bone substitute

8/3/2019 Bone Substitute

1/8

REVIEW ARTICLE

Year : 2002 | Volume : 48 | Issue : 2 | Page : 142-8

Bone graft substitutes: past, present, future.

Parikh SN. Bone graft substitutes: past, present, future. J Postgrad Med 2002;48:142

Bone grafts are often necessary to provide support, fill voids, and enhance biologic repair of

skeletal defects. Although autogenous bone is the gold standard that all alternatives must meet

or exceed, autograft has significant limitations, including donor site morbidity, inadequate

amount, and inappropriate form.[1],[2],[3] These limitations have prompted increasing interest

in alternative bone grafts. Allografts may be cancellous, cortical, or a combination of each.

Though they are attractive sources, there are several problems encountered in using them,

including the risk of disease transmission, immunogenicity,[4] loss of biologic and mechanical

properties secondary to its processing, increased cost, and non-availability world-wide due to

financial and religious concerns. Consequently, significant efforts are being made to develop

ideal bone graft substitutes. This article is an attempt to review the past and existing bone graft

substitutes, and future directions of research.

Bone grafts and their substitutes can be divided according to their properties of

osteoconduction, osteoinduction, and osteogenesis [Table - 1]. A comparison of allograft and

autograft bone, based on these properties, is shown [Table - 2].


2/8

:: Osteoconductive materials

Osteoconduction is a three-dimensional process that is observed when porous structures are

implanted into or adjacent to bone. Porosity alone, however, is not adequate for bone ingrowth.

Porosity with interconn-ectivity is the most essential prerequisite. This is based on the three-

dimensional interconnections between the lacunae in the bone that provide intercellular

commu-nication. Although there are alternative views, the consensus of research indicates that

the requisite pore size for bone ingrowth into porous implants is 100 to 500 ?m, and the

interconnections must be larger than 100 ?m.[6]

:: Calcium sulphate (plaster of paris)

Gypsum, also referred to as Plaster of Paris, owes its name to a village just north of Paris.

Although its external use for creation of hard setting bandages dates back to the seventeenth

century, the first internal use to fill bony defects was reported in 1892 by Dressmann.[7] The

application of Plaster of Paris as a bone void filler, and the use of antibiotic-laden plaster in the

treatment of infected bony defects, has been supported by various studies[8],[9],[10],[11]

Calcium Sulphate (CaSO4) has long been used in its partially hydrated form. Medical grade

calcium sulphate is crystallised in highly controlled environments producing regularly shaped

crystals of similar size and shape. It possesses a slower, more predictable solubility and

reabsorption. One such material is OsteoSet (Wright Medical Technology, Arlington, TN), which

was approved by FDA in 1996. The material comes in the form of 30 and 48 mm pellets that

typically dissolve in vivo within 30 to 60 days depending on the volume and location. The chief

advantages are that it can be used in presence of infection and it is comparatively cheaper. Since

it is bioabsorbable, it has inherent advantages over other antibiotic carriers, such as

polymethylmethacrylate, which become a nidus for further infection after elution of the

antibiotics, thus requiring a separate operation for removal from the surgical site. When this is

combined with the eradication of dead space and the acidic environment created during itsresorption, the compound can be an extremely effective treatment for acute bony infections

with bone loss. However, three cases of inflammatory response and a single case of allergic

reaction have been reported with the use of this compound.[12]


3/8

:: Calcium phosphate (ceramics)

The earliest application of calcium phosphate salts was in the form of powders.[13] The most

commonly used calcium phosphate ceramics are hydroxyapatite (coral based or synthetic) and

tricalcium phosphate, used in the form of implant coatings and defect fillers. These materials

require high temperature and high pressure processing to produce dense, highly crystalline,bioinert ceramics, which are not mouldable intraoperatively and also have poor fatigue

characteristics.

:: Porous coralline ceramics

Chiroff et al[14] first recognised that corals made by marine invertebrates have skeletons with a

structure similar to both cortical and cancellous bone, with interconnecting porosity. There are

two processes for manufacturing coralline implants One approach is to use coral directly in

calcium carbonate form. These materials are called natural corals. The trade name for natural

coral is Biocoral (Inoteb, Saint-Gonnery, France). The other process is Replamineform process

that converts calcium carbonate to hydroxyapatite.[6] Although there are hundreds of genera of

stony corals, Porites and Goniopora are the only two genera meeting the required standards of

pore diameter and interconnectivity.[6] The exoskeleton of the genus Porites is similar to

cortical bone and the exoskeleton of the genus Gonipora has a microstructure similar to

cancellous bone. The products are trade named either Pro Osteon or Interpore porous

hydroxyapatite (Interpore Cross International Inc, Irvine, CA), depending on the market to which

they are directed. The number following the trade name designates the nominal pore diameter,

either 500 or 200 ?m A version of hybrid, coralline product (Pro Osteon 200R and 500R) has also

been developed. It is a composite of calcium carbonate and calcium phosphate. A calcium

phosphate layer, largely hydroxyapatite, is formed on the calcium carbonate pores. The

thickness of the hydroxyapatite layer is adjusted to alter the resorption rates. In December

2001, a synthetic porous coated hydroxyapatite (PCH) bone substitute, OsSatura PCH (IsoTis NV,

Bilthoven, The Netherlands) has been launched in Europe. It is a porous calcium phosphate

scaffold with a biomimetic coating - first generation tissue engineered product. Its surface

structure resembles that of natural bone, which makes it osteoconductive.

:: Tricalcium phosphate (tcp)

Like hydroxyapatite, TCP is bioabsorbable and biocompatible but its inadequate porosity,

comparatively small grain size and its rapid dissolution (six weeks), makes it a poor bone graft

substitute. Biocompatible and resorbable calcium phosphate cement - Norion Skeletal RepairSystem (Norion SRS, Norion Core, Cupertino, CA) has been introduced for augmentation of

fracture repair. The chemical composition and crystallinity of the material are similar to those of

the mineral phase of bone. It undergoes the same in vivo remodelling as normal bone to re-

establish the bone morphology and strength. It appears to offer mechanical integrity for

augmentation of fixation of sliding hip screw, pedicle screw, distal radius fracture, femoral and

humeral neck fractures and recently, calcaneal fractures.[15] Since it is applied in a liquid stage


4/8

as a paste, it may be difficult to control; it may leak into the joint or prevent sliding of a sliding

device.[16],[17] ?-BSM - Bone Substitute Material (ETEX Corp, Cambridge, MA) is a poorly

crystalline calcium phosphate cement with favourable absorption characteristics and easy intra-

operative handling characteristics.[18] It is hydrated with saline to form a workable paste, which

remains formable for hours at room temperature but hardens within 20 minutes at physiologic

body temperature. It is marketed in Europe as Biobon (Biomet Merck, The Netherlands).

:: Collagen

Type I collagen is the most abundant protein in the extra-cellular matrix of bone. It has a

structure that is conducive to promoting mineral deposition and it binds the noncollagenous

matrix proteins, which initiate and control mineralisation by itself. Collagen functions poorly as a

graft material, but when coupled with bone morphogenetic proteins, osteoprogenitor

precursors, or hydroxyapatite, it enhances incorporation of grafts significantly. Collagraft

(Zimmer, Warsaw, IN) is a composite of suspended fibrillar collagen and a porous calcium

phosphate ceramic, in a ratio of 1:1. The fibrillar collagen is highly purified collagen obtained

from bovine dermis. Autologous bone marrow aspirate can be added to these materials or it canbe mixed with autologous bone as a bone graft extender. It does not offer structural support by

itself and its movement may be difficult to control.[19],[20] Healos (Orquest, Mountain View,

CA) is a mineralised collagen sponge, launched in Europe for clinical use in 2000. Each

microscopic Type I collagen fibre is coated with hydroxyapatite These fibres are then fabricated

and cross-linked into a three-dimensional, continuously porous and stable final format. It can be

mixed with bone marrow aspirate to provide osteogenic and osteoinductive potential. Another

novel bone-inducing protein, MP52, is integrated with Healos bone graft substitute, to induce

bone formation. MP52 is a member of the BMP family. This product, Healos/MP52, is expected

to improve the overall success rate of current spinal fusion procedures.

:: Nonbiologic substrates

Considerable interest has developed in creating osteoconductive matrices using nonbiologic

materials. Degradable poly-mers, bioactive glasses, and various metals have been studied. The

advantage of nonbiologic materials includes the ability to control all aspects of the matrix,

avoidance of immunologic reaction, and excellent biocompatibility. Polylactic and Polyglycolic

acid polymers have been used extensively as suture materials, and biodegradable fracture

fixation implants. These materials have the advantage of being assembled in various forms and

can be integrated with growth factors, drugs, and other compounds to create multiphase

delivery systems. Immix (Osteobiologics Inc, San Antonio, TX) is a synthetic bone graft scaffold,

tissue-engineered from amorphous D, L-Polylactide-co-glycolide (PLG), and is designed to resorb

within 12- 20 weeks following implantation. They provide a porous architecture for the ingrowth

of new bone and then fully degrade.


5/8

A variety of porous metal surfaces and coatings have been used as surfaces for bone ingrowth

intended to fix prosthetic joint replacement components to bone. These include sintered cobalt-

chrome beads, titanium alloy fibre metals, and plasma-sprayed surfaces. New metallurgy

techniques are creating metallic matrices of much greater porosity. Tantalum can be fabricated

as metallic foam-like structure with interconnecting pores, which allows exceptionally rapid and

complete ingrowth. Hydroxyapatite coating of metal surfaces enhances ingrowth and direct

bonding of bone to porous surface.[21],[22] Essentially, these coatings can be used on implants

with relatively simple surface geometry and use excessive high temperatures. This means that it

is difficult to coat implants with complex surface geometry (e.g. porous surface) and that no

biologically active agents can be added to the coating during the spraying process. A technology

has been developed by IsoTis NV (Bilthoven, The Netherlands), that allows the growth of a thin

layer of bone-like ceramic over medical devices.[23] The calcium phosphate coating is grown

from an aqueous fluid at ambient temperatures. In contrast to conventional technologies, these

biomimetic coatings can be applied on to surfaces with complex geometry, and active agents

such as growth factors or antibiotics can be co-precipitated. This creates the possibility of using

these coatings as slow release systems.[24]

:: Osteoinductive agents

Osteoinductive agents are bone graft substitutes, generally proteins, which induce

differentiation of undifferentiated stem cells to osteogenic cells or induce stem cells to

proliferate. Several osteoinductive agents have been identified. Among these compounds are

transforming growth factor (TGF-?),[25] bone morphogenetic proteins (BMPs),[25],[26],[27],[28]

fibroblast growth factors (FGFs),[29],[30] insulin-like growth factors (IGFs),[31] and platelet-

derived growth factors (PDGFs).[32]

:: Demineralised bone matrix (dbm)

Since the initial studies performed by Urist,[33] the osteoindu-ctive capacity of DBM has been

well established.[34] DBM is produced by the acid extraction of human cortical bone and the

components of the bone that remain behind include the non-collagenous proteins; bone

osteoinductive growth factors, the most significant of which is BMP; and type I collagen. DBM

provides no structural strength, and its primary use is in a structurally stable environment.

Hydroxyapatite, autograft, allograft or bone marrow cells may be added to DBM. A carrier may

be added to DBM to improve its handling characteristics and mechanical properties [Table - 3].

DBM obtained from allogeneic human cortical bone shows variable efficacy and osteoinductive

index. A reproducible and rapid bioassay (AlloSource bioassay, AlloSource, Centennial,

Colorado), using human cells of osteoblastic lineage, SAOS-2 cells, has been developed to

correlate the activity of DBM.[35]

:: Bone morphogenetic proteins

The BMPs (BMP 1-7) are low-molecular-weight non-collagenous glycoproteins that belong to an

expanding TGF-? superfamily of atleast 15 growth and differentiation factors. They make up only


6/8

0.1% by weight of all bone proteins. Unlike DBM, which is a mixture of BMPs and immunogenic,

non-inductive proteins, the pure form of BMPs is non-immunogenic and non-species specific.

Currently single BMPs are available through recombinant gene technology, and mixtures of

BMPs are available as purified bone extracts for clinical studies. The recombinant human BMPs

extensively studied are rh-OP-1 (osteogenic protein 1), rh-BMP-2 (Genetics Institute, Cambridge,

MA) and rh-BMP-7 (Creative Biomolecules, Hopkinton, MA).

In October 2001, approval was granted by the FDA for recombinant OP-1 implant, for use as an

alternative to autograft in recalcitrant long bone nonunions. This is the first BMP approved for

clinical use in the US. The approved product, OP-1 Implant (Stryker Corporation, Kalamazoo, MI)

is a combination of rh-OP-1 and a bovine collagen carrier. The rh-OP-1 is derived form a

recombinant Chinese Hamster Ovary cell line, and the bovine collagen is derived from the

diaphyseal bone and is primarily Type I. It is a white lyophilised powder, which has to be

reconstituted with two to three ml of saline, prior to use. It forms a paste which is then

surgically implanted at the fracture site. The osteogenic activity of OP-1 has been proven in a

validated critically-sized fibular defect in human subjects.[36] In November 2001, the first two-

year results of a clinical study of rh-BMP-2 (Genetics Institute, Cambridge, MA), were presented

at the North American Spine Society meeting. InFuse (Medtronic Somafor Danek, Minneapolis,

MN) is a new investigational material containing genetically engineered recombinant human

BMP-2 with a collagen sponge carrier. The results of the clinical study for the evaluation of

InFuse bone graft substitute along with titanium cages for lumbar spinal fusion were promising.

Earlier, a prospective randomised controlled human clinical pilot trial had shown definite

evidence of osteoinduction with the use of rh-BMP-2 in inter-body fusion cages for single-level

lumbar degenerative disc disease.[37]

:: Other growth factors

Besides the growth factors expressed from the extra-cellular matrix of the bone (DBM, BMP),

there are other factors in the circulating blood, which play a role in bone healing. TGF-? is the

most extensively studied growth factor in the field of bone biology. It comprises an entire family

of molecules that includes the BMPs. In 1994, Genentech, Inc (San Francisco, CA) was issued the

patent for developing TGF-? through recombinant technology. This covered the nucleic acids,

vectors and host cells used for production of recomb-inant TGF-?. In an animal study, it was

found that BMP, and not TGF-?, enhanced bone formation[38]. PDGF is another factor whose

effect was studied on the bone healing of unilateral tibial osteotomies in rabbits. It was

concluded that PDGF had a stimulatory effect on fracture healing.[32] Autologous Growth

Factors AGF (Interpore Cross International Inc, Irvine, CA) is an innovative concept. AGF gel is

obtained from the buffy coat of the blood collected in the cell saver during surgery, through the

process of centrifugation. It is rich in growth factors, especially TGF-? and PDGF. Approximately

20 ml of AGF is derived from 500 ml of blood in ten minutes and it is placed at the fracture site.

Bovine-derived bone morpho-genetic protein extract (NeOsteo, Intermedics Orthopaedics,

Denver, CO) is a cocktail of growth factors and is currently being evaluated for its role in human


7/8

spine fusion and periodontal repair. It can be combined with either DBM or a coralline calcium

carbonate carrier. Basic fibroblast growth factor (bFGF) is produced locally in bone during the

initial phase of fracture healing and is known to stimulate cartilage and bone-forming cells.[29]

Ossigel (Orquest, Mountain View, CA) is a formulation of bFGF and hyaluronic acid (Hy). It is

delivered as a single minimally invasive injection into the fracture site. Hy is a viscoelastic

polymer found throughout the body that cushions and protects soft tissues. The synergistic

combination of bFGF and Hy appears to accelerate the fracture healing process and underscores

the importance of using an appropriate carrier not only for bFGF but also possibly for other

growth factors. Ossigel is currently under clinical trials in the US and Europe.

:: Bone marrow aspirate

Bone marrow has been used to stimulate bone formation in skeletal defects and nonunions.[39]

The major advantage of this technique is that it can be performed percutaneously, without

almost any patient morbidity. The bone marrow is aspirated with a large bore needle from the

iliac crest and injected percutaneously with fluoroscopic guidance into the nonunion site.

Approximately one of every 100,000 nucleated cells aspirated from bone marrow is a stem cell.Centrifugation of aspirated bone marrow at 400 times gravity for ten minutes separates the

marrow cells from plasma and preserves the osteogenic potential of the cells, decreasing the

volume of material injected.[40] It may be possible to increase the proliferation and speed-up

differentiation of stem cells by exposing them to growth factors,[41] or by combining them with

collagen.[19]

:: Future directions

Tissue engineering

Advances in tissue engineering and the integration of the biological, physical, and engineering

sciences, will create new carrier constructs that regenerate and restore functional state. These

constructs are likely to encompass additional families of growth factors, evolving biological

scaffolds, and incorporation of mesenchy-mal stem cells. Ultimately, the development of ex vivo

bioreactors capable of bone manufacture with the appropriate biomechanical cues will provide

tissue-engineered constructs for direct use in the skeletal system. VivescOs (IsoTis, Bilthoven,

The Netherlands) is a tissue-engineered bone, developed for application in revision surgery,

spinal fusion and dental implants. The bone marrow cells are harvested from the patient, then

multiplied in culture, shaped in appropriate structure on a scaffold, and implanted into the

patient. The process takes 4 weeks. This fully tissue-engineered bone is expected to be launched

in 2004.

Gene Therapy

Once considered a fantasy, there is a compelling evidence to support the utility of gene therapy

for bone induction in humans.[42] Studies have successfully demonstrated several safe,

effective strategies to form new bone via gene therapy in animals. Gene therapy involves the

transfer of genetic information to cells. When a gene is transferred to a target cell, the cell

synthesises the protein encoded by the gene. The duration of protein production that is


8/8

required and the anatomic location where the protein must be delivered determine the strategy

employed. The gene therapy used for bone induction is short-term, regional therapy. The gene

can be introduced directly to a specific anatomic site (in-vivo technique) or specific cells can be

harvested from the patient, expanded, and genetically manipulated in tissue culture, and then

reimplanted (ex-vivo technique). The vehicle for gene delivery can be either viral (adenovirus,

retrovirus) or non-viral (liposomes, DNA-ligand complexes). The gene can be selectively

transferred to a targeted cell (osteoblast, fibroblasts) at the bone induction site.

bone substitute

Documents