Biomedical Engineering Reference
In-Depth Information
nanoparticles. Micro/nanoparticles or spheres may increase the life span of active con-
stituents and control the release of bioactive agents [82]. Since their size varies from nano-
meters to several micrometers, micro/nanoparticles have a large surface area for multivalent
bioconjugation [83] and can be used for controlled release of insoluble drugs. It is neces-
sary to fulfill some criteria in order to design effective micro/nanoparticle DDSs [84]. The
first criterion is that micro/nanoparticles should be stable enough to circulate in the blood-
stream for a long time. Instability of these particles may result in burst release of therapeu-
tics, bringing about adverse side effects. Effective ligands for certain cells should be
incorporated on their surface for targeting drug release. The second criterion is that the
dimension of nanoparticles should be less than 200 nm in diameter. This can facilitate
cellular uptake of the nanoparticles through a receptor-mediated endocytosis (RME) to
cross cell membranes as well as reduce nanoparticle uptake by the mononuclear phago-
cyte system, simultaneously increasing their circulation time in blood. The last criterion is
the biodegradability of micro/nanoparticles. Biodegradation should not only modulate the
release behaviors of drugs for a desired period of time, but also enable removal of the empty
device after drug release.
There are several common methods for fabricating micro/nanoparticle DDSs.
6.4.2.1 Emulsification
Emulsification is the most popular technique to obtain micro/nanoparticles [85,86]. The
general methods for emulsification include inverse (mini) emulsion, inverse microemul-
sion (or the reverse micelle method), and membrane emulsification [87].
Thr inverse (mini) emulsion method yields kinetically stable water-in-oil (w/o) macro-
emulsions at, below, or around the critical micellar concentration (CMC) of surfactants.
Tween 80 as an oil-soluble surfactant is often used to implement colloidal stability of the
inverse emulsion. Cyclohexane, hexane, and mineral oil are hydrophobic organic solvents
commonly used for the inverse (mini) emulsion method. Micrometer-sized microparticles
are often obtained by this method. Chitosan microparticles may be produced as follows:
Aqueous droplets of chitosan are added via a syringe into an oil phase (mineral oil) as the
suspension medium, forming a w/o emulsion. Chitosan is stably dispersed in continuous
organic phase with the aid of oil-soluble surfactants. To this suspension, a chemical cross-
linking agent that can react with the functional amine group of chitosan, usually a bifunc-
tional chemical reagent such as glutaraldehyde, hexamethylene diisocyanate or ethylene
glycol diglycidyl ether, is added [16]. A schematic representation of the technique is given
in
Figure 6.12
[16]. The chitosan microparticles obtained are washed with petroleum ether,
sodium bisulfide, and acetone, respectively, to remove excess cross-linking agent and oil.
The final chitosan microparticles are well-shaped, spherical particles varying in the size
range of tens to hundreds of micrometers in diameter [86]. The size and size distribution
of chitosan microparticles can be changed by stirring rate, concentration of chitosan, chi-
tosan molecular weight, chitosan/solvent ratio, and extent of cross-linking.
Another emulsification method for producing micrometer-sized particles is membrane
emulsification [87]. It involves the use of a membrane with a highly uniform pore size
ranging from 0.1 to 18 μm. Through the membrane, an aqueous solution of biopolymers
permeates under adequate pressure into an organic solvent containing oil-soluble surfac-
tants, producing a w/o emulsion. The aqueous droplets of biopolymers are hardened by
physical or chemical cross-linking, producing microparticles with a uniform-sized distri-
bution. Chitosan-based microparticles loaded with insulin prepared via this method had
diameters in the range from 4 to 15 μm.
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