after treatment. These examples show the innovative approach to tumor treatment enabled by nanoparticles.

Theranostics

One of the most exciting opportunities that nanotechnologies have brought to the therapeutic field is the possibility of integrating the diagnosis, therapy and follow-up of disease. This is referred to as theranostics, and could be enabled by nanoparticles incorporated inside a drug that can change some property — such as color — once the drug has reached the target (e.g. quantum dots). Drugs could, therefore, have a feedback action. Together with a slow, targeted release system, the nanoparticles could gradually change colour during the drug action, thereby informing doctors of the progress of therapy. This approach is called ‘find, fight and follow’ and could become a reality as a result of the parallel progress in the field of molecular imaging. One vision is that, one day, the entire process of diagnosis, pre-imaging, therapy and post-imaging of a specific disease will be integrated. An example of theranostics is the use of gold nanoshells for imaging and treating cancer cells at the same time.

Regenerative medicine

At times, the only way to treat a disease is the removal of the infected organ or tissue. Such loss can  also derive from an injury or a congenital condition (e.g. vision or hearing impairment). To compensate for the lost or impaired body function, an artificial construct is implanted in the body. Depending on the type, site and extent of the loss, this construct can be in the form of an engineered tissue or an implant.

Tissue and biomaterial engineering

Tissue engineering deals with the fabrication of artificial scaffolds to support the growth of donor cells, which differentiate and grow into a tissue that mimics the lost natural one. This tissue-engineered construct is then implanted in the patient and, in time, resorbed by the body and fully integrated by the host tissue. Current applications of tissue-engineered constructs include engineering of skin, cartilage and bone for autologous implantation (i.e. the implantation of a tissue regenerated by seeding cells of the patient).

The ‘scaffold’ that supports cell growth is the core of this technique. In the body, cells are supported in their growth and function by a natural scaffold, called the extracellular matrix (ECM). This is a very complex and intricate ‘web’ of nanofibres that provide the mechanical architecture for cellular growth.

Moreover, the ECM is filled with small molecules (e.g. growth factors) and proteins that direct many cell processes, such as adhesion, migration, growth, differentiation, secretion and gene expression. The three-dimensional spatial organisation of these ‘cues’ is critical in controlling the entire life cycle of the cell. Ultimately, this three-dimensional nano-architecture guides cells to form tissues as complex as those found in bone, liver, kidney and heart. The biggest challenge in regenerative medicine is the artificial replication of this ‘perfect nano-scaffold’. The ability to engineer materials having a similar level of complexity is now becoming a reality through nanotechnology.

Micro-fabrication techniques derived from the semiconductor industry (such as photolithography or ion beam lithography) have long been used for the fabrication of microstructures to support and control cellular growth: one of the pioneering works in this field was published in the late 1970s. In recent years, new nanotechnology techniques have enabled studies at higher and higher resolution, reveal-  ing the nanoscale detail of the ECM. Analytical tools, such as the AFM, and nanofabrication tools have allowed scientists to fabricate scaffolds with nanoscale features. A great deal of research is now dedicated to engineering scaffolds with tailored material composition and properties, including nanotopog raphy and controlled alignment, to study how these can support and direct cellular growth. The aim is the fabrication of scaffolds that most closely resemble natural ECM. Researchers now have access to techniques that produce macroscale structures with nanometre details. Conventional polymer chemistry combined with new nanofabrication methods is now used to manufacture a wide range of structures, such as nanofibres of different and well-defined diameters and surface properties; nanofibrous and porous scaffolds; nanowires, nanotubes, nanospheres and nanocomposites.

Close to the field of tissue engineering, and in many cases an integral part of it is biomaterial engineering. Materials used in regenerative medicine are called biomaterials in the sense of being able to trigger and support a biological response. One of the distinguishing features of nanotechnologies is its ability to create new functional materials. This can be exploited in the fabrication of new biomaterials that have better mechanical properties: to increase implant stability and reduce fatigue failure in orthopedic implants for example and materials that have enhanced electrical properties, needed in neural prostheses, for example. Nanotechnologies can also be used to fabricate implants made of materials that are more resorbable, to increase functionality and durability. For example, nanocoatings are being studied which will better integrate synthetic implants with the biological tissue, in order to prevent tissue inflammation and the onset of rejection.

Nanotechnologies are also employed in the fabrication of biomaterials that are responsive to the environment (e.g. responsive to pH or the presence of specific biomolecules) and, for this reason, are called ‘smart biomaterials’. Moreover, research is being conducted to include nanoscale patterns in the biomaterial, which will simulate the natural cues and mimic molecular signaling mechanisms, in order to trigger desired biological events, such as cell adhesion, differentiation and spreading. This could facilitate the fabrication of dynamic implants that are not limited to simply replacing a lost organ but truly restore the loss.

Finally, nano-sized sensors could be inserted inside a biomaterial (e.g. nanowire biosensors) functionalized with receptors that can monitor the presence of small organic molecules, proteins, cells (e.g. cancer cells) and viruses. This could be used to collect information on implant status and activity. This feedback information could be used to maximize implant efficacy and safety.

Tissue and biomaterial engineering have applications in basically all aspects of regenerative medicine  (i.e. neuroprosthetics and neuron regeneration (e.g. spinal cord repair), bone restoration, hearing and vision restoration, motor restoration, etc.).

Nanoengineering bone regeneration

Bones and teeth are material that have to bear complex loads of moving bodies, provide a protective cage for vital organs, anchor tendons and muscles, and act as joints and levers. This functional complexity is reflected in structural complexity. Bones have a complex hierarchical structure at the nano, micro and macro-levels, which determines their amazing properties.

The ‘classic’ way to promote the regrowth of bone after an injury is to provide a scaffold into which bone-forming cells can migrate and grow attached (fused) to the scaffold (Figure 11). In the past, numerous scaffolds have been used, mainly coated with hydroxylapatite which is a natural bone component. More recently, research has focused on trying to mimic the nanostructure of the scaffold. This involves working on the topography of the scaffold (surface nano-roughness) but also at anchoring specific biomolecules to the nano-surface of the scaffold. The idea is to mimic the natural fine organisation of natural bone, which is a combination of nano-topography and (bio)chemistry.

A novel approach is a development of ‘artificial bone’, which means using macromolecules that self-assemble into large structures that mimic the natural structure of bone. This is a bottom-up approach to bone engineering which leads to materials with nanoscale-level control. For example, some researchers have developed a bone scaffold by the biomimetic synthesis of nano-hydroxyapatite and collagen. Collagen is the most plentiful protein in the human body. It is found in most human tissues including bone, cartilage, the heart, eye and skin and gives these tissues their structural strength. These biomaterials assemble into 3D mineralized fibrils that mimic key features of human bone. This material shows some similarities with natural bone in terms of hierarchical micro and nanostructure and three-dimensional porosity. Cells seeded in vitro over this scaffold grew and proliferated well. The advantage of this approach is that the ‘building blocks’ are biomimetic macromolecules: once assembled, the final ‘macro’ material can integrate with natural tissues, opening the way to new clinical approaches to bone regeneration.

When these synthetic nanofibres form, they make a gel that could be used as a sort of glue in bone fractures or to create a scaffold for other tissues to regenerate on to. As a result of its chemical structure, the nanofibre gel would encourage attachment of natural bone cells which would help to patch up the fracture. The gel could also be used to improve implants or hip and other joint replacements.

Nanoengineering neuron regeneration

The loss of neuron functions is one of the most dramatic medical conditions in terms of consequences for the patient: it can interfere with basic functions (e.g. movement) and cognitive capabilities. There are numerous neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, etc.) that are connected with neurological damage (neurodegenerative diseases). Neuron function loss can also derive from a severe accident (spinal cord injury) or a minor one (peripheral neuron damage). The loss or impairment of a person’s neurological function has detrimental effects on their life. The research in this field is therefore massive and covers a very wide range of disciplines and sub-disciplines. There are basically two main approaches to neuron regeneration: tissue engineering and neuron prosthetics. Until recently, these two approaches were fairly separate, mainly due to the type of materials employed in the two approaches: ‘soft’ biomaterials in the first case (biopolymers, proteins, peptides, etc.), and microchip-type materials in the second case (semiconductors, metals, etc.). With the advent of nanotechnologies, these two types of materials are starting to integrate not just in terms of physical attachment (e.g. protein coatings) but in terms of function: for example, in nanotechnologies, biomolecules are used as nanoscale motors, or as energy-harvesting materials. Therefore, in the future the approach to neuron regeneration will be in the form of hybrid nanoscale devices. A short review of neuron tissue engineering now follows and neuroprosthetics are discussed in the next section.

Neuron tissue engineering

The use of scaffolds to encourage neuron regrowth after an injury is an established method. At first, simple biocompatible polymers were used but, nowadays, the need to engineer the scaffold at the nanoscale level in two ways is recognised: physically, by inserting nanoscale ‘paths’ to encourage directional growth, and biochemically, by adding ‘cues’ in the form of neuron growth factors and other essential biomolecules to encourage regrowth (Figure 12). These two elements must be engineered so that their coordinated action results in neuron regrowth. In the last few years, the research in this area has been impressive and nanotechnologies have been the enabling tool. For example, researchers at the Stupp Laboratory (Northwestern University, USA) have fabricated a nanogel of elongated micelles arranged in a nanofibre matrix and demonstrated that this can support the directional growth of neurons. The aim of this and other work is to engineer nano-scaffolds that can support the regrowth of neurons to heal patients affected by neurodegenerative disease or severe neuronal losses, as in the case of spinal cord injury.

Neuroprosthetics

A ‘neuron prosthesis’ is a device implanted to restore a lost or damaged neuron function. There are two main kinds of neuron prostheses: motor and sensory. Much progress in the last decade has been facilitated by miniaturisation. Nanotechnologies offer opportunities to continue this miniaturisation trend but also to introduce new features, such as electrodes that actively interface with the nerves, smaller and more powerful sensors, actuators, and control systems throughout the prosthesis to render it more natural and effective.

A motor neuroprosthetic device takes signals from the brain or motor pathway and converts that information to control an actuator device which executes the patient’s intentions. Examples include artificial limbs or hands. The task is extremely complicated since the motor neuroprosthesis must also be integrated with the owner’s nervous system. Therefore, prostheses have a sophisticated distributed network of control, actuation and feedback. Limb and hand prostheses also need to be mechanically similar to natural limbs, otherwise the task of learning to use them will be difficult. Therefore, to be effective, the device must be designed with nano actuators and nanosensors fully integrated into the control system from design to implementation, including the very special ergonomic interface between patient and device.

What can nanotechnologies do? Progress in current motor neuroprosthetic devices has already been made possible by nanotechnologies, which are enabling more natural prosthesis by providing:

  • smaller and more affordable sensors, processor elements, and the wiring and interconnectors needed to network them in a distributed control system;
  • smaller, more powerful, efficient and responsive actuators that move smoothly, resembling natural movement — possible because these actuators are based on molecular forces;
  • engineering materials that match the strength/weight ratios, elasticity/rigidity, and mechanical energy storage characteristics of key components of natural.

A key contribution of nanoscience is in the form of novel materials (e.g. carbon nanotubes) that can become elements of new sensors, computing elements and even artificial muscles. Nanoscale magnetometers, accelerometers, pressure sensors and gyroscopic devices will be able to detect even minute movements and angle changes more precisely. These nanomaterials will support the design of internal movement devices to render the prosthetic movement more natural and to ensure the accurate transmission of control and feedback information between device and patient. The impact of nanotechnologies will not be in the form of miniaturized robots but rather assemblies of cooperating interconnected networks that compute, communicate, sensing, actuate, etc., to make up a prosthesis that resembles as much as possible the naturally lost limb.

Motor neuroprosthetics commonly integrates sensory neuroprosthetics as well, since the reconstruction of motor functions needs to be associated with the reconstruction of haptics — the sense of touch (or more specifically, the sense of pressure and force feedback from the body to the brain). Haptics, along with vision, hearing, and balance, is an essential component of the stream of feedback information that the nervous system sends to the brain. So-called smart materials (or dynamic materials, meaning materials that change their shape or function in response to an external stimulation) and nanosensors are expected to provide many options to implement sensory neuroprosthetics.

Research in the area of motor and sensory prosthetics is very active and is not only directed to the fabrication of human motor prosthesis but also to robotics for computer-assisted surgery, deep-marine investigation, astronomy, etc.

In addition to neuroprosthetics that restores motion functions, vision and auditory neuroprosthetics are also extremely important. Both technologies have made enormous progress in the last decade and much has been enabled by micro and nanotechnologies. One such example is cochlear implants, which are a type of electronic neuroprosthesis implanted in the middle ear, where they stimulate the ossicles electromechanically, rather than acoustically, through either electromagnetic or piezoelectric transducers. Nanotechnologies have enhanced microelectronics, batteries and micromechanical transducers in cochlear implant devices. Problems in those devices still exist, in the particular refinement of the signal processing (e.g. to recognise voice pitch in music), improvement in their long-term biocompatibility (build-up of biofilms and plaques) and prevention of bacterial fungal infections. Nanomaterials are expected to have an important impact in all these areas.

Neuronal stimulation, monitoring and pain management

The cardiac pacemaker is one of the best-known and most widely used neuroprosthetics. Other types of electronic stimulators are cardiac defibrillators, cochlear implants, bone-growth stimulators, neural stimulators for the deep brain to control tremors in Parkinson’s disease, neuronal stimulators for spinal cord restoration, sacral and other nerve stimulators. Nanotechnologies are impacting these electronic stimulators through improved battery technologies, biocompatible materials and surface treatments for enclosures and leads, electrode miniaturisation and efficiency improvements, and smaller-sized integrated circuits for control and power with increased speed and processing capabilities.

Electrical stimulation of neural tissue by surgically implanted neuroelectronic devices is already an established modern therapy. Integrated micro and nanoscale devices allow many more electrodes to be applied to the target site with fine resolution and in a coordinated, dynamic way. Recording of neural activity is also implemented using nanoscale electrodes since a much larger number of recording sites is possible. These implanted probes must be resistant to challenging environments, so the nanoscale surface engineering of these probes is essential. In addition to protecting the probes, nanotechnologies are contributing in developing improved active interfaces between neurons and electrostimulation devices.

An example of an electronic stimulator is a deep brain stimulator. This device will make it possible to treat patients with severe Parkinson’s disease — a disorder of the central nervous system that often impairs the sufferer’s motor skills, speech and other functions. It has been found that the uncontrollable tremor of patients can be prevented if a fine nano-size electrode delivering a continuous electrical stimulus is inserted into the brain. This precise electrical stimulus has the effect of eliminating the tremors.

Reduction in size and power requirements with the integration of microelectronic devices makes it feasible in many cases to power an implanted device by RF electromagnetic transmission of power, thus eliminating wires and batteries. This is already the case for implanted pacemakers. Improvements in energy storage through nanoengineered energy materials, such as supercapacitors and conductive polymers, coupled with the low power requirements of nanoengineered electronics, will allow huge improvements in terms of size and the capabilities of such devices. These devices make it possible to perform electrical stimulation at selected points of nervous, sensory and neuromuscular systems. Such improvements might eventually make it possible to use implanted electrical stimulation for bone and tissue grafts and to stimulate functions in the endocrine system and other organs.

Non-invasive brain-machine interfaces

The control of physical objects by the power of thought alone has always captured the imagination of man. Until recently, this possibility was only envisaged in science fiction. Now, with the aid of new technologies, and as a result of decades of studies on neuron activity in the brain, the control of machines and computers by the brain is becoming a reality. Systems are being developed where the patterns of neuronal firing in the brain are translated into electronic controls to support the communication, mobility and independence of paralyzed people. This is possible because the firing of neurons and the travel of ion currents along axon membranes generate an electrical current, which, in turn, generates a magnetic field. A steady electrical current generates a static magnetic field, but if the electrical current changes (due to neuronal activity), so does the magnetic field. Conversely, a change in the external magnetic field can induce a change in electrical (neuronal) activity. Therefore, magnetism can become a non-invasive communication tool with nerves without implanted electrodes and painful transcutaneous shocks.

The technique is called magnetic monitoring and it requires extremely sensitive magnetometers because the magnetic fields produced by brain activity are very small. Today, magnetoencephalography (MEG) can map brain activity on a 1 mm grid or less. The first generation of MEG equipment was very bulky, requiring shielded rooms, high power consumption, cryogenic cooling of detectors and significant processing time. The technique has so far been limited to research labs or extremely specialized medical investigations. Nanofabrication is enabling a reduction in the size of most of the components of MEG equipment (sensors, magnets, etc.) and new concepts are being developed: in prototypes, this progress has already led to thousandfold improvements in sensitivity and reductions in size and power requirements by factors of 10 to 100.

Magnetism can also be used to induce electrical currents in the neuron cell membrane such as those induced by implanted electrodes but without physical contact. Magnetic stimulation is a new medical technique that requires strong magnetic fields that must vary or pulse in order to generate an electric field. The impact of nanotechnologies, in this case, is the nanofabrication of compounds and alloys that produce better high-temperature conducting materials. This will make it possible to reduce the size of the device and the cryogenic environment needed for the performance of superconducting magnets. Nanoparticle thin films are also being developed as shielding materials.

Numerous new nanoscale magnetometer designs are being developed, one of which is the optical atomic magnetometer. This instrument is based on the interaction of laser light with atoms oriented in a magnetic field in a gas phase. The instrument measures the change in alignment when atoms with a magnetic spin moment interact with a beam of a laser. In the absence of a magnetic field, the atoms will align with the electrical and magnetic field of the laser beam crossing the atoms. Any disturbance by a magnetic field will disorient the alignment with the beam, reducing the amount of light transmit- ted through the gas. A prototype of such a system has been developed by NIST (USA) containing about 100 billion atoms of rubidium gas in a vial the size of a grain of rice. The change of spin was easily detectable and scalable to much smaller sizes. The NIST prototype was able to detect the heartbeat of a rat. Researchers predict that with their small size and high-performance such sensors could lead to magneto cardiograms that provide similar information to an electrocardiogram (ECG) without requiring electrodes on the patient’s body, even outside clothing. This technique could become a realistic alternative to MRI and PET imaging, without the injection of contrast-enhancement agents or tracers. What is really exciting is that, even with the laser and heating components, this new device uses relatively low power and can be extremely small compared to any current magnetic stimulation device. It might one day be possible to use sensors to make portable MEG helmets for brain-machine interfaces.

Although much progress has been made and much research is underway, there are some major obstacles to overcome before brain-machine interfaces become a reality. Wireless signal transmission from brain implants is still futuristic, along with wearable magnetic brain-machine interfaces. Another challenge is the optimization of the microelectrodes that record neuronal activity, which tends to degrade in time due to biofilm formation. The risk of infection is also a major problem. Better engineering of interfaces using nanoengineered materials is needed to improve biocompatibility and durability and to allow lower stimulation potentials.

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