Biomedical Engineering
Biomedical Engineering
Biomedical Engineering
ANNIVERSARY ARTICLE
Origins and Development of Biomedical
Engineering within Chemical Engineering
Nicholas A. Peppas
Dept. of Chemical and Biomedical Engineering, and Pharmaceutics, The University of Texas at Austin, 1 University Station
C0400, Austin, TX 78712
Robert Langer
Dept. of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
Over the past 45 years, the field of biomedical engineering has found a welcome home
in academic chemical engineering departments and in companies working with artificial
organs, medical devices, and pharmaceutical formulations. The contributions of chemical
engineers to the definition and the growth of the field have been important and at times
seminal. The development and early contributions in the biomedical field with special
emphasis on the contributions of chemical engineers is examined. 2004 American Institute
of Chemical Engineers AIChE J, 50: 536 546, 2004
Keywords: biomedical engineering, blood rheology, hemodialysis, biomaterials, controlled release, tissue engineering
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Researcher
Ref.
Blood Rheology
Artificial Kidney Design
Analysis of Hemodialysis
Biomembranes
Heparinized non-Thrombogenic Biomaterials
Radiation Produced Biomaterials
Contact and Intraocular Lenses
Protein Delivery from Polymer Matrices
Intelligent Hydrogels in Drug Delivery
E. W. Merrill, MIT
E. Leonard, Columbia
C. K. Colton, MIT
A. Michaels, MIT
E. W. Merrill, MIT
A. Hoffman, MIT, U. Washington
N. A. Peppas, Purdue Univ.
R. Langer, MIT
N. A. Peppas, Purdue Univ.
(1959)
(1959)
(1966)
(1966)
(1967)
(1969)
(1976)
(1976)
(1979)
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Figure 1. Diffusion cell from the mid 1960s used in detailed studies of solute permeation in biocompatible membranes with possible use in hemodialyzers
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Chemical Engineering in Medicine and Biology, Plenum Press, New York (1967)
Biomedical Applications of Heat and Mass Transfer, Iowa State University Press, Ames
(1971)
Transport Phenomena in the Cardiovascular System, Wiley, New York (1972)
Fluid Mechanics and Mass Transfer in Artificial Organs, ASAIO, Washington, DC (1973)
Transport Phenomena and Living Systems, Wiley, New York (1973)
Biomedical Engineering Principles, Dekker, New York (1976)
Biomaterials
In the early days of biomedical engineering, chemical engineers became pioneers in the development of biomaterials
science and engineering. This is probably associated with significant ChE contributions to the broader field of polymer
science whose chemical engineers were early pioneers. From
1965 to the early 1980s, contributions by Allan Hoffman,
Edward Merrill, Buddy Ratner, Stuart Cooper, Nicholas Peppas, Robert Langer, Larry McIntire, Michael Sefton, David
Tirrell and others opened up the field of biomaterials science.
Table 3 summarizes some groups of biomaterials to which
chemical engineers made contributions in the early days of the
biomedical engineering field.
Some of the early contributions in biomaterials involve the
research of Merrill and his coworkers who did some of the first
studies, understanding what would cause compatibility of biomaterials in contact with blood. Merrills initial studies examined whether heparin might allow a surface to be anti-thrombogenic (Merrill et al., 1966; Britton et al., 1968). He and
others conducted studies to test whether it was the high water
content of hydrogels that could be useful in preventing thrombogenicity, but recognized that this was not sufficient (Merrill
et al., 1970). Merrill and colleagues followed these studies by
examining hydrophobic polymers such as poly(dimethyl siloxane), but they recognized that these too were thrombogenic
(Gifford et al., 1976).
As early as 1974, Merrill and coworkers then turned to
poly(ethylene oxide) (PEO), and showed that it could be useful
as a biomaterial (Merrill and Salzman, 1982). They found that
when PEO was absorbed onto glass vessel walls, subsequent
absorption of proteins, or viruses from solution was prevented.
Other water-soluble polymers that they studied were not nearly
as effective. Building on these studies, Merrill then went on to
produce materials in which PEO chains were crosslinked by
phase separation of segmented polyurethane ureas (Sa da Costa
et al., 1980). He and his colleagues studied PEO and poly(ethylene glycol) monomethyl ether in crosslinked polyfunctional
siloxane networks (Pekala et al., 1986), and synthesized PEO
networks crosslinked by polyfunctional siloxanes (Sung et al.,
1990; Chaikof and Merrill, 1990). They then synthesized PEO
networks formed by radio crosslinking (Merrill, 1992), and
along with Rempp and colleagues developed PEO star molecules for biomedical applications (Rempp et al., 1990).
Meanwhile, Hoffman studied the use of radiation polymerization techniques to prepare biocompatible hydrogels. Hydrogels are crosslinked hydrophilic polymers that form networks
that can swell but not dissolve in biological fluids. Although
available for chemical applications as early as 1935, they
became the subject of intense medical studies after the pioneering work of Wichterle and Lim (1960), who prepared the
earliest poly(hydroxyethyl methacrylate) (PHEMA) hydrogels.
These materials became the contact lenses of choice (known
Table 3. Some Significant Contributions to Biomaterials Science and Engineering by Chemical Engineers
Biomaterials
Contributors
Ref.
C. Colton, MIT
A. Hoffman, MIT
E. Merrill, MIT
E. Merrill, MIT
N. Peppas, Purdue
M. Sefton, U. Toronto
S. Cooper, U. Wisconsin
B. Ratner, U. Washington
E. Merrill, MIT
R. Langer, MIT
(1966)
(1966)
(1966)
(1969)
(1975)
(1976)
(1972)
(1973)
(1974)
(1982)
Poly(vinyl alcohol)
Polyurethanes
Poly(hydroxyethyl methacrylate)
Poly(ethylene oxide)
Polyanhydrides
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also as soft contact lenses) in the 1970s. Hoffman and associates became major contributors to this field.
Ratner, who joined the University of Washington first as a
postdoctoral fellow and then as a ChE professor in the 1970s,
made numerous contributions to the field of surface characterization of biomaterials (for example, see Ratner et al., 1990).
Cooper and associates were early pioneers of the structure and
analysis of polyurethanes as biomaterials (Cooper et al., 1997).
Applied thermodynamics and molecular theories were beginning to be applied to the design and understanding of the
dynamic behavior of a wide range of biomaterials, and notably
hydrogels. Early contributions to the development of heparinized poly(vinyl alcohol) hydrogels (Peppas and Merrill, 1977)
and ultrapure polymers led to inert hydrogels for long term
potential applications in articular cartilage, contact lenses and
linings for artificial hearts (Hassan and Peppas, 2000). McIntire
also made a number of important early contributions to biomaterials. For example, he developed new models for studying
viscoelastic materials (Yen and McIntire, 1972).
Studies of the mechanisms of blood coagulation were contributed by several chemical engineering researchers including
Channing Robertson of Stanford University (Watkins and Roberston, 1977), who developed the earliest internal total reflection technique for examination of protein adsorption on polymer/biomaterial surfaces. The coagulation cascade mechanism
as understood in 1975, is shown in Figure 2. The work of
Robertson, Merrill, Michael Sefton of the University of Toronto, Stuart Cooper at the University of Wisconsin, and other
chemical engineers led to a better understanding of the function
of various components in this cascade mechanism, notably
kallikrein, fibronectin, and the prothromin/thrombin mechaAIChE Journal
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Figure
system.
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Tissue Engineering
Chemical engineers have also played a central role in creating novel approaches for forming new tissues. In one approach,
cells are placed on highly porous polymer matrices. The concept is that when isolated cells are injected in the body at
random, they are not able to form tissue structures. However,
when they are placed close enough to each other they actually
do form such structures, presumably because of signals they
are able to give to each other. This has been shown, for
example, by placing endothelial cells close together in vitro
where they can form capillaries (Folkman and Haudenchild,
1980), and when mammary epithelial cells are placed close
together, they from acini and make milk (Bissell and BacellosHoff, 1987).
Langer and Vacanti (Vacanti et al., 1988) hypothesized that
by creating the appropriate polymer structures, and with the
correct tissue culture medium, an environment could be created
where there would be a very large surface area per unit volume,
enabling a large number of cells to be grown in such a way that
they would be in close contact with each other. The polymers
were also designed to be degradable so that possible long-term
biologic reactions to them many years later would not be able
to occur. The concept was to initially design a tissue outside the
body, which could then be transplanted into the body where it
could function. The first polymers that were studied were lactic
and glycolic acid, which have biodegradability, biocompatibility, and good physical processing properties. A variety of other
polymers have been synthesized, such as poly(lactic acid)
lysine copolymers that have the ability through the lysines
amino terminus to attach various informational molecules, such
as peptide sequences, which could be helpful for specific cells.
Bioreactors also play an important role in growing these
cells. An example has been the work of Niklason et al. (1999)
who found in trying to create blood vessels, that it was very
difficult to create such vessels simply with the conventional
approach of growing cells on a polymer under normal tissue
culture conditions. However, by connecting the cells on a
polymer tube in a bioreactor to a pulsatile pump that could beat
at a 165 beats per m simulating a heart, Niklason and coworkers were able to make a fully functional blood vessel that could
be implanted in pigs, and stay patent for months. Tissue engineering has already led to the point where new skin can be
created for burn victims, and where cartilage is being placed in
patients. Various other tissues such as tendons, ligaments,
livers, ureters, bones, and others are in animal trials and, in
some cases, clinical trials (Langer et al., 1995; Vacanti and
Langer, 1999).
A different type of approach in which chemical engineers
have played a major role has been to encapsulate cells in
polymers, which serve as immunoisolation membranes. Here,
the concept is to create membranes that allow small molecules,
such as glucose or other nutrients to diffuse through, but can
prevent large molecules, such as immunoglobulins or immune
cells from entering the membrane. Pioneering work by Chick
and Solomon (Sullivan et al., 1991) has shown that hollowVol. 50, No. 3
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Future Directions
We believe that biomedical engineering is taking on a continually increased role within the field of chemical engineering.
This is reflected by increased student demand, new job opportunities in the newly emerging biotechnology industry, faculty
hiring, and even departmental name changes in a number of
cases. This increased role reflects the challenges ahead in
training and research. From a training standpoint, new courses
are being designed to teach fundamentals combining engineering and biology to instruct students on critical aspects of this
rapidly changing field (Saltzman, 2001). From a research
standpoint, molecular design and engineering principles will be
applied in a range of new areas including gene therapy delivery, biosensor design, new imaging agents, novel biomaterials,
and other areas where chemistry and engineering will undoubtedly impact medicine. We believe that chemical engineering
has played a major role in biomedical engineering in the past,
but that it is importance in the future will be even more
profound.
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