Mosquitoes are known to cause millions of deaths worldwide annually due to their transmission of pathogens, such as malaria, when feeding on hosts. Mosquitoes use a combination of numbing agents, slow vibrations, and their proboscis (feeding tube) in order to pierce blood vessels and suck the blood of hosts without causing pain. To combat infectious diseases, vaccines are often injected using man-made needles. Unfortunately, these needles are often painful for the recipient and in some cases, can cause tissue deformation. To address this, researchers have studied the anatomy and mechanism of mosquito feeding to further elucidate the painless process and to propose mosquito-inspired microneedle designs.

Microanatomy of the Mosquito Proboscis

Mosquitoes use their proboscis to feed on hosts. With a length of 2 mm and diameters of only 40-100 μm, the proboscis is composed of a fascicle surrounded by a retractable outer cover called the labium (Figure 1). The labium has hairs at its blunted tip that assists mosquitoes in finding ideal piercing locations on the host. Additionally, the blunted ends of the labium allow mosquitoes to support the fascicle and promote blood vessel piercing. The fascicle is comprised of several elements, or stylets. One of these stylets is the labrum, which is pointed, hollow and responsible for sucking host blood. Further studying of the mosquito labrum revealed that it is a viscoelastic material, meaning its properties change with different frequencies. The serrated-shaped maxilla and sharp mandibles are other stylets that are main contributors to the mosquito’s ability to pierce blood vessels. The final stylet is called the hypo-pharynx and is responsible for releasing mosquito saliva just before the piercing and after blood sucking is complete.

Figure 1. Illustrated microanatomy of mosquito proboscis

Mechanism of Painless Mosquito Piercing

Upon finding a host, mosquitoes use the tip of the labium to search for a suitable spot for feeding. Mosquitoes then begin to insert their fascicle into the host’s skin at a frequency of approximately 15 Hz, with a vibratory motion of 40-90 μm and an insertion force of 10-20 micronewtons (three times lower than the lowest insertion force reported by a standard man-made needle). Because the maxilla is serrated, and the mandibles are sharp, little insertion force is required to pierce the skin. The lowered insertion force has been reported to reduce tissue deformation, thus reducing nerve sensation or pain. Once the tip of the fascicle is inserted, the hypopharynx releases saliva containing pain-reducing numbing agents under the skin of the host. The search for blood vessels involving the tip of the labrum is a hit or miss process, and sometimes requires several attempts. Once located, a vibratory motion is used again to pierce the blood vessel, however because the blood vessel is softer than skin, only the labrum of the fascicle pierces and at a much lower frequency of 5 Hz. Once the mosquitoes replete, the hypopharynx releases more saliva which contains anti-blood clotting agents.

Biomedical Advancements for Mosquito-inspired Microneedles

Researchers have proposed and developed designs for microneedles inspired by the mosquito proboscis and feeding mechanism. Strategies to reduce the penetration force have been explored in the last few years, including creating more pointed tips which effectively reduce penetration force. The angle of the needle also impacts penetration force, with studies showing that a 15-degree needle tip has a penetration force 3 times lower than a 75-degree needle tip. Gurera et al. proposed a design to modify commercially available microneedles made up of a medical grade polymer (Figure 2). In this proposed design, the microneedle would have a channel for fluid passage, a serrated design, and a numbing agent secretor, similar to the labrum, maxilla, and hypopharynx of the mosquito proboscis, respectively. It is proposed that the microneedle be made of a viscoelastic material similar to that of the labrum. Additionally, a vibratory actuation is necessary for the piercing to take place. All of this will be within a shell that ensures microneedle stability and prevents buckling. Advancements since have described several microneedles inspired by the mosquito proboscis. Suzuki et al. employed three-dimensional laser lithography to develop a two-part microneedle that consisted of half-needles with a semi-circular channel and jagged edges representing both the mosquito labrum and serrated maxillae. Fluid can be introduced into these channels through small holes and capillary action is used to draw up liquids or blood. Researchers were able to confirm that the microneedle could penetrate a layer of polydimethylsiloxane using vibratory motion. The use of microneedles to efficiently deliver protein subunit vaccines have also been reported in ex vivo studies on healthy human skin tissue. In these studies, microneedles successfully administered vaccines transcutaneously, an administration method that has been reported to generate stronger immune responses than deeper subcutaneous injections. In a recent study, Li et al. explored the use of a mosquito-proboscis-inspired needle as a more accurate method of acquiring needle biopsies that reduce tissue deformation and displacement, which are issues commonly seen using standard needles. The needle is designed to have harpoon-shaped notches at the tip and needle-cannula reciprocating motions for incremental insertions. The notches on the tip mimic the mosquito maxillae by reducing friction during penetration, anchoring the surrounding soft tissue, and reducing tissue deformation or displacement. The reciprocating motions of the needle and cannula mimic the insertion vibratory motions of the mosquito fascicles. However, further work is required to establish optimal notch shape and geometry and to investigate the pain associated with using this mosquito-inspired needle.

Figure 2. Microneedle schematic and working mechanism

The Future of Mosquito-inspired Microneedles

While the biomedical field continues to investigate the use of mosquito-inspired microneedles as tools for drug delivery, some caveats of the technology remain. Drawing large volumes of blood or pumping large quantities of intravenous fluids through microneedles is likely not possible simply due to the capacity of the needle. Additionally, as the microneedle design becomes more complex, the cost will be much higher than traditional needles. Despite this, the development of microneedles that reduce pain is beneficial for administering therapeutics in children and adults with trypanophobia (phobia of injections/needles), thereby warranting further engineering developments.


References

1. Gurera, D. et al. Lessons from mosquitoes’ painless piercing. (2018) J. Mech. Behav. Biomed. Mater. 84. doi: 10.1016/j.jmbbm.2018.05.025.

2. Lenau, T. A. et al.Mosquito inspired medical needles. (2017) Proc. SPIE. 10162, Bioinspiration, Biomimetics, and Bioreplication. doi: 10.1117/12.2261399

3. Sharma, S. et al. Recent advances in microneedle composites for biomedical applications: Advanced drug delivery technologies. (2019) Mat. Sci. Eng.:C., 103. doi: 10.1016/j.msec.2019.05.002

4.Suzuki, T. et al. 3D laser lithographic fabrication of hollow microneedle mimicking mosquitos and its characterisation. (2018). Int. J. Nanotechnol. 15. doi:10.1504/IJNT.2018.089545

5. Li, A.D.R.et al. Mosquito proboscis-inspired needle insertion to reduce tissue deformation and organ displacement. (2020). Sci. Rep. 10.doi:10.1038/s41598-020-68596-w

6. Uppu, D. S. S. M. et al. Temporal release of a three-component protein subunit vaccine from polymer multilayers. (2020) J. Control. Release. 317. doi: 10.1016/j.jconrel.2019.11.022

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Baweleta Isho

Baweleta is a Ph.D. student at the University of Toronto in the Department of Immunology. She is currently under the supervision of Dr. Jennifer Gommerman and researching how maternal mucosal immunity influences autoimmune diseases. Apart from research, Baweleta enjoys hiking, attending musicals, and engaging in scientific outreach events for the general public.
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