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Part VI
Achieving Intersegmental Arthodesis
Bone Graft Extenders
Sonia Teufack , James Harrop , and Srinivas Prasad
3 3
33.1 Introduction
The goal of spinal arthrodesis is to eliminate pathologic motion between adjacent vertebral segments.
Several spinal conditions which are managed and
treated operatively after failure of conservative
measures require surgical intervention such to
achieve a solid fusion. Presently at the time of surgery intervention, spinal instrumentation is often
used to further stabilize adjacent levels, but true
arthrodesis is independent of the hardware and
requires growth of bone across the immobilized
spinal segments forming one unifi ed structure. The
use of autologous bone grafting has been shown to
signifi cantly improve the rate of spinal fusion [ 1 – 4 ].
However, presently, a wide variety of materials are
used due to the morbidity of autologous bone graft
harvesting either alone or in combination to facilitate fusion; these include autogenous graft, allogenic graft, dematerialized bone matrix, bone
morphogenic proteins (BMP), synthetic graft
extenders, and synthetic cages. In this chapter we
will focus on bone graft extenders.
S. Teufack , M.D. • J. Harrop , M.D. (*)
S. Prasad , M.D.
Department of Neurosurgery ,
Thomas Jefferson University Hospital ,
Philadelphia , PA , USA
e-mail: james.harrop@jefferson.edu
33.2 Bone Formation
Bone is a connective tissue primarily made of a
mineralized matrix structure. Bone formation
begins with osteoblasts producing type I collagen
to form an osteoid matrix. Subsequently, osteoblasts secrete vesicles containing alkaline phosphatase that cleave phosphate groups and allow
deposition of calcium and phosphate in the
matrix. Over time, this process results in mineralization and hardening of the bone matrix with
carbonated hydroxyapatite.
Four types of cells are involved in bone formation, maintenance, and healing. Osteoblasts
produce bone matrix; osteocytes are mature
osteoblasts that maintain the bone; osteoclasts
are cells that breakdown and remove bone matrix;
and bone lining cells cover bone surfaces.
Bone grafts can regenerate bone through
three different processes: osteogenesis, osteoinduction, and osteoconduction. Osteogenesis is
the formation of new bone by the osteoblasts
within the graft material. Osteoinduction is a
process by which chemical substances contained within the graft stimulate patients’ osteoprogenitor cells to differentiate into osteoblasts
to form new bone. Osteoconduction occurs
when a graft provides a scaffold for new bone
to grow. Successful arthrodesis relies on a
combination of these processes.
M.Y. Wang et al. (eds.), Minimally Invasive Spinal Deformity Surgery,
DOI 10.1007/978-3-7091-1407-0_33, © Springer-Verlag Wien 2014
337
338
S. Teufack et al.
33.2.1 Autograft
Autograft, also known as autologous bone graft,
has long been considered the “gold standard” for
bone fusion in spine surgery [ 5 , 6 ]. It can be
obtained locally during the principal procedure
or may require a separate incision for harvesting
from another site, such as the iliac crest or fi bula.
Autograft is biologically ideal because it promotes all dimensions of bone regeneration without the risk of a foreign body. It typically contains
a structural scaffold for osteoconduction, live
osteoprogenitor cells in the marrow for osteogenesis, as well as intrinsic growth factors for
osteoconduction. It is important to note that not
all graft sites carry equivalent concentrations or
proportions of these factors.
Nonetheless, the process of harvesting
autologous bone graft comes with a few morbidities, namely, nerve or vascular injury during harvesting, pelvic fractures, wound infection, and
signifi cant postoperative acute and chronic pain
[ 7 – 9 ]. Current technological advancement offers
alternatives to autografts, with the intent to minimize surgical risk while maintaining similar rates
of successful spinal fusion.
33.2.2 Allograft-Based Extenders
Allogenic graft, often referred to as allograft, is
typically comprised of cadaveric donor bone
used alone or in conjunction with other materials.
Before allograft bone can be used, it goes through
debridement of soft tissues, removal of blood
products, and a sterilization process that destroys
any live cells. The resulting product is a mineralized bone. Mineralized allograft is considered a
bone graft replacement, as it maintains its
mechanical strength; however the sterilization
process renders then biologically inactive.
Tricortical iliac crest and fi bula allografts are
successfully used in interbody fusion surgery as
structural graft and promote bone fusion by
osteoconduction. Mineralized allograft chips are
also often used to supplement the patient’s own
bone (autograft) in a posterolateral intertransverse process fusion.
Allografts are available as mineralized
structural strut or as demineralized bone matrix.
Demineralized bone matrix (DBM) is allograft in
which inorganic minerals have been removed. To
prepare DBM allograft bone is fi rst morselized
then processed through acid demineralization
and a few rounds of freeze-drying. The resulting
demineralized bone powder is a composite of
collagens, noncollagenous proteins and growth
factors, a variable percent of residual calcium
phosphate mineral, and some small percent cellular debris [ 10 ]. DBM can be formulated into
putties, pastes, and fl exible, preformed strips for
implant use.
The process of demineralization signifi cantly
diminishes allograft mechanical properties but
conversely increases its biological activity [ 10 ].
In 1965, following the work of Ray and Holloway
[ 11 ], Urist published a landmark paper in Science
[ 12 ] which demonstrated that ectopic osteogene-
sis occurred when demineralized bone was
implanted into a non-bony site. DBM is now
known to have both osteoconductive and osteoinductive properties that prompt bone regeneration.
DBM is thought to contain bone morphogenic
proteins (BMPs) and other bone growthproducing substances that stimulate bone development and fusion.
About 20 % of the $1 billion per year bone
grafting market [ 13 ] is focused on DBM products
in bone repair and regenerative strategies. There
is a wide range of DBM products approved by
the Food and Drug Administration for clinical
use. Several factors regarding DBM as a humanderived tissue product are important to understand, as it is commonly used as a bone repair
matrix and vehicle for delivering bioactive
agents. Factors that infl uence the behavior of
DBM include bone procurement techniques from
human donors, donor age and gender, and the
specifi c DBM composition and properties
[ 14 – 17 ]. Examples of allograft-based bone graft
extenders currently offered by pharmaceutical
companies are listed in Table 33.1 .
33 Bone Graft Extenders
Human research
Osteoinduction
Bioresorbable
Osteoconduction Case reports
Osteoinduction
Bioresorbable
Bioresorbable Human studies
Osteogenesis (when
mixed with LAG)
(Accell TBM,
DynaGraft
II,Ortho blast II)
Bioresorbable
Osteoconduction Case reports
Human studies
(optium)
Osteoinduction
Bioresorbable
Osteoinduction
Used with BMA or blood
Bioresorbable
339
(continued)
Osteoinduction
Bioresorbable
Injectable gel and putty Osteoconduction Case reports
DBM
Heat sensitive copolymer with
TM
Product name Composition Forms Additional property
composite granules
Dry mix kit with buffered saline Osteoinduction
carrier
®
DBM in a hydrogel carrier Dry mix kit with buffered saline Osteoconduction Case reports
DBM in a lecithin carrier Paste, putty and mix with HA/CC
®
+ CCC DBM + CCC in a hydrogel
®
®
Optecure
DBM in gelatin carrier Injectable bone paste, dry powder
®
Optefi l
DBM + CCC in gelatin carrier Formable putty, dry powder
®
Opteform
Injectable putty Osteoconduction Case reports
Injectable putty
phase medium
phase medium
DBM, Accell BM, Reverse
Accell Evo3TM DBM, Accell BM, Reverse
Accell Connexus
Particles or chips in delivery
Injectable putty
reverse phase medium
DBM particles and cancellous
®
DBM, Accell BM Various sized strips Osteoinduction Human studies
®
DynaGraft II DBM, reverse phase medium Injectable putty
OrthoBlast II DBM, cancellous bone,
Accell TBM
chamber
chips
DBM in glycerol carrier Formable putty and injectable gel
®
DBM DBM in porcine gelatin Injectable paste and moldable strips Osteoconduction Case reports
®
Optium DBM
Injectable putty
Putty with demineralized cotical
bone chips
collagen and sodium alginate
collagen and sodium alginate
Progenix™ Putty DBM in type-1 bovine
ProgenixTM Plus DBM in type-1 bovine
Viable cellular bone matrix Multiple volumes available Osteoconduction Case reports
EvolutionTM
Table 33.1 Examples of commercially available allograft-based and mixed bone graft extenders
Company
AlloSource AlloFuse
Biomet Osteobiologics InterGro
Exactech Optecure
Integra Orthobiologics/(IsoTis
OrthoBiologic)
LifeNet Health IC Graft Chamber
Medtronic Spinal & Biologics Osteofi l
MTF/Orthofi x Trinity
340
S. Teufack et al.
Human research
Osteoinduction
Bioresorbable
Paste, putty mix and strip Osteoconduction Case reports
Osteoinduction
Osteoconduction Human studies
Formable putty Osteogenesis Case reports
Bioresorbable
Osteoinduction
Packable graft
Human studies
(level I-II
evidence)
Bioresorbable
Osteogenesis (when
mixed with LAG or
graft
BMA)
Packable graft
Osteoconduction Case reports
Packable moldable graft
Injectable paste, & putty, strips and
irrigation
Human studies
Osteoinduction
Bioresorbable
blocks with CCC
carrier
Plus Allograft cellular matrix w/
DBM in sodium hyaluronate
®
®
Product name Composition Forms Additional property
Table 33.1 (continued)
MTF/Synthes DBX
Company
NuVasive Osteocel
viable mesenchymal cells
DBM fi ber technology Round fl exible sheet Osteoconduction Case reports
®
®
DBM fi bers with
demineralized cortical cubes
DBM fi ber technology Various sizes of fl exible sheets
®
Flex
®
®
®
GRAFTON
A-Flex
Crunch
GRAFTON
Osteotech GRAFTON
DBM fi ber technology Single and double troughs
DBM fi ber technology Various sizes of strips
Gel DBM in a syringe MIS and Percutaneous injectable
®
GRAFTON
Matrix PLF
®
GRAFTON
®
GRAFTON
DBM fi bers with crushed
cancellous chips
®
GRAFTON
Matrix Scoliosis
Strips
Orthoblend Large
Defect
DBM fi bers with larger
cancellous chips
DBM in a syringe Injectable MIS graft, resists
®
®
GRAFTON
Orthoblend Small
Defect
GRAFTON Plus
gelatin carrier
Putty DBM fi ber technology Packable moldable graft
®
Paste
GRAFTON
RegenerationTechnologies BioSetTM DBM combined with natural
33 Bone Graft Extenders
Human studies
Osteoinduction
Bioresorbable
Osteoinduction
Bioresorbable
IGNITE to be mixed with
BMA
Osteoinduction
Bioresorbable
341
technology in calcium sulfate
powder
RCS
Percutaneous graft
powder
DBM in calcium sulfate
®
IGNITE
Injectable/formable putty Osteoconduction Case reports
DBM with/without CBM in
®
Various volumes of formable putty
DBM with CACIPLEXTM
calcium sulfate powder
®
ALLOMATRIX
Injectable paste/formable putty
40 % DBM, 50 % calcium
PRO-STIM™
Putty and putty with chips Osteoconduction
sulfate, 10 % calcium
phosphate
donor CCC
DBM Allograft DBM with same
®
Injectable
Inductive Graft
Smith &Nephew VIAGRAF DBM combined with glycerol Putty, paste, gel, crunch and fl ex Osteoconduction
Wright Medical Technology ALLOMATRIX
Zimmer Puros
Abbreviations : CCC cortical cancellous chips, LAG local autologous graft, HA hydroxyapatite, BM bome matrix, DBM demineralized bone matrix, BMA bone marrow aspirate
342
S. Teufack et al.
33.2.3 Growth Factor-Based Extenders
Growth factor-based bone graft substitutes are
natural or recombinant growth factors that are
used alone or in combination with other materials. They include transforming growth factorbeta (TGF-beta), platelet-derived growth factor
(PDGF), fi broblast growth factor (FGF), insulinlike growth factor-1 (IGF-1), and bone morphogenetic proteins (BMP).
Naturally occurring growth factors and proteins in extracellular bone matrix are responsible
for cell activity regulation. These factors interact
with cell surface receptors, producing an intracellular cascade resulting in intra- and extracellular
activity. TGF-beta and PDGF are growth factors
that play crucial roles in tissue regeneration and
remodeling, cell differentiation, and embryonic
development. FGF is a “pluripotent” growth factor involved in angiogenesis, wound healing, and
vertebral development [ 18 , 19 ]. IGF-1 is a pri-
mary mediator of the effects of growth hormone
(GH) that has growth-promoting effects on
almost every cell in the body, including bone,
cartilage, and hematopoietic cells. BMPs are a
group of growth factors also known as cytokines
and as metabologens that play a crucial role in
induction of bone and cartilage formation [ 20 ,
21 ] BMPs are covered in more details in Chap.
38 . The combined simultaneous action of these
factors is responsible for controlled bone production, resorption, and remodeling.
Most of these proteins have been isolated and
in some case synthesized by recombinant technology. Examples of preparations of growth
factor- based bone graft extenders currently
offered by pharmaceutical companies are listed
in Table 33.2 .
33.2.4 Cell-Based Extenders
Cell-based bone graft extenders facilitate in vitro
generation of an osteoblastic cell lineage from
progenitor mesenchymal stem cells. For instance,
bone marrow stem cells grown in media enriched
with growth factors such as TGF-beta and BMP
as well as various additives such as dexamethasone, ascorbic acid, and beta-glycopyrrolate can
be directed to differentiate into the osteoblast lineage. However, these mesenchymal stem cells
also require the presence of a polymer scaffold
such as bioactive ceramics. Commercially available cell-based extenders generally combine a
progenitor cell for osteogenesis, growth factors
for osteoinduction, and a scaffold for osteoconduction. Table 33.2 includes examples of cell-
based bone graft extenders.
33.2.5 Ceramic-Based Extenders
A ceramic is an inorganic nonmetallic solid prepared by the action of high temperature followed
by cooling; it may be crystalline, partly crystalline, or amorphous like glass. Sixty percent of
commercially available bone graft extenders use
ceramics as a primary component or adjunct. As
they tend to be brittle, ceramics are frequently
combined with other materials. Medical grade
ceramic substitutes can be divided into three
main categories based on their composition: calcium phosphate, calcium sulfate, and bioactive
glass.
The use of ceramics was inspired by the fact
that the primary inorganic component of bone is
calcium hydroxyapatite, a subset of the calcium
phosphate group. Calcium phosphates are
thought to be osteoconductive, osteointegrative
as they are incorporated in the new bone, as well
as possibly osteoinductive. Examples of calcium
phosphates currently used are tricalcium phosphate, synthetic hydroxyapatite, and coralline
hydroxyapatite; these are available in pastes, putties, solid matrices, and granules.
Bioactive glass is a biologically active
silicate- based glass. It is less frequently use,
because it is very brittle and has to be used in
combination with other materials such as polymethyl methacrylate to form bioactive bone
cement or as a coating for metal implants.
Table 33.2 includes examples of ceramic-based
bone graft extenders.
33 Bone Graft Extenders
Published research
Osteoconductive Case reports
Osteoinduction
Bioresorbable
Bioresorbable
Osteoinductive
Bioresorbable
Osteogenesis when mixed with
Osteoinduction
BMA or blood
Bioresorbable
Osteoinduction
Bioresorbable
Osteoinduction Case reports
Require additional structural graft
Osteoconduction
Bioresorbable
Osteoconductive Case report
Osteoinduction
Bioresorbable
Bioresorbable
Osteoconductive Case reports
Osteoinductive
Bioresorbable
Human studies
(Level I-II evidence)
Osteogenesis when mixed with
BMA
343
Bioresorbable
Injectable, mixable granules,
moldable strips and graft
Granules Osteoconductive Case reports
phosphate
carbonate mix
Product name Composition Forms Additional property
ApaTech Limited Actifuse 0.8 % silicate substituted calcium
Table 33.2 Examples of commercially available non-allograft-based bone graft extenders
Company
Biomet ProOsteon 200R Hydroxyapatite and calcium
Moldable strips Osteoconductive Case report
Granules, preform shapes and strips Osteoconductive Case reports
Mordable strips
resorbable polymer mix
with hydroxyapatite
Healos Cross linked collagen fi bers coated
Depuy Synthes ChronOs Beta-tricalcium phosphate and
Integra LifeSciences MOZAIK™ 80 % beta-tricalcium
Granules Osteoconductive Case report
phosphate + 20 % type 1 collagen
beta-tricalcium phosphate mix
mix
OsSatura TCP 75 % porous hydroxyapatite and
Integra Orthobiologics/
(Isotis Orthobiologics)
collagen sponge
rhBMP-2 soluble powder 1.5 mg/mL rhBMP-2 infused
Bone
®
INFUSE
graft
Medtronic Spinal &
Biologics
2 mg/mL rhBMP-2 infused graft Osteoinduction Human studies
rhBMP-2 with ceramic matrix (15:85
HA:β-TCP)
AMPLIFY™
Matrix
particles, morsels
Formable and injectable paste Osteoconductive Case report
NovaBone Products Novabone Silicate calcium phosphate matrix MIS injectable and moldable putty,
Stryker Hydroset Self setting calcium phosphate
Powder, pellets, moldable strip,
injectable putty
cement
phosphate
90 % porous beta-tricalcium
®
Vitoss
Powder, pellets, moldable strip,
injectable putty
phosphate with bioactive glass
BA 90 % porous beta-tricalcium
®
Osteoset Calcium sulfate cement Injectable pellets; formable paste Osteoconductive Case reports
Vitoss
Wright Medical
Technology
344
S. Teufack et al.
33.2.6 Polymer-Based Extenders
A polymer is a macromolecule composed of
repeating structural units; it can be natural or synthetic. Polymers have a wider range of mechanical, physical, and chemical properties compared
to other bone extenders. Degradable synthetic
polymers are resorbed by the body, thus resulting
in a fusion without any residual foreign body.
Examples are polylactic acid and polylactic-coglycolic acid; they can be used alone or in combination with autograft and allograft. Table 33.2
includes examples of polymer-based bone graft
extenders.
33.3 Clinical Research
Spinal fusion surgery is paramount to the treatment of spinal instability resulting from degenerative disease, trauma, infection, neoplasm, or
iatrogenic causes. In recent years, the number of
spinal fusion surgery increased to an estimated
500,000 procedures annually in the United States
alone [ 22 ]. Emerging biotechnologies are now
focused on developing alternatives to autologous
iliac crest bone graft in order to minimize the
morbidity associated with spinal fusion while
maintaining similar rates of fusion.
The majority of the work in osteobiology has
focused around osteoinductive bone graft extenders such as demineralized bone matrix (DBM)
and recombinant human bone morphogenic protein (rhBMP, rhBMP-7). Initial reports of serious
complications with the use of rhBMP2 have
fueled further research focused on the safety and
effi cacy of biologic and synthetic extenders.
Abdullah et al [ 6 ]. recently conducted a sys-
tematic review of 19 clinical human studies,
including case series, cohorts, and randomized
controlled trials, evaluating the use of BGEs in
lumbar fusion surgery. Regarding demineralized
bone matrix (DBM), only two studies of Class II
level evidence were published [ 23 , 24 ]. They
both showed similar fusion rate between ICBG
and ICBG + DBM in posterior lumbar fusion,
suggesting that DBM can be used to supplement
ICBG with the intent to decrease the size of the
harvested autograft bone. No adverse events
were reported with DBM. Beta-tricalcium phosphate (TCP) has been extensively reviewed. Two
Level I studies using TCP in adolescent scoliosis
surgery have been published [ 25 , 26 ]. TCP com-
bined with local allograft (LAG) had similar
fusion rates compared to ICBG, with elimination
of graft site complication and a trend toward
lower blood loss.
Alsaleh et al [ 27 ]. published a systematic
review focused on the use of osteoconductive
bone graft extenders in posterolateral thoracolumbar spinal fusion for scoliosis and degenerative conditions. They evaluated 13 case control
and randomized controlled trials comparing the
use of BGEs mixed with local autograft (LAG) or
bone marrow aspirate (BMA) versus ICBG alone
or with LAG in 768 patients. The patients were
evaluated for fusion at a minimum of 1 year postoperatively. Their conclusion was that BGEs had
similar pooled fusion rates compared to ICBG
for degenerative conditions but not scoliosis.
Subgroup analysis revealed that beta-tricalcium
phosphate ( ß -TCP) alone and mixed with
hydroxyapatite (HA) had similar pooled fusion
rates as ICBG. However, calcium sulfate had a
trend toward lower fusion rates compared to HA
alone as well as ICBG. LAG and BMA were both
used in the control and experimental arms. The
review also showed a trend toward lower fusion
rate when BMA was used alone to supplement
BGEs as opposed to LAG alone or a combination
of LAG + BMA. Overall they had a signifi cantly
lower incidence of adverse events in the BGE
groups, including delayed wound healing, infection, and hematoma.
Conclusion
The ideal bone graft has properties of osteo-
conduction, osteoinduction, and osteogenesis.
Autograft has been considered the “gold stan-
dard” of bone grafting; however the morbidity
associated with the harvesting lessens its pop-
ularity. As technology develops there is an
increased demand for an ideal bone graft sub-
stitute and extender. Several classes of bone
graft extenders have been created and evalu-
ated in spinal fusion. Combination products,
33 Bone Graft Extenders
345
particularly those using demineralized bone
matrix, ceramic- based bone graft extenders,
and local bone graft, have gained popularity
and have been shown to offer similar rates of
fusion with fewer complications compared to
iliac crest bone graft in lumbar spine fusion.
There still remains signifi cant research to be
conducted on the use of BGEs for specifi c
pathologies, risks profi les, and long-term
fusion rates.
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