Tissue engineering - Biomedical Engineering Desk Reference - page 645

been widely used and can be produced from synthetic
or naturally derived materials ( Table 7.1.3-1 ). Examples
of hydrogel matrices include alginate, agarose, and
poly(ethylene oxide), and examples of scaffold matrices
include poly(ethylene terephthalate) yarn, poly(vinyl
alcohol) foam, and cross-linked chitosan. This matrix
serves two basic functions. The first is to provide me-
chanical support for the encapsulated cells in order to
maintain a uniform distribution within the device. In the
absence of this support, the cells often gravitate toward
one region of the device and form a large necrotic cluster.
The matrix also serves a biological function by stimulat-
ing the cells to secrete their own extracellular matrix,
regulating cell proliferation, regulating secretory function,
and maintaining the cells in a differentiated phenotype.
Selection of a matrix for a particular cell type involves
several design considerations. Generally, suspension
cell cultures prefer a hydrogel-based matrix, whereas
anchorage-dependent cells prefer the attachment sur-
faces of a solid scaffold. The matrix must also be physi-
cally and chemically compatible with the permselective
membrane. For example, scaffold matrices should not
damage the integrity of the permselective membrane and
soluble matrix components should not significantly affect
the pore size. The stability of the matrix should also be
considered and in general must at least match the lifetime
of the device. Finally, the transport characteristics of the
matrix candidates need to be considered. Certain matri-
ces may exhibit significant resistance to the transport of
small or large solutes, and thus affect overall performance.

ovary (CHO) line, the Hs27 human foreskin fibroblast,
and the BHK line.
Different cell types have different requirements for
survival and function in a device and may result in a va-
riety of levels of performance in any given implant site.
These cell-specific considerations include metabolic re-
quirements, proliferation rate within a device, and anti-
genicity and are assessed to ensure long-term device
performance. For example, a highly antigenic encapsulated
cell may be rapidly rejected in a nonimmunoprivileged site,
such as the peritoneal cavity. This same encapsulated tissue
may result in very satisfactory performance in an immu-
noprivileged site, such as the central nervous system.
Similarly, a cell with a high nutrient requirement may
provide superior performance in a nutrient-rich site, such as
a subcutaneous pouch, and fail in a nutrient-poor site such
asthecerebralspinalfluid.
Safety is another consideration in sourcing cells for
eventual human implants. Grafts must be derived from
healthy donors or from stable, contaminant-free cell
lines. Before approving human clinical trials, regulatory
bodies require testing for known transmittable diseases,
mycoplasma, reverse transcriptase, cultivable viruses,
and microbial contaminants.

Applications

At this writing (mid-1999) several applications of im-
munoisolated cell therapy are in clinical trials but none
have reached the stage of approval by regulatory agencies
and routine clinical utilization. Table 7.1.3-2 summarizes
the

Cells

application status of the bioartificial liver, the

The final component of the immunoisolation device is the
encapsulated cells used to secrete the therapeutic mole-
cules. These cells may be derived from ''primary'' cells,
(i.e., postmitotic cells dividing very slowly if at all), con-
tinuously dividing cell lines, or genetically engineered
tissue. All three cell types have been successfully encap-
sulated. Cell sourcing for a device begins with a definition
of the desired secretory function of the implant. For ex-
ample, chromaffin cells are a known source of the opoid
peptide norepinephrine and have been used as a cellular
delivery system to treat chronic pain. Such chromaffin
cells are obtained as primary cultures from an enzymatic
isolation of the bovine adrenal gland. Islets of Langerhans
for the delivery of insulin to replace pancreatic function
represent another widely investigated primary cell type.
The PC12 rat pheochromocytoma line is an example of an
immortalized cell line derived from a tumor that has been
used for the delivery of L -dopa and dopamine in the
treatment of Parkinson's disease. Cells engineered to se-
crete a variety of neurotrophic factors have been used in an
encapsulated environment for the treatment of neuro-
degenerative diseases and include the Chinese hamster

Table 7.1.3-2 Application status of immunoisolation (late 1999)

Bioartificial liver Several reports of clinical investigations in

literature for bridge to transplant two
successful phase I a trials.
Two ''pivotal b trials'' underway.

Bioartificial pancreas One case report of a single patient

receiving a therapeutic dose of islets (and
immunosuppression). Several reports of
''survival studies'' at smaller doses.
Preclinical trials report outstanding success
in rodents but not in dogs and nonhuman
primates.

Delivery of cell
and gene therapy

Pain: Successful phase I study completed;
pivotal trial failed to show efficacy.
ALS: Human clinical trials reported;
Huntington trial is in progress.
Numerous studies in primates, other large
animals, and rodents.

a

Phase I. Small trial to determine safety in w 10 patients.

b

Pivotal. Large trial to determine efficacy. Includes control arm.