9/10/12

Bone Grafting 101

UNDERSTANDING BONE GRAFTS

AND BONE GRAFT SUBSTITUTES
Dr. Salvatore J. Monopoli, DABPS, FACFAS
Alumnus, Cambridge Hospital of Harvard Medical School
Parent Orthopedic Dept Mass General, Foot & Ankle sub division
Clinical Training Manager
BioSurgery US Sales Training

RM1166

Objectives
Rationale
Epidemiology

Terminology

Existing Materials

Characteristics and Challenges

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The Need for Bone Grafts and Bone Graft Substitutes1

3

Bone grafts are used to:

Fuse joints to prevent movement
Spine and extremities
Repair injured bone that has not healed
Delayed union or non-union
Repair fractures that have bone loss
Accelerate bone healing
Repair bone voids
Surgical, traumatic, disease, infection

Bone Graft Need2

4

Percentage of total number of bone grafting

procedures performed in the U.S.

Thoracolumbar fusion

3%
11% Cervical fusion
28%
8% Trauma surgery

Large joint revision and

reconstruction

18% CMF surgery

32%

Extremity surgery

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Mechanisms of Bone Formation3

5

Osteoconduction:
Biocompatible material
that provides a physical
structure into and along
which bone may grow

Osteoinduction:
Capable of inducing bone
formation in a non-bony site
by recruiting and inducing
(pluripotent) cells to become
osteoblasts

Osteogenesis:
Graft already contains the
cells required to produce
bone

Bone Graft Characteristics / Types4 6

Osteogenic
Autograft

CELLS

SCAFFOLD FACTORS

Osteoconductive
Allograft (Cortical & Cancellous)
Calcium Sulfate Ceramics
Collagen Composites
Calcium Phosphate (CaP) Ceramics
Osteoinductive
Recombinant Human Bone
Morphogenetic Proteins (rhBMP)
Demineralized Bone Matrix (DBM)
Allografts

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REVIEW OF BONE GRAFTS

AND SUBSTITUTES
The following overview of characteristics and considerations is not meant to be a
comprehensive list, practitioners should evaluate each bone graft carefully

Autografts
8

Characteristics4 Considerations
Established historical Time of overall surgical
standard of bone grafting procedure4
Autograft exhibits all three Second site surgery to
bone formation procure autograft or ICBG4
mechanisms:
Limited quantity of 50-55
osteoconduction,
cm35
osteoinduction, and
osteogenesis Complication rates
reported include4
No potential for disease
Blood loss
transmission or
Hematoma and arterial
immunogenic response injury
Nerve injury and
numbness
Hernia formation
Infection
Fracture and pelvic
instability
Cosmetic defects
Chronic pain at donor site

Proposed Mechanism of Action: Presence of osteoblasts provides direct

osteogenesis, presence of growth factors permits osteoinduction, bone tissue
allows osteoconduction4

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Allograft
9

Characteristics Considerations
Available in various Potential for disease
geometric and shapeable transmission and immune
forms4 rejection11

Cortical allografts may Variable clinical results and

provide structural support inconsistent graft incorporation11
and may be immediately Must have reputable tissue
load bearing4 bank11
Osteoconductive and Freeze-dried allograft has low
weakly osteoinductive if compressive strength10
growth factors remain after FDA classification of
processing (cancellous)4, 10 reprocessed human tissues
allows clearance of DBM
products without proof of
efficacy12
Some have 510K clearance

Proposed Mechanism of Action: Primarily acts through osteoconduction.

Cancellous allograft may have some osteoinductive potential but it will vary
depending on the source and how it was processed and sterilized4

DBM (Allograft Sub-set)

10

Cortical bone with mineral removed (via acid extraction) leaving collagenous and
non-collagenous proteins with a low concentration of growth factors10

Characteristics Considerations2
Contains type I collagen, Availability of prospective
non-collagenous proteins, randomized studies to
and a low concentration of support osteoinductive
growth factors (BMP) claims in humans
which may impart Bone producing ability
osteoinductivity11 depends on processing
Osteoinductivity of DBMs methods which vary from
have been proven in product to product
animal studies12 FDA classification of
DBM is the least reprocessed human
immunogenic of the tissues allows clearance
allograft types due to the of some DBM products
extensive processing10 without evidence of
efficacy. Some have 510K
clearance.

Proposed Mechanism of Action: Primarily acts through osteoconduction,

studies report that the presence of growth factors (e.g. BMP) imparts
osteoinductivity11

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11

Growth Factor Based (BMP, etc.) 3

Growth factors bind to receptors on cell surfaces stimulating the

formation of proteins to be used inside the cell or externally (e.g.
formation of extracellular matrices like bone tissue)

For example
Platelet Derived Growth Factor
Insulin-Like
Growth Factor (PDGF)
1&2
(IGF-1), (IGF 2)

Bone Morphogenetic
Proteins (BMPs)
(aka recombinant human bone
morphogenetic protein or rhBMP)

Fibroblast Growth
Factor
Transforming Growth (FGF)
Factor Beta
(TGF-)

12

How does rhBMP work?

Mesenchymal stem cells (MSCs) have the ability to change or differentiate
into various types of cells which make different types of tissues13
Bone Morphogenetic Proteins (BMPs) direct MSCs to differentiate into an
osteogenic bone line3

Mesenchymal Stem Cell (MSC)

BMP

Osteoblast Chondrocyte Myoblast Stromal Cell Fibroblast

Bone Cartilage Muscle Marrow Tendon /

Ligament

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13

Growth Factor Based (BMP)

Characteristics Considerations
Optimal BMP dosage and
Osteoinductive14
carrier yet unknown14
rhBMP-2 and rhBMP-7
Most common complications
have published clinical
include osteolysis, swelling/
efficacy studies14
edema, heterotopic bone
rhBMP-2 clinical formation, and antibody
studies have shown reaction16
that BMP + collagen
Precise rate of complications
worked as good, if not
and strategy to reduce
better, than autograft14
number of complications is
still not known16

Proposed Mechanism of Action: Acts via osteoinduction, BMP binds to

mesenchymal stem cell receptors resulting in proliferation and differentiation into
osteoblasts.14

Cellular Based: Bone Marrow Aspirate

14

The bone marrow is aspirated with a large bore needle from the iliac crest and injected
percutaneously with fluoroscopic guidance into the non-union site19

Characteristics Considerations
Autogenic source of Failures can occur due to
osteogenic precursor cells10 inconsistent aspiration
Has been used alone or in methodology18
conjunction with other bone Osteoprogenitors may only
graft substitutes10,18 represent ~0.001% of nucleated
Minimally invasive harvesting cells in healthy adult marrow19
technique reduces donor site It may be difficult to obtain enough
morbidity10 bone marrow with sufficient number
Fractures/non-unions can be of osteoprogenitor cells for bone
treated by percutaneous healing19
injection of marrow18 Aging or disease may reduce the
number of osteogenic precursor
cells in marrow19

Proposed Mechanism of Action: Bone marrow aspirate contains

osteoprogenitor cells with the potential to differentiate into osteoblasts able
to produce new bone tissue10

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Cellular Based: (PRP) 15

Platelet Rich Plasma (PRP) is obtained by fractioning whole autologous

blood by centrifugation 20
Characteristics20 Considerations
PRP contains PDGF, Outcome is donor
EGF, and FGF-2 which dependent and varies with
stimulate proliferation of preparation technique20
osteoblast progenitors Proteases present in the
Also contains TGF- platelet fraction may
which increases type I degrade some of the
collagen synthesis growth factors20
VEGF and FGF-2 factors Addition of PRP to bone
in PRP can potentially graft seems to reduce the
enhance early spinal fusion rate in
angiogenesis and animals as well as in
vascularization humans20
Ideal factor concentration
and delivery system still
not known18

Proposed Mechanism of Action: Platelet gels provide a rich source of growth

factors that direct mechanisms involved in bone healing and subsequent
osteogenesis.18

16

Bone Graft Alternatives

Ceramics
Calcium Sulfate
Calcium Phosphate Collagen Based
Synthetic Hydroxyapatite Materials
Coralline Hydroxyapatite Typically composites with
ceramic materials
Tricalcium Phosphate
(TCP)
Calcium Phosphate
Cement
Silicon containing BGS

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Collagen Based
17

Characteristics Considerations
Collagen is the most Animal derived
abundant protein found in Potential for
bone tissue22 immunogenicity27
Osteoconductive matrix with Weak structural and
a favorable physical and mechanical properties27
chemical matrix for bone
regeneration21 Collagen is usually coupled
with other bone substitutes
Collagen contributes to (HA, -TCP, bone marrow,
mineral deposition, vascular etc.)4
ingrowth, and growth factor
binding4 Collagen composites have
had mixed results27

Proposed Mechanism of Action: Primarily acts through osteoconduction and/

or via mechanisms from the component that is added to it.4

18

Bioactive Materials - attributes23

Bioactive material elicits a specific biologic response at the
interface of the material, which results in the formation of a
bond between the tissue and the material with a strength
equal to or greater than bone.
Interfacial bone bonding occurs because of the biological equivalence of
the inorganic portion of bone and the growing HCA (hydroxl-carbonate
apatite) layer on the bioactive implant.

Osteostimulatory Osteostimulation is a property of some bioactive materials

to enhance, actively stimulate both the proliferation and differentiation of progenitor cells
(e.g.mesenchymal stem cells)

Class B Bioactive particulates: Osteoconductive, ie, characteristic of

bone growth and bonding along a surface.

Class A Bioactive particulates: Ostoconductive and Osteostimulative.

Slow resorption of Class A Bioactive particles permits enhanced
proliferation and differentiation of osteoprogenitor cells.

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19

CLASS B BIOACTIVE MATERIALS

20

Ceramic Based: Calcium Sulfate (Plaster of Paris)

Characteristics
Osteoconductive matrix
with long clinical history24
Can be used in the
presence of infection22
Resorption profile (5-7
week period) is ideal for
antibiotic delivery 24
Considerations
Due to dissolution rate,
mechanical properties are
variable and implantation
should be limited to
confined defects24
Complications associated
with inflammatory reactions
have been reported with
calcium sulfate22,25
In-vivo animal studies have
shown that quick resorption
and inflammatory response
may preclude adequate
bone formation26

Proposed Mechanism of Action: Calcium sulfate serves as an osteoconductive

matrix for the ingrowth of osteogenic cells.24

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21

Ceramic Based: -Tricalcium Phosphate (-TCP)

Characteristics24 Considerations
Osteoconductive matrix Difference in -TCP
with a long clinical history resorption rate and new
Available as porous or bone formation rate
solid, and as granules or (usually less bone volume
blocks produced versus -TCP
volume resorbed)21
Undergoes resorption via
dissolution and Brittle and breakable under
fragmentation over a 6-18 tension and shear loads24
month period In-vivo animal studies
have showed that -TCP
particles formed during
dissolution may cause an
inflammatory response and
bone resorption26

Proposed Mechanism of Action: The resorption of -TCP stimulates cellular

activity27 and bone formation while the -TCP scaffold provides an osteoconductive
matrix.24

Ceramic Based: Synthetic Hydroxyapatite

22

Most synthetic HA is produced by an aqueous combination of calcium containing

and phosphate containing solutions26 followed by an optional heat treatment
(sintering)12

Characteristics
Osteoconductive matrix
with a long clinical history24
Non-sintered HA is readily
reabsorbed in-vivo24
Considerations
HA products have variable bone
formation rates depending on
crystallinity, density, and
stoichiometry12

After bone incorporation Sintered HA preparations are

and healing, HA implants
attain mechanical strength
similar to cancellous bone11
resistant to in-vivo resorption
(1-2% per year)24
Due to its brittle nature and slow
bone formation, HA is commonly
combined with various grafting
agents when being used as an
osteoconductive bone substitute12

Proposed Mechanism of Action: HA bonds to bone, stimulates cellular

activity27, and provides an osteoconductive matrix for subsequent bone
formation.17

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23

Ceramic Based: Coralline Hydroxyapatite

Coral (calcium carbonate) is converted into hydroxyapatite via hydrothermal
processing10

Characteristics4 Considerations
Osteoconductive matrix Must be shielded from
Interconnected porous loading until bone ingrowth
matrix is structurally occurs 10
similar to cancellous bone Typically used in non
Pore size encourages weight bearing applications
bone ingrowth such as maxillofacial,
periodontal augmentation,
and distal radial fractures24
Brittle properties make it
difficult to shape and
handle24

Proposed Mechanism of Action: HA bonds to bone, stimulates cellular

activity27, and the interconnected porous structure provides an osteoconductive
matrix for subsequent bone formation.24

24

Ceramic Based: Calcium Phosphate Cement

Characteristics Considerations
Components are mixed with Resorption and remodeling rate
water into a paste, injected occurs over ~2 years24
into a defect, and then Potential risk of the paste
hardens into a porous extruding into surrounding soft
hydroxyapatite24 tissues12
Sets into porous HA24 which Resultant matrix has a small
is osteoconductive21 pore size (1 m) which limits
Conformable paste can rapid bone ingrowth21
custom-fill defects12 To be used in either low or non-
Sets in the physiological load bearing applications or in
environment without combination with metal fixation21
producing heat21

Proposed Mechanism of Action: Porous HA that forms bonds to bone,

stimulates cellular activity21, and provides an osteoconductive matrix for
subsequent bone formation17

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25

CLASS A BIOACTIVE MATERIALS

26

Ceramic Based: Silicon(Si) containing Bone Graft Substitutes

Bioactive glass (SiO2)46.1 (CaO)26.9 (Na2O)24.4 (P2O5)2.6

There are two types of Bioactive glasses:

Sol-gel derived
Melt-derived
a specific composition of melt-derived bioactive glass,
called Bioglass is used as a bone filling material.23
Existing products:
45S5Bioglass 23
45S5 Bioglass + Bovine Type I Collagen + -TCP 28
Silicate Substituted HA (new class): Several methods for the
synthesis have been reported including solgel, hydrothermal, solid-
state reaction, chemical precipitation, and crystallization. Chemical
precipitation and crystallization are the most commonly used methods.
29

Existing products:
Si-HA (Ca)10(PO4)(6-x)(SiO4)x(OH)(2-x) 9

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27

Ceramic Based: 4S5S Bioglass

Characteristics
In a physiologic environment
in-vitro, Bioglass induces
formation of an HCA layer23
Osteostimulatory Stimulation
of osteoblast proliferation and
differentiation during in vitro
osteoblast cell culture studies
as evidenced by increased
DNA content and elevated
osteocalcin and alkaline
phosphatase levels.30
Biochemically evaluated
cultures revealed statistically
greater apa activity levels
observed for Bioglass than for
HA, Ti and stainless steel.31
Considerations
Osteoblast apoptosis has
been identified in vitro on the
bioactive substrate, possibly
due to high Si release.30,33
Pores have been introduced
into melt-derived bioactive
glasses but the pores are few
in number and
interconnectivity is limited32
Particles of 100 um in
diameter have been found to
(SiO2)46.1 (CaO)26.9 (Na2O)24.4 (P2O5)2.6 either absorb or are
phagocytized by
macrophages in vivo23

Proposed Mechanism of Action: Osteoconductive matrix. In vitro assays have revealed

genes associated with osteoblast growth and differentiation, maintenance of extracellular
matrix, and promotion of cell-cell and cell-matrix adhesion were up-regulated in vitro by
conditioned cell culture media containing the dissolution products of bioactive glass.30, 34

28

Ceramic Based: 45S5 Bioglass + Bovine Type I Collagen + -TCP

Characteristics Considerations
See 45S5 slide for Bioglass in a rabbit model, healing of
shared characteristics defect sites were nearly
-TCP and 45S5 have a long identical to adjacent cancellous
clinical history as bone after 24 weeks but also
osteoconductive matrices24 between Collagen + -TCP and
Collagen + -TCP + Bioglass.28
(-TCP) scaffold is engineered
to mimic the structure of Tissue analysis showed an
cancellous bone 28 increase in new bone formation
in the Collagen + -TCP +
Animal testing resulted in bone Bioglass group vs Collagen + -
that was 23% and 30% TCP at 12 & 24 weeks,
Stronger at 12 and 24 weeks however, the results were not
respectively, compared to just statistically significant.28
Collagen + -TCP 28
Animal studies have showed
that -TCP particles formed
during dissolution may cause an
inflammatory response and
bone resorption26

Proposed Mechanism of Action: Osteoconductive matrix. Per in-vitro studies, ionic

constituents are released into the local environment35 stimulating osteoblasts35,36 to the
scaffold surface35, increasing osteoblast proliferation35 and protein production35, resulting in
increasing the rate of bone formation.28

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29

Ceramic Based: Synthetic Si substituted Calcium Phosphate

Characteristics Considerations
Osteostimulatory - cell culture
studies demonstrated that the The bioactive and
time to new apatite surface osteostimulatory nature
layer formation was reduced by have not been correlated
29% when compared to an with human clinical
identical calcium phosphate experience.37
material that did not contain
0.8wt% silicate.37 Limited to non-load bearing
applications or in
Structure and chemistry permits combination with metal
adsorption of extracellular fixation37
proteins critical in promoting
osteogenic cell attachment6 Si release has not been
measured39
In vitro, increased strut
microporosity permitted Not indicated to be mixed
capillary penetration at earlier with autograft bone37
time points, promoting
apposition of greater volumes
of dense, new bone.38

Proposed Mechanism of Action: In vitro, the interconnected porous structure and silicate
substituted chemistry demonstrates adsorption of key proteins6, osteoblasts7 and
mesenchymal stem cells8; as well as differentiation of mesenchymal stem cells to an
osteogenic cell line.17 Vascularized bone is formed that can be resorbed via cell-mediated
remodeling.9

Summary 30

Graft Overview
Autograft Osteogenic, Osteoconductive, Osteoinductive4

Cortical - Osteoconductive (moderately)41

Allograft Osteoinductive (weakly)41
Cancellous - Osteoconductive (weakly)41

DBM Osteoconductive, Osteoinductive (variable)18

BMP Osteoinductive18

BMA Osteogenic, Osteoinductive18

Collagen Osteoconductive27

Class B Bioactive:
Ceramics Osteoconductive27

Class A Bioactive:
(Bioglass and Si
substituted HA) Si Osteoconductive18, Osteostimulatory23
containing BGS

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31

Choices41
So what material do we use where?

Selection should be based on reasoned burdens of proof. These include

examination of the product claims and whether they are supported by
preclinical and human studies in site-specific locations where they are to be
utilized in surgery. It is imperative to appreciate the level of evidence claimed
in the latter studies.

Different healing environments (e.g. metaphyseal defect, long bone

fracture, segmental diaphyseal defect, interbody spine fusion,
posterolateral spine fusion) may have differing levels of difficulty in
forming new bone.
Validation of any bone graft substitute in one clinical anatomic site may
not be predictive of its performance in another location.

Currently marketed products are variable in their composition and their

claimed mechanisms of action. It is reasonable that not all bone-graft
substitute products will perform the same.

32

References
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4. Giannoudis PV. Bone substitutes: An update; Injury, Int. J. Care Injured (2005) 365, 520-527
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Pa 1976). 2010 Aug 1;35(17):1621-8
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SURGEONS 75TH ANNUAL MEETING 2008

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