Biological Constraints in Using

Biomaterials- Inflammation
Readings for September 2, 4 & 9:
Biomaterials: The Intersection of Biology and
Materials Science, J.S. Temenoff and A.G. Mikos,
Pearson/Prentice Hall, 2008, pp. 327-335, 369-384, 385-393

BIOMATERIALS-TISSUE
INTERACTIONS

Hemostasis/Thrombosis

SEQUENCE of EVENTS of
BIOMATERIAL RESPONSES
Surgery, Material Implanted
Cell Injury and Necrosis
Acute Inflammation
Chronic Inflammation
Healing, Fibrosis

Granulation Tissue,
Granulomas

CAUSES of CELL INJURY

Materials (biomaterials)
Surgery
Hypoxia
Physical Agents
Chemicals and Drugs
Microbiologic Agents
Immunologic Reactions
Genetic Defects
Nutritional Imbalances

CELL/TISSUE INJURY
CELL

INJURY

reversible vs. irreversible

point of no return

CELL

DEATH

Necrosis- the summation of the morphologic changes

following cell death in living tissue

Apoptosis- programmed cell death

ADAPTATION-

cells responses to stress

Materials &
Biomaterials

CELL INJURY CAUSES NECROSIS

Normal Heart
Tissue

CELLS ADAPT to INJURY/STRESS

REGENERATIVE CAPACITY of CELLS

The growth
response
depends on the
cell type:
Labile
Stable
Permanent

ATROPHY

HYPERTROPHY

Wheresthebeef?

HYPERTROPHY

Cor bovinum

Hyperplasia
(Fibrosis around Biomaterials)
Fibroblast Proliferation

+
Increased ECM (collagen)

Fibrosis

FIBROSIS & FIBROUS

ENCAPSULATION
Polymer

Collagen and
other ECMs

Cells

SEQUENCE of EVENTS of
BIOMATERIAL RESPONSE to INJURY
Surgery, Material Implanted
Cell Injury and Necrosis
Acute Inflammation
Chronic Inflammation
Healing

Granulation
tissue

INFLAMMATION, HEALING & BIOMATERIALS

Local reaction of vascular (or vascularized) tissue to

injury

Occurs in both acute and chronic inflammation!!

TWO MAIN THEMES:

Destruction of tissue- or walling off of biomaterial
Repair- by normal parenchyma or by scar (fibrosis)

TEMPORAL PATTERN
ACUTE- short duration, exudative- cells + proteins, PMNs
CHRONIC- long duration, macrophages/lymphocytes,
proliferative cells-fibroblasts and blood vessels

CELLS of INFLAMMATION
Bone Marrow stem cells + Growth factors

White Blood cells

Megakaryocytic
Erythrocytic
Platelets

Granulocytic
PMNs=neutrophils

Eosinophils

Basophils

Mononuclear
Monocytes

T & B Lymphocytes

WHERE DO THESE CELLS COME FROM?

EPO

TPO
PMN

CSF

CSF

INTERLEUKINS

INTERLEUKINS

Bone Marrow

Fat

Bone

Eos
PMN-band

Platelet

PMNseg
Lympho
Baso
Mono

INFLAMMATION and BIOMATERIALS

Sequence of Events

Injury
Acute inflammation
Chronic inflammation
Granulation tissue
Foreign body reaction
Fibrosis

ACUTE INFLAMMATION
Short
Hours

duration
to a few days

Hemodynamics, Vascular
permeability, Leukocyte migration

Exudative or exudates

Are protein and cells which bind to biomaterials,

pus is an exudate

Calor

Rubor

Tumor

Dolor

HEMODYNAMICS and INFLAMMATION

Q or Jv = ([Pc Pi] [c i])

Pc-Pi

c i

Q or Jv = ([Pc Pi] [c i])

TRANSUDATES vs. EXUDATES

CHARACTERISTIC

TRANSUDATE

EXUDATE

Definition & Etiology

Hemodynamic, an

Inflammatory

ultrafiltrate of plasma

Inflammatory cells

None

Yes

Bacteria

None

Often

Protein

Low (<2%)

High (>4%)

Specific Gravity

<1.012

>1.020

Examples

Congestive heart
failure, blister

Pneumonia,
abscesses, pus

TRANSUDATE

This is a right pleural effusion (in

a baby). Note the clear, pale
yellow appearance of the fluid.
This is a serous effusion. Fluid
appears grossly clear.
Effusions into body cavities can
be further described as follows:
Pleural effusions
Ascites
Pericardial effusion

from Webpath 7.0

EXUDATE

PUS!!!!

LEUKOCYTES in INFLAMMATION
Also

known as White Blood Cells (WBCs)

Granulocytes- PMNs, Eosinophils, Basophils

Monocytes

Lymphocytes

Mast cells- are tissue cells, not in circulating blood

Normal value (blood) is 10,000 cells/cubic mm

Leukocytosis (or philia)- >10,800/cubic mm, increased numbers

Leukopenia- <4,500/cubic mm, decreased

INFLAMMATION & BIOMATERIALS

Cell & Tissue Response
HEALING

Leukocytes in Inflammation
Acute

Chronic

PMNs

Mononuclear
cellS

Other Cells/Components of Inflammation

LEUKOCYTES in INFLAMMATION
Capillary
(Blood) Side

Material with
Bacteria
from Webpath 7.0

Leukocytes in Inflammation

Phagocytosis

Click on the link above, need to be in full slide mode

Chemical Mediators of Inflammation

Plasma-derived
Circulating precursors
Have to be activated

Cell-derived
sequestered intracellularly
synthesized de novo

Most mediators bind to receptors on cell

surfaces but some have direct enzymatic or toxic
activity

Mediators are tightly regulated

INFLAMMATION-MEDIATORS

ARACHIDONIC ACID PATHWAY

COMPLEMENT SYSTEM
Complement binds to biomaterials and is activated by biomaterials
Biomaterials

and biomaterial
surfaces

FEVER

, IL-6

SEQUENCE of EVENTS of
BIOMATERIAL RESPONSE to INJURY
Surgery, Material Implanted
Cell Injury and Necrosis
Acute Inflammation
Chronic Inflammation
Healing, Fibrosis

Granulation Tissue,
Granulomas

CHRONIC INFLAMMATION
Long
Few

duration

days, weeks, months

Proliferative-

vessel divide

fibroblasts and blood

But also- macrophages & lymphocytes

Note- macrophages do not divide

Leukocytes in Inflammation
Acute

Chronic

MACROPHAGES and FBGCs

(Biomaterials)

MACROPHAGES, FBCGs and

BIOMATERIALS

Foreign Body Giant Cells

Suture

IN VIVO BIOCOMPATIBILITY TESTING

Cage Implant System

Days 7, 14 and 21
Material

Exudates Analyzed
for Cell Counts

Insert

Cage
Surfaces Explanted and
Adherent Cells Analyzed
syringe

Implantation

MACROPHAGES and
FOREIGN BODY GIANT CELLS

Fusion

MACROPHAGES and BIOMATERIALS

The Big Mac Attack--- Degradation

OH

H202

-O2

BIOMATERIAL DEGRADATION

Enzymes
Pits, holes etc.

FREE RADICALS

FREE RADICALS- any atom or molecule with an unpaired electron in its

outer orbit, that can exist independently for a period of time

Reactive Oxygen
Species, Free
Radicals &
Antioxidants

Antioxidants

PACEMAKER LEAD DEGRADATION

Adherent
macrophages &
FBGC release
degradative enzymes
and radicals.

Macrophage adhesion

Foreign body giant cells

(FBGC)

DEVICE FAILURE

Explanted pacemaker lead

Full thickness cracking

Surface cracking

Surface pitting

FBGC - Mediated Surface Degradation

ACUTE INFLAMMATION & ROS

SEQUENCE of EVENTS of
BIOMATERIAL RESPONSE to INJURY
Surgery, Material Implanted
Cell Injury and Necrosis
Acute Inflammation
Chronic Inflammation
Healing

Granulation Tissue,
Granulomas

INFLAMMATION & BIOMATERIALS

Cell & Tissue Response
HEALING

GRANULATION TISSUE

A complex of macromolecules and cells,

macrophages, blood vessels, fibroblasts

Blood vessels formation is referred to as

neovascularization or angiogenesis

Biomolecules are produced by cells that

results in a soft, watery, connective tissue
Glycosaminoglycans (GAGS)
Glycoproteins- fibronectin, laminin
Collagens

HEALING RESPONSE to BIOMATERIALS

Biomaterial

Infection
following Implantation

Granulation
Tissue:
GAG-rich

Fibrosis:
Collagen-rich

GRANULATION TISSUE
GAGS

Blood Vessels

ANGIOGENESIS in GRANULATION TISSUE

TISSUE RESPONSE to BIOMATERIALS

GRANULATION TISSUE-H&E

Granulation tissue:
Blood vessels
GAGs
Some Macs
Some fibroblasts

GLYCOSAMINOGLYCANS

Highly Sulfated-binds to water

GLYCOSAMINOGLYCANS

SEQUENCE of EVENTS of
BIOMATERIAL RESPONSES
Surgery, Material Implanted
Cell Injury and Necrosis
Acute Inflammation
Chronic Inflammation
Healing, Fibrosis

Granulation Tissue

INFLAMMATION & BIOMATERIALS

Cell & Tissue Response
HEALING

HEALING RESPONSE to BIOMATERIALS

Biomaterial

Granulation
Tissue

Fibrosis

FIBROUS TISSUE
or Scar Tissue

A complex of macromolecules and cells,

macrophages, blood vessels, fibroblasts

Biomolecules are produced by cells that

results in a hard, tough, connective tissue
Glycoproteins- fibronectin, laminin
Elastin
Collagens- type III than type I, type I collagen makes
up the final scar tissue

FIBROSIS & FIBROUS ENCAPSULATION

Polymer

Collagen and
other ECMs

Cells

EXTRACELLULAR MATRIX- COLLAGEN

Type III
collagen
is produced
first than
cells
(fibroblasts)
produce Type I
collagen

7 days

14 days

21 days

28 days

FIBROUS
ENCAPSULATION

GROWTH FACTOR FAMILIES

GROWTH FACTORS

Cell responses:
growth, migration,
shape etc.

CELL

FIBROBLAST RESPONSES

Growth Factors
and Cytokines

FIBROBLAST
RESPONSES

CYTOKINES and LYMPHOKINES

Important in Biomaterials Applications

CYTOKINES- from cells, Cell derived productsSoluble or membrane bound

INTERLEUKINS- 1-37

Key Interleukins for Biomaterials (IL-1, IL-4, IL-6, IL-13)

TUMOR NECROSIS FACTOR- TNF-

COLONY STIMULATING FACTORS- GM-CSF

Cytokines and Lymphokines

SUMMARY of the INFLAMMATORY RESPONSE to

BIOMATERIALS
Cell & Tissue Response
HEALING

SUMMARY

Cellular Injury and adaptations

Acute vs. chronic inflammation- fluids, cells, time

Transudates vs. exudates

Macrophages and Foreign body giant cell response to biomaterials

Free radicals and material degradation

Granulation tissue vs. scar (fibrous encapsulation) tissue

Fibroblast responses and healing phase- cell types, growth factors, cytokines