The drug molecules that are supposed to be curing us also need to overcome our body’s defense mechanisms. Let’s look at some of the body’s defenses and the way drugs overcome them, before we examine an unexpected inspiration for a new method of delivering drugs.

Our skin is the largest barrier preventing toxic substances from getting inside our bodies. The intestinal mucosa or the blood-brain barrier is a physiological defense barrier. If a drug molecule can pass through these barriers, the next step to be overcome is the biochemical barrier, where myriad enzymes play a role. Therefore, drug molecules have to be designed with optimal physicochemical properties. These include the proper size, charge, and hydrophilicity (water solubility) to ensure their permeation across our bodies’ biological barriers.

There are a few types of drug delivery systems. They are oral, pulmonary (via inhalation), intravenous (via injection), and transdermal. All of them have their own advantages and limitations.

For oral applications, a drug molecule needs to traverse the epithelial layer of the gastrointestinal tract. Thus, there are many factors which have to be taken into consideration for enhancing the delivery of molecules through the intestinal mucosal barrier. Many of the newer drugs on the market are composed of peptides and proteins, and they cannot be administered orally due to their relatively larger size compared to smaller drug molecules.

The delivery of drugs via traditional injection provides better bioavailability; however, this route has low patient compliance due to injections being painful and accidental needle-sticks. Hypodermic injections also generate dangerous medical waste and pose the risk of disease transmission by needle re-use, especially in developing countries.

Transdermal drugs have become an important form of medication in recent years, as they are non-invasive or minimally invasive. Transdermal drugs have many advantages over other drugs, such as high patient compliance due to the easy accessibility of skin, the avoidance of the gastrointestinal tract, and that they can be self-administered.

The main problem with transdermal drugs is that the skin is a highly effective barrier. The outermost layer of skin, the stratum corneum, is mainly composed of dead carneocytes embedded in lipid layers, and has a thickness of 10-15 μm. This packed structure offers a substantial barrier to the delivery of both small hydrophilic (water soluble) and high molecular weight drugs. Only small lipophilic molecules, which can dissolve in lipids, can pass through the skin. Therefore, alternative methods and devices are needed to deliver hydrophilic and macromolecular (larger) drugs through the skin in a controlled manner.

Numerous chemical and physical methods have been attempted with the purpose of increasing skin permeability for easier drug delivery. As the name suggests, micro-needles are micron-size needles that are applied for transdermal vaccinations, as well as drug and gene delivery. Researchers hope they will increase skin permeability via forming micron-sized channels in the skin, thereby allowing the delivery of therapeutics across the skin barrier. In addition, by careful control of the micro-needles’ mechanical strength and length, it is possible to deliver drugs across the dermal barrier while evading the nerves, thus resulting in a painless administration.

Micro-needles must have a high degree of stiffness (resistance to bending) and enough strength for a successful insertion into the skin. If they’re too flexible, they won’t insert; if they’re not strong enough, they’re fracture. A variety of materials are used to manufacture micro-needles, and they include silicon, glass, metals (e.g. stainless steel, titanium, and nickel-iron), and polymers. Current micro-needle technology is based on imitating the present hypodermic needle geometry and miniaturizing it utilizing a silicon micro-machine process. The designs are fabricated onto a substrate where hundreds of micron-sized needles are formed, and then these micro-needles can be either pressed or scraped on the skin, forming microscopic holes. As a result, skin permeability increases by approximately four degrees of magnitude, allowing the easier delivery of medicine.

The ideal micro-needle needs to be extremely small, with an inner diameter of 10-20 μm. It is very challenging to prepare such small needles, ones that are also strong and flexible. Fortunately, we have a living example to guide our designs: female mosquitos.

The world’s most advanced micro-needles are found in mosquitos. Thus, scientists and engineers have begun trying to mimic a female mosquito’s bite – that is, the way they suck blood from our bodies while also leaving behind their itch-causing enzymes. If such a breakthrough can be achieved, blood drawing or drug injection may be performed painlessly. Researchers from North Carolina State University indicate that if a “synthetic mosquito” capable of drawing blood painlessly can be developed, millions of diabetics worldwide who must draw blood several times a day for glucose monitoring will be able check their glucose numbers without pain.

Mosquito needles are made of two main parts: the fascicle and proboscis. The general shape of a female mosquito needle is a core-sheath structure where the fascicle is the main needle puncturing the skin and drawing blood and the proboscis acts as a surrounding and protective layer for the inner needle. Interestingly, only female mosquitos bite, since their need for human blood is only for the purpose of developing their eggs, not for their nutrition.

Ideally, a micro-needle would mimic the structures of a mosquito’s needle, including the mechanism by which the mosquito penetrates the skin and draws blood. This would make for the painless treatment of many diseases.

To prepare a micro-needle based on a mosquito needle would require extensive knowledge of chemistry, material science, mechanical and structural engineering, and fluid dynamics. After resolving any scientific challenges, these needles would need to be manufactured in high quantities to reach the many people in need. This would require scaling up the fabrication methods in a safe and compliant facility. For such widespread production to happen, the process would have to be widely adopted by patients.

In summary, if researchers can mechanically mimic a mosquito needle, it would be a great achievement in the development of advanced micro-needle technology. It’s incredible that the solution to a major medical problem – the efficient delivery of drugs and vaccines – is already present in nature, at our disposal.

REFERENCES

1. Wang B, Siahaan T, and Soltero R. Drug delivery : principles and applications. Hoboken, N.J.: Wiley-Interscience, 2005.
2. Kalluri H and Banga AK. Journal of Drug Delivery Science and Technology 2009;19(5):303.
3. Arora A, Prausnitz M, and Mitragotri S. Int J Pharm 2008;364(2):227.
4. Prausnitz MR and Langer R. Nat Biotechnol 2008;26(11):1261.
5. Betancourt T and Brannon-Peppas L. Int J Nanomedicine 2006;1(4):483.
6. Ramasubramanian MK, Barham OM, and Swaminathan V. Bioinspir Biomim 2008;3(4).
7. The magical world of the Mosquito, Ibrahim Yildiz, January-February 2010 Issue: 73, Fountain magazine.

Mosquitoes like climates with high humidity and rainfall. While a single raindrop can weigh 50 times as much as a mosquito, how can mosquitos fly and survive under what seems to be a devastating weather condition for them? Andrew Dickerson and co-workers at Georgia Institute of Technology examined the effects of falling raindrops on the flying mosquitoes using high-speed video capture and found that rain does no damage to flying mosquitoes. Upon impact with mosquitoes, the raindrops do not splash and scatter but they merely deform and hold together. This was calculated to be due to the small diameter and the velocity of the drop. On the other hand, given the relatively small mass of the mosquito, the drop does not significantly alter its speed. A partial hit on the mosquito by the falling drop causes the mosquito to rotate around its flight path. Mosquitoes were found to easily recover and resume their flight immediately after the impact. In the case of a direct hit by a raindrop, the mosquitoes were still able to literally separate themselves from the drop after traveling with the drop for a while without lethal damage and resume flight. The researchers further analyzed the impact force of the raindrops on the mosquitoes and found the direct impact to exert around 80 times the gravitational force. This is an extremely high force for larger organisms however, for mosquitoes with a very strong exoskeleton, this turned out to be a minor fraction of 1500 X g, which the researchers tested the mosquitoes and found them to be still able to fly! The outstanding resilience of such a small organism already inspired scientists to start designing very small robots that may serve as airborne search-and-rescue vehicles. But scientists are still very much limited by the basic factor of how small they can go.

What exactly happened in AD 774?

Researchers in Nagoya University of Japan have recently discovered a cosmic mystery when they were analyzing the growth rings of two cedar trees that are as old as 1200 years. All trees are known to incorporate particles from the atmosphere during photosynthesis. Carbon-14 (C14), one of the exceptional elements in the atmosphere, is generally formed by massive solar flares or by supernovae and it is present in very low percentages. Interestingly, researchers found that the cedar tree ring produced during the growth season of AD 774 had about 1.2% more C14 than in the previous years, that is about 20-times more than the usual range of 0.05%. These results indicate that some cosmic event during AD 774 generated a major influx of radiation leading an excessive amount of C14. Only a massive supernova explosion might have been strong enough to create this much radiation. However, if this was a supernova, we should either be able to catch the traces with modern telescopes, or find historic documents reporting this extraordinary cosmic event. But, we simply have no record of anything unusual happening in our skies in that period. Alternatively, a massive solar flare might have created such a radiation. In fact, 13th-century English chronicler Roger of Wendover mentions a cosmic event that could possibly be a solar flare. However, a flare with that magnitude would have been the biggest solar flare ever recorded by our sun and probably would have destroyed the Earth’s protective ozone layer leading to disastrous ecological consequences. Thus, the flare hypothesis seems also unlikely. By now, scientists are only positive that some very energetic event occurred in 774. But what exactly was it? Frankly, their guess is as good as ours.

(Al-Hajj 22:73)

In some verses of the Qur’an, mosquitoes and other small creatures are mentioned; when these verses were revealed to Prophet Muhammad, peace be upon him, some unbelievers sarcastically responded, saying: “This does not seem like the word of God.” They mocked these verses as they thought that God Almighty would not give examples of such “trivial and non-significant” animals in His Book. Later, Almighty God revealed another verse related to these responses:

God does not disdain to strike any parable – (that of) something like a gnat or something greater or lower than it. Those who have already believed know that it is the truth from their Lord. As to those whose unbelief has long been established in their hearts, they say, “What does God mean by such a parable?” Thereby He leads many astray, and thereby He guides many. He thereby leads none astray save the transgressors. (Al-Baqara 2:26)

During the revelation of the Qur’an, biological and physical sciences were not adequate to explain and shed light onto some of the sublime verses regarding these small creatures. However, in this century we have witnessed astounding advances in science and now we are better able to understand the extraordinary structure of such creatures. Once again, we are amazed at the accuracy, precision and eloquence of the Qur’an, which illuminated not only the Age of Ignorance, but also the modern world. Even though for believers the harmony of the universe testifies to the existence of the All-Knowing One without a need for understanding the details of physics or biology, for non-believers masses of learning or years of scientific education may have led them astray. In this article, even though the Qur’anic verses mentioned above speak of flies in general, our focus will be given in particular to the biological aspects of mosquitoes.

Mosquitoes are two-winged flies that belong to the family Culicidae. In nature there are approximately 3,500 species of mosquitoes. They have a pair of scaled wings, a pair of halteres,1 a slender body, and long legs. Their length varies, but is rarely greater than 16 mm (approximately 0,6 inches), and they can weigh up to 2,5 mg. A mosquito can fly for 1 to 4 hours continuously at up to 1 mile/h, traveling up to 6 miles in a night.2 Most species are nocturnal or crepuscular (dawn or dusk) feeders. During the heat of the day most mosquitoes rest in a cool place and wait for evening.

It is widely thought that mosquitoes are insects that live on blood. On the contrary, this is not true, because not all mosquitoes suck blood; only female mosquitoes do. Mentioning the mosquito in the feminine form in the Qur’an can be considered to be one of its miracles, not only because the female mosquitoes are more powerful and complex than the males, but also because they transmit and spread diseases. The male mosquitoes appear only in breeding seasons and they feed only on plant juices.

Females do not require blood for their own survival, but they do need supplemental substances (like protein and iron) found in blood to develop eggs. Prior to and during blood feeding, they inject saliva into the bodies of their source(s) of blood. Female mosquitoes hunt their blood host by detecting carbon dioxide (CO2) and 1-Octen-3-ol from a distance. Circulating blood in animals and humans radiates body heat. Thanks to the sophisticated heat sensors installed in their body, mosquitoes follow body heat and exhaled gases and fly to their target. From an unbiased point of view, that who led to the creation of carbon dioxide and 1-Octen-3-ol must have led to the creation of the sensors of female mosquitoes, allowing them to sense these chemicals. That who created the eggs of mosquito must have been aware of the needs of these eggs. This process alone proves the extensiveness of mercy, knowledge, wisdom and encompassment of a Conscious Sustainer Who is operating behind all these processes.

When mosquitoes land on their prey they search for a thin place on the skin where a great deal of blood is passing. In order for the mosquito to obtain blood it must circumvent the physiological responses of the prey. The mosquito sprays the place from where it is to suck blood with a type of local anesthetic. When blood flows from a cut, with the help of enzymes the blood quickly coagulates. The mosquito uses an elusive mechanism to effectively block the clotting of blood with their saliva, which contains a complex mixture of secreted proteins. Mosquito saliva also contains enzymes that facilitate in sugar feeding as well as antimicrobial agents that control bacterial growth in the sugar. Mosquito saliva contains fewer than 20 dominant proteins.3 Although there has been great progress in determining these molecules and their role in bloodfeeding, scientists are still unable to ascribe functions to more than half of the molecules found in mosquito saliva.

In general, there are four distinct stages in the life cycle of the mosquito: egg, larva, pupa, and adult. The adult is a flying insect, while the larvae and pupae are aquatic and live only in fresh water. All mosquito species lay their eggs on fresh water or on a moist surface. These eggs will not hatch until covered by rising water caused by rainfall, melting snow in the spring, or other such phenomena. The larvae of all mosquitoes live in water and have four developmental periods. In this stage, the larva actively feeds on organic material in the water. The larvae of most species have a breathing tube and come to the surface of the water to get oxygen. The durations of this stage depends on the species and the water temperature. The mosquito pupa is very active and lives in water. The pupa has a comma-shaped body with two visible separate regions. The tail of the comma is the developing abdomen of the mosquito. The abdomen is composed of nine segments. Between each abdominal segment are flexible areas that allow the pupa to swim. Active movement is unusual for most insect species during the pupal stage; however, mosquitoes will dive under water when the surface is disturbed or there is a disruption in light penetrating the water. The pupa has two large “paddles” on the eighth segment of the abdomen that propel it through the water as the abdomen flexes up and down. When the abdominal movement stops, the pupa floats back to the top of the water. A float hair, found on the first segment of the abdomen, helps the pupa to stabilize on the water’s surface. The pupal stage lasts for a few days and this is the stage when all the larval tissues change into adult tissues. The adult mosquito is capable of flying long distances. Males and females mate during the first 3 to 5 days after they have emerged from the pupal stage. Females mate only once. Males generally live for only a week and their primary function is reproduction.

The entire body of the adult mosquito is covered by an exoskeleton layer which provides the body with strength and support. The body of an adult mosquito has three regions, the head, thorax, and abdomen. The head contains the eyes, antennae, palpi,4 and mouthparts of the mosquito. Mosquitoes have compound eyes. This means their eyes are made up of numerous facets. Each facet is capable of forming a separate image. Therefore, the multi-imaging eye allows the mosquito to see movement over a large area, helping it to react quickly. The antennae are important sensory organs for the adult mosquito. They house a very significant sensory structure called the Johnston organ that helps to transmit movements of the antennae to the brain. The antennae differ according the sex of a mosquito. Males have many hairs on their antennae, making them look fury, while females have very few hairs. The mosquito has two sets of wings, the fore wings and the hind wings. The fore wings are used to propel the mosquito through the air, while the hind wings are highly modified structures that help to balance the mosquito during flight. Mosquitoes do not have lungs; rather, they receive oxygen through holes on their skins. These holes open and close according to the amount of oxygen the insect needs to function. Oxygen exchange takes place by diffusion. The mosquito has a needle, a hollow in the upper lip, which has a special cover used while sucking the blood from the skin of prey. The skin is not pierced by this needle, as thought, but by the upper mandible which look like a knife, and the lower mandible which has teeth leaning inward, that works and moves as a saw. The hollow lower lip has a lubricant that gathers the parts of the mouth as one organ. The skin of the prey is pierced by the upper mandible, which works as a knife, and in piercing the needle is inserted until it reaches a vein, and then the mosquito starts to suck blood. This process clearly indicates that mosquitoes have the necessary equipment to survive and sustain life in an amazing manner.

However, mosquitoes tend to carry various disease that spread viruses and parasites; they do not succumb to these diseases themselves. The principal mosquito-borne diseases are viral diseases, like yellow fever, dengue fever and malaria. Mosquitoes are thought to transmit disease to more than 700 million people annually in Africa, South America, Central America, Mexico and much of Asia, with millions resulting in deaths. At least 2 million people annually die of these diseases. The first Qur’anic verse mentioned above is also quite striking in terms of the disease spreading aspect of these insects. A powerless animal can snatch away the health of person who could be regarded as powerful; however, both of them are weak against the will of the One who created them.

Dr. Ibrahim Yildiz is a research associate at University of Miami Chemistry Department.

Notes

1. Halteres are small knobbed structures found as a pair in some two-winged insects.

2. Kaufmann C, Briegel H (June 2004). J. Vector Ecol. 29 (1): 140–53.

3. Valenzuela JG, Pham VM, Garfield MK, Francischetti IM, Ribeiro JM (2002). Insect Biochem. Mol. Biol. 32 (9): 1101–22.

4. Palpi, plural of palpus, are jointed sense organs attached to the mouth of insects.

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