Tissue Engineering - Introduction to Biomedical Engineering - page 345

Strongly Interacting Variables
Primary cell cultures are sensitive to many of the variables that define the microenvi-
ronment. Many of these variables interact strongly. Thus, any change in a single cell
culture variable will change the optimal value for all the others. Statistical experimental
design procedures that optimize the search over many experimental variables can be
employed to lessen this effect. An example of such a two-dimensional search is shown
in Figure 6.35, where the optimal progenitor production performance of human cell
cultures is shown as a function of the inoculum density and the medium flow rate. The
top panel shows the optimal number of progenitors produced per unit cell growth area.
Optimizing this objective would lead to the smallest cell culture device possible for a
specified total number of cells that is needed. The bottom panel shows the optimal expan-
sion of progenitor cells—that is, the output number relative to the input. This objective
would be used in situations where the starting material is limited and the maximum
number of additional progenitors is desired. Note that the two objectives are found under
different conditions. Thus, it is critical to clearly delineate the objective of the optimization
condition from the outset.
Immune Rejection
Allogeneic transplants face immune rejection by the host. A variety of situations are
encountered in such transplantations. Dermal fibroblasts, used for skin ulcers, seem to be
effectively nonimmunogenic, though the reason is not clear. This fact makes it possible to
make a large number of grafts from a single source and transplant into many patients. In
contrast, pancreatic beta cells and islets face almost certain rejection (see Figure 6.6). In allo-
geneic bone marrow transplantation, the graft may reject the immunocompromised host.
This so-called “ Graft-vs-Host disease ” is the main cause for the mortality resulting from
allogeneic bone marrow transplants.
The cellular and molecular basis for the immune response is becoming better under-
stood. The rejection problem is a dynamic process that relies on the interaction between
subsets of CD4 þ cells (CD4 þ is a surface antigen on certain T-cells) Th1 and Th2 that differ
in their cytokine secretion characteristics and effector functions. The components of the
underlying regulatory network are becoming known. Quantitative and systemic analysis
of this system is likely to lead to rational strategies for manipulating immune responses
for prophylaxis and therapy.
Tissue Procurement
The source of the starting material for a growth process is of critical importance. For
example, the source of dermal fibroblasts used for skin replacements is often human fore-
skin obtained from circumcisions. This source is prolific and can be used to generate a large
number of grafts. Since the source is always the same, the biological variability in the
growth process is greatly diminished. The costs associated with tissue procurement as
reflected in the final product are minimal. Conversely, an adult autologous source may
be expensive to obtain and will display highly variable performance.