Bone Graft Substitutes
Doron I. Ilan, MD, and Amy L. Ladd, MD
Today’s surgeon faces many situations that require bone graft-
ing. Autologous bone is the traditional standard for treating
conditions requiring bone graft. However, autologous bone graft-
ing has drawbacks such as donor site morbidity and increased
operative time. Graft substitutes for autologous bone are an
appealing alternative. Substitutes include allograft, mineral com-
posites, ceramics, mineral cements, bioactive glass, proteins,
and growth factors. The use and availability of these products
has expanded exponentially. The large number of alternatives
available and the relative lack of quality information regarding
their indications and effectiveness leave the surgeon desiring to
use the products with a daunting task. This article provides the
surgeon with an overview of the basic concepts of bone grafting
and discusses the most commonly used bone-graft substitutes
and their potential indications.
© 2003 Elsevier Inc. All rights reserved.
one grafting is a commonly performed procedure. It is
B estimated that more than 500,000 bone-grafting proce-
dures are performed annually in the United States.1 The indi-
cations for bone grafting include fractures with bone loss, com-
minution, metaphyseal defects, delayed unions and nonunions,
bone lesions, and arthrodesis.2 Bone grafting is intended to
stimulate bone healing and fill bone defects, with autologous
bone grafting as the standard method of achieving these goals.
Problems with using an autograft, however, exist. Harvesting
bone involves increased operative time, blood loss, postopera-
tive pain, length of hospital stay, and cost. A study reported an
8.6% rate of major complications and a 20.6% rate of minor
complications associated with autologous grafting.3 The supply
of autologous bone is limited and successful healing and re-
modeling may not always be achieved. Alternatives to bone
grafting potentially expand traditional indications for use.
The surgeon’s desire for new bone grafting tools and their
potential marketability has provided the stimulus for develop-
ing innovative and effective products over the last decade. Al-
though these products promise to revolutionize surgical prac-
tice, the present options and available information are
confusing to most practitioners. The choice of a bone-graft
substitute may be influenced more by marketing strategies than
scientific basis. An absence of comparative human studies that
clearly demonstrate the benefits of one agent over another fur-
ther confounds critical analysis. This article will discuss the
basic principles of bone grafting, identify the major types of
graft substitutes available, and review their unique features and
From the Robert A. Chase Hand and Upper Limb Center, Palo Alto, CA.
Address correspondence and reprint requests to Dr Amy Ladd, Pro-
fessor of Orthopaedics, Stanford University School of Medicine, 900
Welch Road, Suite 15, Palo Alto, CA 94304.
© 2003 Elsevier Inc. All rights reserved.
1071-0949/02/0904-0007$35.00/0
doi:10.1053/j.optr.2003.09.003
Operative Techniques in Plastic and Reconstructive Surgery, Vol 9, No 4: pp 151-160
capabilities. The indications and potential future indications
for graft substitutes will be discussed.
Basic Concepts of Bone Grafting
The character of a fracture or bone defect dictates the expecta-
tions of a graft. A distal radius fracture may require a void filler
to provide compressive support or a scaffolding for new-bone
formation, for example, while a comminuted ulnar shaft frac-
ture may require structural graft to fill a gap. Immediate needs
and dynamic processes describe fundamental attributes of graft
substitutes. Although interplay exists between them, they may
be characterized as follows: (1) structural support/strength
(immediate and static) (2) osteoconduction, (3) osteoinduc-
tion, and (4) osteogenesis.
Structural Support/Strength
One of the common indications for bone grafting is bone loss,
requiring mechanical support or structural replacement. Al-
though cortical bone, both autologous and allograft, confers
mechanical stability, a method to provide rapid incorporation
into bone has not been established. To date this mechanical
stability is largely met with internal, external, and adjunctive
fixation techniques. Synthetic injectable materials now exist
which confer mechanical stability in compression but largely
require intact or reducible cortical bone.4
Osteoconduction
Osteoconduction is the process which provides scaffolding for
ingrowth of new bone. The protein matrix and mineral phase of
bone graft provide this structure. Autograft, allograft, many of
the mineral bone graft substitutes (Fig 1), coralline hydroxyap-
atite and bioactive glass provide this quality. It is most com-
monly used to fill bone voids, with anticipated ingrowth of new
bone into, and possibly replacing, the osteoconductive graft.
Osteoinduction
Osteoinduction is the process which stimulates new bone pro-
duction in bone-forming cells. Blood-borne proteins, peptides,
growth factors, and a specific group of named cytokines pro-
vide this stimulation. Cytokines are low-molecular weight,
pharmacologically active proteins derived from a specific cell
line, which have a hormonal-like influence on the cells associ-
ated with the immune response. Growth factors, a subset of
cytokines, are polypeptides that promote cell growth by bind-
ing to specific receptors. The intensely researched group of
cytokines known as the “superfamily” of Transforming Growth
Factor type ␤ (TGF-␤) has shown a role in regulation from
embryonic development to wound and bone healing.5 The Bone
Morphogenic Proteins (BMPs), an influential subclass of TGF-␤,
induce cartilage and bone forming elements (osteoprogenitor
151

Fig 1. Ultrastructure of Vitoss demonstrating an osteocon-
ductive scaffolding (with permission from Orthovita).
cells) from undifferentiated mesenchymal (multipotential)
cells6,7,8 Members of the TGF-␤ family may exist in blood, bone
marrow, autograft, allograft, and demineralized bone matrix
(DBM) and more recently can be reproduced in a purified
recombinant form. The presence of growth factors in DBM and
allograft in humans has not been specifically identified, despite
marketing claims, but have been identified in animal studies.
Osteoinduction is desired for stimulation of bone growth in an
unfavorable environment or, in the future, may be used to
accelerate fracture healing and bony fusions.
Osteogenesis
Osteogenesis is the process of direct bone formation and is only
present in cells (osteoblasts and osteoblast precursors). The
only material, to date, that has true osteogenic properties is
autograft. A hypothetical synthetic osteogenic substitute might
contain genetically engineered osteoblasts in a favorable envi-
ronment, one that provides a matrix and pattern for bone de-
velopment.
Other Considerations
Other considerations temper the potential attributes of grafts.
Resorption refers to the disappearance of the graft, which may
represent chemical dissolution, phagocytosis, or remodeling
into new bone. The latter, in general, is most desirable. The
resorption time varies greatly among substitutes.
The safety and efficacy of a graft is very important and is the
defining criteria required by the FDA to market a product.
Innovation and marketing activity currently outpaces the sci-
entific data available on new products, and current regulation is
TABLE 1. Human Allograft Banked Bone Osteoinductive/Osteoconductive
Product Company Type
Allograft Bone Osteotech, U. of ● Bone/joints with soft
Florida Tissue Bank, tissue attachments
Sofamor Danek, ● Machined or shaped
CryoLife, bone
Regeneration ● Corticocancellous
Technologies Inc blocks
(RT), and others ● Cancellous cubes,
chips, morsels
152
confusing. Bone graft substitutes are regulated by a several
branches of the Food and Drug Administration. Human tissue,
for example, does not require the stringent evaluation required
of marketing new devices, although the processing of human
tissue does. Devices used in humans that precede the presence
of the FDA also lack this scrutiny. The wide variety in regula-
tion of products which appear similar to clinicians adds to this
confusion.9 Most of the studies performed on these products
are industry sponsored, given the high cost required to bring a
device to market. Many of the products are approved by the
FDA via 510(k) process, which is approval based on demon-
strating similar safety and efficacy to existing products, rather
than undergoing the rigorous trials necessary for new device
approval. The requirement is to demonstrate “equivalency,”
which is a highly relative term. In addition no objective, quan-
titative parameters exist to compare the different substitutes
available.
Bone Graft Substitutes
Allograft—Cortical and Cancellous Bone (Table 1)
Banked human bone is available in different forms. Morphology
retaining bone ranges from fresh and frozen, which have stron-
ger mechanical properties but greater infection and rejection
potential; to freeze-dried, which is weaker, but with potentially
less toxicity. Corticocancellous allograft is classically used for
tumors, large defects from nonunions such as the humerus, and
areas of large defects. Cancellous allograft chips are used more
commonly for smaller nonunions and metaphyseal voids, ei-
ther as autograft extender or as replacement. Its disadvantages
include the lack of rich osteoinductive potential seen with au-
tograft, the quality of bone is variable and usually unknown to
the surgeon before surgery, and carries a theoretical risk of
disease transmission. Only recently has disease transmission
been reported; this more likely represents increased surveil-
lance and centralized database collection rather than first-time
occurrences. By 2002 the Centers for Disease Control (CDC)
have reported 26 cases of bacterial infections associated with
musculoskeletal tissue allografts, all associated with a Clostrid-
ium organism, potentially related to the relative decomposition
of the donor. Tissues had been processed aseptically, but did
not undergo terminal sterilization, a process that minimizes
disease transmission but also sacrifices biologic incorpora-
tion.10 A documented case of HIV transmission from allograft is
known,11 and the FDA has cited tissue banks when bacterial
and viral contamination has been identified in harvested hu-
man tissue. The disconcerting news of contamination of spec-
imens, as well as recipient infection and death, supports the
Indications Advantages Disadvantages
Replacement or ● Provides structural ● Variable quality
extension of support ● Compared to autograft
Autograft ● Osteoconductive ● Less potential for bone formation
● Osteoinductive ● Weaker
● Possibility of disease transmission
● CryoLife temporarily closed by
FDA and CDC in 2002 for safety
reasons (CDC ref)
● RTI cited by FDA for blood
pooling practices in 2001
ILAN AND LADD
 TABLE 2. Allograft Demineralized Bone Matrix (DBM) Potentially Osteoinductive
Product Company Type Indications Advantages Disadvantages

Grafton DBM Osteotech Glycerol carrier Nonunion, delayed ● Potentially Human derived:
Available in gel, and potentially osteoinductive ● Variable starting material
flexible sheet, delayed unions ● Solid formulations ● Potential for disease
putty and provide some transmission
semisolid structural support ● Potential immunogenicity
(“Crunch”) ● Large clinical Gel offers no structural
forms experience support
● Recent concerns about
toxicity of glycerol
(Bostrom)
Allogro Allosource Particulate DBM, Nonunion, delayed ● Potentially ● Human derived, as above
reconstitute and potentially osteoinductive
with saline delayed unions
DBX Synthes USA, DBM ⫹ hyaluronic Nonunion, delayed ● Potentially ● Human derived, as above
Musculoskeletal acid ⫹ collagen and potentially osteoinductive ● Critics claim hyaluronic
Tissue Foundation carrier delayed unions acid carrier (xenograft
(MTF) & Lifecore coxcomb) is untested
DynaGraft, Accell, GenSci DBM ⫹ polymer Nonunion, delayed ● Potentially ● Human derived, as above
OrthoBlast Regeneration carriers and potentially osteoinductive ● Relatively less clinical
Sciences delayed unions experience compared to
Grafton
Osteofil Regeneration DBM (24%) with Nonunion, delayed ● Potentially ● Human derived, as above
Technologies Inc gelatin carrier and potentially osteoinductive
(RTI) (17%) and water delayed unions ● Moldable but hardens
Metaphyseal at body temperature
fractures ● Does not wash away
with irrigation
● Potential for
remodeling exists
(not yet proven)

quest for developing synthetic materials that lack potential dis-
ease transmission.
Allograft—Demineralized Bone Matrix (Table 2)
Demineralized Bone Matrix (DBM) is allograft bone that has
been demineralized and processed, with a denatured form of
the protein matrix remaining. The processing, which includes
chemical and radiation treatment, weakens the bone and its
bone formation potential. Growth factors may survive process-
ing, although their actual presence is not documented in the
literature. DBM confers osteoinduction in an animal model12
and therefore suggests the presence of factors. A human model
for osteoinduction does not exist. Dry, moldable, or injectable
forms exist as powder, paste, or putty, using a carrier that
renders it suitable for placement. The safest and best carrier
agent remains to be identified. Companies claim more rapid
ossification via osteoinduction, and infer that potential dangers
characterize other carrier substances. Patent infringement suits
currently exist among several companies.
Grafton DBM (Osteotech, Inc, Eatontown, NJ) has several
formulations in a glycerol carrier, including semirigid and
putty forms to improve delivery and integrity. The manufactur-
ers report no disease transmission in 1.5 million procedures
since introduction in 1991. A recent study raises concerns
about glycerol carrier toxicity in animals,13 although this tox-
icity has not been documented in humans. Dynagraft (GenSci
Regeneration Sciences Inc., Toronto, Canada) is another form
of DBM, with its carrier a combination of a polymer, ethylene
oxide and propylene oxide. DBX (Musculoskeletal Transplant
Foundation and Synthes, Paoli, Pennsyvania) is DBM with col-
lagen and xenograft hyaluronic acid. Osteofil (Regeneration
Tecnologies Inc, RTI) is DBM in a gelatin and water medium.
Minerals (Table 3)
Mineral substitutes are osteoconductive. A ceramic is a mineral
salt heated to high temperatures, greater than 1000°C, in the
process known as sintering. Sintering provides strength to a
finished material, but when applied to bone or similar minerals,
decreases remodeling and resorption capability of bone. Most
ceramics are composed of hydroxyapatite (HA), tricalcium
phosphate, or both. These brittle materials have little tensile
strength. More extensive interconnected porosity of a sub-
stance permits faster bony ingrowth but weakens the material;
the ideal pore size is thought to be between 150 and 500 mi-
crons.14 Both sintered and nonsintered porous substances exist,
the latter of which permit faster resorption. Whether resorption
correlates with remodeling depends on the material and the
local environment.
Endobon (Biomet/Merck/Lorenz Surgical, Zwijndrecht,
Netherlands) is a bovine-derived ceramic comprised of cancel-
lous bone, sintered and processed to eliminate all but the min-
eral components. The potential lack of immunogenicity is per-
haps counter-balanced by the poor remodeling capability
rendered by sintering. There has been a large European expe-
rience for orthopedic, maxillofacial, and craniofacial fractures
and bone defects.15 It currently has FDA approval for maxillo-
facial indications.
Coralline HA is coral that is thermochemically treated with
ammonium phosphate, which demonstrates porosity similar to
bone. The thermochemical conversion process for Pro Osteon
(Interpore Cross International, Irvine, CA) converts 95% of the
coral’s calcium carbonate into more slowly resorbed HA.
Whereas not a sintering process, and therefore not technically a
ceramic, the conversion has a similar effect of minimizing its
resorption. Bone ingrowth has been demonstrated in the inter-
connected pores, with osteoblasts evident on the surface of the
material.16 Remodeling has not been identified. Formulations
include different pore sizes, with the larger (approximately 500
␮m) pore size more appropriate for cancellous bone defects. Its
compressive strength is reported as approximately 4 MPa.16
Human cancellous bone ranges markedly depending on age and
location, but typically measures somewhere between 0.5 and 10

BONE GRAFT SUBSTITUTES 153

 TABLE 3. Minerals/Ceramics Osteoconductive Solid Formulations (blocks, granules, pellets)
Product Company Type Indications Advantages Disadvantages

Endobon Biomet/Merck/ Sintered bovine Bone defects, used ● Osteoconductive ● bovine origin (potential
Lorenz cancellous extensively in Europe for ● Porosity permits bone immunogenicity)
Surgical bone craniofacial, maxillofacial, ingrowth (100 to ● Resorption/remodeling slow
(hydroxyapatite) and orthopaedic 1500 ␮)
indications: FDA approval
for dental applications
ProOsteon Interpore Corraline HA Metaphyseal defects ● Interconnecting pores ● Variable quality, strength
Cross granules or allow bone ingrowth
blocks
200, 500 and R Can be used in with ● Can be cut to fit defect ● Lacks elasticity of bone
forms autologous growth ● Slow resorption; remodeling
factors (AGF) unlikely
● Radiopacity renders healing
difficult to assess
Osteoset Wright Medical Calcium Sulfate Bone graft ● Totally resorbable ● Resorbs very quickly, 3 to 8
Technology pellets substitute/Autograft ● Provides temporary weeks
extender; filling of bone defect filler ● Non-physiologic Calcium salt
defects in non-weight ● Hard to confine to desired
bearing structures site
(metaphyseal defects) ● Structural support Insufficient
to replace or support
hardware
Calceon Synthes USA Calcium Sulfate Metaphyseal defects ● Totally resorbable ● Same as above
pellets ● Provides temporary
defect filler
Stimulan Encore Calcium Sulfate Bone void filler ● Totally resorbable ● As above: no clinical studies
Orthopedics and stearic ● Provides temporary in the literature
acid pellets defect filler
Vitoss Orthovita ␤-Tricalcium Cancellous bone substitute ● “polyporosity” size ● Needs structural
phosphate ranging from 1 to 1000 augmentation
␮m ● Bone marrow harvest
● Osteoconductive morbidity
● Potential osteogenesis
if used with bone
marrow aspirate
(Imbibe system)
ChronOS Synthes USA ␤-Tricalcium Cancellous bone substitute ● 7.5 MPa compressive ● Needs structural
(Ceros and Mathys phosphate strength augmentation
82 in (Europe) ● Resorbs/remodels 6 to ● Osteoconductive only
Europe) 18 months
Cerasorb curasan ␤-Tricalcium Cancellous bone substitute ● Resorbs/remodels 3 to ● Needs structural
(Europe), phosphate 24 months augmentation
CryoLife & ● Osteoconductive only
Spinal
Concepts
Inc.

MPa.17 A formulation with calcium carbonate on its surface
(Pro Osteon R) permits some resorption, and potentially better
ingrowth.
Pro Osteon was the first calcium phosphate-based bone graft
substitute to receive FDA approval for fracture treatment in
1992, and received general use approval in 1998. The 500-␮m
pore size formulation has found widespread orthopedic appli-
cations,18 and shown to be useful in fractures of the distal
radius for both internal and external fixation.19
Tricalcium phosphate (TCP) is a physiologic mineral salt that
exchanges readily with HA molecules. The structure, particu-
larly its porosity, strongly influences its ability to resorb or
remodel.20 Alpha and Beta forms exist with the Beta form hav-
ing a more rapid resorption. The first product released in the US
in 2001 is Vitoss (Orthovita, Malvern, PA), a ␤-TCP, whose
ultrastructure demonstrates “polyporosity,” with its pores of
varying diameter, ranging from 1 to 1000 ␮m.21 This size range
correlates histologically with biologic activity. It is posited that
larger osteoclasts position in the large pore size, whereas plate-
lets and leukocytes that secrete chemotactic cytokines lodge in
smaller pores (Fig 2).
ChronOS (Synthes USA; Ceros 82 in Europe developed by
Mathys, Switzerland) is ␤ TCP released in 2002 under the
510(k) approval of the FDA, its predicate devices being ProOs-
teon and Vitoss.22 This underscores the arbitrary nature of the
term “equivalency,” since ProOsteon— coralline HA—is a dif-
ferent material than porous ␤-TCP. It also has variable pore size
and it demonstrates 7.5 MPa compressive strength, with re-
sorption in 6 to 18 months (company estimates). Cerasorb
(curasan in Europe, marketed by CryoLife and Spinal Concepts
Inc, Austin, TX in the US) is another ␤ TCP used extensively in
Europe in dental and orthopedic applications.23
Calcium sulfate, better known as plaster of Paris, results from
the calcination of gypsum (CaSO4, 2 H2O), which partially
dehydrates to produce a hemi-hydrate (CaSO4, 1/2 H2O). It is a
nonphysiologic salt, but has been used for bone implantation
for over 100 years. Dreesmann in Germany was able to docu-
ment healing in six of eight bone defects using plaster of Paris
and phenol.24 Its use, however, was slow to develop despite
acceptances of asepsis and sterile technique in the 20th Century.
Peltier wrote his landmark article on the utility of use with bone
defects in 1959,25 documenting the bone activity in animal
studies and correlating it with clinical cases. Since the clinical
use of calcium sulfate predated the existence of the FDA, it was
designated a class II “special controls” device in 1998, requiring
institution of voluntary consensus standards for its use.26 The
consensus findings designate “surgical grade” CaSO4 as reflect-
ing purity and consistency of the material. The first calcium
sulfate marketed was Osteoset (Wright Medical Technology,
Inc, Arlington, TN), available in pellet form, and more recently

154 ILAN AND LADD

Fig 2. The cyst as outlined (A) demon-
strates the rim surrounding a silastic im-
plant, originally placed to prevent physeal
closure. (B) represents new bone forma-
tion five months after removal of the im-
plant, curettage, and replacement with
␤-TCP (Vitoss) in a slurry of venous blood.
The previous cyst margins are outlined.
The inner radio-opacity probably repre-
sents residual ␤-TCP, the surrounding lu-
cency represents osteiod formation, not
yet mineralized (creeping inward, com-
pared with previous radiographs), and the
outer radio-opacity represents mineral-
ized new bone.

as an injectable (Minimally Invasive Injectable Graft, MIIG).
Other marketed calcium sulfate products include Calceon (Syn-
thes USA) in pellet form, and BonePlast (InterporeCross), avail-
able in pellet, block, and injectable forms.
Resorption of calcium sulfate is rapid, with total resorption
observed as early as a few weeks to potentially longer times.
Manufacturers’ information is scant on the rate of resorption,
but it depends on the formulation and configuration of the
material, the size and local environment of the defect, and the
formulation. Whereas fast resorption occurs by dissolution and
arguably renders no advantage to bone healing, replacement
with trabecular bone has been shown.27 It is currently approved
for filling metaphyseal defects. Calcium sulfate potentially ren-
ders immediate stability, but requires augmented fixation,
given its rapid resorption.
Injectable Cements (Table 4)
The first injectable biologic cement marketed in 1998 by the
FDA, Skeletal Repair System (SRS) (Norian /Synthes USA, Paoli,
PA), is a powdered calcium phosphate and calcium carbonate,
mixed with soluble sodium phosphate. Initially approved for
augmenting fractures of the distal radius, it is now approved for
general orthopedic use in metaphyseal defects. Injectable min-
eral cements have an advantage over blocks, granules, and
pellets, in that a custom fill of the defect is possible. Vigilant
application technique is required, since unwanted material may
extrude into the joint and soft tissues in comminuted fractures
if the fracture pattern is not well understood. Its compressive
strength is greater than cancellous bone (55 MPa).28
Biomechanical studies of SRS in a distal radius fracture model
suggest initial strength rivals that of K-wire fixation.29 The
cement poorly resists torsion and shear, so augmented hard-
ware is required for complex metaphyseal fractures.
The presence of dahllite (carbonated HA) in SRS contributes
to an unstable crystallinity, similar to the behavior of host bone,
which reportedly provides a favorable environment for oste-
oclastic remodeling.30 Remodeling with cutting cones and os-
teoclastic activity has been demonstrated histologically in ani-
mals and humans.28,31 SRS, as the first in situ setting injectable
calcium phosphate material, required Pre-Market Approval
(PMA) by the FDA, which mandates large multicenter clinical
trials. These studies demonstrated the safety and efficacy of this
device32.33 The radiographic appearance of SRS decreases ap-
proximately by 30 to 60% at one year, with a pattern of remod-
eling initially at the cortices and last in the intramedullary canal
consistent with Wolff’s Law,34 therefore supporting the concept
of bone remodeling.
BoneSource (Howmedica Leibinger Inc., Dallas, TX) is an-
other calcium phosphate cement approved for craniofacial de-
fects. A multicenter FDA-monitored study demonstrated the
effectiveness of BoneSource for metaphyseal fractures in vari-
ous open and closed injuries in 38 patients, showing effective-
ness and healing at least as comparable to autograft bone.35 A
distinct difference compared with SRS is that it requires a dry
setting medium, which can be troublesome in a fracture setting.
An additional calcium phosphate cement named alpha BSM
(ETEX Inc, Cambridge, MA and Depuy) is supported by animal
studies,36 and is approved for dental applications. It has ortho-
paedic approval as Calcibon and a malleable Biobon in Europe
(Biomet/Merck).
Additional cements from other manufacturers are likely im-
minent, and new formulations of existing cements will likely
focus on improving the handling properties, as well as improv-
ing the ability of the cement to resist torsional and shear stress.
This desired mechanical feature suggests adding pliable mate-
rials such as collagen, which have better tensile properties.
Bioactive Glass and Polymers (Table 5)
Long an interest in the dental industry, bioactive glass repre-
sents a combination of silica based material with a biocompat-
ible material such as calcium phosphate, forming a bond be-
tween the implant and the host tissue. The bond is comprised of
a carbonated apatite, as with the calcium phosphate cements.37
The material Bioglass (USBiomaterials Corporation, Alachua,
Florida) has shown rapid replacement with native bone in a
rabbit tibial defect at 2 weeks, compared with 12 weeks re-

BONE GRAFT SUBSTITUTES 155

 TABLE 4. Cements
Product Company Type Indications Advantages Disadvantages

Injectable cements
Calcium sulfate
MIIG (Minimally Wright Injectable calcium Same as above: ● Resorbs quickly ● Does not remodel—is it
Invasive Medical sulfate metaphyseal ● Suggested replacement dissolution or truly
Injectable Graft) Technology (Osteoset) defects with trabecular bone conductive?
BonePlast Interpore Injectable calcium Same as above: ● Resorbs quickly ● Same as above
Cross sulfate metaphyseal ● Suggested replacement
International defects with trabecular bone
Calcium phosphate
SRS (Skeletal Synthes/ Calcium Injection or insertion— ● Good compressive ● Poor shear/torsional strength
Repair System) Norian phosphate ⫹ distal radius strength (requires augmentation for
carbonated fractures ● Provides structural complex fxs)
apatite Studies also in spine, support for transverse ● Slow resorption/remodeling
injectable hip, tibial plateau, metaphyseal fractures ● Setting time may be longer in
cement calcaneus; ● Remodels cold/tourniquet environment
approved Jan 2002 ● Sets in 10 min. ● Not inductive
general orthopaedic
use
BoneSource Howmedica Calcium Cranial defects (burr ● Can be shaped and ● Subject to blood washout
Leibinger phosphate holes), maxillofacial placed manually or ● Requires dry field
cement (no injected ● Sets in 15 to 20 min. (longer
CaCO3) Studies in distal radius ● Good compressive working time arguably an
and other sites strength advantage)
reported (Dickson) ● Remodels
Alpha BSM ETEX with Calcium Dental application for ● Presumed similar to ● Orthopaedic studies pending
dePuy phosphate bone defects other CaPO4 cements ● Presumed similar to other
(USA), cement CaPO4 cements
and Clinical trials in
marketed progress
as
Calcibon
by BioMet
Merck
(Europe)
Biobon Biomet/Merck Calcium Marketed in Europe ● Presumed similar to ● No clinical studies reported
phosphate other CaPO4 cements,
putty more pliability
Mimix Biomet/Lorenz Synthetic Cranial defects ● Not reported in the ● Presumed similar to other
Surgical hydroxyapatite orthopaedic literature/ CaPO4 cements
tetra-tricalcium Presumed similar to
phosphate other CaPO4 cements

quired for HA granules.38 Cortoss威 (Orthovita, Malvern, PA) is
a polymeric cement with bioactive glass which forms a bond,
but the material itself does not resorb. It is currently available in
Europe, and a pilot study to evaluate its utility in vertebral
fractures is underway in the US. These and other polymeric
injectables are in pursuit of a material that is as ubiquitous and
as strong as poly(methyl methacrylate) (PMMA), creating a
material that is bioactive rather than toxic. The bioactive glasses
are potentially a useful tool for osteoporotic fractures (such as
vertebral compression fractures) and hardware augmentation
in osteoporotic bone. PMMA was first reported as useful in
unstable distal radius fractures by Charnley,39 and is currently
popular for use in vertebroplasty. Its potential systemic and
local toxicity, however, makes it an unpopular choice for the
distal radius when other materials are available.
injectable varieties. The combination of DBM with calcium
sulfate has been shown to be relatively safe and effective in
treating bone defects (Kelly). Another mineral composite is
Collagraft (Zimmer, Inc., Warsaw, IN and NeuColl, Campbell,
CA), one of the first substitutes approved by the FDA in 1993.
It is a composite of bovine collagen matrix, HA, and tricalcium
phosphate. It was approved for treatment of diaphyseal and
metaphyseal defects to provide osteoconduction, and when
used with autologous bone marrow aspirate demonstrates both
osteoconductive and osteoinductive capabilities, perhaps even
osteogenic40 It possesses no structural support. A prospective,
randomized study compared autograft and Collagraft,41 report-
ing 213 patients with 249 long bone fractures. The radiographic
outcomes were comparable to autograft, and patients demon-
strated similar complications.

Mineral Composites (Table 6) Proteins and Growth Factors (Table 7)

Cancellous bone and mineral substitutes combined with DBM
provide potential osteoinduction and osteoconduction. Opte-
form includes both DBM (using Osteofil, RTI) and cancellous
bone, (Exatech, Alachua, Florida), which can be molded to suit
the needs of the defect or problem. Allomatrix (Allosource ⫹
Wright Medical) is DBM combined with calcium sulfate (Os-
teoset, Wright Medical). Each composite has varying capabili-
ties and indications, although, like most substitutes, its use is
largely based on surgeon’s preference. The formulations in-
clude putty (“Custom”), a block (“DR” for distal radius), indi-
cated for periarticular fractures with purported stability, and
The fractured bone triggers the clotting cycle and the cascade of
inflammation that ultimately promotes healing, if the environ-
ment is favorable. The effect of specific proteins on the cascade
of inflammation and bone healing—from the peptide precur-
sors of the clotting cycle, to growth factors, to changes in cel-
lular gene expression—represents the most intense area of re-
cent research focused on bone stimulation.
Growth factors that promote bone formation are readily
found in autogenous bone harvest. Autogenous bone marrow
aspirate (BMA) is easily obtainable from the anterior iliac crest;
although bone marrow may not provide true stem cells, or cells

156 ILAN AND LADD

 TABLE 5. Bioglasses and Polymers Osteoconductive
Product Company Type Indications Advantages Disadvantages

Novabone US Bioactive Glass (SiO2 Reconstructive procedures ● Resorbable and ● Silica is

(particulate form Biomaterials and minerals) and bone defect filling eliminated by body non-physiologic
of Bioglass) ● Allows cell ingrowth and ● Hard to confine to
remodeling desired site
● Can be combined with ● Little structural support
autograft ● Resorption rate not yet
established
Cortoss Orthovita Polymer system with Augmentation of screws in ● Forms biological ● Not yet marketed in
reinforcing particle osteoporotic bone (hip, interface US (spring 2003)
bioactive glass spine, etc.) ● US pilot study to
(available in Europe) assess vertebral
fractures in progress
2003
Rhakoss Orthovita Polymer implants with Immediate stability for ● Potential bone/implant ● in development
bioactive glass bone defects, especially interface band with
spinal fusion bioactive glass
Immix OsteoBiologics, PGA/PLA polymer to be Bone graft extender and ● versatile ● Still in development
Inc produced in chip, flex scaffold ● May prove a good ● Nonphysiologic
and honeycomb growth factors carrier material
forms ● Inexpensive
Ceredex ETEX Resorbable matrix for in Carrier for in vivo biologic ● Unknown ● Unknown
vivo delivery of materials
growth factors,
antibiotics, vaccines
Poly(methyl Various; Vinyl polymer Immediate stability, bone ● Easy to mold ● Toxicity of monomer
methacrylate) Howmedica defects, implant ● Excellent compressive ● Exothermic reaction,
PMMA most interface strength local cellular toxicity
common

with pluripotential capabilities as once believed,42 the aspirate
is highly cellular, including osteoprogenitor cells, and provides
concentration of protein factors that stimulate bone growth in
favorable conditions.43,44 Initially promoted as a complement
to supplement Collagraft, BMA has become popular again as a
potential cost-effective alternative to recombinant osteoinduc-
tive materials. A Jamshidi needle and syringe, most commonly
used for core biopsies, is used for the technique; a packaged
harvest system exists as Imbibe (Orthovita, Malvern, PA).
Another rich autogenous source of growth factors is an ul-

TABLE 6. Mineral Composites—Osteoinductive/Osteoconductive

Product Company Type Indications Advantages Disadvantages

Opteform ExacTech ⫹ RTI Compacted cortico- Reconstruction of ● Potentially ● Human derived, as above
cancellous human bone acetabulum, tibial osteoinductive and
chips mixed with plateau, calcaneus, osteoconductive
Osteofill (RTI) etc. ● Moldable but hardens
at body temperature
● Does not wash away
with irrigation
● Potential for
remodeling exists
(not yet proven)
Allomatrix Allosource ⫹ DBM ⫹ calcium sulfate Nonunion, delayed ● Potentially ● Human derived, as above
Wright as carrier: and potentially osteoinductive and
Medical ● Putty (Custom) delayed unions, Osteoconductive
● Block (DR) metaphyseal ● Potential stability with
● Injectable defects DR form
Periarticular ● Potentially better
fractures (DR) carrier (inert,
nonprotein) than
other carriers for
DBM
Collagraft Zimmer/NeuColl Bovine collagen, HA and Grafting of long bone ● Osteoconductive ● Requires aspirated
tricalcium phosphate fractures and filling ● Osteoinductive when marrow
(TCP) of traumatic used with marrow ● Hard to confine to
defects desired site
Available in granular or ● Bovine collagen
strip forms antigenicity in some
patients
● Reluctance of bovine use
in Europe (Mad Cow
Disease) despite US
source
Healos Orquest HA coated bovine Replacement of ● Osteoinductive when ● No structural support
collagen sponge, autograft/autograft used with marrow ● Potential immunogenicity
approved in Europe extender for spinal ● Requires aspirated
fusion marrow
rhCollagen FibroGen Recombinant human Use in development ● Lacks immunogenic ● No data available spring
collagen potential of xenograft 2003
Collapro/ GenSci Human collagen in Use in development ● Lacks immunogenic ● No data available spring
Matrix Regeneration lyophilized strip potential of xenograft 2003
Sciences

BONE GRAFT SUBSTITUTES 157

 TABLE 7. Factors and Proteins Osteoconductive/Osteogenic (?)
Product Company Type Indications Advantages Disadvantages

Autologous Bone Jamshidi needle: Iliac crest autogenous Need for osteoinduction/ ● Osteoinductive, ● Invasive (minimally)
Marrow Orthovita harvest osteogenesis (usually osteogenic (?) ● Requires osteoconductive
Aspirate Imbibe needle supplemented with ● Inexpensive, low material or structural
system additional graft morbidity support
Autologous Graft Interpore Cross Buffy coat isolate of Need for osteoinduction ● Cost-effective ● Requires large blood loss
Factor (AGF) International autotransfusion when bone defect is compared to or donation of 1-2 units
system (white cells and large (for simultaneous recombinant ● More expensive than bone
platelets) known as transfusion) techniques marrow aspirate
platelet rich plasma Typically used with ● Usually requires additional
(PRP) additional graft conductive graft
material ● Possibly inhibits bone
growth in animals studies
(Li)
Symphony DePuy/LifeCell PRP Same as above ● Cost-effective ● Same as above
Platelet compared to
Concentration recombinant
System techniques
Cell Saver 5 Haemonetics PRP Same as above ● Cost-effective ● Same as above
compared to
recombinant
techniques
Chrysalin Chrysalis Proprietary amino Wound healing; fracture ● Early healing in ● Unknown
Biotechnology/ acid peptide, healing wounds, radius
OrthoLogic thrombin precursor fractures (Phase
III FDA trial)
OP-1 Stryker Biotech Recombinant growth Nonunions and large ● Osteoinductive ● Potential toxicity unknown
factor BMP-7 and bone defects in humans
collagen carrier
(Humanitarian
Device Exemption,
HDE by FDA)
rhBMP-2 Wyeth/Medtronic Growth factor and Approved for use with ● Osteoinductive ● Approval only with cages
(inFUSE) Sofamor collagen sponge LT-CAGE Lumbar for spinal applications
Danek carrier Tapered Fusion
Device
Ossigel Orquest/DePuy Basic fibroblast Potentially accelerates ● Unknown ● Unknown
growth factor fracture healing
(bFGF) in solution
with a hyaluronic
acid; clinical trials
in Europe
NeOsteo Centerpulse Bovine derived BMP Periodontal disease; ● Osteoinductive ● Studies incomplete
and collagen bone defects
carrier; dental
approval in Europe

traconcentrate of centrifuged blood. This autotransfusion sys-
tem is most useful when blood loss is large, and the blood-
saving centrifuge system (Cell Saver, Haemonetics Corp,
Braintree, MA) might be used. Traditionally known as the
“buffy coat,” which is comprised of leukocyte and platelets, it is
now often referred to as “platelet-rich plasma” (PRP), and dem-
onstrates substantial presence of growth factors.45 Several sys-
tems are currently marketed: AGF (Autologous Growth Factor,
Interpore Cross), Symphony, DePuy/LifeCell), and the Cell
Saver 5 (Haemonetics). Recent concerns have been raised about
the bone healing enhancement of PRPs, suggesting the high
white cell count in PRP causes bone inhibition in animal stud-
ies.46 Further substantiation may curb the enthusiasm for this
technique.
The current growth factors in clinical use include BMP-7 and
BMP-2. BMP-7 is known as OP-1, (Osteogenic Protein-1,
Stryker Biotech, Hopkinton, MA) is a human-recombinant ma-
terial that has received Humanitarian Device Exemption (HDE)
by the FDA. This Humanitarian Use Device (HUD) permits a
more rapid introduction than required for Pre-Market Approval
(PMA). Intended for relatively small populations, it is not sub-
ject to the effectiveness component of the PMA, which would
require clinical trials where both safety and efficacy are demon-
strated. OP-1 has shown dramatic effect in animal studies, and
has shown advantageous healing over autograft in tibial non-
unions.47 It is currently gaining use in difficult spinal fusions.
Its carrier is a bovine-derived collagen sponge. Antibodies to
both the bovine collagen and OP-1 have been identified in
patients.47 No adverse events have been correlated with the
antibodies in over 1000 patients (manufacturer’s information);
however, the significance of antibody formation is not known.
The other factor approved as a device is BMP-2 using recom-
binant techniques, under the name rhBMP-2 and marketed as
INFUSE (Wyeth, Andover, MA and Medtronic Sofamor Danek,
Memphis, TN). In animal studies, healing of bone defects was
shown using rhBMP-2,8 and a prospective, randomized trial
evaluating spinal fusion demonstrated healing and improved
outcome in the patients treated with rhBMP-2 and a HA/␤-TCP
substitute, compared with fusion with autograft.48 Its FDA ap-
proval, however, at this time only permits use with the LT-
CAGE Lumbar Tapered Fusion Device.
Bovine BMP in a collagen carrier, NeOsteo (Centerpulse, Zu-
rich, CH) has been reported in the literature49 and has dental
application in Europe, but orthopaedic trials are not known.
Fibroblast Growth Factor (FGF) and Platelet-Derived Growth
Factor (PDGF) promote bone regeneration through the early
healing phase. FGF has both mitogenic and angiogenic proper-
ties, and potentially promotes fracture repair. Ossigel (Orquest/
DePuy, Raynham, MA) is a form of FGF currently in European
clinical trials.
The cytokine vascular endothelial growth factor (VEGF) has
shown to stimulate bone repair by promoting angiogenesis and

158 ILAN AND LADD

bone turnover in animal studies;50,51 although currently in on-
cology related human clinical trials (Genentech, South San
Francisco, CA), nothing currently exists to examine its efficacy
in human bone.
The synthetic peptide representing the receptor binding site
of thrombin known as Chrysalin (Chrysalis Biotechnology/Or-
thoLogic, Tempe, AZ) has demonstrated earlier wound healing
in animal and human studies,52 and is currently in phase III
FDA trials to examine its effect on fracture healing of the distal
radius. The phase I/II double-blind study of Chrysalin in radius
fractures showed earlier healing, average of 4 weeks, compared
with placebo.53 Since the synthesis of Chrysalin does not re-
quire recombinant or genetic techniques, it may herald eco-
nomically viable materials of the future.
Conclusion
With the many bone grafting options available to the surgeon,
one must carefully match the clinical problem with the capa-
bilities of graft material. This can be a difficult task, as the
indications for use are seldom clear cut and often lack substan-
tial scientific backing. Adherence to biomechanical principles
and selecting a graft which addresses the clinical needs will
potentially provide optimal treatment.
References
1. Boden SD: Osteoinductive bone graft substitutes: Burden of proof.
Bull Amer Acad Orthoped Surg 51(1):42-43, 2003
2. Friedlaender GE, Goldberg VM (eds): Bone and Cartilage Allografts:
Biology and Clinical Applications. American Academy of Orthopedic
Surgeons: Park Ridge, IL, 1991
3. Younger EM, Chapman MW: Morbidity at bone graft donor sites.
J Orthop Trauma 3:192-195, 1989
4. Ladd AL, Pliam NB: The use of bone graft substitutes in distal radius
fractures. J Amer Acad Orthop Surg 7:279-290, 1999
5. Blobe GC, Schiemann WP, Loish HF: Role of transforming growth
factor ␤ in human disease. N Engl J Med 342:1350-1358, 2000
6. Schmitt JM, et al: Bone morphogenetic proteins: an update on basic
biology and clinical relevance. J Orthop Res 17:269-278, 1999
7. Kawabata M, Imamura T, Miyazono K: Signal transduction by bone
morphogenic proteins. Cytokine Growth Factor Rev 8:49-61, 1998
8. Lieberman JR, Daluiski A, Einhorn TA: The role of growth factors in
the repair of bone. Biology and clinical applications. J Bone Joint
Surg 84A:1032-1044, 2002
9. Ladd AL, Pliam NB: The role of bone graft and alternatives in
unstable distal radius fracture treatment. Orthop Clin N Amer 30:337-
351, 2001
10. Centers for Disease Control and Prevention: Update: Allograft-asso-
ciated bacterial infections—United States, 2002. MMWR 51:207-
210, 2002
11. Epidemiologic notes and reports transmission of HIV through bone
transplantation: case report and public health recommendations,
Oct 7, 1988, MMWR
12. Urist MR, et al: The bone induction principle. Clin Orthop 53:243-
283, 1967
13. Bostrom MP, et al: An unexpected outcome during testing of com-
mercially available demineralized bone graft materials: How safe are
the nonallograft components? Spine 26:1425-1427, 2001
14. Truumees E, Herkowitz HN: Alternatives to autologous bone harvest
in spine surgery. Univ of Pennsylvania Orthoped J 12:77-88, 1999
15. Werber KD, et al: Osseous integration of bovine hydroxyapatite
ceramic in metaphyseal bone defects of the distal radius. J Hand
Surg 25A:833-841, 2000
16. Shors EC: Coralline bone graft substitutes. Orthop Clin North Amer
30:599-613, 1999
17. McCalden RW, McGeough JA, Court-Brown CM: Age-related
changes in the compressive strength of cancellous bone. The rela-
BONE GRAFT SUBSTITUTES
tive importance of changes in density and trabecular architecture.
J Bone Joint Surg 79A:421-427, 1997
18. Bucholz RW, Carlton A, Holmes R: Interporous hydroxyapatite as a
bone graft substitute in tibial plateau fractures. Clin Orthop 240:53-
62, 1989
19. Wolfe SW, et al: Augmentation of distal radius fracture fixation with
coralline hydroxyapatite bone graft substitute. J Hand Surg 24A:816-
827, 1999
20. Toth JM, et al: Evaluation of porous biphasic calcium phosphate
ceramics for anterior cervical interbody fusion in a caprine model.
Spine 20:2203-2210, 1995
21. Resnick DK: Vitoss bone substitute. Neurosurgery 50:1162-1164,
2002
22. Chronos FDA approval, 2002
23. Hinz P, et al: A new resorbable bone void filler in trauma: early clinical
experience and histologic evaluation. Orthopedics 25:s597-s600,
2002
24. Dreesman H: Ueber Knochenplombierung. Bietr Klin Chir 9:804-810,
1892
25. Peltier LF: The use of plaster of Paris to fill large defects in bone. A
preliminary report. Am J Surg 97:11-15, 1959
26. Proposed Rules 5753-5756. Orthopedic Devices; Proposed Classi-
fication for the Resorbable Calcium Salt Bone Void Filler Device, Feb
7, 2002, Federal Register Docket # 01N-0411/ Vol. 67, No. 26
27. Kelly CM, et al: The use of a surgical grade calcium sulfate as a bone
graft substitute: results of a multicenter trial. Clin Orthop 382:42-50,
2001
28. Constantz BR, et al: Skeletal repair by in situ formation of the mineral
phase of bone. Science 267:1796-1799, 1995
29. Yetkinler DN, et al: Biomechanical evaluation of intraarticular distal
radius fracture treatment stability: K-wires vs calcium phosphate
bone cement. J Bone Joint Surg 81A:391-399, 1999
30. Vaes G: Cellular biology and biochemical mechanism of bone re-
sorption. A review of recent developments on the formation, activa-
tion, and mode of action of osteoclasts. Clin Orthop 231:239-271,
1988
31. Frankenburg EP, et al: Biomechanical and histological evaluation of
a calcium phosphate cement. J Bone Joint Surg 80A:1112-1124,
1988
32. Jupiter JB, et al: Repair of five distal radius fractures with an
investigational cancellous bone cement: a preliminary report. J Or-
thop Trauma 11:110-116, 1997
33. Cassidy C, et al: Norian SRS vs conventional therapy in distal radius
fractures: Multicenter study of 323 patients. J Bone Joint Surg, in
press
34. Wolff J: The Law of Bone Transformation. New York, Springer-
Verlag, 1986
35. Dickson KF, et al: The use of BoneSource hydroxyapatite cement for
traumatic metaphyseal bone void filling. J Trauma 53:1103-1108,
2002
36. Knaack D, et al: Resorbable calcium phosphate bone substitute.
J Biomed Mater Res 43:399-409, 1998
37. Hench LL, Paschall HA: Histochemical Responses at a Biomaterials
Interface. J Biomed Mater Res 5:49-54, 1974
38. Oonishi H, et al: Particulate bioglass compared with hydroxyapatite
as a bone graft substitute. Clin Orthop 334:316-325, 1997
39. Charnley J: The healing of human fractures in contact with self-
curing acrylic cement. Clin Orthop 47:157-163, 1966
40. Scaglione PH, Buchman MT: Collagraft bone substitute in upper
extremity fractures: a preliminary study. Surg Forum Amer Coll Surg
XLVIII:563-564, 1997
41. Chapman MW, Bucholz R, Cornell C: Treatment of acute fractures
with a collagen-calcium phosphate graft material. A randomized
clinical trial. J Bone Joint Surg 79A:495-502, 1997
42. Wagers AJ, et al: Little evidence for developmental plasticity of adult
hematopoietic stem cells. Science 297:2256-2259, 2002
43. Muschler GF, et al: Age- and gender-related changes in the cellular-
ity of human bone marrow and the prevalence of osteoblastic pro-
genitors. J Orthop Res 19:117-125, 2001
44. Muschler G, Midura RJ: Connective tissue progenitors: practical
concepts for clinical applications. Clin Orthop 395:66-80, 2002
45. Weibrich G, et al: Growth factor levels in platelet-rich plasma and
correlations with donor age, sex, and platelet count. J Craniomaxil-
lofac Surg 30:97-102, 2002
159
46. Li H, et al: Anterior lumbar interbody fusion with brantigan cages
loaded with bioceramics and platelet rich plasma. Orthopaed Res
Trans 28:0265, 2003
47. Friedlaender GE, et al: Osteogenic protein-1 (bone morphogenetic
protein-7) in the treatment of tibial nonunions. J Bone Joint Surg
83A:S151-S158, 2001
48. Boden SD, et al: Use of recombinant human bone morphogenetic pro-
tein-2 to achieve posterolateral lumbar spine fusion in humans: a prospec-
tive, randomized clinical pilot trial. Spine 27:2662-2673, 2002
49. Boden SD: Bioactive factors for bone tissue engineering. Clin Orthop
367(Suppl):S84-S94, 1999
50. Street J, et al: Vascular endothelial growth factor stimulates bone
160
repair by promoting angiogenesis and bone turnover. Proc Natl Acad
Sci USA 99:9656-9661, 2002
51. Bouletreau P, et al: Factors in the fracture microenvironment induce
primary osteoblast angiogenic cytokine production. Plast Reconstr
Surg 110:139-148, 2002
52. Norfleet AM, et al: Thrombin peptide TP508 accelerates closure of
dermal excisions in animal tissue with surgically induced ischemia.
Wound Repair Regen 8:517-529, 2000
53. Levine BP, et al: Phase I/II evaluation of a thrombin-related
peptide for acceleration of distal radius fracture healing. in Amer-
ican Society for Surgery of the Hand Annual Meeting, Phoenix, AZ,
2002
ILAN AND LADD