SECTION

II.1

Some Background Concepts

CHAPTER II.1.1 INTRODUCTION:

BIOLOGY AND MEDICINE KEY
CONCEPTS IN THE USE OF
BIOMATERIALS IN SURGERY
AND MEDICAL DEVICES
Buddy D. Ratner
Professor, Bioengineering and Chemical Engineering, Director of University
of Washington Engineered Biomaterials (UWEB), Seattle, WA, USA

Biomaterials Science: An Introduction to Materials in

Medicine directly addresses the multidisciplinary nature
of the biomaterials field by providing concise tutorials in
the key concepts essential for practitioners of biomaterials science. The word biomaterials implies biology
and materials. This section addresses the fundamental
bio science relevant to biomaterials (Section I.2 serves
a similar function for the fundamental materials science
relevant to biomaterials). The background biology is
important, because this scientific foundation will help us
to understand, predict, and engineer the in vivo bioresponses observed by the biomaterials scientist, the physician, and the patient.
When a synthetic material is placed in a biological
milieu (implantation in a living organism, for example),
a series of reactions is initiated almost instantaneously.
Water molecules (and H+ and OH), being the lowest
molecular weight species, should reach the biomaterial
surface first (in milliseconds). Their considerable impact
on subsequent reactions is elaborated upon in Chapters
I.1.6 and I.2.10. Although water is not considered a biomolecule, it sets the stage for the biological reactions to
follow.
Proteins, dissolved in serum at a concentration of
approximately 7 g/dL, arrive next at the surface by diffusion or in some cases by convection. There are 700
or more proteins in blood. Some are relatively non-
bioreactive, such as albumin, and others have numerous
biological activities, such as fibrinogen or fibronectin.
When proteins diffuse to a biomaterial interface, they
will arrive in order of molecular weight (small proteins
like thrombin, 35 kDa, arrive before heavier proteins
like IgG, at 160 kDa). Once at the surface, proteins can
adsorb, desorb, exchange with other proteins, denature,

increase their biological activity or decrease their biological activity. This complex landscape, comprised of
many proteins in many states of organization and elaborated upon in Chapter II.1.2, becomes the environment
to which cells will respond (and cells do indeed respond
to proteins).
The fundamentals of invitro cell interaction with surfaces (or more accurately, interactions with the protein
layer on biomaterial interfaces in water) are described in
Chapter II.1.3. This chapter is particularly relevant for
surface diagnostic devices (ELISA assays, DNA microarrays, protein microarrays), cell culture, and for biosensors, but also pertains to many reactions observed
invivo.
Chapter II.1.4 discusses the biology of cells, with an
emphasis on what the cells do under various conditions
and what happens when they are injured (you cant
have a surgical site without cell injury; also rubbing and
mechanical forces associated with medical implants can
induce cell injury).
Single cell types rarely exist alone. They aggregate
or interact to form tissues (Chapter II.1.5). Some principles that govern tissue formation from individual cell
types are relatively simple and have been elaborated
upon by researchers such as Malcolm S. Steinberg,
who demonstrated that a cell membrane surface tension associated with cell surface cadhedrin molecules
can drive cell aggregation into organized multicellular
structures. Other aspects of tissue formation are governed by the complex mechanisms observed in studying
the developmental biology of organisms. Biomaterials and medical devices are interfaced against tissues,
so understanding tissues, their organization, and their
properties is important. Furthermore, the cells in tissues
make a grout that holds them together; this material is called extracellular matrix (ECM). ECM serves
a mechanical function in stabilizing the tissues but is,
in its own right, highly biologically active. For example, it has been shown that triple-helical collagen I, the
primary component of ECM, can bind in a biospecific
manner to more than 50 other biomolecules, including
some with high biological activity such as fibronectin.
Thus, the ECM presents to the cells bioactive biomolecules in optimal conformation and orientation, and thus
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SECTION II.1 Some Background Concepts

directs their functions and actions. This concept is particularly important to tissue engineering (Section II.6).
Also, the degradation products of ECM can be highly
bioactive. For example, the work of Judah Folkman and
colleagues demonstrated that degradation fragments of
some collagens are inhibitory to angiogenesis. Since
ECM is synthesized by tissue cells and is broken down
by cells such as the macrophage, the bioactive fragments from the breakdown can impact tissue formation
and biological reaction.
Chapter II.1.6 addresses mechanical forces, their
effects on cells and tissues, and their importance for biomaterials (Chapter I.1.4 on biomechanics provides some
of the concepts needed to appreciate Chapter II.1.6). Living organisms move, and blood flows. Thus, all implants
in living organisms are subjected to mechanical forces.
Although Chapter II.1.6 focuses on the liquidbiomaterial
interface (e.g., blood interactions), the concepts of force
communication from the environment external to the
cell, to the cell membrane, particularly from an engineering standpoint, are elaborated upon. The work of
Donald Ingber and others helps us to understand how
this mechanical trigger at the cell membrane can signal to
the cell nucleus, leading to downregulation or upregulation of specific genes, which then leads to expression of
new cytokines and/or other signaling molecules.

Mechanical forces can impact cells macroscopically, but also impact at a microscopic level. In 1965,
S. B. Carter published a paper in Nature in which he
showed that cells follow micron-dimension scratches in
a plastic film, a phenomenon he named contact guidance.
We use that term to this day to describe this mechanically-induced response of cells to micron scale features.
Chapters I.2.13 and I.2.15 give us patterning, texture,
and porosity tools to manipulate cellmechanical interactions at the micro- and even the nanolevel.
Section II.1 ends with Chapter II.1.7, which is on key
concepts relating to stem cells. When the second edition
of this textbook was being assembled, one could hardly
imagine the importance that stem cells would assume for
biomaterials and tissue engineering. Now, some 10years
later, stem cells are seen to be of critical importance to
tissue engineering, but are also important for wound healing, tissue development, and even for the evolution of cancerous tumors. Furthermore, stem cell differentiation to
specific tissue cells seems to be significantly impacted by
mechanical forces communicated to the cells by surface
modulus and surface topographies (textures and porosities) at the micron scale (surface chemical composition can
also impact differentiation). Thus, we see relationships
between this chapter and Chapter II.1.6 (effects of mechanical forces on cells) and Section II.6 (tissue engineering).

CHAPTER II.1.2 ADSORBED PROTEINS

ON BIOMATERIALS

of adhesion proteins to the biomaterial converts it into

a biologically recognizable material, as illustrated in
Figure II.1.2.1. The protein adsorption event is rapid
(seconds) and happens on all materials implanted into
biological systems. Note: familiarity with protein structure is essential to appreciate the content of this chapter.
All introductory biochemistry textbooks can provide this
critical background material.
The interaction of adhesion receptors with adhesion
proteins thus constitutes a major cellular recognition
system for biomaterials. Therefore, the role of adsorbed
adhesion proteins in mediating cellular interactions with
biomaterials will be the primary focus of this chapter.
Examples illustrating the ability of adsorbed adhesion
proteins to influence cellular interactions with foreign
materials are presented first. Then, some of the major
physicochemical characteristics of protein adsorption are
illustrated and discussed, including rapid kinetics, monolayer adsorption, and competitive adsorption. Molecular
spreading events related to the conformational stability of
the protein are presented at some length, as background
for a section on how the biological activity of adsorbed
adhesion proteins is affected by the substrate. The final
section summarizes the principles underlying the role of
adsorbed proteins in mediating platelet response to biomaterials, as an illustrative case study representative of
many other types of cellular responses.

Thomas A. Horbett
Bioengineering and Chemical Engineering, University of Washington,
Seattle, WA, USA

INTRODUCTION
The replacement of injured or diseased tissues with
devices made from materials that are not of biologic
origin is the central approach in current biomaterials science and clinical practice. The prevalence of this
approach is due largely to the fact that these materials
are not attacked by the immune system, unlike donor tissues or organs. This fundamental difference arises from
the presence of immunologically recognizable biologic
motifs on donor tissue, and their absence on synthetic
materials.
Nonetheless, there are other types of biological
responses to implanted biomaterials that often impair
their usefulness, including the clotting of blood and the
foreign-body reaction. Clearly, the body does recognize and respond to biomaterials. The basis for these
reactions is the adsorption of adhesion proteins to the
surface of the biomaterials that are recognized by the
integrin receptors present on most cells. The adsorption