Biomedical Engineering Reference
In-Depth Information
dilute hydrogel solution. Next, small droplets are formed
by extruding this mixture through an appropriate nozzle,
followed by the cross-linking of the hydrogel to form the
mechanically stable microcapsules with an immunoiso-
latory layer. In an alternative process, water-insoluble
synthetic polymers are used in place of hydrogels to
prepare the cell slurry. These microcapsules and the
immunoisolatory layer are then formed upon interfacial
precipitation of the polymer solution. The process to
manufacture macrocapsules typically involves phase in-
version of a thermoplastic polymer solution cast as a flat
sheet or extruded as a hollow fiber. During phase in-
version, the polymer solution is placed in controlled
contact with miscible nonsolvent, resulting in the for-
mation of the mechanically stable and immunoisolatory
membrane. At a later stage, the living cells are aseptically
introduced into the fiber or chamber, which is sub-
sequently sealed.
The processes developed to manufacture macro-
capsules and microcapsules are very versatile and allow
for the formation of membranes with a wide variety of
different transmembrane pore structures and outer sur-
face microgeometries. Membrane selection has a strong
influence on microcapsule or macrocapsule device per-
formance and is characterized in terms of membrane
chemistry, transport properties, outer surface morphol-
ogy, and strength. Optimum parameters are dictated by
the metabolic requirements of the encapsulated cells, the
size of the therapeutic agent to be delivered, the required
immunoprotection, and the desired biocompatibility.
Membrane transport properties are chosen to maintain
viability and functionality of the encapsulated cells and
provide release of the therapeutic agent. This selection
involves designing membranes that provide sufficient
nutrient flux to meet the requirements of the encapsu-
lated cells, while preventing flux of immunological spe-
cies that would reject the tissue.
Biocompatibility is defined by the host reaction to the
implant and has a significant impact upon device per-
formance. Biocompatibility depends upon the nature of
the encapsulated cell and both the transport properties
and outer morphology of the membrane barrier.
Transport properties are routinely evaluated in combi-
nation with a physical characterization of the membrane to
develop structure-property relations. Physical parameters
such as inner diameter, wall thickness, wall morphology,
and surface morphology can influence the transport be-
havior. Light micrometry is used to characterize mem-
brane geometry, and scanning electron microscopy is used
to analyze membrane morphology. The high-resolution
techniques of atomic force microscopy and low-voltage
scanning electron microscopy have been exploited to
image the porosity and pore size of the permselective skin
of ultrafiltration membranes. A wide range of membrane
wall morphologies can be produced using the phase
Fig. 7.1.3-3 Photograph of an implantable macrocapsule. The
pencil and tweezers are included for scale.
beads containing up to several thousand cells. Typically,
hundreds to thousands of microcapsules are implanted
into the host to achieve a therapeutic dose. This design
minimizes transport resistance, allows for easy implanta-
tion, and provides good dose control. However, micro-
capsules are difficult to explant and are usually quite
fragile. Macrocapsules are much larger in size with the
capacity to hold millions of cells, generally requiring
a single device for a given therapy. These devices are
implanted as tubular or flat sheet diffusion chambers with
an inner diameter dimension of 0.5-2.0 mm and a length
of 1-10 cm. Macrocapsules provide mechanical and
chemical stability superior to those of microcapsules and
are easily retrieved. A significant concern with this design
is the geometric resistance to mass transport, which limits
viability of encapsulated tissue. An alternative macro-
capsule design involves connecting the device directly to
the patient's circulatory system. The cells are contained in
a chamber surrounding the macrocapsule, and the flowing
blood can provide an efficient means of nutrient transport.
A major challenge with this vascular design is maintaining
shunt patency of the device.
Membranes
A wide variety of different materials have been used to
formulate the permselective membranes for microcap-
sules and macrocapsules. In general, the membranes for
macrocapsules have been engineered from synthetic
thermoplastics, whereas those for microcapsules have
been engineered using hydrogel-based materials.
Table
7.1.3-1
and
Fig. 7.1.3-2
illustrate the materials and ap-
pearance of hydrophilic and hydrophobic membrane
materials used for immunoisolation.
The process to manufacture microcapsules typically
starts with the creation of a slurry of the living cells in a
