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.
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4. Prausnitz MR and Langer R. Nat Biotechnol 2008;26(11):1261.
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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.