Bio-MEMS

RECENT DEVELOPMENT IN NOVEL DRUG DELIVERY BIO-MEMS: A REVIEW
A Project Report
Submitted To
RAJASTHAN UNIVERSITY OF HEALTH SCIENCES, JAIPUR (RAJ.)
In the fulfillment of the requirements for the award of the degree of
BACHELOR OF PHARMACY
2016 – 2017
Submitted by Supervised by
Akshay Mehta Ms. Seema Wadhwani
B. Pharm Part IV Assistant Professor
Enrollment No – 2013/1304 Dept. of Pharmaceutics
SHRINATHJI INSTITUTE OF PHARMACY, NATHDWARA (RAJ

LIST OF CONTENTS
 Introduction
 History
 Approaches
 Bio-Mems As Miniaturized Biosensors
 Devices
 Applications Of Bio-Mems
 Bio-Mems In Medical Implants And Surgery
 Future Technologies
 Summary
 References

INTRODUCTION
 Bio-MEMS is an abbreviation for biomedical (or biological)
microelectromechanical systems. Bio-MEMS have considerable
overlap, and is sometimes considered synonymous, with lab-on-
a-chips (LOC) and micro total analysis system (uTAS).
 Bio-MEMS is typically more focused on mechanical parts
and microfabrication technologies made suitable for biological
applications.
 MEMS combines material sciences, clinical sciences, medicine,
surgery, electrical engineering, mechanical engineering, optical
engineering, chemical engineering and biomedical engineering.
 Some of its major applications include genomics, proteomics,
molecular diagnostics, point-of-care diagnostics, tissue
engineering, and implantable micro devices. MEMS techniques
were originally developed in the microelectronics industry.

BIO-MEMS Device
A Venn diagram outlining and contrasting some aspects of the fields of BIO-
MEMS, lab-on-a-chip, uTAS.

HISTORY OF BIO-MEMS
 Drug discovery in the last decades leading up to the 1990s had
been limited due to the time and cost of running many
chromatographic analyses in parallel on macroscopic equipment.
 The Human Genome Project (HGP), which started in October
1990, created demand for improvements in DNA sequencing
capacity. Capillary electrophoresis thus became a focus for
chemical and DNA separation.
 DARPA of the US Department of Defense supported a series of
microfluidic research programs in the 1990s after realizing there
was a need to develop field-deployable microsystems for the
detection of chemical and biological agents that were potential
military and terrorist threats.
 Researchers started to use photolithography equipment
for microfabrication of microeletromechanical systems (MEMS)
as inherited from the microelectronics industry.

 In 1993, George M. Whitesides, a Harvard chemist, introduced
inexpensive PDMS-based microfabrication and this
revolutionized the bio-MEMS field. Since then, the field of bio-
MEMS has exploded.
 Selected major technical achievements during bio-MEMS
development of the 1990s include:
A. In 1991, the first oligonucleotide chip was developed
B. In 1998, the first solid micro needles were developed for drug
delivery
C. In 1998, the first continuous-flow polymerase chain
reaction chip was developed
D. In 1999, the first demonstration of heterogeneous laminar
flows for selective treatment of cells in micro channels.
 Today, hydrogels such as agarose, biocompatible photoresists,
and self-assembly are key areas of research in improving bio-
MEMS as replacements or complements to PDMS.

APPROACHES
1. MATERIALS
A. Silicon and Glass
 Conventional micromachining techniques such as wet etching, dry
etching, deep reactive ion etching, sputtering, anodic bonding,
and fusion bonding have been used in bio-MEMS to make flow
channels, flow sensors, mixers, filters, pumps and valves.
 Due to being single-use only, larger than their MEMS counterparts,
and the requirement of clean room facilities, high material and
processing costs make silicon-based bio-MEMS less economically
attractive.

B. Plastics and Polymers
 Using plastics and polymers in bio-MEMS is attractive because
they can be easily fabricated, compatible with micromachining
and rapid prototyping methods, as well as have low cost. Many
polymers are also optically transparent and can be integrated into
systems that use optical detection techniques such
as fluorescence, UV/Vis absorbance, or Raman method.
 The most common polymers used in bio-MEMS
include PMMA, PDMS, OSTEmer and SU-8.
C. Biological Materials
 Micro scale manipulation and patterning of biological materials
such as proteins, cells and tissues have been used in the
development arrays, microarrays, microfabrication based tissue
engineering, and artificial organs.
 Biological micropatterning can be used for high-throughput single
cell analysis, precise control of cellular microenvironment, as well
as controlled integration of cells into appropriate multi-cellular
architectures to recapitulate in vivo conditions.

(A) Micropatterning of fibronectin on PNIPAM glass surface.
(B and C) Single fibroblasts are spatially constrained to the geometry of the
fibronecting micro pattern.
D. Paper
 Paper microfluidics (sometimes called lab on paper) is the use of
paper substrates in microfabrication to manipulate fluid flow for
different applications.
 Paper microfluidics have been applied in paper electrophoresis
and immunoassays, the most notable being the commercialized
pregnancy test, Clearblue.

 Advantages of using paper for microfluidics and electrophoresis in
bio-MEMS include its low cost, biodegradability, and
natural wicking action.
 Techniques for the micropatterning paper
includes photolithography, laser cutting, ink jet printing, plasma
treatment, and wax patterning.
2. ELECTROKINETICS
 Electro kinetics have been exploited in bio-MEMS for separating
mixtures of molecules and cells using electrical fields.
In electrophoresis, a charged species in a liquid moves under the
influence of an applied electric field. Electrophoresis has been used to
fractionate small ions, charged organic molecules, proteins,
and DNA.
 Electrophoresis has been used to fractionate small ions, charged
organic molecules, proteins, and DNA.

An experimental example of electrophoresis
3. MICROFLUIDICS
 Microfluidics refers to systems that manipulate small ( µL, nL, pL, fL)
amounts of fluids on micro fabricated substrates.
 Microfluidic approaches to bio-MEMS confer several advantages:
a. Flow in microchannels is laminar, which allows selective treatment of
cells in microchannels, mathematical modelling of flow patterns
and concentrations,
b. Microfluidic features can be fabricated on the cellular scale or smaller,
which enables investigation of (sub)cellular phenomena,

c. Integration of microelectronics, micromechanics, and micro optics
onto the same platform allows automated device control, which
reduces human error and operation costs,
d. Microfluidic technology is relatively economical due to batch
fabrication and high-throughput,
e. Microfluidic devices consume much smaller amounts of reagents, can
be made to require only a small amount of analytes for chemical
detection,
f. Appropriate packaging of microfluidic devices can make them suitable
for wearable applications, implants, and portable applications
in developing countries.
When multiple solutions are added into the same microchannel, they flow in separate
flow lanes (no mixing) due to laminar flow characteristics.

BIO-MEMS AS MINIATURIZED
BIOSENSORS
 Biosensors are devices that consist of a biological recognition
system, called the bioreceptor, and a transducer.
 The interaction of the analyte with the bioreceptor causes an effect
that the transducer can convert into a measurement, such as
an electrical signal.
 The most common bioreceptors used in biosensing are based on the
antibody-antigen interactions, nucleic
acid interactions, enzymatic interactions, cellular interactions, and
interactions using biomimetic materials.
 Common transducer techniques include mechanical detection,
electrical detection, and optical detection.
 A biosensor is an analytical device, used for the detection of an
analyte, that combines a biological component with a
physicochemical detector.

TYPES OF BIOSENSORS
I. Micromechanical Sensors
 Mechanical detection in bio-MEMS is achieved through micro- and
nano-scale cantilevers for stress sensing and mass sensing, or
micro- and nano-scale plates or membranes.
 In stress sensing, the biochemical reaction is performed selectively
on one side of the cantilever to cause a change in surface free
energy.
 When a biochemical reaction takes place and is captured on the
cantilever, the mass of the cantilever changes, as does the
resonant frequency. The advantage of using cantilever sensors is
that there is no need for an optically detectable label on
the analyte or bioreceptors.

II. Electrical and Electrochemical Sensors
 Electrical and electrochemical detection are easily adapted for
portability and miniaturization, especially in comparison to optical
detection.
 In amperometric biosensors, an enzyme-catalyzed redox reaction
causes a redox electron current that is measured by a working
electrode.
 Amperometric biosensors have been used in bio-MEMS for
detection of glucose, galactose, lactose, urea, and cholesterol, as
well as for applications in gas detection and DNA hybridization.
 Conductive measurements are simple and easy to use because
there is no need for a specific reference electrode, and have been
used to detect biochemicals, toxins, nucleic acids, and bacterial
cells.
III. Optical Sensors
 A challenge in optical detection is the need for integrating detectors
and photodiodes in a miniaturized portable format on the bio-
MEMS.

 Optical detection includes fluorescence-based
techniques, chemiluminescence-based techniques, and surface
plasmon resonance (SPR).
 Fluorescence-based optical techniques use markers that emit light at
specific wavelengths and the presence or enhancement/reduction
(e.g. fluorescence resonance energy transfer) in optical signal
indicates a reaction has occurred. Surface plasmon resonance
sensors can be thin-film refractometers or gratings that measure the
resonance behaviour of surface plasmon on metal or dielectric
surfaces.
 SPR is the resonant oscillation of conduction electrons at the interface
between a negative and positive permittivity material stimulated by
incident light.
 SPR is the basis of many standard tools for measuring adsorption of
material onto planar metal (typically gold or silver) surfaces or onto the
surface of metal nanoparticles.
 It is the fundamental principle behind many color-based biosensor
applications and different lab-on-a-chip sensors.

IV. Reasons For Miniaturization
 In general, the use of micro and nano-scale detection technologies is
justified by-
 reducing the sensor element to the scale of the target species and
hence providing a higher sensitivity single entity/molecule
 reduced reagent volumes and associated costs
 reduced time to result due to small volumes resulting in higher
effective concentrations
 amenability of portability and miniaturization of the entire system
 point-of-care diagnostic
 Multi-agent detection capability
 Potential for use in vitro as well as in vivo

DEVICES
 Through the use of MEMS technology and micro fabrication
techniques, drug delivery research has been able to make a
significant departure from traditional methods.
Reservoir Chip Schematic

 These MEMS devices can be positioned in the body by implantation or
by the traditional pill. Biocompatibility issues are very significant in
these devices since the devices are meant to remain in the body for
extended periods of time.
 One promising such device is a chip that contains micro reservoirs full
of the prescribed drug.
 The reservoirs are created on the substrate using micro fabrication
techniques and are then filled with the drug.
 The drugs contained in the reservoirs are released by a variety of
different techniques.
 The extremely small volume of the reservoirs means the concentration
of the drug needs to be sufficient to obtain the desired effect.

TYPES OF DEVICES
I. Transdermal Devices
 As opposed to in vivo devices, transdermal devices deliver the drug
through the skin.
 Most commercially available transdermal devices are passive,
meaning the drug is applied to the skin and is allowed to just soak in.
The Smart Pill

 Unfortunately, due to the nature of skin, this technique only works on
small, lipophilic molecules.
 Thus, passive transdermal devices are minimally invasive, but are
often not very effective.
 To improve the effectiveness of transdermal drug delivery, active
devices have been created that utilize iontophoretics, chemical
enhancers, and ultrasound.
 MEMS devices have also been used in this respect.
II. Reservoir Implantation Device
SEM Picture of a 350 micron high microneedle, with a base of 250 microns, the flow
channel is 70 microns in its widest direction.

 The implantation devices were found to be the best choice based on
the fact that they offer a greater deal of control and are more effective
than the transdermal techniques.
 Another advantage of this device is its versatility.
 The reservoir implantation device was chosen over the smart pill
because of its design simplicity, which makes it easier to
manufacturer.
 For the most part, the reservoir implantation device can be
manufactured using simple micro fabrication techniques.
Schematic Representation of Iontophoresis Circuit.

 The device can be activated in several different ways.
 It can be activated by remote control, giving control to the doctor or the
patient. It can be activated on a set time basis.
 Some devices are even automatically triggered by sensors built into
the device that detect when the drug needs to be administered.

APPLICATIONS OF BIO-MEMS
I. Genomic and Proteomic Microarrays
A. Oligonucleotide Chips
 Oligonucleotide chips are microarrays of oligonucleotides. They
can be used for detection of mutations and expression monitoring,
and gene discovery and mapping.
 Using gel pads, prefabricated oligonucleotides are attached to
patches of activated polyacrylamide
 Using microelectrodes, negatively charged DNA and molecular
probes can be concentrated on energized electrodes for interaction
B. cDNA Microarray
 cDNA microarrays are often used for large-scale screening and
expression studies. In cDNA microarrays, mRNA from cells are
collected and converted into cDNA by reverse transcription.

 For detection, fluorescently-labelled single strand cDNA from cells
hybridize to the molecules on the microarray and a differential
comparison between a treated sample (labelled red, for example) and
an untreated sample (labelled in another color such as green) is used
for analysis.
 Red dots mean that the corresponding gene was expressed at a
higher level in the treated sample.
 Conversely, green dots mean that the corresponding gene was
expressed at a higher level in the untreated sample.
Differential comparison in cDNA microarray.

 Yellow dots, as a result of the overlap between red and green dots,
mean that the corresponding gene was expressed at relatively the
same level in both samples, whereas dark spots indicate no or
negligible expression in either sample.
C. Peptide and Protein Microarrays
 The motivation for using peptide and protein microarrays is firstly
because mRNA transcripts often correlate poorly with the actual
amount of protein synthesized.
 DNA microarrays cannot identify post-translational modification of
proteins, which directly influences protein function.
II. PCR Chips
 The polymerase chain reaction (PCR) is a fundamental molecular
biology technique that enables the
selective amplification of DNA sequences, which is useful for
expanded use of rare samples e.g.: stem cells, biopsies, circulating
tumor cells.

Continuous flow-based PCR microfluidic system with thin film heaters, syringe pump, and
continuous flow PCR channel.
III. Point of Care Diagnostic Devices
 The ability to perform medical diagnosis at the bedside or at the point-
of-care is important in health care, especially in developing countries
where access to centralized hospitals is limited and prohibitively
expensive.
 To this end, point-of-care diagnostic bio-MEMS have been developed
to take saliva, blood, or urine samples and in an integrated approach
perform sample preconditioning, sample fractionation, signal
amplification, analyte detection, data analysis, and result display.

TYPES-
i. Sample Conditioning
ii. Sample Fraction
IV. Bio- MEMS in Tissue Engineering
i. Cell Culture
The lung-on-a-chip device simulates the contraction of the diaphragm, which triggers the
intrapleural pressure to decrease, leading to an expansion of alveoli.
ii.. Stem Cell Engineering
iii. Biochemical Factors
Iv. Fluid Shear Stress

v. Cell-ECM Interactions
vi. Cell-Cell Interactions
vii. Embryoid Body Formation and Organization
viii. Assisted Reproductive Technologies
Murine embryoid bodies in suspension culture after 24 hours of formation from
embryonic stem cells.

BIO-MEMS IN MEDICAL IMPLANTS AND
SURGERY
1. Implantable Microelectrodes
 The goal of implantable microelectrodes is to interface with the
body’s nervous system for recording.
 Sending bioelectrical signals to study disease, improve prostheses,
and monitor clinical parameters.
 Microfabrication has led to the development of Michigan probes and
the Utah electrode array, which have increased electrodes per unit
volume, while addressing problems of thick substrates causing damage
during implantation and triggering foreign-body reaction and
electrode encapsulation via silicon and metals in the electrodes.
2. Microtools for Surgery
 Bio-MEMS for surgical applications can improve existing functionality,
add new capabilities for surgeons to develop new techniques and
procedures, and improve surgical outcomes by lowering risk and
providing real-time feedback during the operation.

 Incorporation of sensors onto surgical tools also allows tactile
feedback for the surgeon.
 Identification of tissue type via strain and density during cutting
operations, and for the blood diagnostic catheterization to measure
the bloodflows, pressures, temperatures, oxygen content, and
chemical concentrations.
A cardiac balloon catheter with temperature sensors, electrocardiography sensors,
and LEDs is a surgical bio-MEMS.

3. Drug Delivery
 Microneedles, formulation systems, and implantable systems are bio-
MEMS applicable to drug delivery.
 Microneedles of approximately 100μm can penetrate the skin barrier
and deliver drugs to the underlying cells and interstitial fluid with
reduced tissue damage, reduced pain, and no bleeding.
 Microneedles can also be integrated with microfluidics for automated
drug loading or multiplexing.
Transdermal microneedles patch is less invasive compared to conventional drug
delivery by hypodermic needle.

FUTURE TECHNOLOGY
 The future of MEMS is integrally linked to market trends in general
and driven by the increasing demand to monitor and control our
environment and the equipment and instruments we use in our daily
lives.
 This demand does, undoubtedly, lead to the need for more sensors
in cars, more sensors in industrial equipment and installation and,
more sensors for our ambient intelligence.
 In order to avoid the need for a multitude of wires, such sensors must
be self sustaining and able to communicate 46 wirelessly.
 As a result, not only more sensors are needed, but also small energy
generating modules and wireless transmission components.
 There is also a tendency to explore more flexible and more
affordable production technologies. This will be driven by the
production research into typical low cost, large surface area devices
like solar cell, displays, wearable electronics and disposable
diagnostics devices.

SUMMARY AND CONCLUSION
 MEMS are a class of miniature devices and systems fabricated by
micromachining processes. MEMS devices have critical dimensions
in the range of 100 nm to 1000 µm (or 1 mm).
 MEMS technology is a precursor to the relatively more popular field
of Nanotechnology, which refers to science, engineering and
technology below 100 nm down to the atomic scale.
 Occasionally, MEMS devices with dimensions in the millimeter-range
are referred to as meso-scale MEMS devices.
 As drug delivery systems improve, the components of the systems
continue to decrease in size.
 Many of the future and developing technologies are based on the
nano-scale.
 These nano-particles are particularly useful when a drug must target
certain areas of the human body.

REFERENCE
 Abushagur, A. A., Arsad, N., Reaz, M. I. & Bakar, A. 2014. Advances
in bio-tactile sensors for minimally invasive surgery using the fibre
bragg grating force sensor technique: A survey. Sensors, Vol.14,
pp.6633-6665.
 Aguirregabiria, M., Blanco, F., Berganzo, J., Ruano, J., Aranburu, I.,
Garcia, J. & Mayora, K. 2004. Novel su8 multilayer technology based
on succesive cmos compatible adhesive bonding and kapton
releasing steps for multilevel microfluidic devices. SPECIAL
PUBLICATION-ROYAL SOCIETY OF CHEMISTRY, Vol.297, pp.49-
51.
 Cao, C., Birtwell, S. W., Høgberg, J., Wolff, A., Morgan, H. & Bang,
D. D. Surface modification of photoresist su-8 for low autofluo-
rescence and bioanalytical applications. 15th International
Conference on Miniaturized Systems for Chemistry and Life
Sciences, 2011. pp.1161-1163.

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