Bone Healing and Bone Substitutes

Peter D. Costantino, M.D., FACS,1,2 David Hiltzik, M.D.,1 Satish Govindaraj,

M.D.,1 and Jason Moche1

ABSTRACT

With the advent of new biomaterials and surgical techniques, the reconstructive
surgeon has a wider range of treatment modalities for the rehabilitation and reconstruc-
tion of craniofacial skeletal deformities than ever before. These innovative substances act
as true bone graft substitutes, thereby allowing the surgeon to avoid the use of autogenous
bone grafts and their associated donor site morbidity. Surgeons have long been interested
in producing a composite graft that can heal faster by induction, incorporate with sur-
rounding tissues, and be remodeled to resemble native bone. Currently, there are a host of
bone graft substitutes available that vary in both their composition and properties. Cran-
iomaxillofacial surgeons must therefore become comfortable with numerous biomaterials
to best tailor the treatment for each patient individually. Ongoing investigations into the
next phase of tissue engineering will continue to bring us closer to the ability to regener-
ate or replace bone.

KEYWORDS: Bone substitutes, bone implants, craniofacial reconstruction,

bioactive cements

A dvancements in biomaterials over the last 30 whereas osseointegration refers to the direct chemical
years have given the reconstructive surgeon new and bonding of an alloplast to the surface of bone without
innovative techniques in the rehabilitation and recon- an intervening layer of fibrous tissue. It is this property
struction of craniofacial skeletal deformities. These new of an intimate implant-bone interface without an inter-
substances now function as true bone graft substitutes, vening layer of fibrous tissue that imparts a significant
avoiding the use of autogenous bone grafts with their rigidity to the bone-implant system. In contrast, when
resultant donor site morbidity. Surgeons have long been fibrous tissue is present between an implant and bone,
interested in producing a composite graft that can heal there is an absence of rigid fixation of the alloplast
faster by induction, incorporate with surrounding tis- to the underlying skeleton, and at least some implant
sues, and be remodeled to resemble native bone.1 There mobility persists. This mobility predisposes to implant
is now a range of bone graft substitutes that vary in infection and to the resorption of bone under the im-
their composition and properties; however, the most plant.3 Although materials such as titanium and alu-
important of these synthetic materials are composed of minum osseointegrate, they are not considered bone
calcium or aluminum. Biomaterials composed of these graft substitutes. Therefore, only bioactive materials
substances have been termed bioactive, referring to that osseointegrate and osseoconduct should be consid-
materials capable of osseoconduction and osseointe- ered true bone graft substitutes.4
gration.2 Osseoconduction refers to the ability of an al- In the search for the ideal bone implant, the ma-
loplast to support the growth of bone over its surface, terial should possess several characteristics: it should (1)

Recent Biological Advances in Facial Plastic Surgery; Editors in Chief, Fred Fedok, M.D., Gilbert J. Nolst Trenité, M.D., Ph.D., Daniel G.
Becker, M.D., Roberta Gausas, M.D.; Guest Editor, David B. Hom, M.D., FACS. Facial Plastic Surgery, Volume 18, Number 1, 2002. Address
for correspondence and reprint requests: Dr. Peter D. Costantino, Center for Cranial Base Surgery, St. Luke’s-Roosevelt Hospital Center,
425 West 59th Street, 10th floor, New York, NY 10019. 1Department of Otolaryngology, Mount Sinai Medical Center, New York, NY; 2 Center
for Cranial Skull Base Surgery, St. Luke’s-Roosevelt Hospital Center, New York, NY. Copyright © 2002 by Thieme Medical Publishers, Inc.,
333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 0736–6825,p;2002,18,01,013,026,ftx,en;fps00413x.

13
14 FACIAL PLASTIC SURGERY/VOLUME 18, NUMBER 1 2002

be chemically inert, (2) be incapable of causing hyper- Bioactive Glasses

sensitivity or producing a foreign body reaction, (3) be Bioactive glasses are hard, solid, transparent materials
easily contoured, (4) retain stable shape over time, (5) be composed of varying combinations of sodium oxide,
noncarcinogenic, and (6) become ingrown or replaced calcium oxide, phosphorus pentoxide, and silicon diox-
by living tissue.2 As newer materials have been devel- ide, with silicate as the primary component. Forms can
oped, this concept has been pushed further to incorpo- be produced that range from those that are completely
rate bioactive substitutes that can replace bone at will. soluble in vivo to those that are nonreactive with bone
This article focuses first on the current array of bioac- and approach inertness.8 The actual mechanism that al-
tive bone graft substitutes and later discusses the new lows bone to bond with bioactive glass is dependent on
horizon of fully synthetic materials that are both bio- a reactive microenvironment consisting of a silica-rich
logically active and capable of bone replacement. gel that forms at the surface of bioactive glass implants
after implantation. Within this gel layer, the calcium
and phosphate contained within the implant nucleate to
BACKGROUND MATERIALS form crystals of hydroxyapatite (HA), which interact
The use of autogenous bone grafts has long been con- with bone surface substances, such as collagen and gly-
sidered the gold standard of comparison for new bone coproteins, to form a strong bond between the implant
graft materials. It has the advantages of being progres- and bone.8,9 Despite forming a strong molecular bond,
sively incorporated into the craniofacial skeleton (os- bioactive glass is not replaced by bone over time.
seointegrate), resisting infection, and being potentially Numerous studies have been carried out using
capable of growth (osteogenesis).5 Cranial bone is the bioactive glass for experimental osseous replacement in
most commonly used graft material in craniofacial re- most areas of the skeleton,10 but the main use for bio-
constructive surgery.6 Donor site morbidity continues active glass has been for middle ear ossicular recon-
to be a factor limiting the use of autogenous grafts, struction. In clinical studies, bioactive glass performed
and additional site-specific complications of harvesting equally well compared with ceramic HA middle ear im-
must be taken into consideration particularly if a second plants11; however, when failure occurred, it was sec-
operative site is needed.5–7 In addition, bone may un- ondary to implant degradation, not implant extrusion.11
dergo varying degrees of resorption with unpredictable Certain bioactive glasses are strong enough to function
contour changes.4 These issues underscore the high in- in stress-bearing sites in the head and neck, for ex-
terest in the search for an ideal alloplastic implant mate- ample, for mandible replacement. However, such im-
rial. Recent advancements in novel bone graft materials plants cannot be easily contoured in the operating room
have narrowed the search for a “supergraft,” a composite and screws cannot be easily placed into bioactive glass
bone graft that heals faster, incorporates into surround- blocks as they resist drilling and have a tendency to
ing structures, and remodels to a degree similar to the shatter during creation of screw holes.4
original bone.1

Glass-Ionomer Cement
SILICATE-BASED ALLOPLASTS Glass-ionomer cements represent a hybrid biomaterial
Bone graft substitutes that contain silicon-based mate- containing both organic and inorganic species. They are
rials incorporate that element in the form of silicate (sil- synthesized by a two-component reaction resulting in
icon dioxide; O=S=O—silicate [SiO2]) or silicone (di- a material that can be thought of as a bioactive glass
methylsiloxane). Although both materials are derived with a high Al2O3 content that has been combined with
from silicon, they are chemically and bioactively dis- a polymeric carbon matrix.12,13 Through a series of re-
similar and distinct. Silicone is composed of polymeric actions, the final implant is a composite of silicate,
strands of dimethylsiloxane that then form silicone rub- calcium, and aluminum ions dispersed throughout a
ber, the well-known implant material used in facial porous polymeric carbon matrix. This matrix results in
plastic surgery. Although well tolerated by the body, sil- an interconnecting system of micropores (1 to 10 m)
icone rubber does not have a crystalline structure and and macropores (100 to 300 m), the latter resulting
has no ability to osseointegrate or osseoconduct bone. from the evolution of CO2 gas during the reaction
In contrast, only certain silicate-based compounds have phase of the setting process.12
the potential to bond directly to bone. All bioactive The mechanism of osseointegration of solid
silicate-based materials combine other compounds with bioactive glass systems and glass-ionomer cements is
silicate to alter its physical properties to achieve bio- similar in that both bond to bone through the formation
activity. Silicate is used as the key component in two of a surface-active calcium phosphate crystal interface
successful biomaterials used in facial plastic and recon- with the bone. With the cements, however, alumina ions
structive surgery. These biomaterials are bioactive glass and crystals are found at the bone-implant interface in
and glass-ionomer cement or solid implants. addition to calcium phosphate, resulting in a decrease in
 BONE HEALING AND BONE SUBSTITUTES/COSTANTINO ET AL. 15

calcium phosphate crystal formation at the surface of conduction and osseointegration) to varying degrees de-
these implants. Because the formation of surface-active pending on the preparation and specific chemical com-
calcium phosphate crystals is critical to the bioactivity of position. In addition, some of these apatites are even
bioactive glasses, the high proportion of Al2O3 in glass- resorbable, being replaced by bone through a process of
ionomer materials may decrease bone bonding in com- osseoconduction and implant substitution. In the past,
parison with non-aluminum-containing bioactive glass the apatites have been used primarily in the form of
implants. Glass-ionomer implants should be considered ceramics, referring to the fact that the implant is heated
nonresorbable; bone cannot resorb and replace glass- to high temperatures (sintered) to fuse the crystals to-
ionomer implants owing to the silicate, aluminum, and gether. The two most important apatite preparations are
acrylic content of these biomaterials. tricalcium phosphate (TCP) and HA.4
Ionogran® (Ionos Medizinische Producte GmbH
& Co KG, Seefeld/Obb, Germany) is a porous granu-
lar form of glass-ionomer. It is osseoconductive when Tricalcium Phosphate
placed in contact with viable bone and can be used as Porous beta-TCP was one of the earliest calcium phos-
nonresorbable scaffolds (upon which bone can grow) to phate compounds to be applied as a bone graft substi-
fill osseous defects. One drawback is that this compound tute.16 It is formed from calcium carbonate coral, which
does not set and has no intrinsic structural stability is porous, with parallel channels and interconnecting
until surrounded by fibro-osseous tissue, similar to what fenestrations that allow the ingrowth of bone and fi-
occurs with HA granules.4 Ionomeric Cement® (Ionos brous tissue into the implant.17 Unlike ceramic HA,
Medizinische Producte GmbH & Co KG, Seefeld/Obb, which is nearly nonresorbable when implanted, ceramic
Germany) is based on the same chemical composition as beta-TCP slowly dissolves in vivo.16 With this material,
Ionogran granules and is a true self-setting cement that it is possible to induce osseoconduction of bone into a
can be mixed and contoured intraoperatively.12,14 The defect followed by the resorption of the beta-TCP scaf-
cement is formed by the reaction of a calcium aluminisil- fold so that no biomaterial is permanently left within
icate glass powder with a polyalkenoic acid, which after a the reconstruction site. Unfortunately, the replacement
period of mixing is applied as a cement and hardens in of beta-TCP by bone does not occur in a 1:1 ratio, that
approximately 5 minutes to form a water-insoluble solid. is, less bone volume is produced in comparison with the
Again the cement can be shaped for several minutes volume of TCP absorbed.4 For this reason, the clinical
prior to hardening but can be dissolved by any ambient use of beta-TCP has been primarily adjunctive by com-
liquid in the wound until fully set. As with other silicate- bining them with other materials to prevent premature
based alloplasts, bone can bond to this material but volume loss. Breitbart et al.18 combined TCP with os-
cannot replace the hardened cement. Ionomeric Cement teogenin, an osteoinductive protein, as an onlay bone
has a compressive strength and modulus of elasticity graft substitute for the frontal bone of rabbits. Results
comparable with cortical bone12 and has been used to showed a higher level of bone ingrowth and a higher
augment and reconstruct the craniofacial skeleton for percentage of mature lamellar bone when compared
both calvarial defects5 and for rebuilding parts of the with controls with no change in volume, suggesting a
ossicular chain in otologic surgery14 with overall fa- 1:1 ratio of bone replacement for implant loss. Future
vorable results. Although initially a promising mater- studies will need to document whether the TCP is com-
ial, Ionomeric Cement was commercially withdrawn in pletely resorbed over time and if the new composite
1995 due to four cases of aluminum encephalopathy re- retains the original implant volume and the long-term
ported in the literature.14,15 survival of the newly formed bone.18

CALCIUM PHOSPHATE-BASED Hydroxyapatite Preparations

ALLOPLASTS HA [Ca(PO4)6(OH)2] forms the principal mineral
Perhaps the most promising and well-tolerated allo- component of bone and constitutes 60% of the calcified
plastic material developed thus far has been the calcium human skeleton.4 It has been produced synthetically
phosphate-based compounds stemming from the fact since the early 1970s19 and used clinically for over 25
that bone contains a high percentage of this mineral. years.16 HA is biocompatible and does not cause a
The primary focus in the use of calcium phosphate chronic inflammatory response, toxic reactions, or a for-
alloplasts has been with the “apatite” forms of this eign body giant cell response.20 There are two general
compound, defined as those calcium phosphate-based categories of HA: ceramic and nonceramic. All forms
materials that have the approximate general formula are capable of osseoconduction and osseointegration
Ca5(X)(PO4)3, where X = fluorine (F), chlorine (Cl), and are resistant to absorption in vivo.4
hydroxide (OH), or 1⁄2(CO3). The calcium phosphate Ceramic HA is synthesized in crystal form at low
apatite compounds are all bioactive (capable of osseo- pH and then heated (sintered) to form a solid mass of
16 FACIAL PLASTIC SURGERY/VOLUME 18, NUMBER 1 2002

HA.16 It is available in two forms: dense and porous. following facial osteotomies.28 A porous granular form
Dense ceramic HA is entirely synthetic, has no pores, is also available and has been used for craniofacial de-
and can be fabricated into blocks or granules. Blocks fect repair and augmentation with good success; on fol-
of dense HA are not useful in facial plastic surgery be- low-up at 5 years, resorption has not occurred in any of
cause they are difficult to shape and do not permit these patients.29 Biologically active bone growth pro-
fibro-osseous tissue ingrowth. Dense HA granules have teins have also been added to porous ceramic HA to
greater contour adaptability than solid blocks but have alter its physical properties, expanding the applicability
no intrinsic structural integrity, do not become mechan- of HA to stress-bearing areas.30 Although the use of
ically stable until surrounded by fibro-osseous tissue, these inductive factors greatly speeds the ingrowth of
and thus retain the potential for migration for several bone into the pores of HA implants, the physical limi-
weeks to months.21 To solve the problems of implant tations of ceramic HA are retained even if these biolog-
migration and poor structural stability, HA granules ically active materials are added.4
have been combined with resorbable carrier compounds Nonceramic HA, or HA cement (HAC), is pro-
to aid in granule containment.21,22 Among these sub- duced by direct crystallization of HA at physiologic pH
stances, fibrin glue has been used as a control medium and temperature and does not require heating for the
and is known to promote wound healing and stimulate formation of a structurally stable implant.31 This unique
angiogenesis and plays a probable role in bone develop- cement consists of tetracalcium phosphate and dical-
ment.23–26 Fibrin glue was mixed with porous HA gran- cium phosphate anhydrous, which react in an aqueous
ules to secondarily reconstruct craniofacial defects in environment to form a paste that can be applied and
postoperative patients.23 This combination was shown easily sculpted in situ to precisely conform to the surgi-
to prevent granule migration after initial implantation, cal defect.32 The paste sets into cement in 10 to 15 min-
and long-term follow-up (2.5 to 8 years) revealed a level utes and converts to HA within 4 hours after which it is
of osseoconduction and osseointegration that main- no longer water soluble.33,34 Until this conversion oc-
tained functionality and cosmetic outcome with an ab- curs, it is imperative that the excess blood and serous
sence of adverse reactions.23 fluid be prevented from collecting adjacent to the im-
Porous ceramic HA can be entirely synthetic or plant. If the cement contacts an aqueous environment
formed chemically, based on the skeleton of marine before being converted to HA (4 hours), it sets in parti-
coral of the genus Porites (Fig. 1).4 It has the advantage cle form and portions of the implant can be resorbed
of being able to undergo fibro-osseous ingrowth, thus with a loss of volume over time.4 The addition of so-
fixing the implant to the recipient site for weeks. Stud- dium phosphate to the aqueous phase accelerates the
ies have been done in Japan with Apaceram®, a synthetic conversion of the paste into hardened cement and has
dense form of porous HA, to fill surgical skull defects greatly improved the delayed setting time associated
with good results27; however, the majority of clinical ex- with this material.2 Like ceramic HA, HAC is capable
perience with porous HA has been with the use of In- of osseoconduction and osseointegration, but, in con-
terpore, a semisynthetic HA based on the skeleton of trast, HAC is converted to new bone over time without
marine coral (Interpore International). Porous ceramic a loss of volume at the recipient site.33 This slow re-
HA usually comes in block form but is difficult to shape placement of bone minimizes the potential for contour
and fractures easily, thus limiting its use to non-stress- changes in the reconstructed areas.
bearing applications in the head and neck. It has been Animal testing has shown that HAC is appro-
used successfully as an onlay graft of spacer material priate for a number of head and neck applications.
Although the compressive strength of HAC is in the
range of 60 Mpa, which is relatively strong, it has lim-
ited shear resistance and should not be used for stress-
bearing applications.35 HAC was successfully used to
augment the supraorbital ridges of dogs.36 Histologic
specimens demonstrated osseointegration and osseo-
conduction by the implant as well as progressive re-
placement of the implant by bone.36 In yet another
study, Friedman et al. examined the use of HAC for
cranioplasty in cats and found there was a stable im-
plant volume and significant implant conversion to
bone (approximately 65%) at 18 months.35
Three nonceramic calcium phosphate cements
(CPCs) have been approved for clinical use by the Food
Figure 1 Porous HAC is made of naturally occurring calcium and Drug Administration, of which BoneSource® HAC
carbonate from marine coral and is chemically converted to HA. (BoneSource HAC, Leibinger, Dallas, TX) has been the
 BONE HEALING AND BONE SUBSTITUTES/COSTANTINO ET AL. 17

A B
Figure 2 HA in paste form (A) is easily applied and contoured (B) for a variety of craniofacial defects.

most widely studied.34 Clinical studies in humans using underlying dural pulsations, thus allowing adequate set-
BoneSource HAC for non-stress-bearing cranial de- ting time (Fig. 3A, B). BoneSource HAC has also been
fects have documented the unique properties of HAC successfully applied for the repair of cerebrospinal fluid
with long-term follow-up. Friedman et al.32 demon- (CSF) leaks, some of which was applied endoscopi-
strated a success rate of 97% in the repair of cranial de- cally by placing the cement at the skull base through the
fects using the outcome determinants: implant mainte- nose.4 Lumbar drains were used in all patients during
nance and implant volume at 24 months (Fig. 2A, B). the first 12 hours to prevent excess CSF from eroding
The overall wound infection rate was 5.8%, which ap- the implant prior to its conversion to water-insoluble
proached that of clean contaminated surgical sites. This HA.4 Similar success was found in another study of
result was reported despite the fact that over 60% of the eight patients using HAC to obliterate the frontal sinus
HAC implants were in contact with the paranasal si- and nasofrontal duct after undergoing frontal cran-
nuses or mastoid air cells. HAC in combination with ti- iotomy.37 Only one patient had prophylactic placement
tanium mesh has demonstrated stable reconstruction in of a lumbar drain that was removed within 36 hours.
the repair of large (>5 cm2) cranial defects. The addition There was no evidence of CSF rhinorrhea, implant re-
of titanium mesh offers protection to the HAC from sorption, or infection noted in any of the patients.37 In

A B
Figure 3 With a titanium mesh scaffold (A) HAC can be utilized for repair of large cranial defects (B).
18 FACIAL PLASTIC SURGERY/VOLUME 18, NUMBER 1 2002

cranial base reconstruction following lateral skull base CALICUM SULFATE AS AN IMPLANT
surgery, Kveton et al. reported on 15 patients followed Calcium sulfate hemihydrate, commonly known as
over 2 years with no evidence of complications after plaster of Paris, has been used as an osseous alloplast
HAC placement. They concluded that exposure to CSF with variable results. It is composed of partially dehy-
does not appear to alter the stability of the cement and drated calcium sulfate, which is made by heating gyp-
confirmed this by serial radiographic analysis.38 sum (calcium sulfate dihydrate) such that it loses three-
Recently, HAC has been reported for the first fourths of its bound water to form a calcium sulfate
time to be effective in pediatric patients as well.39 In 61 hemihydrate.42 When plaster of Paris is mixed with
patients who underwent secondary craniofacial recon- water, it forms a dense paste that can then be shaped
struction for contour defects, there was excellent reten- and contoured. This paste sets in approximately 5 min-
tion of implant volume, no recurrence of contour defects, utes via an exothermic reaction, although the amount of
and no interference with craniofacial growth over the heat released in this reaction is believed to not cause tis-
3-year study period.39 Currently, HAC is particularly sue damage.43 Once the plaster of Paris has hardened, it
appropriate for craniofacial defect repair and augmen- has the compressive strength in the range of 24 MPa,
tation. Its uniqueness as a customizable, nonresorbable which is less than the 70 MPa for methylmethacrylate
implant material represents a major advancement in cos- and 60 to 70 MPa for HA. Plaster of Paris also has
metic and reconstructive facial surgery.40 limited flexural resistance and is prone to fracture in
shear-loaded situations. For this reason, calcium sulfate
preparations are not appropriate for stress-bearing
applications. Like HAC, plaster of Paris will not set to a
Other Calcium Phosphate Cements structurally stable form if excess blood or aqueous fluid
The Norian Skeletal Repair System (Norian SRS®; SR, is present. Further, when the set plaster of Paris is ex-
Norian Corp., Cupertino, CA) is a fully resorbable CPC posed to water a second time, it softens and becomes
that consists of monocalcium phosphate, TCP, and cal- structurally weak and unstable.4
cium carbonate, which are mixed with sodium phos- Beeson44 studied the use of plaster of Paris for
phate to form a paste.41 The paste is then injected in situ, use in frontal sinus obliteration in a canine model. He
hardens within 10 minutes, and creates an implant-bone performed a frontal osteoplastic flap procedure on dogs
composite with a compressive strength of 55 MPa and and unilaterally obliterated their frontal sinus cavities
a tensile strength of 2.1 MPa. The material converts with plaster of Paris. Progressive replacement of the
within 12 hours to 85 to 90% dahllite, a carbonated ap- calcium sulfate with fibro-osseous tissue was seen over
atite that is similar to bone and is biocompatible.41 Over the next 24 weeks. Histologically, bone ingrowth into
time, the material is replaced completely by new bone, as the calcium sulfate-filled cavities was confirmed, and
early as 16 weeks after implantation.41 Clinical uses in no significant inflammatory response was seen, leading
humans in the head and neck have included frontal sinus Beeson to conclude that plaster of Paris stimulates os-
augmentation, but Norian SRS has been mainly used in teoneogenesis when implanted in contact with bone or
orthopedic applications for upper- and lower-extremity periosteum. Pecora et al.45 found calcium sulfate to be
long bone fractures and spinal reconstruction.34 potentially useful as an onlay graft material for sinus
Embarc® (-bone substitute material, Embarc, augmentation; however, this clinical report was limited
ETEX Corp, Walter Lorenz Surgical, Jacksonville, FL) to two cases. Recently, a larger study of over 50 patients
is composed of amorphous calcium phosphate, crys- undergoing maxillary sinus augmentation with calcium
talline calcium phosphate precursors, and saline, which sulfate implants noted an overall success rate of 98%.46
hardens to form a poorly crystalline apatitic calcium Clinical and radiologic evaluations revealed the aug-
phosphate.34 It is injected as a paste, sets endothermi- mentations to be stable with new tissue formation
cally at body temperature within 15 to 20 minutes, and within the sinus and a slowdown in material resorption.
is fully remodeled into new bone when set.34 It has been Plaster of Paris has also been studied as a graft material
reported to form new bone that has the strength of nor- for cranial defects,14,43 but these studies lacked objective
mal, nonoperated bone in a dog femoral bone model.34 measurement of the compound’s contour stability, an
At the time of this writing, the authors are not aware of important issue to consider in the use of alloplasts in fa-
any human cases that have been reported with Embarc. cial plastic and reconstructive surgery.
For both Embarc and Norian SRS, further indepen- The main uses of calcium sulfate have been in
dent investigational studies using critical size defect the field of orthopedics for casting extremity fractures;
models need to be performed to better document their however, recently it has been approved by the FDA as
long-term effects on shape and form before widespread part of a composite implant called Hapset® (Lifecore
clinical application proceeds. To date, there is still insuf- Biomedical, Inc., Chaska, MN). In its pure form, plaster
ficient evidence to substantiate their use over the pro- of Paris is quickly resorbed within 5 to 8 weeks,42 mak-
toypical CPC, Bonesource HAC.34 ing it inappropriate for contour reconstruction or as an
 BONE HEALING AND BONE SUBSTITUTES/COSTANTINO ET AL. 19

onlay bone graft substitute in the adult craniofacial and by 1 year the coral skeleton appeared to be almost
skeleton. The composite implant Hapset combines completely resorbed in 50% of the cases. The resorption
porous ceramic HA granules and calcium sulfate, the of the larger implants did not exceed 40% of its volume
latter of which binds the HA granules, so that they are at 1 year.48 A smaller study from Bulgaria using Bio-
easier to implant and remain within the reconstruction coral as an onlay graft for facial contour augmentation
site until the resorbed calcium sulfate is replaced by reported on 14 patients (16 augmentations) followed
fibro-osseous tissue. The fibro-osseous tissue that grows postoperatively up to 34 months in a primarily pediatric
around the HA granules then holds them in place so population.48 One graft had to be removed secondary to
that the augmented height and volume of the recon- inadequate fixation, persistent mobility, and infection.
structed area are preserved. Given the limitations of pure A second patient had “delayed healing” due to persistent
calcium sulfate previously described, its role in craniofa- graft mobility. Although the graft material was reported
cial reconstruction is limited to its use as a composite as being contour stable over the observation period, ser-
material, Hapset, and with careful selection toward cran- ial axial, coronal, and three-dimensional CT scans were
iofacial defects rather than cosmetic surgery and aug- not performed to confirm the maintenance of the aug-
mentation. mented height, volume, and surface contour. Based on
these observations, the long-term performance of cal-
cium carbonate implants needs to be evaluated with fur-
ther clinical testing.
CALCIUM CARBONATE-BASED IMPANTS Like porous ceramic HA, calcium carbonate im-
Marine coral-based calcium carbonate implants are de- plants are not strong enough to withstand significant
rived from the same coral as porous HA implants. The flexural stresses, thus for stress-bearing applications it
biochemical difference between the two implants is that would need some form of structural reinforcement, such
the chemically unaltered marine coral implants are as a mandibular reconstruction plate. The combination
composed of calcium carbonate, whereas in coralline HA of resorptive ability and rapid fibro-osseous replacement
implants calcium carbonate skeletons have been con- makes this type of implant ideal for orthopedic surgery,
verted to calcium phosphate. The functional difference in which contour is not important and complete implant
between these two implants is that HA implants (Inter- resorption and replacement by bone are desirable. In the
pore 200 and 500) are nearly nonresorbable, whereas adult non–stress-bearing craniofacial skeleton, bone re-
the calcium carbonate implants (Biocoral®, Inoteb CY, placement is neither needed nor desirable because of the
Saint-Gonnery, Noyal Pontivy, France) are resorbed and potential contour changes that can develop over time.
replaced by bone (fibro-osseous tissue) over time when This property may be preferable in the growing pedi-
implanted subperiosteally.4 This bone replacement oc- atric craniofacial skeleton in which bone remodeling is
curs over many months and may undergo postoperative rapid and revision procedures more common. In this in-
contour alterations,4 however, without a loss of recon- stance, Biocoral may also give the advantage of allowing
structed volume.47 Like HA, Biocoral osseoconducts revision procedures to be performed without the inter-
bone over the internal surface area of its pores; however, ference by previously implanted alloplastic material or
once bone growth into the Biocoral pores is complete, the implantation of additional bone graft substitutes.
osteoclasts begin to resorb the calcium carbonate scaffold
and osteoblasts deposit bone.47 Thus far, there have been
no histomorphometric analyses of the fibro-osseous tis-
sue replacement of calcium carbonate implants. Evidence MISCELLANEOUS ALLOPLASTS
suggests that this replacement occurs more rapidly than
that seen with porous ceramic apatite implants (e.g., Aluminum Oxide
Interpore 200 and 500).4 What remains to be seen is Alumina (Al2O3) is an important component of several
whether the ratio of bone to fibrous tissue, like that seen bioactive materials and can serve as a bone graft substi-
with porous HA implants, would continue to persist fol- tute on its own.49 In its pure form (alumina ceramic), it
lowing the resorption of the Biocoral scaffold. is the least bioactive of the materials discussed in this
Biocoral has been used for cranial defect recon- article but is considered to be the prototype of bioinert
struction in humans, mainly to obliterate burr holes.48 materials. Alumina ceramics are hard and resist fracture
Cranial defects approximately 10 mm in diameter were under flexion. In contrast to more bioactive materials
filled with coral “corks” in 150 patients, with an ad- such as bioactive glass, glass-ionomer, and HA, alumina
ditional 5 patients having defects of 20 to 40 mm, and ceramic bonds to bone only in response to mechani-
12 others where coral blocks were used to reconstruct cal stresses and strains between the implant and adja-
the floor of the anterior cranial fossa. By 8 to 10 months cent bone.49 Over time, this bone remodels and devel-
after implantation, a significant decrease in volume was ops more intimate contact with the alumina ceramic,
seen with the small implants (10-mm burr hole “corks”), thereby resulting in osseointegration.
20 FACIAL PLASTIC SURGERY/VOLUME 18, NUMBER 1 2002

As a result of its bioinert qualities, the applica- illofacial trauma.56,57 They possess pore sizes in the
tion of alumina ceramic has been limited. Within the range of 100 to 300 m, which aid in tissue ingrowth
field of otolaryngology, alumina ceramic implants have and implant fixation (Fig. 4). Foreign body reaction to
been used as ossicular replacement prostheses. Animal polyethylene is minimal and long-term stability has
studies have shown that the middle ear mucosa prolifer- been achieved.53 An advantage of this material is that a
ates normally on the surface of dense, pure alumina ce- portion of the tissue ingrowth is vascular, thus adding to
ramic.50 More recently, tracheal supporting rings have infection resistance and potential salvage of the implant
been introduced into clinical application in Europe.49 in the face of exposure.55 However, its rigid nature and
In addition to the higher cost of this material, the use difficulty in contouring to the surface of complex skele-
of smaller sizes of alumina ceramic in the head and tal structures limit its use over other more flexible but
neck is also fraught with statistical variation in strength equally tolerated materials.
that can lead to fracture.51 Although currently in use Hard-tissue-replacement (HTR) polymer (HTR
on weight-bearing surfaces in joint replacement surgery, Sciences, United States Surgical Corp., Norwalk, CT) is
no alumina ceramic implants have been approved by the a porous biomaterial composed of PMMA coated with
FDA at this time for use in facial plastic and reconstruc- polyhydroxyethylmethacylate (PHEMA) and calcium
tive surgery. hydroxide. Its coating of calcium hydroxide enhances
and promotes its bioactivity with bone.58 The PHEMA
coating absorbs approximately two-thirds of its weight
Polymethylmethacrylate in water, resulting in a very hydrophilic gel with calcium
Polymethylmethacrylate (PMMA) has been used as an ions at its surface. It is this calcium-containing gel that
alloplastic implant alone and as a component of other is bioactive with adjacent bone. The actual implant ma-
biomaterials. PMMA, when formed, causes an extreme terial is structurally composed of PMMA beads that
exothermic reaction associated with its setting process, have been sintered (fused by heating) together. This
which has been shown to be deleterious to adjacent technique of sintering also preserves the spaces between
bone and soft tissue even with vigorous saline irriga- the beads, creating an overall porous structure with pores
tion.52 For this reason, it is also available in preformed ranging from 100 to 300 m. The interconnecting
implants or can be fashioned intraoperatively outside of nature of these pores, along with the biomaterial’s hy-
the patient prior to implantation. PMMA is biocom- drophilic nature and calcium coating, results in osteo-
patible, and foreign body reaction is minimal with long- conductivity and a fibro-osseous matrix that eventually
term stability.53 PMMA has been used successfully as ingrows the implant. As with the Medpor implants, this
an implant material for cranioplasties, frontal bone re- ingrowth material serves to aid in its fixation as well as
construction, and forehead augmentation.54 add to the infection resistance and potential salvage of
High-density polyethylene implants (Medpor) the implant in the face of exposure.55
represent a group of carbon-based alloplasts that are HTR polymers can be used in block form or as
fused into a porous solid material by a sintering pro- granules. The granules do not have any structural in-
cess.55 These implants have been studied in the repair tegrity until they are ingrown by fibro-osseous tissue
of congenital craniofacial deformities, nasal reconstruc- over several weeks to months. Granules are thus most
tion, and acquired skeletal defects associated with max- appropriate for bony cavities where particle contain-
ment and structural stability can be provided by sur-
rounding bone. Block forms can be contoured intra-
operatively with some difficulty, and for that reason
preformed facial implants have also been produced. Fix-
ation of the implants can be difficult because they are
difficult to suture and must be drilled carefully so that
they do not fracture. If drill holes are used, a gliding
hole should be drilled to prevent the screw threads from
purchasing with the sides of the drill hole, which causes
disintegration of the implant material.4 The use of
HTR was used to eliminate large bone defects of the
mandible in 29 patients followed over a 5-year period.59
Histological examination revealed complete bony re-
generation in all cases at the end of the study period.
Although HTR polymer has shown promise as a cran-
Figure 4 Fibro-osseous ingrowth around Medpor implant.
iomaxillofacial graft material in some studies, conflict-
There is some osseoconductive activity between the implant ing results regarding host response19,60 need to be stud-
and the surrounding tissue with little fibrous encapsulation. ied further.
 BONE HEALING AND BONE SUBSTITUTES/COSTANTINO ET AL. 21

A new acrylic bone cement based on a methyl- death from screened donors and processed immediately
methacrylate monomer has been developed in Japan to prevent bacterial overgrowth from the donor skin.63
containing 4-methacryloyloxyethyl trimellitate anhy- The soft tissue is stripped from the bone and marrow is
dride (4-META) as an adhesion-promoting agent removed. Demineralized bone is then formed by placing
that can adhere to both bone and prostheses in animal the harvested bone in an acid bath and defatting it.
studies.61 HA particles were also added as a bone- After washing the bone to remove the strong chemicals,
compatible filler. Despite the increase in the percent- the bone is freeze-dried to allow storage at room tem-
age of HA particles, the resulting cement retained the perature. The demineralizing process involves both
mechanical strength of an acrylic material without dis- virucidal and bactericidal chemical baths, making the
turbing bony ingrowth. risk of HIV transmission extremely remote.64
The result after processing is a cross-linked os-
teoconductive collagen matrix admixed with insoluble,
BIOLOGICALLY ACTIVE AGENTS adherent proteins.63 The majority of proteins, however,
are removed after processing65 and the demineralized
Autogenous Bone Grafts bone is considered nonimmunogenic.63 Of the remain-
Autogenous bone grafts are materials where both the ing proteins present after processing, bone morphogenic
donor and recipient are the same. Sections of bone can proteins (BMPs) impart the osteoinductive properties
be transplanted to a distant site in the patient (hetero- to the demineralized bone.66 The role of demineralized
topic) or used within the same anatomic region (ortho- bone in craniofacial surgery is based on its unique han-
topic). Calvarial grafts are commonly used as orthotopic dling properties. Completely demineralized bone is
grafts. These grafts are most commonly harvested from extremely flexible and easily contoured and can be cut
the calvarium, iliac crest, and ribs.5 As previously men- with scissors to a tapered paper-thin edge. When par-
tioned, the morbidity of the donor site can be a limiting tially demineralized, the graft maintains greater struc-
factor in choosing a harvest site. For this reason, the tural rigidity, thus permitting the acceptance of plates
Tessier concept of “self-sufficiency” developed whereby and screws without concern for excess compression.63
bone grafts used in craniofacial surgery are harvested The main disadvantage of demineralized bone is its
from the same exposed area as the primary reconstruc- high resorption rate, which has been reported to be as
tion.62 Thus, calvarial bone grafts are believed to be the much as 49% of the original graft.67 As a result, the role
ideal graft not only because the harvest site is within the of demineralized bone is mainly in noncosmetic aug-
operative field but they also are associated with minimal mentation procedures where variable resorption may be
donor site morbidity as measured by persistent donor acceptable. It has demonstrated efficacy in the recon-
site pain and overall cosmesis.5 Furthermore, the calvar- struction of orbital and orbitocranial defects,68 the re-
ium is a membranous bone, which has less predilection pair of burr holes and small cranial defects,69 and for
for resorption.5 The main advantages to autogenous secondary cranioplasty in children too young to un-
bone grafts are their resistance to infection, their abil- dergo the harvest of split-thickness skull autografts.70 It
ity for staged overlapping reconstruction, and their has also been combined with other grafting materials
potential for bone growth after incorporation into the such as autogenous bone for repair of alveolar clefts71
host site.5 and osteogenin, a bone morphogenetic protein, for re-
There have been numerous reported applications pair of calvarial defects in nonhuman primates.72
of bone autografts used in the craniofacial skeleton,
which are beyond the scope of this article. The majority
have been used to correct cranial and orbital defects and Bone Morphogenetic Proteins
contour irregularities, although purely cosmetic appli- Bone is well known for its ability to repair and regener-
cations are also reported. Presently calvarial bone auto- ate.1 Urist first described the osteoinductive properties
grafts are the graft of choice; however, other types of of demineralized bone matrix,73 which led to further
bone grafts should be used as clinically indicated for elucidation of the variety of growth factors associated
site-specific reconstruction.5 The use of noncalvarial with bone morphogenesis.74 Once initiated, bone for-
autografts has been limited secondary to an increase in mation is promoted and modulated by growth and dif-
donor site morbidity (iliac crest graft) and a faster rate ferentiation factors20 that proceed through a complex
of resorption (rib grafts).1 physiologic process. BMPs are a subdivision of the
transforming growth factor- (TGF-) superfamily
that plays a crucial role in this process of cell growth and
Demineralized Bone differentiation.48 There are eight classes of BMPs that
Demineralized bone is an alternative allograft for cran- have been identified as osteogenic regulatory molecules,
iofacial surgery that has been used for over a century BMP-2 through BMP-9 (BMP-1 is not part of the
since its discovery in 1889.9 It is harvested soon after TGF- family; it is a proteinase and possesses different
22 FACIAL PLASTIC SURGERY/VOLUME 18, NUMBER 1 2002

properties). These have been further subdivided into months, the osteogenin-treated implants showed a
three subsets based upon similarities in their amino acid statistically significant increase in bone ingrowth and a
sequences. BMP-3 is the sole member of its subset; decrease in TCP. Furthermore, they contained predomi-
BMP-5, BMP-6, and BMP-7 form a second set; and fi- nantly mature lamellar bone compared with the imma-
nally BMP-2 and BMP-4 are categorized together and ture woven bone in the controls. All implants main-
are the two most closely related BMPs.75 tained their original volume at intervals of 1, 3, and 6
When a bone is fractured, local pluripotent prog- months after implantation.18 Further studies comparing
enitor cells, called osteoprogenitor cells, are activated by the use of resorbable HAC, which is more easily con-
the immune system. Additional inducible osteoprogeni- toured than TCP, with osteogenin would be of interest
tor cells are introduced to the site of injury by develop- with regard to the determination of long-term implant
ing capillary sprouts after approximately 3 to 5 days.76 volume and shape (Fig. 5).
The BMPs play a key role in the conversion of osteo- Recent studies have shown increased expression of
progenitor cells to mineralizing osteoblasts76,77 by bind- BMP-2, -4, and -7 in primitive mesenchymal and osteo-
ing to the progenitor cell membrane receptors and initi- progenitor cells present at fracture sites.84 In addition,
ating an intracellular response.78 This causes activation these three BMPs were present in newly formed trabecu-
and production of the osteoblast-specific factor-2 gene lar bone and osteoclast-type cells,85 leading to the con-
and its protein, resulting in activation of the osteocalcin clusion that they work synergistically to promote fracture
gene.79,80 The activated osteocalcin gene transcribes a healing and bone regeneration.86 BMP-2 and -4 have
signal protein that eventually causes the cell to differen- been shown to increase dramatically during ossification
tiate into an osteoblast.79,81 at fracture sites after injury, particularly in osteoblasts.84
This cascade of events triggered by exogenous BMP-2 also has been shown to promote undifferenti-
BMPs leads to the differentiation of mineralizing os- ated mesenchymal cells into osteoblasts.62 Based on this
teoblasts, resulting in the production of new bone as part property, recombinant human bone morphogenic pro-
of a larger multistep cascade.1 Clinical interest has fo- tein-2 (rhBMP-2) has been successfully used in the re-
cused on the application of BMPs in bone-engineering generation of calvaria87 and critical-sized radial defects7
therapies to initiate and promote osteogenesis. BMP-3 in animal studies. RhBMP-2 has also been added to
(osteogenin) has been localized in perichondrium, carti- porous ceramic HA as a combined implant in a rabbit
lage, periosteum, and bone but also in the membranous skull model.88 After 1 month, the subperiosteal place-
bones of the craniofacial skeleton.82,83 It has been shown ment of the composite implant demonstrated an en-
to have the highest bone-inductive activity of all the hanced osseointegration at the host-bone interface com-
BMPs.18 This was confirmed in a study by Khouri et pared with HA alone. Given that the extent and rate of
al.83 and tested in irradiated skull defects in the rat. bone induction determine the overall clinical outcome of
When the defects were treated with both the BMP-3 the implant, the early osseous fixation of the BMP-2-
and a microvascular nonradiated muscle flap, there was embedded implants serves to prevent host bone resorp-
96% healing at 4 months and 100% healing at 8 months. tion as well as decrease the risk of implant extrusion.88
The transplanted muscle was entirely formed into bone Further studies continue to elucidate the ideal
and was indistinguishable from the surrounding calvarial carrier and delivery system for embedded BMPs, in-
tissue.83 cluding absorbable collagen sponge,17,89,90 poly(alpha-
BMP-3, or osteogenin, has also been combined hydroxy acids),91,92 and other promising biopolymers.87
with TCP, a resorbable ceramic alloplast, as an onlay The BMPs are not identical in their osteoinductive po-
bone graft implant in a rabbit calvarial model.18 At 6 tential and remain difficult to compare due to differ-
ences in the carrier and delivery systems used. Nonethe-
less, clinical studies are currently under way to examine
the therapeutic response and pharmacologic effects of
the various classes of BMPs. Early results from ortho-
pedic trials confirm the osteoinductive effect of BMPs
in humans.92

NEW TECHNIQUES FOR BONE

REPLACEMENT

Distraction Osteogenesis
Figure 5 Demonstration of BMP with HAC in a cat skull
Distraction osteogenesis (DO) is a surgical technique
model. After 3 months new bone formation can be seen sur- for growing new bone within a surgically created gap
rounding the HAC implant. between two ends of preexisting bone. Initially reported
 BONE HEALING AND BONE SUBSTITUTES/COSTANTINO ET AL. 23

in orthopedic medicine for long bone lengthening, the

procedure has recently been applied to the craniofacial
region. The procedure involves creating an osteotomy
through the cortical bone and then gradually separating
the two segments. The separation, in the presence of
viable periosteum, allows a callus to form at the os-
teotomy site within a period of 7 to 10 days. The bones
on either side of the site are then distracted at approxi-
mately 1.0 mm per day, allowing osteoid tissue to be
laid down on bone surfaces abutting the site, effectively
lengthening the bone. This slowly widening gap will
eventually become structurally stable new bone. The
gradual expansion also produces a concomitant increase
in the soft tissues and musculature during the distrac-
tion process.94 In addition to obviating the need for au-
togenous bone or cartilage grafts, DO also has the ad-
vantage of decreased operating time and morbidity from
donor sites. Figure 6 External bifocal distraction device demonstrating the
The use of DO for the lengthening of bone in use of a transport for mandibular defect repair.
the craniofacial skeleton was first described in 1973 by
Snyder et al. in the canine model.94 Since then numer-
ous experimental and clinical reports have demon- still in its nascent stages. Costantino et al. was the first
strated that DO is an effective technique for the treat- to demonstrate that bifocal DO was effective in the re-
ment of various congenital, traumatic, and postresection construction of a segmental mandibular defect in the
craniofacial deformities. Facial bone distraction was ini- canine model (Fig. 6).97 Oda et al. showed that DO
tially developed for lengthening the mandible but has could be used while being covered by a skin flap.98
also been applied to the maxilla, zygoma, palate, and en- Annino et al. described the use of DO for the recon-
tire midface region.95 Currently, DO is predominantly struction of symphyseal defects in the dog.99 Sawaki et
performed for the correction of a variety of vertical, al. reported a case in which an irradiated mandible was
transverse, or anteroposterior bone deficiencies. reconstructed using trifocal DO with some assistance
To create the distracting forces, percutaneous pins from small free flaps.100 Costantino et al. also reported
for external devices (via skin incision) or bone screws for the first use of distraction in an adult human for the re-
internal devices (via transoral mucosal incision) are used construction of a 5-cm mandible defect in 1995.101
to rigidly fixate the native bone to the distraction de- More recently, DO has been applied to the treat-
vice.93 Depending on the specific bone to be distracted, ment of neonates with severe congenital deformities of
activation of the device is begun a few days after the ini- the lower jaw.93,96 Children with severe mandibular hy-
tial surgery at an appropriate rate—usually 1⁄2 mm twice poplasia (micrognathia) such as hemifacial microsomia
daily—until the desired distraction length is complete.94 (unilateral) and Treacher-Collins, Pierre-Robin, and
Presently available distraction devices apply one- Nager syndromes (bilateral craniofacial anomalies) are
dimensional forces that limit the clinician to a single predisposed to airway obstruction and frequently re-
vector during any given episode of distraction.93 These quire airway intervention.96 Tracheotomy is often re-
devices have traditionally involved external fixation re- quired for refractory cases where less-invasive interven-
quiring a skin incision; however, new internal devices tions have failed.96 Expedient decannulation, however,
have been developed that eliminate the resultant scar- can mitigate the long-term sequelae associated with tra-
ring from external fixation.93,96 This is advantageous cheotomy in this patient population, including adverse
both for cosmetic reasons and for minimizing potential effects on language acquisition and social interac-
trauma and infection in the active pediatric popula- tion.101–103 Nunn et al.104 reported six cases of children
tion.96 Given the three-dimensional nature of the facial with craniofacial anomalies with secondary airway ob-
bones, further refinements are being made with the ad- struction aged 3 to 10 months who were treated with
vent of three-directional distraction devices. These de- mandibular advancement using cranial bone grafts that
vices, although still external, have the added advantage permitted earlier decannulation. Mandibular DO elimi-
of simultaneous multidirectional distraction, thereby nates the morbidity of bone graft donor sites while pro-
lengthening and widening the mandible at the same viding a cosmetically pleasing mandible and the ability
time and allowing the repair of segmental defects. to breathe safely without a tracheotomy.93 Cohen et
DO for the reconstruction of mandibular seg- al.104 demonstrated that this approach could be an ef-
mental bone defects from tumor resection and trauma is fective intervention in definitive airway management.
24 FACIAL PLASTIC SURGERY/VOLUME 18, NUMBER 1 2002

In a study of 16 patients with significant obstructive 7. Younger EM, Chapman MW. Morbidity at bone graft donor
sleep apnea secondary to craniofacial anomalies, 7 of sites. J Orthoped Trauma 1989;3:192–195
8 tracheotomy patients were successfully decannulated 8. Hench LL, Wilson J. Surface active biomaterials. Science
1984;226:630–636
after mandibular distraction. Of the other eight pa- 9. Glowacki J, Mulliken JB. Demineralized bone implants. Clin
tients, all underwent immediate grafting procedures to Plast Surg 1985;12:233–241
provide temporary immediate relief for an unstable air- 10. Merwin G, Atkins J, Wilson J, et al. Comparison of ossicu-
way. Tracheotomy was then avoided in seven of these lar replacement material in a mouse ear model. Otolaryngol
patients while mandibular DO was completed.105 Head Neck Surg 1981;90:461–469
11. Merwin GE. Bioglass middle ear prosthesis: a preliminary re-
port. Ann Otol Rhinol Laryngol 1986;95:78–82
12. Jonck LM, Grobbelaar CJ, Strating H. Biological evaluation
CONCLUSION of glass-ionomer cement (Keta-O) as an interface in total
In the search for the ideal bone graft material, surgeons joint replacement. A screening test. Clin Mater 1989;4:
must balance the reconstructive needs of the patient 201–224
with the unique characteristics of each available graft 13. Wilson J, Pigott GH, Schoen F, et al. Toxicology and bio-
compatibility of bioglasses. J Biomed Mater Res 1981;15:
material. Craniomaxillofacial surgeons must be com-
805–817
fortable with a wide variety of biomaterials to tailor the 14. Geyer G, Helms J. Reconstructive measures in the middle ear
treatment to each patient individually. Current investi- and mastoid uing a biocompatible cement—preliminary clin-
gations into the next phase of tissue engineering will ical experience. Clin Implant Mater 1989;4:201–224
continue to bring us closer to the ability to regenerate or 15. Baier G, Geyer G, Dieler R, et al. Long-term outcome after
replace bone. BMPs represent a crucial pathway to un- reconstruction of the cranial base with ionomer cement.
derstanding the process of bone formation, but obsta- Laryngorhinootlogie 1998;77:467–473
16. Jarcho M. Calcium phosphate ceramics as hard tissue pros-
cles remain in selecting the ideal carrier and dosage and
thetics. Clin Orthoped 1981;157:259–278
overcoming confounding clinical factors (medications 17. Boyne PJ, Marx RE, Nevins M, et al. A feasibility study eval-
and diseases).93 Particular attention has been placed on uating rhBMP-2/absorbable collagen sponge for maxillary
the delivery system that releases BMPs, ensuring their sinus floor augmentation. Int J Periodont Restor Dent 1997;
interaction with mesenchymal cells that can then differ- 17:11–25
entiate into osteoblasts.7 New studies have developed an 18. Breitbart AS, Staffenberg DA, Thome CHM, et al. Trical-
immortalized human osteoprecursor cell line (OPC1) cium phosphate and osteogenin: a bioactive onlay bone graft
substitute. Plast Reconstr Surg 1995;96:699–708
that can provide a consistent and reproducible culture
19. Isaksson S, Alberius P, Klinge B. Influence of three alloplastic
system to advance this knowledge.106 The materials and materials on calvarial bone healing. An experimental evalua-
studies highlighted in this article represent only the tion of HTR-polymer, lactomer beads, and a carrier gel. Int J
“core” of synthetic biomaterials that can be used for Oral Maxillofac Surg 1993;22:375–381
craniofacial skeletal augmentation and replacement. 20. Reddi AH, Muthukumaran N, Ma S, et al. Initiation of bone
development by osteogenin and promotion by growth factors.
Connect Tiss Res 1989;20:303–312
ACKNOWLEDGMENT 21. Harvey WK, Pincock JL, Matukas VJ, et al. Evaluation of a
Dr. Peter D. Costantino receives research funding from subcutaneously implanted hydroxyapatite-Avitene mixture in
rabbits. J Oral Maxillofac Surg 1985;43:277–280
LifeCell Corporation and is a consultant for both Life-
22. Rawlings CE, Wilkins RH, Hanker JS, et al. Evaluation in
Cell Corp. and Stryker-Leibinger, Inc. cats of a new material for cranioplasty: a composite of plaster
of Paris and hydroxyapatite. J Neurosurg 1988;69:269–277
23. Fortunato G, Marini E, Valdinucci F, et al. Long-term results of
REFERENCES hydroxyapatite-fibrin glue implantation in plastic and reconstruc-
tive surgery. J Craniomaxillofacial Surg 1997;25:124–135
1. Habal MB, Reddi H. Bone graft and bone induction substi- 24. Jabs AD Jr, Wider TM, DeBellis J, et al. The effect of fibrin
tutes. Clin Plast Surg 1994;21:525–542 glue on skin grafts in infected sites. Plast Reconstr Surg 1992;
2. Scales JT. Discussion on metals and synthetic materials in re- 89:268–271
lation to soft tissue: tissue reaction to synthetic materials. 25. Marini E, Valdinucci F, Silverstrini G, et al. Morphological
Proc R Soc Med 1953;45:647 investigations on bone formation in hydroxyapatite-fibrin im-
3. Berghaus A, Mulch G, Handrock M. Porous polyethylene plants in human maxillary and mandibular bone. Cells Mater
and proplast: their behavior in a bony implant bed. Arch Oto- 1994;4:231–246
laryngol Head Neck Surg 1984;240:115–119 26. Pini Prato GP, Cortellini P, Clauser C, et al. Basi biologiche
4. Costantino PD, Hlitzik DH, Sen C, et al. Sphenoethmoid della sintesi tissutale con colla di fibrina umana. Min Stoma-
cerebrospinal fluid leak repair with hydroxyapatite cement. tol 1983;32:903–914
Arch Otolaryngol Head Neck Surg 2001;127:588–593 27. Yamashima T. Reconstruction of surgical skull defects with
5. Citardi MJ, Friedman CD. Nonvascularized autogenous bone hydroxyapatite ceramic buttons and granules. Acta Neurochir
grafts for craniofacial skeletal augmentation and replacement. 1988;90:157–162
Otolarygol Clin North Am 1994;27:891–908 28. Salyer KE. Orthomorphic surgery. In: Salyer KE, ed. Aes-
6. Habal MB. Bone grafting in craniofacial surgery. Clin Plast thetic Craniofacial Surgery. Philadelphia: JB Lippincott;
Surg 1994;21:349–363 1990:256
 BONE HEALING AND BONE SUBSTITUTES/COSTANTINO ET AL. 25

29. Byrd HS, Hobar PC, Shewmake K. Augmentation of the 49. Heimke G. Aluminum oxide. In: Williams D, ed. Concise
craniofacial skeleton with porous hydroxyapatite granules. Encyclopedia of Medical and Dental Materials. Oxford:
Plast Reconstr Surg 1993;91:15–22 Pergamon; 1990:23–34
30. Andriano KP, Daniels AU. Biocompatibility and mechanical 50. Plester D, Jahnke K. Ceramic implants in otologic surgery.
properties of a totally absorbable composite material for or- Am J Otol 1981;3:104–108
thopedic fixation devices. J Appl Biomat 1992;3:197–206 51. Skinner HB. Ceramic bearing surfaces. Clin Orthop 1999;
31. Chow LC, Takagi S, Costantino PD, et al. Self setting cal- 369:83–91
cium phosphate cements. Mater Res Soc Symp Proc 1991; 52. Cohen MS, Costantino PD, Friedman CD. Biology of im-
179:3–24 plants used in head and neck surgery. Fac Plast Surg Clin
32. Friedman CD, Costantino PD, Takagi S, et al. BoneSource North Am 1999;7:17–33
hydroxyapatite cement: a novel biomaterial for craniofa- 53. Lykins CL, Friedman CD, Ousterhout DK. Polymeric im-
cial skeletal tissue engineering and reconstruction. J Biomed plants in craniomaxillofacial reconstruction. Otolaryngol Clin
Mater Res 1998;43:428–432 North Am 1994;27:1015–1033
33. Costantino PD, Friedman CD, Jones K, et al. Hydroxyapatite 54. Ousterhout DK. Prosthetic forehead augmentation. In:
cement: basic chemistry and histologic properties. Arch Oto- Ousterhout DK, ed. Aesthetic Contouring of the Craniofa-
laryngol Head Neck Surg 1984;240:115–119 cial Skeleton. Boston: Little Brown; 1991:199–219
34. Schmitz JP, Hollinger JO, Milam SB. Reconstruction of bone 55. Friedman CD, Costantino PD. Alloplastic materials for facial
using calcium phosphate bone cements: a critical review. J skeletal augmentation. Fac Plast Surg Clin North Am 1999;
Oral Maxillofac Surg 1999;57:1122–1126 7:95–103
35. Friedman CD, Costantino PD, Jones K, et al. Hydroxyapatite 56. Frodel JL, Lee S. The use of high-density polyethylene im-
cement, part II: obliteration and reconstruction of the cat plants in facial deformities. Arch Otolaryngol Head Neck
frontal sinus. Arch Otolaryngol Head Neck Surg 1991;117: Surg 1998;124:1219–1223
385–389 57. Romo T III, Sclafani AP, Sabini P. Use of porous high-
36. Shindo ML, Costantino PD, Friedman CD, et al. Facial density polyethylene in revision rhinoplasty and in the platyr-
skeletal augmentation using hydroxyapatite cement. Arch rhine nose. Aesthetic Plast Surg 1998;22:211–221
Otolaryngol Head Neck Surg 1993;119:185–190 58. Amler MH, LeGeros RZ. Hard tissue replacment (HTR)
37. Ross DA, Marentette LJ, Thompson BG, et al. Use of hy- polymer as an implant material. J Biomed Mater Res 1990;
droxyapatite bone cement to prevent cerebrospinal fluid leak- 24:1079–1089
age through the frontal sinus: technical report. Neurosurgery 59. Szabo G, Suba Z, Barabas J. Use of bioplant HTR synthetic
1999;45:401–403 bone to eliminate major jawbone defects: long-term human his-
38. Kveton JF, Friedman CD, Costantino PD. Indications for hy- tological examinations. J Craniomaxillofac Surg 1997;25: 63–68
droxyapatite cement reconstruction in lateral skull base sur- 60. Eppley BL, Sadove AM, German RZ. Evaluation of HTR
gery. Am J Otol 1995;16:465–469 polymer as a craniomaxillofacial graft material. Plast Reconstr
39. Burstein FD, Cohen SR, Hudgins R, et al. The use of hy- Surg 1990;86:1085–1092
droxyapatite cement in secondary craniofacial reconstruction. 61. Morita S, Furuya K, Ishihara K, et al. Performance of adhe-
Plast Reconstr Surg 1999;104:1270–1275 sive bone cement containging hydroxyapatite particles. Bio-
40. Stelnicki EJ, Ousterhout DK. Hydroxyapatite paste (Bone- materials 1998;19:1601–1606
Source) used as an onlay implant for supraorbital and malar 62. Thies RS, Bauduy BA, Ashton L, et al. Recombinant human
augmentation. J Cran Facial Surg 1997;8:367–372 bone morphogenetic protein-2 induces osteoblastic differ-
41. Constantz BR, Ison IC, Fulmer MT, et al. Skeletal repair entiation in W-20–17 stromal cells. Endocrinology 1992;130:
by in situ formation of the mineral phase of bone. Science 1318–1324
1995;267:1796–1799 63. Hardin CK. Banked bone. Otolarygol Clin North Am
42. Costantino PD, Friedman CD, Lane A. Synthetic biomateri- 1994;27:911–925
als in facial plastic and reconstructive surgery. Fac Plast Surg 64. Mellonig TJ, Prewett AB, Moyer MP. HIV inactivation in a
1993;9:1–15 bone allograft. J Periodontol 1992;63:979–983
43. Coetzee AS. Regeneration of bone in the presence of calcium 65. Urist MR, Mikulski A, Boyd SD. A chemosterilized antigen-
sulfate. Arch Otolaryngol 1980;106:405–409 extracted autodigested alloimplant for bone banks. Arch Surg
44. Beeson WH. Plaster of Paris as an alloplastic implant in the 1975;110:416–428
frontal sinus. Arch Otolaryngol 1981;107:664–669 66. Hosny M, Sharawy M. Osteoinduction in rhesus monkeys
45. Pecora GE, et al. Short term healing following the use of cal- using demineralized bone powder allografts. J Oral Maxillo-
cium sulfate as a grafting material for sinus augmentation: a fac Surg 1985;43:837–844
clinical report. Int J Oral Maxillofacial Implants 1998; 67. Ousterhout DK. Clinical experience in cranial and facial
13:866–873 reconstruction with demineralized bone. Ann Plast Surg
46. De Leonardis D, Pecora GE. Augmentation of the maxillary 1985;15:367–373
sinus with calcium sulfate: one-year clinical report from a 68. Neigel JM, Ruzicka PO. Use of demineralized bone implants
prospective longitudinal study. In J Oral Maxillofac Implants in orbital and craniofacial reconstruction and a review of the
1999;14:869–878 literature. Ophthalm Plast Reconstr Surg 1996;12:108–120
47. Papacharalambous SK, Anastasoff KI. Natural coral skeleton 69. Glowacki J, Altobelli D, Mulliken JB. Fate of mineralized and
use as onlay graft for contour augmentation of the face. J Oral demineralized osseous implants in cranial defects. Calcif Tis-
Maxillofac Surg 1993;22:260–264 sue Int 1981;33:71–76
48. Roux FX, Brasnu D, Loty B, et al. Madreporic coral: a new 70. Moss SD, Joganic E, Manwaring KH, et al. Transplanted
bone graft substitute for cranial surgery. J Neurosurg 1988; demineralized bone graft in cranial reconstructive surgery.
69:510–513 Pediatr Neurosurg 1995;23:199–204
26 FACIAL PLASTIC SURGERY/VOLUME 18, NUMBER 1 2002

71. Levine SS, Prewett AB, Cook SD. The use of a new form 89. Hanisch O, Tatakis DN, Rohrer MD, et al. Bone formation
of allograft bone in implantation or osseointegrated dental and osseointegration in peri-implantitis defects following
implants—a preliminary report. J Oral Implantol 1992;18: surgical implantation. Int J Oral Maxillofac Implants 1997;
366–371 12:604–610
72. Ripamonti U. Calvarial reconstruction in baboons with 90. Howell TH, Riorellini J, Jones A, et al. A feasibility study
porous hydroxyapatite. J Craniofac Surg 1992;3:149–159 evaluating rhBMP-2/absorbable collagen sponge device for
73. Urist MR. Bone formation by autoinduction. Science 1965; local alveolar ridge preservation or augmentation. Int J Peri-
150:893 odont Restor Dent 1997;17:124–139
74. Reddi AH. Regulation of cartilage and bone differentiation 91. Hollinger JO, Leong K. Poly(alpha-hydroxy acids): carriers
by bone morphogenetic proteins. Curr Opin Cell Biol 1992; for bone morphogenetic proteins. Biomaterials 1996;17:
4:850–855 187–194
75. Riley EH, Lane JM, Urist MR, et al. Bone morphogenetic 92. Boden SD. Bioactive factors for bone tissue engineering.
protein-2 biology and applications. Clin Orthoped Rel Res Clin Orthoped Rel Res 1999;367S:S84-S94
1996;324:39–46 93. Tessier P. Autogenous bone graft taken from the calvarium
76. Brighton CT, Lorich DG, Kupcha R, et al. The pericyte as a for facial and cranial applications. Clin Plast Surg 1982;9:
possible osteoblast progenitor cell. Clin Orthoped 1992;275: 531
287–299 94. Snyder CC, et al. Mandibular lengthening by gradual distrac-
77. Amedee J, Barreille R, Rouais E, et al. Osteogenin (bone tion. Preliminary report. Plast Reconstr Surg 1973;51:506–508
morphogenetic protein 3) inhibits proliferation and stimu- 95. Mommaerts MY. Transpalatal distraction as a method of
lates differentiation of osteoprogenitors in human bone mar- maxillary expansion. Br J Oral Maxillofac Surg 1999;37:
row. Differentiation 1994;58:157–164 268–272
78. Massague J. TGF signaling: receptors, transducers, and Mad 96. Judge B, Hamlar D, Rimell FL. Mandibular distraction os-
proteins. Cell 1996;85:947–950 teogenesis in a neonate. Arch Otolaryngol Head Neck Surg
79. Ducy P, Karsenty G. Two distinct osteoblast-specific cis- 1999;125:1029–1032
acting elements control expression of a mouse osteocalcin 97. Costantino PD, Shybut G, Friedman CD, Pelzer HJ, Masini
gene. Mol Cell Biol 1995;15:1858–1869 M, Shindo ML, Sisson GA. Segmental mandibular regener-
80. Ducy P, Zhang R, Geoffroy V, et al. Osf2/Cbfa1: a transcrip- ation by distraction osteogenesis. An experimental study.
tional activator of osteoblast differentiation. Cell 1997;89: Arch Otolaryngol Head Neck Surg. 1990;116:535–545
747–754 98. Oda T, Sawaki Y, Fukuta K, Ueda M. Segmental mandibular
81. Geoffroy V, Ducy P, Karsenty G. A PEBP2/AML-1- reconstruction by distraction osteogenesis under skin flaps.
related factor increases osteocalcin promoter activity through Int J Oral Maxillofac Surg 1998;27:9–13
its binding to a osteoblast-specific cis-acting element. J Biol 99. Annino DJ, Goguen LA, Karmody CS. Distraction osteoge-
Chem 1995;270:30973–30979 nesis for reconstruction of mandibular symphyseal defects.
82. Vukicevic S, Paralkar VM, Cunningham NS, et al. Autoradi- Arch Otolaryngol Head Neck Surg 1994;120:911–916
ographic localizaton of osteogenin binding sites in cartilage 100. Sawaki Y, Hagino H, Yamamoto H, et al. Trifocal distrac-
and bone during rat embryonic development. Dev Biol 1990; tion osteogenesis for segmental mandibular defect: a techni-
140:209–214 cal innovation. J of Craniomaxillofacial Surg 1997;25:
83. Khouri RK, Brown DM, Koudsi B, et al. Repair of calvarial 310–315
defects with flap tissue: role of bone morphogenetics proteins 101. Costantino PD, Johnson CS, Friedman CD, Sisson GA Sr.
and competent responding tissues. Plast Reconstr Surg 1996; Bone regeneration within a human segmental mandible
98:103–109 defect: a preliminary report. Am J Otolaryngol 1995;16:
84. Bostrom MPG, Lane JM, Berberian WS, et al. Immunolocal- 56–65
ization and expression of bone morphogenetic proteins 2 and 102. Simma B, Spehler D, Burger R, et al. Tracheostomy in chil-
4 in fracture healing. J Orthoped Res 1995;13:357–367 dren. Eur J Pediatr 1994;153:291–296
85. Onishi T, Ishidou Y, Nagamine T, et al. Distinct and overlap- 103. Singer LT, Kercsmar C, Legris G, et al. Developmental se-
ping patterns of localization of bone morphogenetic protein quelae of long-term infant tracheostomy. Dev Med Child
(BMP) family members and a bmp type II receptor during Neurol 1989;31:224–230
fracture healing in rats. Bone 1998;22:605–612 104. Nunn DR, Derkay CS, Darrow DH, et al. Tracheotomy re-
86. Sakou T. Bone morphogenetic proteins: from basic studies to moval after early mandibular advancement in patients with
clinical approaches. Bone 1998;22:591–603 pediatric craniofacial syndrome. Otolaryngol Head Neck
87. Kenley R, Marden L, Turek T, et al. Osseous regeneration in Surg 1997;117:187–191
the rat calvarium using novel delivery systems for recombinant 105. Cohen SR, Simms C, Burstein FD. Mandibular distraction
human bone morphogenetic protein-2 (hBMP-2). J Biomed osteogenesis in the treatment of upper airway obstruction in
Mater Res 1994;28:1139–1147 children with craniofacial deformities. Plast Reconstr Surg
88. Koempel JA, Patt BS, O’Grady K, et al. The effect of re- 1998;101:312–318
combinant human morphogenetic protein-2 on the integra- 106. Winn SR, Randolph G, Uludag H, et al. Establishing an
tion of porous hydroxyapatite implants with bone. J Biomed immortalized human osteoprecursor cell line: OPC1. J Bone
Mater Res 1998;41:359–363 Miner Res 1999;14:1721–1733