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Published: January 2011, MDDI
Microspheres are round microparticles that typically range from 1 to
1000 µm in diameter. In the pharmaceutical and cosmetics industry,
microspheres are well known for their ability to deliver active
materials. This process usually involves the microencapsulation of a
drug or an active cosmetic ingredient to protect it from the
deteriorating effects of the environment or for optimal release and
performance in the final product. Active ingredients are released by
dissolution of the capsule walls, mechanical rupture (rubbing, pressure,
or impact), melting, or digestion processes. Solid microspheres are
widely used as fillers and spacers in a variety of industries.
Microspheres used to manufacture and test medical devices are
typically solid particles that are made from robust and stable raw
materials such as polymers, glass, and in some cases, ceramics.
Different types and grades of microspheres are available and selected
based on specific application requirements.
They are often used as tracers and challenge particles in medical
devices. In these situations, it is beneficial to use larger
microspheres with sphere diameters greater than 50 µm that are vividly
colored (red, blue, black, yellow, or green), since they provide
contrast with the background material and visibility to the naked eye in
daylight. Colored microspheres are typically used in the testing of
filtration media and systems, vial and container cleaning evaluations,
flow tracing and fluid mechanics, centrifugation and sedimentation
processes, pharmaceutical manufacturing, and contamination control.
Fluorescent microspheres are recommended for applications that
require the use of particles that emit distinctive colors when
illuminated by UV light and offer additional sensitivity for observation
through the use of microscopes, lasers, and other analytical methods.
Examples include microcirculation and biological research, imaging, and
flow cytometry. Fluorescent microspheres can be excited and detected by a
wide range of methods and are useful as experimental particles for
acoustical and optical analytical systems.
Other types of microspheres that are relevant to medical devices are
optically opaque and radiopaque, as well as charged and magnetic
microspheres. Opaque microspheres are desirable for maximum contrast in
optical and electron beams. Charged and magnetic microparticles are capable
of being manipulated with electromagnetic fields.
Monodisperse microspheres are used for calibrating microscopes,
light-scattering equipment, and other particle measuring devices. They
are ideal for spacer applications in which uniform bond thickness is a
necessity. Particle-size standard spheres can be used to develop and
test new analytical instruments for particle size materials
Microspheres are particles that are often supplied as dry powder or
in a solution. Superior sphericity and roundness offer omni-directional
spreadability and easy cleanup. Microspheres can be directly observed on
the surface or in the media being tested. In addition, due to their
controlled particle size, they can be filtered out, collected, and
recycled at the end of the testing process.
Fluorescence occurs when a molecule absorbs energy in the form of
light and immediately releases this energy again in the form of light.
The excitation wavelength is the characteristic wavelength that a
molecule absorbs, and the emission wavelength is the characteristic
wavelength that a molecule emits.
Fluorescent microspheres emit bright and distinctive colors when
illuminated by light of shorter wavelengths than the emission
wavelength. The intense color emission improves their contrast and
visibility relative to background materials. In addition to the benefits
of conventional high-quality microspheres, such as sphericity,
smoothness, and spreadability, fluorescent spheres offer extra
sensitivity and detectability for analytical methods. Fluorescent
microspheres can be detected with an epifluorescence microscope,
confocal microscope, fluorometer, fluorescence spectrophotometer, or
fluorescence-activated cell sorter. They can also be detected using a
mineral or UV light.
Fluorescent microspheres are available in a variety of excitation and
emission wavelengths. These wavelength variations enable complex
technical experiments in which colored microspheres represent different
experimental variables or conditions and can be separated on the basis
of either their excitation or emission spectra. For example, using
fluorescent microspheres in different sphere diameters provides an
additional controlled variable that lets scientists and engineers track
the initial location of the microspheres.
A unique property of fluorescent spheres is their ability to appear
translucent and practically invisible under ordinary light and emit
intense visible color when energized. This effect enables blind tests
and controlled experiments in which the microspheres are invisible to
the operator until the procedure has been conducted, eliminating any
operator bias and uncertainty in the validity of experiment. This unique
feature of fluorescent microspheres has numerous applications in the
development and testing of medical devices (e.g., simulating the spread
of contamination and viruses, vial and container cleaning evaluations,
and process troubleshooting and control).
Most fluorescent microspheres are hard-dyed (internally dyed) polymer
beads that use proprietary processes to incorporate the fluorescent
colorant throughout the polymer matrix. This method produces bright
fluorescent colors, minimizes photobleaching, and prevents colorants
from leaching into surrounding media. The spectral properties of the
fluorochromes are dependent on their concentration and physical
environment. The exact excitation and emission maxima may vary depending
on the size and composition of the microspheres. There are several
different types of fluorescent polymer microspheres on the market that
are produced from a variety of raw materials, making them suitable for a
variety of applications.
The specific gravity of fluorescent microspheres can be adjusted to
match the specific gravity of water or other desired media. Particles
that are heavier than the media in which they are dispersed will settle
to the bottom of the container over time. Particles that are lighter
than the media will float to the top and accumulate on the surface.
Matching the specific gravity of the microspheres to that of the base
solution creates a stable suspension of particles, which ensures uniform
distribution and prevents their settling out or collecting at the top
of the container. This matching is achieved by selecting a base polymer
close to the desired density and using proprietary additives that are
incorporated into the polymer matrix during the manufacturing process.
This process matches the specific gravity of the microspheres to water
or other desired media and results in neutrally buoyant particles and an
optimal suspension of particles in solution.
Fluorescent microspheres are often used in fluorescence microscopy
and photography, as well as biomedical technology research and
biomedical diagnostics. They are often used for water- and ?airflow
testing and bead-based diagnostic applications. Unique applications of
fluorescent spheres are continuously being discovered.
Microspheres used as tracers and challenge particles in medical
devices do not necessarily have to be fluorescent. As previously stated,
brightly colored microspheres can provide contrast with the background
material and visibility to the naked eye in daylight.
Solid polyethylene microspheres are smooth, highly spherical
particles that are nonsoluble in water and most solvents. They can be
manufactured in any color and withstand temperatures of up to 100°C.
These spheres can be manufactured with specific gravities from 0.96 to
1.3 g/cc. Solid polyethylene microspheres incorporate pigments and
additives inside the polymer matrix to achieve colorful particles that
are visualized on the surface of a material or in a solution.
The advantage of using solid, colored microspheres instead of
pigments or dyes is that microspheres are much more robust and
controlled particles, and easy to handle and clean up. Pigment particles
are very small, difficult to disperse, and can be hazardous. Typically,
pigments of particle sizes smaller than 1 µm are used to increase tint
strength. However, powders of pigment particles in the submicron size
range are difficult to work with because they tend to clump together,
and as a result, do not disperse properly in a solution. In addition,
powders less than 5 µm in size are considered respirable by the
Occupational Safety and Health Administration because they are small
enough to penetrate the nose, upper respiratory system, and the lungs,
which is a health hazard for workers regularly exposed to the dust.
Because microspheres are usually 5 µm or larger, they are easier to
handle and do not create respiratory hazards.
Microspheres are often supplied as a free-flowing dry powder to
ensure a simple formulation, controlled application, and easy cleanup.
Colored microspheres can be visualized with the naked eye, measured and
filtered out, wiped off, or recycled at the end of the process. For
example, if rinse water is being examined, microspheres can be collected
on filter membranes for visual or microscopic inspection.
Generally, when light strikes an interface between two substances,
some of the light is reflected, absorbed, and scattered, and the
remainder is transmitted. An opaque substance transmits little if any
light and therefore reflects, scatters, or absorbs most of it. The
opacity of the microspheres can be quantified in many ways, including
viewing the spheres under a microscope with a backlight or measuring the
reflectance of the monolayer spheres on white and black backgrounds.
Opaque microspheres do not allow light to pass through, which means
that a monolayer of opaque spheres will not transmit light, resulting in
maximum hiding of material and color underneath. Opaque microspheres
are desirable for maximum contrast in optical and electron beams. They
are also beneficial for applications in which uniform color and hiding
power of the color beneath is desired. Polymer microspheres can be
designed as transparent and invisible to the eye, partially translucent,
or opaque, which provides maximum hiding power.
In general, high levels of opacity become more difficult to achieve
in microscopic particles because opacity is proportional to the material
thickness. Due to the chemistry of glass, it is difficult to create
opaque glass spheres. Most colored glass microspheres are made by
attaching dyes to the surface of the particle and do not achieve
significant opacity. Ceramic microspheres can be opaque but microspheres
in a batch usually do not have the same level of opacity (some are more
opaque than others). The manufacturing process for the polyethylene
microspheres enables the incorporation of colorants and opacifiers
inside the solid sphere, which ensures that spheres are produced with
identical color and opacity.
Optical opacity, as described above, is defined as the degree to
which something reduces the passage of light. It should not be confused
with radiopacity, which is the phenomenon of not permitting the passage
of electromagnetic radiation, otherwise known as opacity, to x-rays or
other forms of radiation. Some medical device development applications
require radiopaque microspheres, which can be achieved by incorporating
magnetic and metallic elements into the microsphere structure. This
process allows the microspheres to be easily detectable by x-ray and
demonstrates superior contrast and reflectivity in optical, ultrasonic,
and electron beam detection methods.
As previously mentioned, monodisperse microspheres have applications
in microscopes, light-scattering equipment, and other particle measuring
devices. Certified particle-size standard microspheres are traceable to
the standard meter through the National Institute of Standards and
Technology (NIST). This feature lets laboratories demonstrate the
traceability of their analytical methods as required by ISO 9000, ISO
10012, ANSI/NCSL Z540, GMP/GLP, and other standards and regulations.
Particle-size standard spheres can be used to develop and test new
analytical instruments for particle size characterization of materials.
It is very difficult to visualize 3-D objects with analytical
instruments. Because the instruments can typically focus on only one
surface, 3-D objects often produce images of distorted shapes. Using
spheres, which have the same dimensions when viewed from all angles,
instead of irregularly shaped particles, minimizes these effects.
Charged, Magnetic, and Metallic Microspheres
To create positive or negative charges, proprietary additives are
embedded into each microsphere during the manufacturing process. This
charge is permanent; it does not dissipate over time and cannot be
grounded. The whole microsphere is charged and will respond to electric
fields. Dark-colored or black microspheres can be made magnetic or
static-dissipative, and a black magnetic coating on a portion of the
microsphere can be used to create functionalized hemispheres. For
example, magnetic half-shells can be manipulated to rotate microspheres
with an electromagnetic field.
One particularly interesting and unique feature of magnetic
half-shell microspheres is their ability to orient themselves in
response to electromagnetic fields and show a visual response to the
observer. This response is achieved by making spheres both bipolar and
bichromal, with the dipole precisely aligned with two differently
colored hemispheres. Due to the dipole, the sphere will rotate in an
electromagnetic field to align the more positive hemisphere to the
negatively charged stimuli and vice-versa. As the spheres align
themselves, the viewer will observe the color of one hemisphere, while
the other hemisphere will be hidden from view to provide a strong
visible indication of the presence of the field. In an alternating
electromagnetic field, these microspheres can spin at hundreds of times
This superior functionality is achieved with a proprietary and
patented process that allows extremely precise coating on one hemisphere
without affecting the other. Each coating is custom formulated for
color, charge, and solvent resistance, and magnetic, electric and
surface properties per a customer’s needs. Hemispherical coatings of
less than 1 µm with tolerances as low as 0.25 µm have been routinely
demonstrated. Color combinations are virtually unlimited—white, black,
silver, blue, green, red, yellow, brown, and purple, as well as
transparent microspheres, have been made. Sphericity exceeding 90% and
custom particle size ranges are available.
The spheres were originally developed for very high-tolerance
electronic paper reflective digital displays in which functionalized
microspheres were used to create an image that appears to the viewer. To
achieve high resolution in display applications, it is critical that
every single sphere responds to the electromagnetic field in the same
way and at the same time and that it aligns precisely with the other
spheres. It is also critical that there are no color gradients in the
The orientation of bichromal microspheres for application in medical
devices requires further exploration but is a promising area of future
development. This technology could potentially be used as a visible
marker of the presence of an electromagnetic field in a medical device,
as well as for tracer or carrier particles manipulated with an
For skin-based medical devices, charged microspheres can be used to
design products that are attracted to or repelled from the skin. Human
skin has a highly positive electrostatic charge. Because like charges
repel and opposite charges attract, the charge of the product can be
manipulated to be more attracted to the skin if the product is designed
to remain on the skin for a long time. It can also be manipulated to be
less attracted to the skin if the product only needs to remain for a
short time, making the product easy for the user to remove.
High-quality polymer microspheres are commercially available in a
wide variety of colors and with controlled fluorescence, opacity,
specific gravity, particle size distribution, and electrostatic charge,
presenting endless possibilities for use in developing and testing
medical devices. To select the right microsphere for the job, one must
rely on detailed knowledge of the application and on the technical
judgment of those working on the project, and employ a simple
Yelena Lipovetskaya is cofounder of Cospheric LLC (Santa Barbara, CA).