4.1.1. Prokaryotic and eukaryotic cells. Main components

We have already studied the different biological macromolecules, which comprise the main components of cell structure. So, we are now in position to deal with a new topic within this section: cell biology.

In the same way that bricks are the basic building blocks of a wall, cells are the building blocks of living organisms.

There is a huge range of cells, each one specialised in a particular function: growth, development and daily maintenance of the organism, but all of them share some fundamental features.
Among the diverse types of cells we find, for example, immune system cells that protect us against bacterial infections, blood cells that carry oxygen and nutrients throughout our body or epithelial cells that protect the body surface and cover organs and body cavities.

Cells are considered the smallest unit of a living being. When several cells of the same class interconnect with each other sharing a common function they become a tissue. Several tissues form an organ and several organs make up a system (nervous, circulatory, digestive systems…). Lastly, the union of several systems working together and in concert comprises an organism like the human being.

Cells are classified into two major groups: prokaryots and eukaryots. But all of them have four basic components: the cell membrane that protects it from outside, the cytoplasm that is composed of the cytosol with a jelly consistency and floating on it other cell components, the DNA that contains the genetic information of the cell and the ribosomes that synthesise proteins..

In prokaryotic cells, the organism (most of the time unicellular) lacks a nucleus with what its DNA located in the cell centre, or ‘nucleoid’. Bacteria and archaea^[1] belong to this category.

On the contrary, protist^[2], fungi, plants and animals cells are eukaryotic cells, which differ from the prokaryotic cells by having a nucleus that encloses its genetic material (DNA) surrounded by a membrane, a large variety of organelles^[3] limited by membranes and several rod-shaped chromosomes.

Due to the purpose of this blog, I will only focus on the components and functions of eukaryotic cells and particularly on animal cells.

The plasma membrane

We start the study of the diverse cell components with the plasma membrane or cell membrane, which separates the interior content of the cell from the external environment.

It consists of a lipid bilayer with many embedded proteins in it, which controls the movement of water, ions, oxygen, organic molecules and waste disposal (carbon dioxide and ammonia) between the inside and outside of a cell.

Microvilli located on the wall of the small intestine are an example of plasma membranes specialised in the absorption task. They are in charge of absorbing the nutrients from the digested food.
In the case of celiacs, the consumption of gluten (a cereal protein) causes an autoimmune respond that attacks these cells causing malnutrition, abdominal pain and diarrhoea.

The cytoplasm

The cytoplasm is the region between the plasma membrane and the nuclear membrane.
It has a jelly-like and semisolid consistency called cytosol, on which the organelles are suspended.

Also the cytoskeleton and a number of biochemical substances, such as amino acids, nucleic and fatty acids, polysaccharides, simple sugars and sodium, potassium and calcium ions form part of the cytoplasm.
In the cytoplasm a large range of metabolic reactions, like the synthesis of proteins, take place.

The nucleus

The nucleus is the most significant organelle in the cell. It contains the DNA and leads the synthesis of proteins and ribosomes.

The nuclear envelope

The nuclear envelope is a double-membrane structure, in which both the inner and the outer membranes are formed by phospholipid bilayers (to revisit what a phospholipid bilayer see the post: “Lipids”).
This structure has a set of pores on its surface to facilitate the movement of ions, molecules and RNA between the nucleoplasm and the cytoplasm.
The nucleoplasm is a semisolid fluid ubicated inside the nuclear membrane where the chromatin and the nucleolus are.

Chromosomes and chromatin

In eukaryotic cells, chromosomes are structures inside the nucleus made up of DNA and therefore, the hereditary genetic material.
Each eukaryotic species has a particular number of chromosomes in its cell nuclei, which in the case of human beings is 46 (23 pairs).
Chromosomes are only distinguishable when the cell is about to initiate the cell division process. When the cell is in the other phases of the cell cycle, the chromosomes join certain proteins (histones) forming a complex known as chromatin, which looks like a tangled skein.
Chromatin characterises the substance that forms the chromosomes both in decondensed and condensed states.

The nucleolus

The nucleolus is the part of the nucleus that aggregates the ribosomal RNA (rRNA) with specific proteins to assemble the ribosomal subunits. These subunits are then transported to the cytoplasm where they are put together. This is the way in which the nucleus performs one of its principal functions, the synthesis of ribosomes.

Ribosomes

Ribosomes are the organelles responsible for protein synthesis. They are made up of two subunits: large and small subunits.
They can be found in groups, or individually next to the cytoplasmic side of the plasma membrane, the endoplasmic reticulum or stuck to the outer membrane of the nuclear membrane.

Ribosomes receive instructions from the nucleus to produce proteins by means of DNA, this DNA is transcripted to mRNA and this one gets to the ribosome. Once there, the code provided by the nitrogenous bases of the mRNA is translated in a set of amino acids with a specific order, giving rise to the required protein.

Ribosomes are abundant in those cells that synthesise large amounts of protein, like pancreatic cells, which produce multiple digestive enzymes.

Mitochondria

Mitochondria are usually known as the energetic centre of cells, they take charge the production of the most crucial energetic molecule for cells: ATP (adenosine triphosphate). This molecule is generated using glucose and other nutrients during cellular respiration. During this process, mitochondria use oxygen and produce carbon dioxide as waste, which is expelled from the organism when we exhale.

Mitochondria are oval-shaped with a double membrane (phospholipid bilayer with embedded proteins) and have their own ribosomes and DNA.
Their inner layer has a set of folds called mitochondrial cristae, surrounded by the mitochondrial matrix. Both develop different roles in the cellular respiration.

Peroxisomes

Peroxisomes are small, spherical organelles surrounded by a monolayer membrane.
They carry out oxidation reactions that break down amino acids and fatty acids, as well detoxifying poisons that enter our body.
For instance, the peroxisomes of hepatic cells must detoxify the alcohol we consume.

Vesicles and vacuoles

These organelles are sac-shaped and their functions are transport and storage. The main difference between them is their size (vacuoles are larger) and the fact that vesicle membranes can fuse with the plasma membrane or with membranes of other components inside the cell.

The centrosome

The centrosome is a microtubule-organising centre (MTOC) located near animal cell nuclei. Centrosomes are made up of two structures that are perpendicular to each other named centrioles. These centrioles are cylinders of nine triplets of microtubules each.

The centrosome replicates before starting cell division and the centrioles pull the duplicated chromosomes to the opposite poles of the cell during its division stage.

Lysosomes

Lysosomes are dumps of cells. Their pH is more acidic than cytoplasm´s, which favours the fact that their enzymes are more active and assist the degradation of nucleic acids, lipids, polysaccharides and even the recycling of organelles that are no longer necessary for the cell by enclosing and digesting them.

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[1] Unicellular microorganisms similar to bacteria.
[2] Unicellular organisms that form colonies at times.
[3] Small organs specialised in cell functions, in a similar way to our body organs.

Sources: OpenStax College, Biology. OpenStax College. 30 May 2013.
              http://michelleburden.weebly.com/cell-types-prokaryotes-v-eukaryotes-plant-v-animal.html
              http://cosbiology.pbworks.com/w/page/11556247/Lesson%204-02%20Prokaryotes%20and%20Eukaryotes
              http://ernsstev.com/bilayer-pattern-in-cell-membrane/
              http://www.biologyexams4u.com/2012/11/difference-between-chromatin-and.html#.Vu1BANI7uSp
              http://jptregularbio.pbworks.com/w/page/79985510/Cells
              https://oggisioggino.wordpress.com/2013/11/01/las-celulas-procariotas-y-eucariotas/
              http://www.studyrankers.com/2015/06/cell-the-unit-of-life-class-11th-ncert-solutions.html

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1.4.1. Clinical research: Overview

Those compounds that have passed the preclinical phase are tested in human beings (clinical research).
This kind of research has significant associated issues of a scientific, ethical, social and economic nature.

In all developed societies it is mandatory to prove the efficacy and safety of drugs before commercialising them, a task that is fulfilled by clinical trials.

Clinical trials are defined as research studies in human beings to determine or confirm clinical, pharmacological, pharmacodynamic effects and/or detect adverse reactions and/or study the absorption, distribution, metabolism and excretion of a drug in order to establish its safety and efficacy.

Clinical tests are based on documentation, both national and international regulation and a series of ethical codes, declarations and international conventions.

Over the last fifty years hundreds of thousands of compounds have been produced, but only 10% of them have passed clinical evaluation, and even within this group some of them were withdrawn after being put on the market due to safety and efficacy reevaluations.

The methodology of clinical research can be carried out via one of the following procedures:

▣      Experimental: In experimental tests, researchers design the study, select the patients, establish the treatments and variables to study.

▣      Observational: Researchers are mere observers, without altering or intervening the habitual clinical practice.

Within the experimental tests, we find:

▣      Randomised trials. In these trials, patients are allocated to one treatment or another (often a placebo) in a random way. This is the procedure demanded by regulatory agencies to avoid bias in data interpretation before giving the authorisation to market the drug.

▣      Non-randomised trials. Here, patients are not allocated randomly.

Among the observational studies to develop the complete efficacy and safety profile of a drug after its commercialisation, we have:

▣      Case-control studies. Participants are chosen according to they have or not a certain disease and it is investigated if they were exposed or not to a factor of interest. The exposed group and the control group are compared.

▣      Cohort studies. The frequency of a sickness is compared between two populations, one exposed to a risk factor and the other population are not.

▣      Cross-sectional studies. They examine the relationship between an illness and a set of variables in a certain population at a given point in time.

Clinical trials chronologically go through three phases until achieving marketing authorisation for the drug. Once the drug is commercialised, it begins its phase IV, which lasts the whole lifespan of the drug. In Phase IV the drug can be removed from the market if undesired effects, not detected in the three previous stages, are identified.
These new side effects can be discovered when the drug is distributed among thousands of patients.

The measured efficacy in these real conditions is called effectiveness to distinguish it from the efficacy measured prior to drug distribution on the market.

Sources: CEU Universidad San Pablo: Farmacología Básica, 2013.
              http://cmidd.northwestern.edu/about/drug-discovery-and-development-process/
              http://indacea.org/desarrollo-de-medicamentos-1/

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3.5. Nucleic acids

DNA and RNA are the most important biological macromolecules for the continuity of life.
DNA molecules contain the genetic material of all living organisms, from bacteria to multicellular mammals.
In prokaryotic cells DNA is not enclosed inside a membranous envelope, but is in eukaryotic cells where it is located inside the nucleus and organelles.

In eukaryotic cells, DNA along with some proteins, called histones, form chromatin (the material from which eukaryotic chromosomes are made), which can contain tens of thousands of genes.
DNA is in charge of controlling the activity of cells by activating and deactivating genes.

The other kind of nucleic acid, RNA, primarily conducts protein synthesis and its regulation through the action of three different sorts of RNA (rRNA or ribosomal RNA, tRNA or transfer RNA and miRNA or microRNA). The fourth type of RNA (mRNA or messenger RNA) acts as communication intermediary between DNA and the rest of the cell.

Nucleotides are nucleic acid monomers, which are combined to generate their polynucleotides (DNA and RNA). Each nucleotide is composed of three components: one nitrogenous base attached to a pentose sugar molecule, which, in turn, is attached to a phosphate group.

Nitrogenous bases are organic molecules made up of carbon (C) and nitrogen (N) that are divided into five kinds: adenine (A) and guanine (G) are known as purines, they have two fused rings of C-N. Cytosine (C), thymine (T) and uracil (U) are known as pyrimidines, they only have a fused ring of C-N.
Both purines and pyrimidines have different functional groups attached to these rings.

The DNA molecule comprises A, T, G and C, while the RNA molecule comprises A, U, G and C, therefore, tymine is substituted by uracil.
Another difference between DNA and RNA is that DNA sugar molecule is a deoxyribose (they have a hydrogen atom attached to the second carbon atom of the molecule) whereas RNA sugar molecule is a ribose (they have a hydroxyl group attached to that second carbon atom instead).

Carbon atoms of the sugar molecule are numbered as 1´, 2´, 3´, 4´ and 5´. The phosphate residue joins the hydroxyl group of the 5´carbon and the 3´ carbon of the sugar molecule of the next nucleotide forming a phosphodiester linkage between them.

DNA double-helix structure

In the DNA double-helix structure, the sugar molecule and phosphate group are located outside this structure, whereas the nitrogenous bases lie in the interior like the rungs of a ladder linked by hydrogen bonds, in such a way that A can only pair with T and G can only pair with C. This rule is known as the rule of complementary base pairing.
Each of these pairs is separated from the next one by 0.34 nm; both strands of the double-helix run in opposite directions in such a way that the 5' carbon of one strand faces the 3' carbon of the complementary strand.

During DNA replication, each of these strands are separated and they are used to synthesise a new complementary strand, in such a way that each daughter DNA double helix contains a new synthesised strand and one parental DNA strand.

RNA

Normally, RNA comprises a single ribonucleotide strand held together by phosphodiester bonds. These ribonucleotides contain, in turn, a phosphate group, a ribose molecule (pentose sugar) and one of the four nitrogenous bases (A, U, C and G).

The DNA that controls the activity of the cell uses the mRNA (messenger RNA) to carry its message
Thus, if a cell requires a certain protein, the gene for this product is activated and the nucleus synthesises the mRNA. This mRNA has a complementary sequence to the coding sequence of the DNA has been copied from.
The mRNA crosses the nuclear membrane, gets to the cytoplasm and there it interacts with the ribosomes and other cellular machinery.
To produce the required protein, the mRNA is read in groups of three bases called codons. Each codon codifies a single amino acid.

The second kind of RNA, rRNA, is responsible for the suitable alignment between the mRNA and ribosomes. It also has an enzymatic activity and catalyses the formation of peptide bonds between two aligned amino acids.

The tRNA is in charge of transporting the correct amino acid to the site where the protein synthesis takes place. The base pairing between the tRNA and the mRNA allows for the appropriate amino acid to be inserted in the polypeptide chain.

Lastly, the major function of the microRNA (the smallest of all types of RNA) is the regulation of gene expression by interfering with the expression of certain messages of the mRNA.

Hence, in an organism the information goes from DNA to RNA and from this one to proteins. During the first stage (transcription), the DNA dictates the structure of mRNA and during the second (translation), RNA rules the structure of a specific protein.
This process is known as the central dogma of molecular biology, which is valid for all living organisms except for some viral infections.

Sources: OpenStax College, Biology. OpenStax College. 30 May 2013.
              https://www.windowssearch-exp.com/images/search?q=Antiparallel+DNA+Replication&view=detailv2&&id=CE5B36CC30
              3DB6E9F7C902454DF516328A0882B8&selectedIndex=1&ccid=uEIdkd5u&simid=608029733518446573&thid=OIP.Mb84
              21d91de6e5ee9db88b338c5b77e9aH0&ajaxhist=0
              http://www.scienceprofonline.com/genetics/ribonucleic-acid-rna-structure-and-function.html
              http://guia.bio.br/tag/purinas/
              http://www.discoveryandinnovation.com/BIOL202/notes/lecture12.html
              http://www.ib.bioninja.com.au/standard-level/topic-3-chemicals-of-life/35-transcription-and-transl.html
              http://thelessonlocker.com/kvhs/biology/biology.html

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2.2. Atomic force microscope (AFM)

In the post titled “Top-down and bottom-up approach” I mentioned that, in order to examine and handle objects at the nanoscale it is necessary to develop devices that enable observation of samples at the atomic scale. These instruments are called scanning probe microscopes (SPMs), from which 3D images are obtained at a very high resolution without damaging the analysed sample (an improvement on electron microscopes (TEMs)).

The scanning probe microscopes are divided, basically, into two types: scanning tunneling microscope (STMs), which we studied in the previous entry within this section, and the atomic force microscopes (AFMs), which we address below.

Atomic force microscopes are based on the following operating principle:
The sample topography is scanned by a microcantilever or strip around a few hundreds of microns (micrometres) long, built in silicon or silicon nitride, whose end has an extremely sharp tip and a curvature radius on the order of nanometers.

When this tip approximates the sample surface, the forces between them produce the cantilever deflection according to Hooke’s law^[1].
Depending on the type of tip-sample interaction (whether there is contact or not), the forces measured by AFMs can be: electrostatic, magnetic, capillary forces or Van der Waals interactions...
The deflection that the cantilever experiences is measured by a laser beam focused on the upper surface of this cantilever and reflected in an array of photodiodes that register the laser spot shift.

In contrast with STMs, AFMs can be used in the study of non-conductive samples, and they can perform two types of measurement depending on the application: image (which, in turn, it is divided into contact mode and dynamic mode) and force.

Contact mode

In this operating mode, the bending of the cantilever is kept constant during the sample scan, hence this cantilever is correspondingly moved up and down to keep invariable the pressure force of the tip on the sample. This up and down movement is registered and a specimen image is obtained.
A relatively fast scan speed and the opportunity to scan rough surfaces are its main advantages. Its principal drawback is that it may damage biological samples (soft and delicate), therefore these samples must be strongly adhered to the surface.

Dynamic mode

In the dynamic mode, the microcantilever tip does not come into contact with the sample surface. Instead the strip oscillates at its resonant frequency or just above by a piezoelectric actuator^[2] that determines the tip height over the sample.

The tip-sample interaction modifies the resonant frequency and amplitude. Depending on which of these two properties keeps constant during the surface scan, we have:

▣      Non-contact mode where the resonant frequency is stable. This mode is specially indicated for the study of soft biological samples and thin organic films. Because there is no contact, the samples can be subjected to countless analyses without being damaged.
Among its disadvantages, we find its low image resolution and samples must be examined in ultra-high vacuum environments, to avoid the presence of pollutants on the specimen surface that could interfere with imaging.

▣      Tapping mode where the resonant amplitude does not vary. This method provides high-resolution images of those samples that are susceptible to be easily damaged or are weakly adhered to the analysis surface. The major disadvantage is that the scanning has to be done at a slower speed.

Force mode

In the force operating mode, the tip oscillates vertically while the cantilever deflection is registered.
This method has as its main applications the examination of specific interactions between molecules (antigen-antibody, the complementary strands of DNA), structural interactions (protein folding) or the study of polymer elasticity.

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[1] This law states that the lenghtening of materials is directly proportional to the applied force on the same.
[2] Mechanical devices whose function is provide force to move another mechanical device.

Sources: http://www.dme-spm.com/funktion.html
              https://es.wikipedia.org/wiki/Microscopio_de_fuerza_at%C3%B3mica
              http://www.phy.mtu.edu/nue/images/atomicforce/Nanoscope2.jpg
              http://slideplayer.com/slide/6856881/  
              http://www.biozentrum.unibas.ch/research/groups-platforms/overview/unit/lim/

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1.3.6. Repurposing drugs

So far, we have studied the basics concerning the drug discovery process.
We have seen how these discoveries were made, at the beginning, by serendipity to give way later to the methodogical method: the target-based approach.
We still do not know how the new drugs will be discovered in the future, but biologics, genetics and phenotypic^[1] screening in drug discovery will increasingly play a critical role.

There is another area of increasing interest within the drug development pipeline that, although it does not belong to the discovery process, should be remarked upon. It is usually named drug repurposing, and it is based on giving a known compound a new use.
This practice consists of choosing a compound from the catalogue of shelved drugs that have failed in their clinical trials, or even have been commercialised, for the purpose of treating a different disease.

The main advantage that pharmaceutical developers find in reexamining these known compounds is that their safety profile and chemical properties are already well studied and understood, which considerably reduces the chances of failure in later stages during the development process.

Existing drugs can be repurposed in two fundamental ways:

The first one is to use them for a new or different therapeutic target. Sometimes drugs are shelved because they are considered too “dirty”, i.e. they bind too many targets and give various undesirable side effects. It may be that a different dosage or route of administration can reach a new target, and hence, be used to treat other pathologies.

The second method is based on taking a known target and a known drug for treating a different disease. We can find an illustrative example of this in the medication called finasteride, which originally was developed against prostate enlargement, and later it was discovered that it could stop or even reverse male pattern alopecia.
In spite of the fact that this medication performs on the same target for both pathologies, its approval to treat male baldness was eight years later than the authorisation for prostate enlargement. This was due to the fact that finasteride had to pass successfully a series of clinical trials before receiving its permission to treat the second indication.

A medication that fulfills both types of repurposing is chlorpromazine, which was originally produced as a antihistamine^[2] and later was used as an antipsychotic on account of its sedative effect. While, these are very different illnesses, the drug acts on the same target for both.
Currently, chlorpromazine is used in combination with chemotherapy since its anticancer potential was discovered some years later. This property was learnt thanks to its ability to bind a previously unknown target.

But the medicine that is many times seen as model of repurposing drugs is thalidomide. In principle, this medication was developed to treat morning sickness^[3] in pregnant women.

When this drug was approved, the safety regulations were not as rigorous as they are today, and some years after it was found out that thalidomide was responsible for serious birth defects; 20,000 people were affected worldwide.
As a consequence, this drug was removed from the market for 50 years until the company Celgene studied it again, in order to use it against leprosy and multiple melanoma. After this new research, this medication was authorised again, warning strictly against its use by potentially pregnant women.

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[1] Phenotype: set of an organism's visible traits such as eye and hair color, height...It is the interaction between a genotype and the environment. 
[2] Drug used to reduce or eliminate allergy effects. 
[3] Nausea in pregnancy, usually in the first few months.

Sources: UTAustinX: UT.4.01x Take Your Medicine - The Impact of Drug Development.
              http://www.imujer.com/salud/4707/tratamientos-naturales-para-la-enfermedad-de-la-manana
              http://www.academica.mx/observatorio/noticias/desarrolla-la-unam-f%C3%A1rmaco-controlar-algunos-tipos-c%C3%A1ncer
              http://www.elsevier.es/es-revista-educacion-quimica-78-articulo-avances-el-diseno-farmacos-asistido-90434983  
              http://www.dddmag.com/articles/2007/09/innovative-strategies-drug-repurposing
              https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Thalidomide

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2.2.3. Nanobiosensors

The great potential that nanotechnology offers enables the progress of new devices in the nanodiagnostic field, mainly in nanobiosensors.
Their properties are characterised by the nanoscale at which they are produced. Unlike biosensors , which we studied in the post: "Introduction to biosensors", where their sensory receptors are distanced by hundreds of micrometers, here they are distanced by a few nanometers.

Thus, even sensors constituted by single molecules bound to their surface have been designed. Consequently the process of diagnosis is performed with a much smaller size device, improving portability and the potential for use anywhere.
Also, only extremely small sample quantities (micro or nanolitres) are required to carry out the analysis, so the sample extraction methods are less traumatic and invasive for patients.

These instruments also facilitate the use of samples without fluorescent or radioactive markers, which are used in biological and clinical analysis. This property is essential, since it has been proven that when a sample is not marked or altered before examining, the detection sensitivity significantly increases.

Within nanobiosensors we can distinguish the following categories:

Nanophotonic biosensors

This class of nanobiosensors, also known as evanescent wave biosensors, is based on how the light is transmitted by multiple internal reflections through the optical waveguide, which is a component of the biosensor.

When light is propagated in a medium and passes into a lower refractive index^[1] medium, it is not totally reflected. As a consequence, a light component (called evanescent wave), in each of these reflections, is propagated in the lower refractive index that covers the waveguide. This propagation is really short, a few hundreds of nanometers, but it permits interaction between the light and the detection surface of the sensor, demonstrating which specific bioreceptors anchored to that surface interact with the analysed sample.

With these devices, only a few microliters of sample are necessary to determine protein concentrations or the variations of just one DNA base.

Also, it is possible to evaluate the metabolic state of just a single cell because some of these nanobiosensors have sharp fibre optic (30-50 nm) filaments, which can be introduced into cells through the plasma membrane without harming the cell.
This method facilitates the study of in vivo cell functions (apoptosis^[2], cell division, biological nanomachines…) and it can detect pathological changes in a single cell.

Nanoplasmonic biosensors

In the Surface Plasmon Resonance (SPR) biosensor, a thin metal layer (normally a 50- nm-thick layer of gold) is placed on a dielectric material (a crystal), and its functioning is based on the detection of changes in the refractive index around the separation area between both elements.
By exciting the interface between these two layers (under conditions of total internal reflection) a plasmonic resonance^[3] is activated with a certain angle of incidence.. This angle, which produces a plasmonic wave (with an evanescent character) is very sensitive to the changes from molecular interactions that happen on the metal surface. Therefore, these interactions between the analyte^[4] of the sample and the sensor surface of the biosensor are shown as variations of the resonance angle.

Currently, new biosensors are being developed, which rely on the plasmon resonance phenomenon in nanoparticles. While their detection range would be very similar to the SPRs, their functioning system can be made simpler by measuring light transmission instead of light reflection, in addition to the advantage of the device miniaturisation.

Due to the tiny size of nanoparticles, the electron oscillations are more localised than in the previous case (SPR), in specific areas of nanoparticles. This phenomenon is called ‘Localized Surface Plasmon Resonance’ (LSPR). The colour (wavelength: λ) changes that nanoparticles experience by adsorbing^[5] the (bio)molecules of the examined sample are used to analyse this sample.

An alternative, within this kind of device,, is DNA sensors detecting colour changes produced by the aggregation of gold nanoparticles marked with stranded DNA complementary to the target DNA.

Nanoplasmonic biosensors are characterised by their real-time detection, specificity, high sensitivity and recognisition rate.
Their main applications are found in veterinarian, biomedical and environmental fields as well as in the food industry.

Nanomechanical biosensors

These sorts of nanobiosensors use the deflection or the resonance frequency variation of a microcantilever (as a transducing^[6] method) when they interact with the studied sample. This position variation (Δx) is just a few nanometers derived from the biomolecular identification of the analysed sample.

Because these microcantilevers can be produced in mass at a low cost by standar microelectronic technology, thousands of them can be manufactured to identify thousands of analytes in a single sample.

The sensor area of these microcantilevers is around 1,000 μm², which provides them to test sample volume lower than femtomole (10^-15 moles).

Both photonic and nanomechanical biosensors could help us to obtain unlimited genetic and proteomic information that would offer the discovery of pathogens, new drugs, vaccines and undiscovered mutations of certain diseases in a faster way than the current technology.

Microfluidic devices or lab-on-a-chip (LOC)

This class of instruments uses an electric field to move liquids, particles, molecules or cells through microcapillaries designed on chips of different materials like silicon, crystal, quartz or plastic.

This kind of chip is configured by a large number of integrated microchannels and microchambers, where the examined sample is subjected to complex chemical and biochemical reactions.
The required volume of the sample fluids is very small, therefore the analysis can be carried out very quickly.
It is a portable and disposable detection method with a high grade of automation.

The ultimate objective for all these biocompatible nanodevices is to finally be implanted in vivo inside our organism, where they would perform a similar function to ‘sentinels’ in the presence of the first diseased cells. Some advances have already been made to that effect at the microscale (pills with built-in image cameras), but, without a doubt, this will become one the major research fields in nanomedicine in the near future.

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[1] It describes how light propagates through a certain medium. It is defined as n = c/v, where c is the speed of light in vaccum and v the speed of light in that medium.
[2] Process of programmed cell death.
[3] Excitation or oscillation of conduction electrons at the interface between two materials, in our case a metal layer on a dielectric substrate.
[4] Substance (ion, compound or element) of interest in an analysed sample.
[5] Adhesion of atoms, ions or molecules to a surface.
[6] Process by one signal or energy is converted to another.

Sources: Nanomedicina: aplicación de la nanotecnología en la salud. Laura M. Lechuga. Grupo de Nanobiosensores y Aplicaciones Bioanalíticas
              Centro de Investigación en Nanociencia y Nanotecnología (CIN2). CSIC
              http://www.kennislink.nl/publicaties/de-opmars-van-de-twentse-lab-on-a-chip
              http://images.slideplayer.es/16/5040279/slides/slide_47.jpg
              http://www.mdpi.com/sensors/sensors-10-09630/article_deploy/html/images/sensors-10-09630f1-1024.png  
              https://www.ifm.liu.se/applphys/molphys/research/biosensing_using_nanopart/
              http://www.tcd.ie/Physics/people/Martin.Hegner/ReviewNSST-The_impact_of_STM_and_AFM.html?ntherodt_01.pdf
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