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Microspheres in biomedical applications

Biomedical applications of microspheres in drug delivery and bone tissue engineering offer many advantages over other particle geometries.

Microspheres can be made to have a uniform size and shape to enhance their delivery to target sites and to have a large surface area to enable sufficient therapeutic coatings.

However, their manufacture is associated with development and production challenges, especially in large-scale production.

Microspheres can be produced with different materials, including glass-, ceramics-, and polymer-based microspheres, which provides them with varying properties and applications.

Porosity

Porosity is an important consideration in microsphere production, particularly for tissue engineering and drug delivery applications. Porous microspheres enable a greater loading efficiency and improved control over the release of medications, growth factors and other components.

Their large surface area also means they are favorable for cell attachment and proliferation. Other important features to consider during porous microsphere production are interconnected and open porosity and favorable pore size.

Porous microspheres can be made with external and/or internal porosity and with or without interconnectivity for cell attachment and proliferation over the surface area.

Although porous microspheres possess these superior features, non-porous microspheres can be useful for certain applications that require higher mechanical properties such as bone tissue regeneration.

Polymer based microspheres

Polymer-based porous microspheres have been a significant focus of attention due to their potential in controlled drug release, either by degradation of the polymer matrix or through the leaching of drug components from the polymer.

During production, the selection of either synthetic or natural biodegradable carrier matrices for drug delivery is an important consideration. Natural polymers such as collagen and protein undergo enzyme degradation, whereas synthetic polymers degrade by hydrolytic activity.

The synthetic polymer polylactic acid (PLA) is a common polymer used for biomedical applications due to its degradation rate and desirable mechanical properties. Solvent and emulsion-solvent evaporation processes can be used to create microspheres with differing morphologies.

For example, in 1991, S Izumikawa and colleagues reported investigating progesterone drug-loaded poly (l-lactide) (PLLA) microspheres prepared using a solvent evaporation process.

They found that removing volatile solvent at atmospheric pressure formed PLA microspheres that were crystalline in structure, whereas at lowered pressures, the removal of the solvent led to the formation of microspheres with amorphous polymer matrices.

The researcher’s study suggested that the crystalline microspheres with rough surfaces and large surface areas enabled rapid drug release compared to the smooth, amorphous structures.

Protein microspheres are widely used as natural polymer microspheres in drug delivery due to their selective uptake by specific cells, their high biological activity and the numerous sites they provide for drug components to attach to. They can also be combined with numerous different drugs to produce derivatives with specific pharmacological properties.

Glass and ceramic based microspheres

Glass and ceramic-based spheres are generally studied for tissue regeneration, radionuclide therapy and applications in dentistry or orthopedics.

Glass based microspheres

The three types of glass-based microspheres are generally borate, silicate and phosphate-based.

Borate-based glass spheres, have become particularly attractive as delivery vehicles of biodegradable radiation, especially in the treatment of arthritis, owing to their uniform size and shape. These spheres were often considered ideal for radiation synovectomy (the removal of the synovium membrane that lines a joint).

The use of silicate-based bioglass, glass–ceramics microspheres and silica nanospheresin biomedical applications has also been investigated. A glass-ceramic phase is a material that has one or more crystal phases placed within a glassy matrix.

Various studies have concentrated on the generation of silicate-based microspheres, but achieving the correct size distribution and surface texture as well as avoiding aggregation has proved challenging.

One method used to manufacture microspheres is the sol-gel method via the Stöber process which was investigated by researchers Hui Liu and colleagues in 2012. Hydrolysing and polycondensing tetraethoxysilane ethanol solution (TEOS) has previously produced monodispersed silica microspheres 0.3µm in size.

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Scheme of production of glass microspheres via Sol–gel

Adding aluminum nitrate and silver nitrate resulted in 0.4µm microspheres coated in finer particles, which led to aggregation of the samples. Subsequent heating at 1000˚C resulted in microspheres 8.8 to 10.1 µm in diameter with smoother surfaces, but particles aggregated. The more aluminum nitrate and silver nitrate that was added, the more aggregation increased.

The antibacterial silver ions were only effective when the microspheres were initially submersed in ultrapure water, indicating that silver nitrate was only incorporated on the microsphere surface, therefore forming a short-term antibacterial shell.

The researchers then instead tried adding aluminum tri-isopropoxide to partially hydrolysed TEOS to form Si–O–Al bonds. Subsequent addition of silver ions to the ATIP/TEOS mixture in ammonia and silver nitrate solution, followed by centrifugation resulted in monodispersed microspheres, 0.4 to 0.6µm in diameter.

Subjecting the spheres to heat treatment did not change the diameters of the spheres or lead to their aggregation. The technique resulted in silver-doped microspheres that released silver ions in water in a much more controlled and gradual way than previously and these microspheres demonstrate great potential as antibacterial materials.

Ceramic based microspheres

Calcium phosphate-based ceramic microspheres are used in dentistry, orthopedics and pharmaceutics, because of their excellent osteoconductivity and biocompatibility.

Using ceramic microspheres, minimally invasive implantation can be achieved and ensures the target site receives adequate mechanical support. However, compared to glass microspheres, these materials are linked with high brittleness and slow resorption rates.

The spherical shape of these ceramic materials means they are thought of as more well suited for bone defect filling because of their packing and the predictability of their flow characteristics during injection, compared with particles of an irregular shape.

In at 2006 study, C.C. Ribeiro and colleagues made porous ceramic microspheres with interconnected porosity by mixing calcium-titanium-phosphate (CTP) and hyaluronic acid (HA) with a solution of alginate, the natural polymer found in brown algae and soil bacteria.

The ceramic phase-to-polymer ratio was critical to altering the size distribution of the resulting microspheres. Using a CTP ceramic-to-polymer ratio of 10:3 and 20:3, the mean microsphere diameters reported were 513 ± 24 µm and 602 ± 28 µm, respectively, whereas with HA the same formulation resulted in mean diameters of 429 ± 46 and 632 ± 40 µm.

Production challenges

Although production procedures have resulted in material-specific microsphere yields of favorable size and sphericity, some challenges still exist.

Mainly problems associated with large-scale production, since multiple steps are involved in the manufacturing process with high time and cost implications that make it difficult to scale-up the process.

The multiple steps involved in production can also cause changes to the spheroidised material. For example, the thermal processing required for the manufacture of silicate-based glass microspheres can result in crystallization of the glass, which can increase brittleness and affect degradation.

The production of ceramic-based microspheres may also be associated with high brittleness, complicated manufacturing processes and high production costs.

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