Role of Micro-electromechanical systems (MEMS) in designing drug delivery systems

Why do we need to consider MEMS for drug delivery?

Micro-electro-mechanical systems (MEMS) have drawn the attention of engineers from all over the world. MEMS is a technology that integrates micro-sensors, micro-actuators and microprocessors to produce a system which is of the order of 10-3 to 10-6 m. The reason behind the popularity of MEMS devices lies in their exceptional performance in several areas where their macro counterparts were not effective.

Drug delivery to some organs of the human body is quite difficult and invasive. This is why researchers are trying to find ways to incorporate MEMS devices in drug delivery. Some of the fields of medical science have achieved great success using MEMS devices. Drug delivery using MEMS devices ensures proper dosage and monitoring of the status of the patient using various sensors and control mechanisms.

What are the different types of MEMS drug delivery devices?

MEMS devices used in drug delivery can be classified as follows:

• Based on position of the device:
• Implantable
• External

• Based on working principle of the device:
• Non-powered
• Powered

Implantable MEMS Drug Delivery Device: 

Implantable drug delivery systems are placed completely under the skin (subcutaneously) for providing controlled delivery of drugs at the site of implantation. Implantable MEMS devices are ideal for localised and precise drug delivery. It is mainly used for delivery of insulin, chemotherapeutics, antibiotics etc.

The implantable devices can be used for both active and passive drug delivery. Active drug delivery uses actuators to deliver drugs in a controlled manner whereas passive drug delivery depends on a non-mechanical process(un-controlled).  

    Since these devices are implanted inside the body, the reservoir material must be biocompatible. Materials which are most commonly used include Poly Methyl Methacrylate (PMMA), poly-Dimethylsiloxane (PDMS), SU-8 photoresist, parylene C, polyacrylamide (PAA), medical grade silicone rubber and Pyrex.

Components:

• Micropump
• Reservoir

Single Reservoir-Based Devices:

    In these devices, the drug stored in a reservoir is dosed using a pump and an actuation mechanism to obtain accurate dosing.

Multi Reservoir- Based Devices:

    To avoid dumping of the drug, the drug can be distributed into multiple micro reservoirs. The drug is released from the reservoir by rupturing the capping membrane through various actuation mechanisms, mostly it’s degraded electrochemically. These devices are manufactured with silicon wafers by applying micro-fabrication processing techniques including photolithography and reservoirs are capped with a gold film.

Figure1: Gold caped Multi reservoir

External Systems:

    Microneedles are needles of micron-scale fabricated using MEMS technology and are mainly used for transdermal drug delivery. The skin’s low permeability acts as a barrier for transdermal drug delivery of high molecular weight drugs. The top 20μm of the epidermal layer is known as the stratum corneum and acts as a barrier for most molecules. The skin's nerves are situated a few hundred micrometres below. Microneedles of length approximately 100μm can penetrate the stratum corneum without causing any pain.

Mechanism of drug delivery through microneedles:

    A microneedle device is produced by arranging an array of hundreds of microneedles on a tiny patch. It pierces the stratum corneum, thus bypassing the barrier layer. 

Types of microneedles:

1. Solid microneedles:

One method to deliver the drug into the epidermis layer is to pierce the skin with the microneedles and replace it with drug containing patch to directly deliver the drug into the skin. Non-biodegradable materials such as silicon, metals and glassy carbon or biodegradable polymers like hyaluronic acid, poly (lactic-co-glycolic acid), gelatinmethacryloyl are used.

2. Coated microneedles:

The microneedles are enclosed with the solution of drug or drug dispersion layer and drug is distributed by dissolution of the coated drug layer. 

3. Dissolving microneedles:

Dissolving microneedles are manufactured by encapsulating the drug into biodegradable polymer. After inserting the microneedle in the skin, the polymer dissolves and releases the drug.

4. Hollow Microneedles:

Hollow microneedles contain a void inside which the drug solution is filled. The drug is released into the epidermis directly through the holes at the tips.

Figure 2: Different types of needles

 

Non-powered MEMS Drug Delivery Devices:

    This kind of drug delivery device does not require external power to operate. Drugs are delivered through diffusion, osmotic transport or response to an environmental stimulus.

1. Diffusion-Based: 

Diffusion-Based devices deliver drugs through a polymer membrane. The membrane is made of non-biodegradable solids such as polyvinyl alcohol (PVA), ethylene-vinyl acetate (EVA), polysulfone capillary fiber (PCF), or from biodegradable materials such as polylactic acid (PLA), polyglycolide acid (PGA), polylactic-co-glycolic acid (PLGA), polycaprolactone (PCL), or polyanhydride.

 

Figure 3: Diffusion based device with polymer membrane

2. Osmotic:

An osmotic flow is defined as a physical process in which any solvent moves into a higher solute concentration, without input of energy, across a semipermeable membrane.

Basic Components of Osmotically Controlled Drug Delivery System (Osmotic Pumps):

• Drug
• Osmotic agent
• Semi permeable membrane

3.  Responsive Hydrogels

Responsive hydrogels are three-dimensional, cross-linked networks of biocompatible water-soluble polymers that swell or collapse in response to environmental stimuli like physical (temperature, electric fields, light, pressure, and magnetic fields), chemical (pH and ions) or biological. The drug is loaded into the gel matrix and released on exposure to environmental stimuli.

Figure 4: Responsive hydrogels used to release drugs stored inside 

Powered MEMS Drug Delivery Devices:

Micro-pump Based Devices:

Micropump is an active device that is electrically controlled and uses actuation techniques to deliver specific volumes of therapeutic agents. Micro-pumps are broadly divided into two categories - mechanical and non-mechanical micro-pumps.

 

Mechanical Micro-pumps:

Mechanical micro-pumps use the motion of oscillating diaphragms to pump fluid by exerting pressure. They contain a flexible membrane or diaphragm, an actuator, a pumping chamber, an inlet, and an outlet. Micro-pumps incorporate a physical actuator to accomplish the pumping action.

Non-mechanical Micro-pumps:

Non-mechanical micro-pumps do not require any physical actuation. The fluid is pumped by converting non-mechanical energy into kinetic momentum.

 

FABRICATION

MEMS are the combination of mechanical functions (sensing, moving, and heating) and electrical functions (switching, deciding) on the same chip using micro fabrication technology.

The block diagram for the complete manufacturing process is shown below:

                      

Fabrication:

It is a system of microsensors, micro actuators, and other microstructures assembled together on a common silicon substrate.

Methods of fabrication:

• bulk micromachining:

• wet etching
• dry etching

• photolithography
• surface micromachining
• high-aspect-ratio-micromachining

Materials Used:

• silicon
•  polymers
•  metals
•  ceramics
•  semiconductors
• composite materials

MEMS Fabrication using Bulk Micromachining:

Figure 5: Bulk Micromachining Technique Involving Photolithography

• Firstly, the circuit diagram has to be designed and the circuit should be drawn on paper otherwise by using software like Proteus etc.
• Then, CAD (Computer – Aided Design) is used for modelling and for the simulation of circuits and also used to design the photolithographic mask consisting of the glass plate coated with a pattern of chromium.
• After that, Silicon Dioxide which is the insulating material of a thin film is placed over the silicon substrate and an organic layer responsive to ultraviolet rays is precipitated over the film with the help of spin coating technique. Then, the photolithographic mask and organic layer are placed in contact with each other.
• This whole layer is exposed to UV radiation which allows the pattern mask to be converted into the organic layer. Hydrochloric acid is used to remove the uncovered oxide. It results in an oxide pattern on the substrate which is utilized as a mask.
• Unused silicon is removed(etching). Either by using wet or dry etching the bulk of a substrate is removed. Most popular etchants are HNA (Hydrofluoric acid, Nitric acid, and Acetic acid) and KOH (Potassium Hydroxide).
• A 3D structure or a multi layered wafer is formed by using fusion bonding (direct bonding between layers) or anodic bonding.
• MEMS device is integrated on the single silicon chip.
• Now, the whole assembly is packed to give minimum electrical interference and to give protection from the outer environment. Generally, the packages are made of metal and ceramic. Either wire bonding or flip-chip technology is used to join the chips to the surface using an adhesive material. 

MEMS fabrication using Surface Micromachining

 

Figure 6: Manufacturing of Cantilever Structure using Surface Micromachining

• By using a low-pressure chemical vapour deposition technique, the temporary layer is deposited (an oxide layer or a nitride layer) on the silicon substrate which provides electrical isolation.
• Then, phososilicate glass (spacer layer) is deposited to provides a structural base.
• With use of dry etching technique, the subsequent etching of layers is done. Reactive ion etching techniques can be used where the surface to be etched is exposed to vapour phase etching or to accelerating ions of the gas.
• After that, to form a structural layer, phosphorus-doped polysilicon is deposited.
• To reveal the underlying layers, the structural layer is removed or dry etching is done.
• Then, the oxide layer is removed in order to make the required structure by the spacer layer.
• It is then followed by bulk micromachining technique.

MEMS fabrication using LIGA technique

Figure 7: LIGA Process

• To form a pattern, the layer of Titanium or copper or Aluminium is deposited on the substrate.
• A thin layer of Nickel is deposited that acts as the plating base.
• An X-ray sensitive material like PMMA (polymethyl meth acrylate) is added.
• Then, PMMA is exposed to x-ray radiation; the area that is exposed is removed and the remaining is covered by a mask.
• PMMA based structure is placed into an electroplating bath whereas the removed PMMA areas are covered with Nickel.
• To reveal the required structure, the residual PMMA layer and plating layer is removed. 

What is MEMS Dosing Control Systems?

Dose monitoring and control is a very important aspect of MEMS devices. This is realised using closed-loop feedback systems. Sensors are used to collect information on pressure, dosage, flow rate and state of the device.

Miniaturized sensors are integrated with microfluidic systems or micro-pumps for the measurement of flow or dosage. These sensors employ various techniques like pressure, thermal or electrochemical impedance (EI) to measure the fluid flow.

Pressure sensors use differential pressure measurement to find the gradient which influences fluid flow. In such devices, piezoresistive sensors are used to measure fluid flow.

Figure 8: Drug delivery device having a piezoresistive pressure sensor

EI sensors can track blockage or dose volume in real-time. These are highly sensitive, easy to fabricate and low power consuming devices and can be incorporated easily in a closed-loop feedback system. The only limitation of such sensors is drift.

Valves:

Valves are an integral part of modern drug delivery devices. They are used for regulating the flow and on/off switching. They are very critical for accuracy of dosing and prevention of backflow. Valves can be classified as active (powered) and passive (non-powered). The valve actuation mechanism can be a solenoid, electrostatic, thermo pneumatic, piezoelectric, etc.

SENSORS

What is a sensor?

A device used to measure physical quantity (such as displacement, pressure) by converting it into an electronic signal of some kind (e.g., a voltage), without modifying the environment.

Examples of sensors are light intensity sensor, humidity sensor, temperature sensor, 2 axis accelerometer, and pressure sensor.

What can be sensed?

Commonly sensed parameters are:

• Pressure
• Flow Rate
• Temperature
• Radiation
• Pathogens

Type of sensors:

• Mechanical sensors- Strain gauges, Pressure Sensor, Gyroscopes, Accelerometers and Microphones
• Optical sensors- Direct sensors, Biological light sensors and Indirect Sensors               
• Thermal sensors- Thermo mechanical, Thermo resistive, Acoustic and Biological 
• Chemical & biological sensors- Electronic nose and Electronic tongue 

Accelerometer:

In an accelerometer, capacitance is used as common sensing. So, acceleration is related to change in capacitance of moving mass.  Advantages of this technique are high accuracy, stability, low power dissipation, and simple structure to build. It doesn’t produce noise and variation with temperature. The bandwidth for a capacitive accelerometer is of the order of a few hundred Hertz due to its physical geometry. The air which is trapped inside the IC acts as a damper.

C = (ε0 × ε × A)/D (Farad)

Here, ε0= Permitted free space; εr = Relative material permitted between plates; A = Area of overlap between electrodes and D = Separation between the electrodes.

Figure 9: Moving mass and capacitance.

Gyroscope:

Gyroscopes are devices that measure or maintain rotational motion. It is used to maintain a reference direction or provide stability in navigation, stabilizers, etc.

What are Micro-Pumps?

These are the devices that are responsible for delivering drugs or therapeutic agents into the human body.

Mechanical Pumps

a) Electrostatic:

The membrane of an electrostatic pump is forced to move towards two oppositely charged electrostatic plates applied with an appropriate voltage. Its original position is restored when the voltage is shut off. The electrostatic force is given by,

F= dW/dx=(εAV^2)/ (2x^2)

Here, F is the electrostatic force; W is the energy stored; ε is the dielectric constant; A is the electrode area; V is the applied voltage and x is the distance between the electrodes.

b) Piezoelectric:

Piezoelectric materials like quartz produce voltage when pressure is applied. This induced voltage results in the deformation of the membrane. This pushes the fluid to the required site. Up to 200 V voltage is required to produce a useful deformation. This is its major disadvantage.

Figure 11: Piezoelectric Micro-pump

c) Thermo-pneumatic:

The air inside the chamber is periodically expanded and compressed with the help of heaters. This change in volume results in a continuous movement of the membrane. It generates better displacement as compared to others. But its response time is very high.

∆P=E(β∆T-∆V/V)

Here, ΔP is the pressure change; E is the elastic modulus; β is the expansion coefficient; ΔT is the temperature change and ΔV/V is the fractional volume change.

       

Figure 12: Thermopneumatic Micro-pump

d) Shape-Memory Alloy (SMA):

The membranes of such devices are made of Nickel-Titanium alloy (NiTi). Actuating deformation is produced by heating the membrane. SMAs restore their original shape when the heat is removed. It maintains linearity, can endure high stress and has a longer life. But the need for special materials and high-power consumption are its major disadvantages.

Non-mechanical Pumps

a) Magnetohydrodynamic (MHD):

The driving force for MHD type micro-pumps is the Lorentz force, which is perpendicular to both electrical and magnetic fields. The working fluid must have a conductivity of 1 s/m or higher. Production of bi-directional flow is its major advantage. It can create bubbles due to ionization, which is of primary concern for such devices.

Figure 13: MHD Micro Pump

b) Electrohydrodynamic (EHD):

The electric body force due to an applied voltage E is given by,

F =qE +P∇.E -1/2 E^2 ∇ε+ 1/2 ∇ [E^2 (∂ε/∂ρ) ₍T₎ ρ]

Here, q is charge density; ρ is fluid density; ε is fluid permittivity; T is the fluid temperature and is the polarisation vector.

   The driving force is due to the common effect of an electric field, dielectrophoretic force, dielectric force and electrostrictive force. The conductivity of the working fluid should be between 10-2 to 10-6 s/m.

c) Electro-osmotic (EO):

The fluid with electric conductivity is driven by applying an external field on the walls of the channel. The interface between silica capillary and the fluid contains SiO- ions and makes the electrolyte near the walls protonated. Hence, Coulomb’s force is used to drive the electrolytes towards the cathode by application of an appropriate voltage at electrodes. It is known as “Electro-osmotic Flow”.

   

Figure 14: Electro-osmotic Micro Pump

d) Chemical:

Electrochemical micro-pumps generate bubbles by the process of electrolysis. The gas bubbles generated in the reservoir exerts pressure to release the drug. The chemical reaction at the electrodes is given as follows:

Anode:        2H2O → 4H+ + 4e- + O2 (g)

Cathode:      2H2O + 2e- → 2OH- + H2 (g)

Figure 14: Electro-osmotic Micro Pump

DRUG DELIVERY TO BRAIN

Localised drug delivery to the brain is necessary to treat brain diseases such as brain tumours and Alzheimer's diseases. The MEMS devices used to deliver drugs to the brain is:

1)Implantable- Neural probes/microneedles

2)Non-invasive- Ultrasound transducers

However, delivering drugs to the brain is challenging due to the presence of blood-brain barrier (BBB). The blood–brain barrier (BBB) is a highly selective semi-permeable border of endothelial cells that prevents the entry of large molecules.

The two drug delivery systems to brain are:

1) Direct brain infusion:

It is an invasive method of delivering therapeutic agents to a specific location in the brain. Intracerebral implantation and ICV infusion use diffusion-based polymers while convection-enhanced diffusion (CED) uses hollow cannula or needle for drug delivery. MEMS-based silicon microneedle with an integrated microfluidic channel is prominently used for direct brain infusion.

Figure 16: Concept of multi-functional neural probe capable of drug delivery

2) Drug delivery to the brain through BBB disruption:

The most prominent way to disrupt BBB is through the use of focused ultrasound (FUS). The BBB is disrupted by sonication and then the drug is delivered through intravascular injection at that site.

OCULAR DRUG DELIVERY

Ocular drug delivery system (ODDS) uses MEMS technology to deliver drugs to the eye against any ailment or disorder involving or affecting vision. It varies from simple sterile eye drop for the ocular surface to complex implants for intraocular tissue.

Figure 17: Routes of drug delivery in eye

Mechanism of ocular absorption:

Non-corneal absorption:

• Penetration across sclera and conjuctiva into intra-ocular tissues.
• Penetrated drugs are absorbed by general circulation and hence this absorption is not productive.

Corneal absorption:

• Outer epithelium: rate limiting barrier, with pore size 60a, only access to small ionic and lipophilic molecules.
• Transcellular transport: transport between corneal epithelium and stroma.

Factors affecting intraocular bioavailability:

• Inflow & outflow of lacrimal fluids
• Efficient naso-lacrimal drainage
• Interaction of drug with lacrimal fluid
• Dilution with tears
• Corneal barriers
• Active ion transport at cornea

 

 GASTROINTESTINAL TRACT DRUG DELIVERY

GI tract doesn’t require surgery for the implantation of MEMS drug delivery devices. This can be achieved by oral delivery of drugs. But oral delivery doesn’t ensure gastrointestinal absorption along the GI tract, which depends on many factors such as regions, gastric emptying time, intestinal motility, etc. Another feasible method of delivery is via traditional endoscopy. But traditional endoscope can’t access the entire GI tract. So, an alternative to all of these problems is a capsule endoscope. It not only enables direct treatment of GI diseases but also helps in targeting the regions with the highest absorption rate such as the small intestine.

 

Design Considerations:

Firstly, the size of the capsule should be very small, so that a patient can swallow it without any difficulty. Secondly, the control mechanism, passive or active, should also be taken into account. In passive control, the capsule moves due to the peristaltic motion of the GI tract and hence doesn’t need an on-chip battery. However, for precise control of the device, active control is very necessary. Anchoring in such devices is obtained through small legs that protrude from the capsule.

Limitations:

Due to complex mechanical structures and high-power consumption, none of these designs has made it to the clinical stage.

Figure 18: Capsule Endoscope with legging mechanism

TRANSDERMAL DRUG DELIVERY

Drug delivery through the skin is a preferred choice over oral delivery or hypodermic injection. This method is advantageous over other existing methods as drug delivery occurs through the widely spread vascular network which ensures proper delivery. Secondly, transdermal drug delivery is suitable for extensive drug administration via biocompatible patches.

Opportunities and Challenges:

Transdermal microneedles are developed to pierce the stratum corneum but should avoid penetrating nerve endings. So, the positioning of microneedles is of great essence especially for extended drug administration.

If internal physiological signals are used as stimuli for drug release, then it forms a closed-loop self-regulatory system. Activation of drug release is found out by monitoring the changes in physiological signals using bioresponsive vesicles. 

 

CONCLUSION

MEMS devices have the potential to be of great importance in the field of medical science in future. It can reduce the cost of medical facilities as well as increase its efficiency. Currently there are some limitations in the use of MEMS devices due to lack of technology. In future, with improvement in additive manufacturing, nanotechnology, and medical science, it can overcome those limitations.

(AIM, NIT Rourkela)