BIOMATERIALS

L2 Biological responses
to materials
Index

• Introduction

• Tissue response continuum

• In vivo evaluation of tissue response

• Do you need help?

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 Introduction

LEARNING OBJECTIVE:

To know and understand the interactions between biomaterials surface and the
environment

Read the following paper:

Anderson, James M., “Biological responses to materials”, Annual Review

of Materials Research. 2001, Vol. 31 Issue 1, p81. 30p. 3 Diagrams, 8 Charts, 2 Graphs.
DOI: 10.1146/annurev.matsci.31.1.81.

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Introduction

Biocompatibility

• The ability of a biomaterial or medical device to perform

with an appropriate host response in its intended
application

• Host Response to Material Implantation is an invasive

procedure that initiates a series of events whose
outcome ultimately determine the biocompatibility
of the material.

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Tissue response continuum

• Initiated when a biomaterial

or medical device is
implanted
• Surrounding tissue is injured
in the process
• Includes inflammation, wound
healing responses, foreing
body reaction and fibrous
encapsulation

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Injury

• Injury is inflicted during the implantation of a medical

device
• Tissue can be repaired in two ways:
• Depends on the extent of injury and cell types present
• Resolution – tissue/organ structure is restored
• Reorganization – replacement of tissue structure with fibrous
tissue

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Blood material interactions

• Early responses involve mainly blood and vasculature due to

injury to vascularized tissue
• Protein adsorption
• Provisional matrix formation

• Adsorbed protein layer determines cellular response

• Biocompatibility is dependent largely on cellular response
• Properties of proteins and biomaterial surface as well as their
interactions are critical in biomaterial and medical device
design

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Blood material interactions

• Extrinsic and intrinsic coagulation system

• Exudation
• Fluid, proteins and blood cells escape from vascular tissue into
tissue
• Response is mediated by chemicals released from
plasma, cells and injured tissues
capillary

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Provisional matrix formation

• Occurs within minutes to hours after injury

• Components:
• Fibrin – shown to play a role in neovascularization
• Inflammatory products
• Adhesive molecules
• Platelet granules
• Stabilized by crosslinking of fibrin by factor XIIIa
• Substrate for cell adhesion and migration
• Control subsequent wound healing processes
• Initiate resolution, reorganization and repair processes
(inflammatory cell and fibroblast recruitment)

Fibrin fibers Human Blood Clot 10 Minutes

after the Wound

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Inflammation

• Reaction of vascularized living tissue to local injury

• Serves to contain, neutralize, dilute or Wall off injurious
agent or process

• Four cardinal signs of inflammation:

• Redness
• Swelling
• Pain
• Heat

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Acute inflammation

• Characterized by neutrophils
• Short life spans (hours to days)
• Monocytes and macrophages are in their
highest concentrations
• Exudation of fluid and plasma proteins
Leukocytes
• Phagocytosis
• Recognition, attachment, engulfment and
degradation of foreign materials by leukocytes

Phagocytosis 11
Chronic Inflammation

• Occurs from persistent inflammatory stimuli

• Macrophages
• Key mediators in immune reaction development
• Releases growth factors
• Lymphocytes and plasma cells
• Blood vessels and connective tissue proliferation
• Related to implant
• Localized at implant site

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Granulation tissue

• Healing inflammation
• Earliest appearance at 3-5 days post-implantation
• Characterized by
• Proliferation of fibroblasts and vascular endothelial cells
• Neovascularization
• Pink, soft granular appearance on surface of healing wounds

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Foreign Body Reaction
• Considered the normal wound healing response to implanted
biomaterials
• May persist for the lifetime of the implant
• Consists of
• Granulation tissue components
• Macrophages, fibroblasts, capillary formation
• Foreign body giant cells
• Fused macrophages
• May be involved in biodegradation of polymeric medical devices

When macrophages encounter a foreign object too large to

be phagocytosed,such as an implant, it is thought that the
macrophages experience “frustrated phagocytosis.”

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Foreign Body Reaction

• Composition of foreign body reaction depends on

surface properties
• Surface roughness
• Rough surfaces recruit more macrophages and foreign body giant
cells which leads to more fibrosis
• Surface chemistry and protein adsorption
• Significant roles in inflammatory and wound healing processes

FURTHER READING

https://www.uweb.engr.washington.edu/research/tutorials/woundhealing.html

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Fibrous encapsulation

• End-stage healing response

• Isolates implant and foreign body reaction from
surrounding tissue
• Extent depends on
• Degree of injury tissue framework
• Types of cells present
• Local and systemic factors
Example of a capsulated breast implant

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Wound healing

https://www.youtube.com/watch?v=zZpMQ_7qiRg
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In vivo tissue response

Assignment 6:

Please, read the following paper: (“Biological responses to

materials”, starting on page 97), and make an scheme of
the different in vivo test referring to the specific biological
properties assessed and upload it to Mudle:

Upload it to Mudle Example: BIOMAT-Assignment6-

Gurutze-Arruebarrena.pdf

-Will not be evaluated, but it is compulsory to do and

submit on time in order to do the exam.

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In-vivo tissue response

• Measure the degree and duration of events pertaining to

host response
• In-vivo assessment
• To determine if device performs as intended and does not have
significant negative effect on patient/user
• Simulated clinical conditions
• Procedures, protocols, guidelines, standards
• US FDA, ASTM, ISO, USP
• ISO 10993 – Biological Evaluation of Medical Devices

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In vivo test selection

• Two perspectives
• Testing of materials during development
• Testing of biocompatibility and function of final product
• Relevant biomaterials and components in vivo testing
• Materials of manufacture
• Intended additives, process contaminants and residues
• Leachable substances
• Degradation products
• Other components and their interactions in final product
• Properties and characteristics of final product

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In vivo test selection

• Can be categorized by nature and duration of body

contact

STANDARDS

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In vivo tests

• Sensitization, irritation and intracutaneous reactivity

• Should reflect intended entry route and type of exposure
• Utilize extracts to determine irritant effects of potential leachables
• Systemic, subacute and subchronic toxicity (includes
pyrogenicity)
• Genotoxicity
• Carried out if indicated by chemistry/composition of material or in
vitro tests
• 3 levels – DNA effects, gene mutations, chromosomal aberrations
• Extracts or dissolved materials

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In vivo tests

• Implantation
• Local pathological effects
• Sample or final product; site appropriate to intended application
• Gross level and microscopic level

• Hemocompatibility
• Effects on blood/blood components by blood-contacting
devices/materials
• Thrombosis, coagulation, platelets, hematology, immunology
• Simulate geometry, contact conditions, flow dynamics
• Blood reactivity differences between species
• Short and long term testing

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In vivo tests

• Chronic toxicity
• At least 10% of animal lifespan
• Carcinogenicity
• Tumour-generating potential
• Single/multiple exposure over majority of life span of animal
• Only if other test suggest tumour induction
• PE of similar shape usually as control

• Reproductive and developmental toxicity

• Reproductive function/embryonic development, prenatal and
early postnatal development
• Only if potential impact exist

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In vivo tests

• Biodegradation
• Effects of biodegradable material and biodegradation products on
tissue response
• Amount/time, nature of products, origin, assessment of
degradation products and leachable agents in tissue and organs

• Immune responses
• Modified tissue implants (ex. collagen)
• Immunotoxicity – any adverse effect on function or structure of
immune system or other systems as result of immune dysfunction

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Animal model selection

• Appropriate animal models important in safety

evaluation of medical devices – not only biological
responses but also immunotoxicity

• Examples
• Animal models heal with endothelial blood-contacting surface but
humans heal with little endothelialization and result is potentially
thrombogenic
• Sheep used to test heart valves because of accelerated
calcification

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