- Link:
- http://hdl.handle.net/1721.1/28661
- Collection:
-
- Subject
- Chemical Engineering.
- Creator:
- Sivaraman, Anand, 1977-
- Contributors:
- Linda G. Griffith. Massachusetts Institute of Technology. Dept. of Chemical Engineering. Massachusetts Institute of Technology. Dept. of
Chemical Engineering.
- Format
- 228 p.
- Format
- 9996716 bytes
- Format
- 10026132 bytes
- Format
- application/pdf
- Language
- en_US
- Publisher
- Massachusetts Institute of Technology
- Rights
- M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See
provided URL for inquiries about permission.
- Rights
- http://dspace.mit.edu/handle/1721.1/7582
- Type
- Thesis
- Description
- (cont.) approaches to improving hepatocyte function
in culture have been described, not all of the important
functions--specifically the biotransformation functions of the
liver--can as yet be replicated at desired in ivo levels,
especially in culture formats amenable to routine use in drug
development. The in vivo microenvironment of hepatocytes in the
liver capillary bed includes signaling mechanisms mediated by
cell-cell and cell-matrix interactions, soluble factors, and
mechanical forces. This thesis focuses on the design, fabrication,
modeling and characterization of a microfabricated bioreactor
system that attempts to mimic the in vivo microenvironment by
allowing for the three dimensional morphogenesis of liver tissue
under continuous perfusion conditions. A key feature of the
bioreactor that was designed is the distribution of cells into many
tiny ([approximately]0.001 cm³) tissue units that are uniformly
perfused with culture medium. The total mass of tissue in the
system is readily adjusted for applications requiring only a few
thousand cells to those requiring over a million cells by keeping
the microenvironment the same and scaling the total number of
tissue units in the reactor. Using a computational fluid dynamic
model in ADINA® and a species conservation mass transfer model in
FEMLAB®, the design of the bioreactor and the fluidic circuit was
optimized to mimic physiological shear stress rates
...
- Description
- Recent reports indicate that it takes nearly $800
million dollars and 10-15 years of development time to bring a drug
to market. The pre-clinical stage of the drug development process
includes a panel of screens with in vitro models followed by
comprehensive studies in animals to make quantitative and
qualitative predictions of the main pharmacodynamic,
pharmacokinetic, and toxicological properties of the candidate
drug. Nearly 90% of the lead candidates identified by current in
vitro screens fail to become drugs. Among lead compounds that
progress to Phase I clinical trials, more than 50% fail due to
unforeseen human liver toxicity and bioavailability issues.
Clearly, better methods are needed to predict human responses to
drugs. The liver is the most important site of drug metabolism and
a variety of ex vivo and in vitro model systems have therefore been
developed to mimic key aspects of the in vivo biotransformation
pathways of human liver-- a pre-requisite for a good, predictive
pharmacologically relevant screen. Drug metabolism or
biotransformation in the liver involves a set of Phase I (or p450
mediated) and Phase II enzyme reactions that affect the overall
therapeutic and toxic profile of a drug. The liver is also a key
site of drug toxicity following biotransformation, a response that
is desirable but difficult to mimic in vitro. A major barrier to
predictive liver metabolism and toxicology is the rapid (hours)
loss of liver-specific functions in isolated hepatocytes when
maintained under standard in itrom cell culture condition. This
loss of function may be especially important in predicting
toxicology, where the time scale for toxic response may greatly
exceed the time scale for loss of hepatocyte function in culture.
Although a wide variety of
- Description
- by Anand Sivaraman.
- Description
- Thesis (Ph. D.)--Massachusetts Institute of
Technology, Dept. of Chemical Engineering, 2004.
- Description
- Includes bibliographical references (p.
180-195).
- Rights
- M.I.T. theses are protected by copyright. They may be
viewed from this source for any purpose, but reproduction or
distribution in any format is prohibited without written
permission. See provided URL for inquiries about
permission.
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