Key Concepts in the Use of Biomaterials

BMEN 344 – BIOLOGICAL INTERACTIONS
AND TESTING
KEY CONCEPTS IN THE USE OF BIOMATERIALS IN SURGERY AND MEDICAL DEVICES
Learning Objectives

 Appreciate the importance of biological testing for medical devices and the present-
day requirement to demonstrate safety and efficacy
 Possess a baseline knowledge of cell and molecular biology that is important for
understanding biological interactions and testing
 Appreciate that medical devices must contend with the body’s protective and
reparative responses
 Be able to describe, in general terms, the sequence of events after a biomaterial is
placed in a biological milieu and what cells are responding to when they encounter an
implanted biomaterial




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 Poll Question

Imagine that your grandmother suffers from cataracts, and over the holidays you
learned that her doctor wants to perform surgery and implant a new intraocular lens
that he and some colleagues have developed. Do you think this is a good idea?




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BMEN344
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 Monet’s Water Lily Pond, a painting of the pond and bridge before any visual symptoms (1899) The Japanese Bridge at Giverny (1918-1924)
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Marmor. Arch Ophthalmol. 2006;124(12):1764-1769.
 Biomaterials History: The Era of the Physician-Hero

 Newly developed high-performance materials (especially polymers)
became readily available after the World Wars
 Government regulatory activity was minimal, and today’s protections
for human subjects were non-existent
 Materials originally manufactured for airplanes, automobiles, clocks,
and radios were taken “off the shelf” by innovative physicians and
applied to medical problems
 Silicones, polyurethanes, Teflon, nylon, methacrylates, titanium, and stainless
steel

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Biomaterials History: The Era of the Physician-Hero

Sir Harold Ridley developed intraocular lenses after observing that plastic shards healed in place
with no further reaction




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 Biomaterials History: The Era of the Physician-Hero
 Willem Kolff devised the first dialysis machine from a Maytag washing machine in the 1960s
 Belding Scribner and Wayne Quinton developed an arteriovenous shunt to enable chronic dialysis




https://ohiomemory.org/digital/collection/p267401coll36/id/24024/ 7
Leonard et al. Blood Purif 2011;31:92–95.
 Biomaterials History: The Era of the Physician-Hero



Published in
1956




Deterling and Bhonslay. AMA Arch 8
Surg. 1956;72(1):76-91
Biomaterials History: Taking Action to Protect Patients

 In 1969 President Nixon called for “certain
minimum standards” for medical devices and
declared that “the government should be given
additional authority to require premarketing clearance
in certain cases [of medical devices].”
 In 1970 The Cooper Report was released (Medical
Devices: A Legislative Plan”) and reported that more
than 700 deaths and 10,000 injuries were
associated with medical devices
 512 deaths and injuries were attributed to
heart valves
 89 deaths and 186 injuries were tied to heart
pacemakers
 10 deaths and 8,000 injuries were attributed
to intrauterine devices
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Biomaterials History: Taking Action to Protect Patients




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Biomaterials History: Taking Action to Protect Patients

 While the Cooper Committee recommendations were being
debated in Congress during 1972 and 1973
 Pacemaker failures were reported
 In 1975, hearings took place on problems that had been
reported with the Dalkon Shield intrauterine device, which
caused thousands of reported injuries
 These incidents helped underscore the need for regulation
 In 1976 the Medical Device Amendments were passed
 Purpose was to ensure safety and effectiveness of medical
devices, including diagnostic products
 Required manufacturers to register with FDA and follow
quality control procedures
 Introduced the concept of premarket approval by FDA for
certain products

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 Takeaway Points
 Simply choosing materials based on their physical
properties is a recipe for disaster
 To design medical devices that are both safe and
effective, we must also consider how materials interact
with biological systems
 This is why the biomaterials field exists
 The word “biomaterials” implies an intersection of
biology and materials
 Put simply, we must perform biologically relevant testing
and ensure biocompatibility
 Discussion: How do we define biocompatibility?




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The Intersection of Materials and Biology
 When a synthetic material is placed in a biological milieu (e.g., implantation in a
living organism), a series of reactions is initiated almost instantaneously
 Water molecules and ions reach the surface of the material nearly
instantaneously
 Subsequently, proteins reach the surface and may coat it
 Cells then interact with this coated surface
 Additionally, materials must contend with the body’s protective and reparative
responses
 Blood coagulation (hemostasis)
Implantation is an Injury
 Inflammation
 Wound healing AND
 Innate immune system Biomaterials are Foreign
 Adaptive immunity Objects
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 Cell and Molecular Biology (prerequisite knowledge)
 The basic functional attributes of cells include
 Protection
 Signaling
 Nutrient absorption and assimilation
 Energy generation
 Macromolecule synthesis
 Growth https://bio.libretexts.org/Bookshelves/Cell_and_Molecular_Biology/Book%3A_Basic_Cell_and_Molecu
 Reproduction lar_Biology_(Bergtrom)/16%3A_Membrane_Structure/16.02%3A_Plasma_Membrane_Structure


 However, most cells in the body are differentiated and exhibit specialization
 Differentiation allows for a division of labor in the performance and coordination of complex
functions carried out in architecturally distinct and organized tissues and organs
 Examples: conductivity (nervous system), contraction (muscle), protection (immune system),
absorption/secretion (gastrointestinal tract), transport (cardiovascular system)
 Receptors on the surfaces of cells enable them to sense and respond to stimuli
 Differentiated cells (e.g., macrophages) can exhibit different phenotypes
www.socrative.com 15
BMEN344
 Discussion Questions
 What cells types do you know?



 What is meant by cell phenotype?



 How are the actions of cells (e.g., secretory activity, proliferation, migration) regulated?




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https://libretexts.org/
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https://bio.libretexts.org/Bookshelves/Cell_and_Molecular_Biology/Book%3A_Basic_Cell_and_Molecular_Biology_(Bergtrom)
Overview of Cell-Matrix Interactions, Signaling, and
Regulation of Cell Behavior
 Stromal cells, parenchymal cells,
capillaries, and nerves are embedded
with an extracellular matrix (ECM) and
physically and functionally integrated
in tissues and organs
 The ECM comprises the biological
material produced by and residing
in between cells
 The ECM provides physical support to
cells (they can adhere to it) but also
regulates cell behavior
 The ECM is dynamic and is
remodeled by cells



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Fig. 2.4.1.4
Overview of Cell-Matrix Interactions, Signaling, and
Regulation of Cell Behavior
 Receptors called integrins bind to
extracellular matrix proteins (e.g.,
collagen, fibronectin, laminin) and
mediate cell-matrix interactions
 Other receptors called cadherins and
Cell Adhesion Molecules mediate cell-
cell interactions
 Other receptors bind soluble
molecules that are secreted by cells
 Growth factors
 Cytokines
 Chemokines
 Key point: Engagement of specific
receptors triggers signal transduction
pathways that affect gene expression
and cell activity
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Fig. 2.4.1.5
Overview of Cell-Matrix Interactions, Signaling, and
Regulation of Cell Behavior
 Receptors called integrins bind to
extracellular matrix proteins (e.g.,
collagen, fibronectin, laminin) and
mediate cell-matrix interactions
 Other receptors called cadherins and
Cell Adhesion Molecules mediate cell-
cell interactions
 Other receptors bind soluble
molecules that are secreted by cells
 Growth factors
 Cytokines
 Chemokines
 Key point: Engagement of specific
receptors triggers signal transduction
pathways that affect gene expression
and cell activity
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Fig. 2.4.1.6
 Overview of Cell-Matrix Interactions, Signaling, and
Regulation of Cell Behavior

 Growth factor – broad class of cell signaling
molecules (generally proteins) that can act on a
variety of cell types or may have a specific target
population
 Promote cell proliferation and differentiation
 Also influence cell movement, contractility,
protein synthesis (i.e., almost any cellular
activity)
 Key regulators of tissue repair and wound
healing
 Some examples: vascular endothelial growth
factor (VEGF), fibroblast growth factor (FGF),
platelet derived growth factor (PDGF),
epidermal growth factor (EGF) 22
https://www.rndsystems.com/pathways/vegf-vegf-r2-signaling-pathways
 Overview of Cell-Matrix Interactions, Signaling, and
Regulation of Cell Behavior

 Cytokine – a more narrow (but still broad) class
of cell signaling molecules
 Historically refers to signaling molecules that
regulate immune cells, but the term is often
used interchangeably with growth factor
 Examples: interferons (IFNs), interleukins
(ILs), and tumor necrosis factors (TNFs)
 Chemokine – class of cell signaling molecules
that guide cell migration
 Chemotaxis is directional cell movement in
response to a chemical gradient


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 Cell and Tissue Injury
 Cells and tissues attempt to maintain their milieu and function
within a relatively narrow range of physiologic parameters
 Adaptative mechanisms exist to preserve tissue function and
homeostasis when physiologic stresses or pathologic stimuli are
encountered…but they have a limit
 Exceeding this limit results in cell injury and death
 Necrosis (cell death due to irreversible injury) results in an inflammatory
response
 Apoptosis (programmed cell death) results in little to no inflammatory response
 Two important causes of injury are toxic injury and trauma
 Chemical agents (components of food, naturally occurring toxins,
hormones, synthetic drugs, environmental pollutants, poisons, ethanol)
can cause cell injury
 Chemicals are used to synthesize materials
 Direct mechanical force (trauma, pressure), temperature extremes,
electric shock, and ionizing radiation can also cause cell injury
 Surgery is traumatic and causes irreversible injury
 Excessive inflammation can also cause injury Fig. 2.4.1.12
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 Response to Tissue Injury and Biomaterials
Macrophages play a key role in the response
 A key protective response of an organism is its to injury
ability to eliminate damaged tissues and
foreign invaders (e.g., microbes, exogenous
nonbiological materials like splinters)
 Immune protection
 To restore homeostasis, damaged tissues
must be repaired
 In limited cases, tissue regeneration is possible
and normal structure and function can be
restored
 More commonly, the damaged tissue is replaced
with fibrotic scar tissue
 When foreign bodies are present and cannot
be eliminated, they are encapsulated in fibrous
tissue to isolate them from the rest of the body
Fig. 2.4.1.16
 Foreign body reaction (FBR) 25
 Introduction to the Foreign Body Reaction


 Discussion:
 What drives this biological
response?
 Does fibrous encapsulation
indicate that a material is not
biocompatible?




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Ratner. Regen Biomater. 2016;3(2): 107-10.
The Intersection of Materials and Biology
 When a synthetic material is placed in a biological milieu (e.g., implantation in a
living organism), a series of reactions is initiated almost instantaneously
 Water molecules and ions reach the surface of the material nearly
instantaneously
 Subsequently, proteins reach the surface and may coat it
 Cells then interact with this coated surface
 Additionally, materials must contend with the body’s protective and reparative
responses
 Blood coagulation (hemostasis)
Implantation is an Injury
 Inflammation
 Wound healing AND
 Innate immune system Biomaterials are Foreign
 Adaptive immunity Objects
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