Drug delivery is about improving the efficacy and safety of therapeutics by getting the right dose of the right drug to the right place at the right rate and time. Approaches to drug delivery have existed for many hundreds of years; Egyptian physicians created oral tablets and ointments, and physicians began to use intravenous delivery after the circulatory system was first described in 1657. Controlled release technologies date back to the mid-1900s. [1]
The benefits of using a drug delivery system include: [1, 2]
• delivery over long periods
• greater patient convenience
• delivery of otherwise hard-to-formulate drugs, such as large biomolecules, poorly water-soluble drugs, or drugs with a narrow therapeutic window
• delivering drugs across physiological barriers, for example the skin, blood-brain barrier and blood-retinal barrier
• localized delivery reducing systemic toxicity and allowing lower doses of drugs.
The challenges that drug delivery development faces include: [1-3]
• incorporating and controlling complex dosing schedules or personalised dosing into a delivery system
• dealing with variable drug responses triggered by periodic biological fluctuations
• delivering multi-drug regimens
• keeping drugs stable while held in the delivery system.
Drug delivery systems range from gels and patches, through microspheres and nanoparticles, to complex devices such as external or implanted pumps and microelectromechanical systems (MEMS).
An introduction to microelectromechanical systems
MEMS are small, integrated devices that combine electrical and mechanical components, and have been made possible by the advances in microfluidics and electronics miniaturisation. These range from simple systems with no moving parts to highly complex systems. MEMS can be aseptically manufactured using biocompatible materials, and they can be hermetically sealed. MEMS drug delivery devices generally consist of three components: drug chamber, drug release mechanism and packaging, and may incorporate sensors, channels, pumps, valves, needles, membranes and single or multiple drug reservoirs. [1-5]
MEMS devices can be implantable or wearable, and have applications in chronic and long-term disease. They can deliver drugs to specific locations, and some can deliver more than one drug. Those with integrated sensors can tailor delivery rates to the patient's needs based on detection of vital signs or biomarkers. [1, 5, 6]
MEMS are small and lightweight and can easily be integrated with electrical and electronic circuits. MEMS devices can be powered or non-powered. Powered MEMS have low power consumption, and may be self-powered. MEMS devices do have a number of downsides, however. They can be fragile, and may fail as a result of contamination, fatigue, friction or wear. [5]
Non-powered MEMS drug delivery
Non-powered MEMS devices can be smaller than powered devices as they need no power supply. Their delivery rate can be modified by the use of different materials or drug formulation, and by the environmental properties at the delivery site. They may have low release rates, however, and only respond slowly to external stimuli. The delivery rate cannot generally be changed or stopped after administration. Non-powered approaches include passive diffusion devices, osmotic pressure, hydrogels and microneedles. [1]
Powered MEMS drug delivery
Powered MEMS devices are more complex and are often larger than non-powered devices, but they have higher release rates, faster responses and can be controlled externally. The micropumps may be electromagnetic, piezoelectric, electrostatic, thermopneumatic, bimetallic, electrochemical or employ a thermal/shape memory alloy, among other approaches. [1]
Powered drug delivery devices allow physicians to tailor drug delivery precisely through real-time monitoring and physical sensors. As an example, an external pancreas combining an insulin pump with continuous glucose monitoring can be programmed and monitored externally via a smartphone or tablet. [1]
MEMS applications: Drug delivery to the brain
Developing effective treatments for central nervous system disorders, including neurodegenerative disorders, stroke and brain cancer, relies on delivering drugs to the brain. The brain, however, is protected very effectively by the blood-brain barrier, blood-cerebrospinal fluid barrier, and the arachnoid barrier, and crossing these is a challenge. MEMS systems that are small enough to be implanted, can be controlled externally with great precision, and can deliver one or more drugs offer a potential solution. [7, 8]
Potential approaches for MEMS drug delivery to the brain include a wirelessly controlled electrolytic probe that could deliver a drug to a region deep in the brain, intratumoral delivery of a chemotherapy drug in glioblastoma, or intracranial drug delivery to brain tumours using a soft biodegradable electronic device where the drug delivery is triggered wirelessly and then the MEMS biodegrades after a specific period of time. [9-11]
MEMS applications: Drug delivery across the skin
Delivering drugs across the skin is a non-invasive route, and is convenient for patients and caregivers. The stratum corneum is the body's first line of defence, retaining water and protecting the body from pathogens. This makes transdermal delivery challenging. Transdermal patches that include chemical penetrating materials can be associated with skin allergies, inflammation and irritation, and these affect adherence to medication. [12]
Arrays made up of hundreds of microneedles can penetrate the stratum corneum and painlessly deliver drugs transdermally and intradermally, including small molecules, proteins, peptides, hormones, genetic material and vaccines. Approaches include: [1, 3, 13]
• Solid microneedles made of silicon, metal, glass, ceramic or polymers can be used to pierce the stratum corneum to improve transdermal absorption via a patch.
Drug coated solid microneedles allow the drug to dissolve into the skin.
• Carbohydrate- or polymer-based microneedles incorporate the drug and break down once inserted, allowing the drug to permeate the skin.
• Hollow microneedles, made of silicon, metal or glass, act as a conduit, delivering the drug from a reservoir.
• Hydrogel microneedles pierce the skin and swell, releasing the drug.
MEMS applications: Drug delivery to the eye
Like the brain, the eye is protected with biological barriers and delivery is challenging. An ex vivo device operated using an externally applied magnetic field could potentially deliver drugs to the sclera, choroid and retina. [14] Microneedles also have potential to deliver drugs to the eye. Approaches studied include a patch in the form of a contact lens with dissolvable needles carrying the drug, antibiotic cryoneedles for bacterial infection, and nanoparticle-loaded microneedles to administer drugs to the back of the eye, facilitated using iontophoresis. [13]
References
1. Cobo, A., R. Sheybani, and E. Meng, MEMS: Enabled Drug Delivery Systems. Adv Healthc Mater, 2015. 4(7): p. 969-82.
2. Mendoza, L.A.V., et al., Recent Advances in Micro-Electro-Mechanical Devices for Controlled Drug Release Applications. Front Bioeng Biotechnol, 2020. 8: p. 827.
3. Lee, H.J., et al., MEMS devices for drug delivery. Adv Drug Deliv Rev, 2018. 128: p. 132-147.
4. Pandey, Y. and S.P. Singh, Recent Advances in Bio-MEMS and Future Possibilities: An Overview. Journal of The Institution of Engineers (India): Series B, 2023. 104: p. 1377-1388.
5. Chircov, C. and A.M. Grumezescu, Microelectromechanical Systems (MEMS) for Biomedical Applications. Micromachines (Basel), 2022. 13(2).
6. Mishra, A., Emerging Market Trends For Drug Delivery Devices. Drug Delivery Leader, 5 October 2023. Available from: https://www.drugdeliveryleader.com/doc/emerging-market-trends-for-drug-delivery-devices-0001.
7. Tian, M., Z. Ma, and G.Z. Yang, Micro/nanosystems for controllable drug delivery to the brain. Innovation (Camb), 2024. 5(1): p. 100548.
8. Villarruel Mendoza, L.A., et al., Recent Advances in Micro-Electro-Mechanical Devices for Controlled Drug Release Applications. Front Bioeng Biotechnol, 2020. 8: p. 827.
9. Yoon, Y., et al., Neural probe system for behavioral neuropharmacology by bi-directional wireless drug delivery and electrophysiology in socially interacting mice. Nat Commun, 2022. 13(1): p. 5521.
10. Saxena, V., DNAtrix signs agreement to utilize Alcyone's MEMS platform for direct drug delivery into glioblastoma. Fierce Pharma, 26 May 2015. Available from: https://www.fiercepharma.com/drug-delivery/dnatrix-signs-agreement-to-utilize-alcyone-s-mems-platform-for-direct-drug-delivery.
11. Cicha, I., et al., Biosensor-Integrated Drug Delivery Systems as New Materials for Biomedical Applications. Biomolecules, 2022. 12(9).
12. Murphrey, M.B., J.H. Miao, and P.M. Zito, Histology, Stratum Corneum, in StatPearls. 2024: Treasure Island (FL).
13. Umeyor, C.E., et al., Biomimetic microneedles: exploring the recent advances on a microfabricated system for precision delivery of drugs, peptides, and proteins. Future Journal of Pharmaceutical Sciences, 2023. 9: p. 103.
14. Pirmoradi, F.N., et al., Controlled Delivery of Antiangiogenic Drug to Human Eye Tissue Using a Mems Device. 2013 IEEE 26th Int Conf Micro Electro Mech Syst MEMS 2013 (2013), 2013. 2013.