Massach
usetts
Massachu
setts Ins
Institute of Technolo
Technology
Harva
Harvarrd Me
Medical
dical School
hool
Brig
ham
m an
Brigha
and Women
men’s Ho
Hospital
VA Bo
thca
are Sy
Boston Heal
Healthc
System
2.782J/3.961J/BEH.451J/HST524J
BIOCOMPATIBILITY:
LOCAL AND SYSTEMIC EFFECTS
M. Spector, Ph.D
BIOMATERIALS-TISSUE
INTERACTIONS
BIOMATERIAL
TISSUE
Strength
Modulu
ticitty
Moduluss of Elas
Elastici
Fracture mechanic
mechanicss
10nm 100
100nm 1µm
1 sec
sec 1 da
day
Protein
Adsorption
Cell
Response
Response
Ion
Release
Time Scale
Scale
10 days 100
100 days
days
Tissue
Remodeling
Particles
Particles
Wear
Metal
Metal corr
corrosion
Polymer degradation
degradation
Length Scale
Scale
10 µm 100
100 µm 1mm
CellCell-cell
cell
interaction
interactionss
ECM pr
proteins
otein
Cytokine
Cytokines
Eicosanoids
Enzy
Enzymes
Page 1
BONE
BIOMATERIALS-TISSUE INTERACTIONS:
Tissue Response to Implant Breakdown
IMPLANT
Fracture
Wear
TISSUE RESPONSE
Fibroblast
Degradation:
Fibrous Tissue
(Cell Cont
Contracti
raction?)
Bone
Particles
Macrophage
Metal Corrosion
Polymer
Degradation
Degradation
Products/Ions
Osteoclast
RESPONSE TO IMPLANTS:
WOUND HEALING
Injury
Mild
Moderate/Severe
Vascularized Tissue
Non-vasc.
Resolution
(Inflammation)
No
Healing
Reparative (Healing)
Process
Repair (Scar)
Regeneration
Page 2
RESPONSE TO IMPLANTS:
WOUND HEALING
Injury
Mild
Moderate/Severe
Vascularized Tissue
Non-vasc.
Resolution
(Inflammation)
No
4 Ti
Tissue Ca
Categor
tegoriies
Healing
Connecti
ve Tissue
Connectiv
Reparative (Healing)
Epithelium
Epithelium
Nerve
Process
Muscle
Muscle
Repair (Scar)
Regeneration
RESPONSE TO IMPLANTS:
WOUND HEALING
Injury
Mild
Moderate/Severe
Vascularized Tissue
Non-vasc.
CT:
Resolution
(Inflammation)
Art. Cart.
rt.
No
4 Ti
Tissue Ca
Categor
tegoriies
Healing
Connecti
ve Tissue
Connectiv
Reparative (Healing)
Epithelium
Epithelium
Nerve
Process
Muscle
Muscle
CT: Derm
Dermis, Lig.
Lig. CT:Bone
Mu:
., Card.
Mu: SM
SM
Mu: Skel
Skel.,
Card. Mu:
Repair (Scar)
Ep:
Ep: Epidermi
Epidermiss
Regeneration
Page 3
RESPONSE TO IMPLANTS:
WOUND HEALING
Injury
Regeneration
Repair
Tissue of Labile
and Stable Cells
Tissue of
Permanent Cells
Framework*
Framework* Framework
Framework
Intact
Destroyed
Scar
Regeneration Scar
* “Stroma
”
Stroma”
RESPONSE TO IMPLANTS:
WOUND HEALING
Surgical Implantation
Acute
Inflammation
Inflammation
Vascular Response
Clotting
Phagocytosis
Neovasculariza
Neovascularization
New Collagen Synthesis
Tissue of Labile and Stable Cells
Inc. time
Granulation
Tissue
Tissue of Perm
Permanent
anent Cells
Cells
Implant
Implant Movement
Movement
Fram
Framework Framework
Framework
Intact
Destroyed
Regen.
Scarring
Regen.
(incorp.
(fibrous encapsulation;
incorp.
encapsulation;
of implant)
synovium
implant)
novium)
Chronic Inflammat
Inflammation
Page 4
Scarring
(fibrous encapsulation;
synovium)
synovium)
Chronic Inflammation
Inflammation
I. Metchnikoff
First identified
“macrophages” and
“microphages”
(polymorphonuclear
neutrophils, PMNs)
in an organism
around a foreign
body
I. Metchnikoff
Page 5
In 1923 a piece of glass was
removed from a patient’s
back; it had been there for a
year. It was surrounded by a
minimal amount of fibrous
tissue, lined by a glistening
synovial sac, containing a few
drops of clear yellow fluid.
Photo removed due to copyright restrictions.
Smith-Peterson
J. Bone Jt. Surg.,
30-B:59 (1948)
Diagrams removed due to copyright restrictions.
I. Silver
Page 6
Synovium:
Macrophage-like (Type A) and Fibroblast-like
(Type B) Cells
Photo removed due to copyright restrictions.
Tissue response to a
cylindrical implant of
polysulfone in lapine
skeletal muscle, 2 yrs.
post-op
Fibrous tissue
Photo removed due to copyright restrictions.
Skeletal muscle
Page 7
Polyethylene
implant,
6 mos. post-op
Polyethylene
Photo removed due to copyright restrictions.
MΦ
MFBGC
Polyethylene
Porous Coated
Co-Cr Tibial Component
(retrieved 1 yr. post-op)
Photo removed due to copyright restrictions.
Page 8
RESPONSE TO IMPLANTS:
WOUND HEALING
Surgical Implantation
Acute
Inflammation
Inflammation
Vascular Response
Clotting
Phagocytosis
Neovasculariza
Neovascularization
New Collagen Synthesis
Tissue of Labile and Stable Cells
Inc. time
Granulation
Tissue
Tissue of Perm
Permanent
anent Cells
Cells
Implant
Implant Movement
Movement
Fram
Framework Framework
Framework
Intact
Destroyed
Regen.
Scarring*
Regen.
Scarring*
(incorp.
(fibrous encapsulation;
incorp.
encapsulation;
of implant)
synovium
implant)
novium)
Chronic Inflammat
Inflammation
Page 9
Scar*
Scar*
(fibrous encapsulation;
synovium)
synovium)
Chronic Inflammation
Inflammation
* Inc
ion
Including
uding cont
contract
raction
FIBROBLAST BEHAVIOR IN FIBROUS
TISSUE AROUND IMPLANTS
• Proliferation and increased matrix
synthesis of fibroblasts leads to an increase
in the thickness and density of the scar
tissue.
• Fibroblast contraction results in scar
contracture.
BREAST IMPLANTS
Capsular Contracture
Photo removed due to copyright restrictions.
Photograph shows Grade IV capsular contracture in the right breast of a 29year-old woman seven years after subglandular (on top of the muscle and under
the breast glands) placement of 560cc silicone gel-filled breast implants.
http://www.
impllantforu
m.com/capsular
/capsular--cont
http://www.imp
antforum.com
contracture/
racture/
BREAST IMPLANTS
Capsular Contracture
What is Caps
Capsular Contra
Contracture?
Scar tissu
nd the implan
tissuee that
that form
forms arou
around
implantt which causes the brea
breasts to
harden (simila
le feels like)
imilarr to what
what a cont
contrracted musc
muscle
like) as the
the natura
aturallly
formi
ng scar
nd th
formin
scar ti
tissue arou
around
the impla
plant tigh
tightens
tens and squ
squeezes
eezes it. Whil
While
capsul
ar co
ble complication, it is al
capsular
contract
ntracture is
is an unpredicta
unpredictable
also the most
common
licat
atio
ion
n of breast augmentat
mmon comp
complic
entatiion.
How can Caps
nted?
Capsular
ular Cont
Contracture be preve
preven
ted?
Textured
Textured implants
plants help dete
deterr contra
contracture because of thei
their rough surface
which is in
age a ha
intend
tended to discour
discourage
hard ca
capsule from
from form
forming.
ing.
Under the muscle (sub
-pecttoral
al sub
musccular')
(sub-pec
oral or 'p
'parti
artia
sub--mus
ular') placement of the
implan
es risk
implantt reduc
reduces
risk of ca
capsular
psular contra
contracture by an avera
average of 8 - 10%.
10%.
Whereas over the muscle (in
-mamm
mmar
ary'
y')) has
(in front
front of the muscle or 'sub
'sub-ma
has 10
- 25% or more
more chance of ca
capsule contra
contracture.
CAUSE OF CAPSULAR CONTRACTION
Myofibroblasts, and the regulatory protein
TGF-β, were found in the contracted
capsules around silicone breast implants
but not in non-contracted capsules.
Mature skin scar tissue did not contain
TGF-β or myofibroblasts.
Lossing C, and Hansson HA,
Plast Recons
Reconstr Surg
Surg 91:1277 (1993)
(1993)
Page 12
α-smooth muscle actin-fusion peptide (SMA-FP) inhibits the tension exerted by lung
fibroblasts on silicone substrates. After washing our of the FP, cells contract again.
Video removed due to copyright restrictions.
Hinz B, et al., J Cell Biol 157:657 (2002)
http://www.
implan
lantforu
tforum.com
m.com/capsular
/capsular--cont
http://www.imp
contracture/
racture/
BREAST IMPLANTS
Capsular Contracture
How can Capsul
ar Cont
nted?
?
Capsular
Contracture be preve
prevented
Massage
Massage and or compressi
ression. This is usually
usually only
only done with smooth
mooth
implants
implants and may be suggested
ggested for a period
period between
between a few
few weeks to
to as
long
long as you have your implants.
plants. Do not ma
massage bruises
bruises!
The "no-touc
h" techni
od includes
ulousl
sly
y
"no-touch"
technique.
que. This meth
method
ncludes metic
meticulou
rewashi
ng surg
re handl
rewashin
surgical glove
glovess befo
before
ndling any
any instrument
rument and
and
implan
ts.. Only
t, using a unique
implants
Only the head surg
surgeon touches
touches the implan
implant,
unique
Teflon
Teflon cutting
cutting boar
board and im
immedi
mediately inserting
inserting the implan
plantt
undernea
ures help
underneath the muscle. All of these meas
measures
help en
ensure that no
foreign subs
tance attach themsel
ves to the implant,
substance
themselv
implant, which
which could
inflame
inflame the surrounding tiss
tissue and cause complicatio
mplications su
such as
capsul
ar co
capsular
contract
ntracture.
Page 13
Chondrocytes (P2 Canine) in a Type I
Collagen-GAG Matrix: Contraction
Photo removed due to copyright restrictions.
40 min
B Kinner
Page 14
Non-Seeded: 8 days
Cell-Seeded: 8 days
Photo removed due to copyright restrictions.
21 days
Non-Seeded and Cell-Seeded
Collagen-GAG Scaffolds
S. Vickers
Human Articular Chondrocytes in Monolayer Culture
IH - Green: α-smooth muscle actin; Orange: type II collagen
Photo removed due to copyright restrictions.
Chondrocytes
express the gene
for α-smooth
muscle actin and
this enables them
to contract
B. Kinner, et al. JOR 2001;19:233
Page 15
MUSCULOSKELETAL CELLS THAT CAN EXPRESS
α-SMOOTH MUSCLE ACTIN AND CAN CONTRACT
•
•
•
•
•
•
•
•
Articular chondrocyte
Osteoblast
Meniscus fibroblast and fibrochondrocyte
Intervertebral disc fibroblast and
fibrochondrocyte
Ligament fibroblast
Tendon fibroblast
Synovial cell
M. Sp
Spector
ector,
Mesenchymal stem cell
Wound Repair
Repair Regen.
Regen.
9:119:11-18 (2001)
POSSIBLE ROLES FOR α-SMOOTH MUSCLE
ACTIN-ENABLED CONTRACTION
Musculoskeletal Connective Tissue Cells
• Tissue engineering Contracture of scaffolds
• Healing
Closure of wounds
(skin wounds and bone fractures)
• Disease processes Contracture (Dupuytren’s)
• Tissue formation Modeling of ECM architecture
and remodeling
(e.g., crimp in ligament/tendon?)
Page 16
IMPLANT MATERIALS/BIOMATERIALS
TISSUE RESPONSE
Soft Tissue (that does not regenerate)
• Fibrous capsule (scar)
Synovium: fibrous tissue interspersed with
macrophages
Wound healing response of repair (scar formation)
coupled with macrophage accretion at the “dead
space” - chronic inflammation
Bone
• Tissue integration and tissue bonding
TISSUE INTEGRATION
TISSUE BONDING
• Tissue Integration (Oss
(Osseointegr
eointegration)
Apposition of tissue (bone) to the implant (con
(contact of
bone wi
with the surface but not necessarily bonding)
Regeneration of tissue up to the surface of the implant
• Tissue Bond
Bonding (Bone Bonding)
Chemical bonding of tissue (viz
., bo
(viz.,
bone) to the surface
Protein adsorption and cell adhesion
Biomaterials: calcium phosphates and
and titanium (?)
Page 17
Photos removed due to copyright restrictions.
Why
Whyare
arethere
thereno
nomacrophages
macrophages
on
onthe
thesurface
surfaceofofthe
theimplant?
implant?
Hydroxyapatite-Coated Implants
Photos removed due to copyright restrictions.
Page 18
Plasma-Sprayed
Hydroxyapatite
Coating
Photos removed due to copyright restrictions.
Photos removed due to copyright restrictions.
Plasma-sprayed HA coating
on a canine femoral stem,
6 mos. post-opc
Page 19
Photos removed due to copyright restrictions.
PROGRESSION OF OSTEOLYSIS:
“HYLAMER” CUP
Photos removed due to copyright restrictions.
Page 20
J. Charnley, 1979
Photos removed due to copyright restrictions.
Titanium Wear
Debris
Co-Cr Particles
Photos removed due to copyright restrictions.
Page 21
MACROPHAGE RESPONSE
TO MOTION AND PARTICLES
UNSTABLE PROSTHESIS
Motion
Particles
Oste
obla
asts
Osteobl
Bone Resorption
(Osteolysis)
BONE
Enz
Enzymes
PGE2
ILIL-1
Macrophage
(15(15-25µ
25µm)
Chemoattractants
Chemoattractants
Oste
ocla
ast
Osteocl
precursor
precursor cell
cells
Oste
ocla
ast
Osteocl
POLYETHYLENE WEAR
PARTICLES
H. McKellop, 1994 Hip Society
The number of particles generated by a hip
prosthesis
7 x 1011 particles/yr.
700,000 particles/step
Page 22
NUMBER OF INHALED PARTICLES
Avg. particle burden of urban atmosphere:
105 particles/liter
Respired volume in man = 1 liter/min.
Therefore, 105 particles are inhaled/min.
10% of the inhaled particles are deposited in the
lungs.
Therefore, 104 particles are deposited in the lungs
per min.
5 x 109 particles/yr.
RESPONSE TO PARTICLES
• Type of material
• Size
– mm, µm, nm
• Location
– Joint fluid
– PeriPeri-prosthetic
prosthetic tissues
– Synovium
– Lymphatic system
• Number
Page 23
RESPONSE TO PARTICLES
• Size
– mm No adverse response.
– µm Able to be phagocytosed by macrophages;
macrophages release molecules that
stimulate bone resorption.
– nm Sub-micrometer (nanoparticles) interfere
with function of cell organelles; enter into
the nucleus and interfere with genetic
functions.
Light Microscopy
Polyethylene Particles
in Peri-prosthetic
Tissues
Polyethylene Particles
Nucleus
in Peri-prosthetic
Photos removed due to copyright restrictions.
Tissues
Transmission
Electron
Microscopy, TEM
1 µm
Page 24
The total of 15 cemented and uncemented total hip replacement prostheses.
100
25
76% < 0.5µm
90
92% < 1.0 µm
80
70
60
15
50
40
10
Percentile
Frequency (%)
20
30
20
5
10
0
0
0 .1 .2 .3 .4 .5 .6 .7 .8 .9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.81.9 2.0 2.1 2.2 2.3 2.4 2.5
Benz E, et al.,
Biomat. 2001;22:2835
Particle Length (µm)
The total of 3 total knee replacement prostheses.
16
100
43% < 0.5µm
90
80
12
72% < 1.0µm
10
70
60
8
50
6
40
4
30
20
2
10
0
0
.1 .2 .3 .4 .5 .6 .7 .8 .9 1
Benz E, et al.,
Biomat. 2001;22:2835
1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5
Particle Length (µm)
Page 25
0
Percentile
Frequency (%)
14
PARTICLE SIZE
• A large percentage of polyethylene particles in
periprosthetic tissues are of nanometer size
– less than 200 nm
• These nanometer size particles would go
through the filters often used to capture
particles from joint fluid
– 200 nm diameter pores in the filter
ISOLATION OF PARTICLES FROM
JOI
NT
JOIN
T FLUID
Page 26
NANOPARTICLE TOXICITY
• Particles from prostheses have become smaller
(from micrometer to nanometer).
• Introduction of nanotechnolgy into medicine
(i.e., engineered nanoparticles for various
applications) has raised questions about the
biological response to nanoparticles.
• Several federal agencies (NIH, EPA) are looking
into this issue.
• 2 major causes of death are cancer and heart
disease; there are indications that nanoparticles
can adversely contribute to these processes
NANOPARTICLE TOXICITY
“Nano's Troubled Waters:”
Waters:”
“Latest toxi
toxic wa
warning shows
shows nanoparticles
nanoparticles cause brain
damage in aquatic species and highlights need for a
moratoriu
m on the release
moratorium
release of new nanomaterials.
nanomaterials.
• A new study revealing
rbon molecules
revealing that engineered ca
carbon
molecule
cause brain damage in fish is one more brick in the wa
wall of
evidence suggesting that
that manufactured
manufactured nanoparticles
nanoparticles are
harmful to the environment and to health.
health.
• How many warnings do government regulator
regulators require
before they take ac
action to ensure that
that uses of
nanoparticles are safe before wo
workers in production
production
facilities are harmed and
and before consumers are further
exposed? ”
http://online.sfsu.edu/~rone/Nanotech/nanobraindamage.htm
Genotype; Thursday, 1 April 2004; www.etcgroup.org
Page 27
RESPONSE TO PARTICLES
• Type of material
• Size
– mm, µm, nm
• Location
– Joint fluid
– PeriPeri-prosthetic
prosthetic tissues
– Synovium
– Lymphatic system
• Number
LYMPHATIC SYSTEM
• Filters out organisms and particles.
• The lymphatic vessels are present wherever
there are blood vessels.
• More than 100 tiny, oval structures (called
lymph nodes).
– scattered all along the lymph vessels.
– filter out particles
• Particles that pass through the lymph node
enter into the blood circulation.
Page 28
Lymphadenopathy
Photos removed due to copyright restrictions.
Benz EB, et al., J. Bone Jt. Surg. 1996;78-A:588
Photos removed due to copyright restrictions.
Benz EB, et al., J. Bone Jt.
Surg. 1996;78-A:588
Page 31
SMALL PARTICLE DISEASE:
LYMPHADENOPATHY
• Enlargement of the node.
• Particles drained from tissue by the
lymphatic system are phagocytosed by
macrophages in the nodes.
• No adverse clinical sequelae yet noted, but
can confound differential diagnosis of
other diseases.
• Concern about the clinical sequelae of
nanoparticles that gain access to the
vascular system.
LOCAL AND SYSTEMIC RESPONSES
SMALL PARTICLE DISEASE
• Local Component
Particle induced focal
destruction of tissue around
the imlant
• Systemic Component
Lymphadenopathy
Page 32
BIOLOGICAL RESPONSE TO
METAL DEBRIS
• Immune responses
PATIENT CONCERNS ABOUT
METAL DEBRIS
Am I allergic to my metal implant?
Page 33
IMMUNE RESPONSE TO METAL
IONS
• "Metal allergy" has been incriminated as
the cause of failure in certain patients.
• However, results obtained to date are not
definitive.
METAL SENSITIVITY IN PATIENTS
• 10-15% of population have dermal sensitivity to metal
(14% to Ni)
• Metal ions bind to proteins to form immunogenic
complexes
• Metals known as sensitizers:
– Ni > Co and Cr >>> Ti and V
• 60% of pts. with failed TJRs were metal sensitive vs.
25% with well-functioning implants
– Did metal sensitivity cause failure or did the failed
implant cause metal sensitivity?
Halla
b, Merritt,
Hallab
Merritt, Jacobs,
JBJS
JBJS 83-A:428
A:428 (2001)
2001)
Page 34
METAL SENSITIVITY IN PATIENTS
• “May exist as an extreme complication in only
a few highly susceptible patients (< 1%), or it
may be a more common subtle contributor to
implant failure.”
• “It is likely that cases involving implant-related
metal sensitivity have been underreported
because of the difficulty of diagnosis.”
• Patients who have displayed sensitivity to metal
jewelry are at higher risk.
Halla
b, Merritt,
Hallab
Merritt, Jacobs,
JBJS
JBJS 83-A:428
A:428 (2001)
2001)
CELL RESPONSE TO METAL
PARTICLES
•
•
•
•
Macrophages in vitro
Particles of Ti alloy not toxic; Co-Cr highly toxic
Ti induced more release of PGE2 than Co-Cr
Exp. to Ti increased the release of PGE2, IL-1, TNF,
and IL-6; exp. to Co-Cr decreased release of PGE2
and IL-6 and had little effect on IL-1 and TNF
• “release of Ti....worse than....Co-Cr”
D.R. Haynes, et al
al.,
JBJS 7575-A: 825 (1993)
Page 35
CELL RESPONSE TO METAL
PARTICLES
•
•
•
•
Bovine articular chondrocytes
Co was toxic to cells at all conc.
At high conc. Cr, Ti, and Ti alloy were toxic
At high conc. all metals decreased enzyme
activity
• PGE2 increased with conc., except for Ti alloy
W.J. Malone
Maloney, et al.,
J. Appl
Appl.. Biomat.
Biomat. 5: 109 (1994)
BIOLOGICAL RESPONSE TO
METAL PARTICLES AND IONS
•
•
•
Summary
Metal particles and ions are released from TJR
prostheses; the amounts can be reduced by careful
design and manufacturing
Cellular response to metal particles has some of the
same elements as the response to particles of other
materials
No indication yet that metal particles and ions are
responsible for profound adverse responses
Page 36