Bone Graft Substitute Materials 

Bone graft substitutes consist of several types and encompass various materials, material sources, and origins (natural vs synthetic). Many are formed from composites of one or more types of material; however, the composite is usually built on a base material.^{[1, 2]}

Category

Bone graft substitute materials

Device details

Allograft-based bone graft substitutes

AlloSource

• AlloGroAlloGro (AlloSource) is demineralized bone matrix.
• AlloFuse
• AlloStem

Exactech

• Opteform
• Optefil

BioHorizons

• Grafton
• MinerOss

Integra OrthoBiologics

• OrthoBlast II

Keystone Dental

• DynaBlast
• DynaGraft-D

minSURG Corp

• TruFuse

Nutech Medical

• NuFix

Wright Medical

• FusionFlex
• AllomatrixOsteoset (left) and Allomatrix (right) are produced by Wright Medical Technology, Inc. Osteoset is a calcium sulfate tablet used for bone defect sites, whereas Allomatrix is a combination of calcium sulfate and demineralized bone matrix that forms an injectable paste or a formable putty. Images courtesy of Wright Medical Technology, Inc.

Growth factor–based bone graft substitutes

• Transforming growth factor-beta (TGF-beta)
• Platelet-derived growth factor (PDGF)
• Fibroblast growth factor (FGF)
• Insulin-like growth factor-1
• Bone morphogenetic protein (BMP)

Recombinant bone morphogenetic proteins

Medtronic Spinal & Biologics

• INFUSE

Olympus Biotech Co

• OP-1 Implant

Cell-based bone graft substitutes

ACE Surgical Supply

• Osteocel® Plus

Ceramic-based bone graft substitutes

DENTSPLY Friadent CeraMed

• OsteoGrafOsteoGraf (DENTSPLY Friadent CeraMed) uses hydroxyapatite as bone graft material in either a block or a particulate form.

Wright Medical Technology

• OsteosetOsteoset (left) and Allomatrix (right) are produced by Wright Medical Technology, Inc. Osteoset is a calcium sulfate tablet used for bone defect sites, whereas Allomatrix is a combination of calcium sulfate and demineralized bone matrix that forms an injectable paste or a formable putty. Images courtesy of Wright Medical Technology, Inc.

Stryker

• BoneSource
• BoneSave
• HydroSet

ApaTech Limited

• Actifuse

Orthovita, Inc.

• Vitoss® Synthetic Cancellous Bone Filler

Integra Orthobiologics

• OsSatura TCP

Integra LifeSciences

• Integra MOZAIK Osteoconductive Scaffold

Synthes

• Norian SRS

Biomet

• ProOsteonProOsteon (Biomet, Parsippany, New Jersey) is produced from hydroxyapatite in either a particulate or a block form by chemically treating sea coral. Image courtesy of Biomet, Inc.
• Biogran (bioglass)

Osteohealth

• Bio-Oss

NovaBone Products

• Novabone (bioglass)

Polymer-based bone graft substitutes

Orthovita

• Cortoss

TMH Biomedical

• Open Porosity Polylactic Acid polymer (OPLA)

Osteobiologics, Smith and Nephew

• Immix

Depuy Orthopaedics Inc

• Healos

Tissue Regeneration Therapeutics

• OsteoScaf

Bone graft classification system

Several categories of bone graft substitutes exist (see the Table below) and encompass various materials, material sources, and origins (natural vs synthetic). Many are formed from composites of one or more types of material; however, the composite is usually built on a base material.^{[1, 2]}

Table 1. Bone Graft Substitutes (Open Table in a new window)

Laurencin et al have suggested a classification scheme of material-based groups.^[3]

Allograft-based bone graft substitutes involve allograft bone, used alone or in combination with other materials (eg, AlloGro, AlloFuse, AlloStem [AlloSource, Centennial, Colorado]; Opteform, Optefil [Exactech, Inc, Gainesville, Florida]; Grafton, MinerOss [BioHorizons, Birmingham, Alabama], OrthoBlast II [Integra OrthoBiologics, Irvine, California]; DynaBlast, DynaGraft-D [Keystone Dental, Burlington, Massachusetts]; TruFuse [minSURG Corp., Clearwater, Florida]; NuFix [Nutech Medical, Birmingham, Alabama]; and FusionFlex [Wright Medical, Arlington, Tennessee]).

Growth factor–based bone graft substitutes are natural or recombinant growth factors that are used alone or in combination with other materials, such as transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), insulin-like growth factor-1, and bone morphogenetic protein (BMP).^[4]

Recombinant bone morphogenetic proteins act as an adjunct to autografts during lumbar fusions and for fracture repair. Examples of rhBMP include INFUSE (Medtronic Spinal & Biologics, Memphis, Tennessee) and OP-1 Implant (Olympus Biotech Co, Hopkinton, Massachusetts).

Cell-based bone graft substitutes use cells to generate new tissue alone or are seeded onto support matrices. Examples include mesenchymal stem cells and Osteocel® Plus (ACE Surgical Supply, Inc, Brockton, Massachusetts).

Ceramic-based bone graft substitutes include calcium phosphate, calcium sulfate, and bioglass, which can be used alone or in combination with other materials. Various examples include OsteoGraf (DENTSPLY Friadent CeraMed, Lakewood, Colorado); Norian SRS (Synthes, Inc, West Chester, Pennsylvania); ProOsteon (Biomet, Parsippany, New Jersey); Osteoset (Wright Medical Technology, Inc, Arlington, Tennessee); BoneSource, BoneSave, HydroSet (Stryker, Kalamazoo, Missouri); Actifuse (ApaTech Limited, Elstree, Hertfordshire, UK), Vitoss® Synthetic Cancellous Bone Filler (Orthovita, Inc., Malvern, PA); OsSatura TCP (Integra Orthobiologics, Plainsboro, New Jersey) and Integra MOZAIK Osteoconductive Scaffold (Integra LifeSciences, Plainsboro, NJ).

Polymer-based bone graft substitutes have been developed into various types. They are degradable or nondegradable polymers and are used alone or in combination with other materials. Examples of this type include Cortoss (Orthovita, Inc, Malvern, Pa); Open Porosity Polylactic Acid polymer (OPLA) (TMH Biomedical, Inc., Duluth, MN); Immix (Osteobiologics, Smith and Nephew, Memphis, Tennessee); and Healos (Depuy Orthopaedics Inc, Warsaw, Indiana).

Allograft-based bone graft substitutes

The use of allografts for bone repair often requires the sterilization and deactivation of proteins normally found in healthy bone. Contained in the extracellular matrix of bone tissue are the full cocktail of bone growth factors, proteins, and other bioactive materials necessary for osteoinduction and, ultimately, successful bone healing. To capitalize on this cocktail of proteins, the desired factors and proteins are removed from the mineralized tissue by using a demineralizing agent such as hydrochloric acid. The mineral content of the bone is degraded, and the osteoinductive agents remain in a demineralized bone matrix (DBM).

DBM has been incorporated into several products currently on the market. Opteform is DBM-based and mixed with cancellous chips. It is osteoinductive, osteoconductive, and osteogenic when mixed with blood. AlloGro is another DBM product. AlloMatrix (Wright Medical Technology, Inc) is AlloGro combined with calcium sulfate; this paste can be formed into an onlay or injected directly into a defect site. DynaGraft II (Keystone Dental) is DBM mixed with a temperature-sensitive polymer and forms a solid, putty, or injectable paste, depending on the composition. OrthoBlast is DBM mixed with the same polymer and cancellous bone chips and is also available as a putty or a paste.

Growth factor–based bone graft substitutes

The growth factors and proteins that exist in bone are responsible for regulating cellular activity. Growth factors bind to receptors on cell surfaces, stimulating the intracellular environment to act. Generally, this activity translates to a protein kinase that induces a series of events, resulting in the transcription of messenger ribonucleic acid (mRNA) and, ultimately, into the formation of a protein to be used intracellularly or extracellularly.

The combination and simultaneous activity of many factors result in the controlled production and resorption of bone. These factors, residing in the extracellular matrix of bone, include TGF-beta, insulin-like growth factors I and II, PDGF, FGF, and BMPs.^{[5, 6]} Researchers have been able to isolate and, in some cases, synthesize these factors. Much work continues in the research setting, and some products for clinical use have appeared on the market.

Recombinant bone morphogenetic substitutes

Since the advent of recombinant technology in this sector, recombinant forms of BMP-2 and BMP-7 have been developed and licensed for clinical use. These two molecules have been used in various clinical conditions including, nonunions, open fractures, joint fusions, aseptic bone necrosis, and critical bone defects. No studies have yet to document adverse systemic effects caused by these substitutes. RhBMP–2 (INFUSE® Bone Graft) is sold in conjunction with specific spinal and nonspecific tibial fusion devices to serve as an alternative to autologous bone graft. RhBMP-7, marketed in the United States as OP-1 Implant, is used in healing fractures of long bones. Additionally, OP-1 putty has been used in spinal fusions.^[7]

Cell-based bone graft substitutes

With current techniques, in vitro differentiation of mesenchymal stem cells toward the osteoblast lineage is possible. Stem cells are cultured in the presence of various additives such as dexamethasone, ascorbic acid, and β-glycerophosphate to direct the undifferentiated cell toward the osteoblast lineage.

The addition of TGF-beta, BMP-2, BMP-4, and BMP-7 to the culture media can also influence the stem cells toward the osteogenic lineage. In research laboratories, marrow cells containing mesenchymal stem cells have been combined with porous ceramics and implanted into rat and canine critical segmental defects, with bony growth occurring as quickly as 2 months. Mesenchymal stem cells have also been seeded onto bioactive ceramics conditioned to induce differentiation to osteoblasts. Recently, ACE Surgical Supply, Inc. has marketed Osteocel Plus, which is a product that contains living bone cells, including mesenchymal stem cells. It also contains a polymer scaffold, which helps to enhance and encourage bone growth.

Ceramic-based bone graft substitutes

Approximately 60% of the bone graft substitutes currently available involve ceramics, either alone or in combination with another material. This area of bone graft research has grown tremendously over the past 5 years and has a promising outlook. Ceramic substitutes can be divided into 3 main categories, including calcium sulfate, bioactive glass, and calcium phosphate. The use of ceramics, especially calcium phosphates, is driven in part by the fact that the primary inorganic component of bone is calcium hydroxyapatite, a subset of the calcium phosphate group. In addition, calcium phosphates are osteoconductive, osteointegrative (the newly formed mineralized tissue forms intimate bonds with the implant material), and, in some cases, osteoinductive. This material often requires high temperatures for scaffold formation and has brittle properties; therefore, it is frequently combined with other materials to form a composite.

Calcium sulfate is also known as plaster of Paris. It is biocompatible, bioactive, and resorbable after 30-60 days. Significant loss of its mechanical properties occurs upon its degradation; therefore, it is a questionable choice for load-bearing applications.

Osteoset is a tablet for use for defect packing. It is degraded in approximately 60 days (see the image below).

AlloMatrix is Osteoset combined with DBM. It forms a putty or injectable paste (see the image below).

Integra MOZAIK Osteoconductive Scaffold is composed of 80% tricalcium phosphate and 20% type I collagen. The synthetic bone filler resorbs at a rate consistent with the formation of new bone.

Actifuse is a silicate-substituted calcium phosphate.

BoneSource, BoneSave, HydroSet (Stryker, Kalamazoo, Missouri) are calcium phosphate–based materials used to fill bone defects.

OsSatura TCP (Integra Orthobiologics, Plainesboro, New Jersey) consists of pure β-TCP; it forms a well-defined interconnected porosity that provides a high level of osteoconductivity.

Bioactive glass (bioglass) is a biologically active silicate-based glass.^[8] Its high modulus and brittle nature make its applications limited, but it has been used in combination with polymethylmethacrylate to form bioactive bone cement and with metal implants as a coating to form a calcium-deficient carbonated calcium phosphate layer. This layer facilitates the chemical bonding of the implant to surrounding bone. Products include Biogran (developed by Orthovita and licensed to Biomet 3i, Implant Innovations, Inc, Palm Beach Gardens, Florida) and Novabone (NovaBone Products, LLC, Alachua, Florida).

Calcium phosphates account for most of the ceramic-based bone graft substitutes currently available. Several types of calcium phosphates exist, including tricalcium phosphate, synthetic hydroxyapatite, and coralline hydroxyapatite, and are available in pastes, putties, solid matrices, and granules.

Such calcium phosphate products include Bio-Oss (Osteohealth, Inc, Shirley, New York) and OsteoGraf (see the first image below).

Both products use hydroxyapatite, either as a particulate (Bio-Oss) or as blocks and particulates (OsteoGraf). Vitoss (Orthovita, Inc) is a tricalcium phosphate available as a solid piece, putties, or pastes. ProOsteon is a unique product based on sea coral, which is converted from calcium carbonate to calcium hydroxyapatite. The advantage of this material is that the structure of the coral, which is similar to that of trabecular bone, is maintained. However, like many of the solid calcium phosphates, ProOsteon is brittle and not suitable for use in load-bearing sites (see the image below).

Polymer-based bone graft substitutes

The final group of bone graft substitutes is the polymer-based group. Polymers present some options that the other groups do not. For example, many polymers that are potential candidates for bone graft substitutes represent different physical, mechanical, and chemical properties. The polymers used today can be loosely divided into natural polymers and synthetic polymers. These, in turn, can be divided further into degradable and nondegradable types.

Healos (DePuy Orthopaedics, Inc, Warsaw, Ind) is a natural polymer-based product, a polymer-ceramic composite consisting of collagen fibers coated with hydroxyapatite and indicated for spinal fusions.

Cortoss is an injectable resin-based product with applications for load-bearing sites.

Degradable synthetic polymers (ie, natural polymers) are resorbed by the body. The benefit of having the implant resorbed by the body is that the body is able to heal itself completely without remaining foreign bodies. To this end, companies have used degradable polymers such as polylactic acid and poly(lactic-co-glycolic acid) as standalone devices and as extenders to autografts and allografts.

Tissue Regeneration Therapeutics (Toronto, Canada) has developed a porous poly(lactic-co-glycolic acid) foam matrix by using a particulate-leaching process to induce porosity. It is currently marketed under the trade name OsteoScaf. Immix (Osteobiologics, Smith and Nephew, Memphis, Tennessee) is a particulate poly(lactic-co-glycolic acid) product that is used as a graft extender.

New materials and approaches

Despite the many advances in bone graft substitutes, new materials and approaches to bone healing continue to be investigated. One exciting area that is emerging as an approach to musculoskeletal tissue repair is regenerative engineering. Regenerative engineering is the integration of tissue engineering, advanced material science, stem cell science, and areas of developmental biology for the regeneration of complex tissues, organs, and organ systems.^[9]

A key element of regenerative engineering is using material-based cues to guide cellular behavior, be they architectural, topographical, or chemical, and to harness these tools toward the regeneration of the interface between musculoskeletal tissues. While considerable success has been achieved in regenerating individual tissue types such as bone, ligament, tendon, and cartilage, it is the challenge of integrating these tissue types that hinders advancing beyond individual tissue repair to more complex structures, such as total joints.

Applying the philosophy of regenerative engineering to the healing of musculoskeletal tissues, Dr. Cato Laurencin and colleagues at the Institute for Regenerative Engineering at The University of Connecticut Health Center (Farmington, CT) are developing novel degradable composite structures. These biomimetic structures are designed to exploit the nanoscale and microscale architecture encountered in different tissue types into one 3-dimensional matrix.

Studies conducted with cells seeded onto the 3-dimensional matrices have revealed that a sintered microsphere ultrastructure can provide mechanical integrity similar to that of trabecular bone, while a nanoscale fiber mesh similar to the extracellular matrix found in tissues can occupy the pore volume of the larger matrix. This nanoscale matrix encourages cell migration throughout the pore volume of the scaffold while promoting cellular phenotypic differentiation, a finding that depended on the presence of the nanoscale fibers, as it was not noted in microsphere matrices that did not have the nanoscale fiber mesh within its pores. These findings are particularly interesting because the cellular changes were due only to the physical presence of the nanoscale cues, as no proteins or factors were added to any of the matrices.^[10]

Other studies within the Institute have included the development of novel matrices from resorbable polymer blends that transform over time as part of the degradation process from solid structures, imparting considerable initial mechanical stability to porous microsphere-based structures suitable for tissue ingrowth similar to those in the preceding study. These matrices would have the advantage of both structural integrity shortly after implantation, when the surrounding tissue is weakest, and a highly porous structure to encourage vascular and bony ingrowth as the defect heals and the implant material degrades and is safely eliminated from the patient.^[11]

Future directions

Many products on the market today fill the need for bone grafts. Several of these products capitalize on the necessities of an ideal substitute: osteoconductivity and osteoinductivity.

Recently, there has been a strong push toward specialization of bone graft materials. Companies have transitioned from nonspecific bone graft substitutes to products designed for specific clinical situations. As a result, there has been an impetus to create a greater variety of bone grafts and ways to introduce them into the body. Consequently, more and nonsetting pastes and putties have been introduced. The production of these materials is often less complex than their cement counterparts, and their biological responses are often better.^[12]

Furthermore, greater interest has been shown in creating substitutes that are more resorbable. The switch toward resorbable materials aims to transform a bone defect into new mature bone as fast as possible.

Finally, there has been a trend to add slight amounts of foreign ions into ceramic bone graft substitutes to improve their biological behavior. Most efforts have been set on silicon, but other ions have been looked at, such as magnesium, sodium, strontium, or zinc.^[12]

As more materials are adapted and discovered, preexisting products are finding new applications and effectiveness in combination with newly emerging technology. In addition, as investigators continue to find new materials and biologic approaches to bone repair, the future of bone graft substitutes continues to be an expanding topic.

Most bone graft procedures are implemented to repair bone defects stemming from a disease or a traumatic event.^[13]

Research in this sector has grown exponentially within this past decade as the result of advances in biomaterial sciences and stem cell engineering. Below are a few studies exemplifying recent advancements in the field, with significant clinical application.

Digiovanni et al performed a prospective, controlled, randomized feasibility trial to study the recombinant form of platelet-derived growth factor (rhPDGF-BB) in a foot and ankle fusion model. The recombinant form of platelet-derived growth factor has been shown to significantly enhance bone formation in human periodontal osseous defects when combined with a tricalcium phosphate carrier (β-TCP). The purpose of this clinical trial was to compare the safety and efficacy of this biosynthetic bone graft substitute, now marketed as Augment™ Bone Graft, to autologous bone graft during ankle and hindfoot fusions. Twenty adults were recruited from 3 US centers and randomized in a 2:1 ratio to receive Augment™ or autologous bone graft. The surgical approach and fixation techniques were standardized, and the patients were monitored for a minimum of 9 months.

At 36 weeks, 77% (10/13) of the Augment™ patients and 50% (3/6) of the autologous bone graft patients experienced fusion, based on radiographic criteria. There were two nonunions in the Augment™ group (9%). Healing rates based on CT scanning at 12 weeks (50% osseous bridging) were 69% (9/13) in the Augment™ and 60% (3/5) in the autologous bone graft groups, respectively. All functional outcome measures (FFI, AOFAS, SF-12), as well as the VAS pain scores, improved in both groups over time. Therefore, the authors concluded that Augment™ had comparable efficacy to autologous bone grafts.^[14]

Mulconrey et al performed a prospective radiographic analysis of anterior and posterior adult spinal deformity fusions with bone morphogenetic protein (rhBMP-2) to determine the ability of rhBMP-2 to achieve multilevel spinal fusion. The patients were divided into 3 groups: group 1 (10 mg/level) contained 47 patients who underwent anterior spinal fusion (ASF) with BMP on an absorbable collagen sponge (ACS) with a titanium mesh cage; group 2 (20 mg/level) included 43 patients who underwent posterior spinal fusion (PSF) with BMP on an ACS with local bone graft (LBG) and bulking agent [tricalcium phosphate/hydroxyapatite (TCP-HA)]; and group 3 (40 mg/level) contained 8 patients who underwent PSF with rhBMP-2 and TCP-HA with no autologous bone. Overall fusion rate was 95% (group 1, 91%; group 2, 97%; group 3, 100%). In multilevel spinal fusion, rhBMP-2 eliminated the necessity for iliac crest bone graft and yielded an excellent fusion rate.^[6]

Williams et al performed a retrospective analysis of all spinal fusion cases submitted by members of the Scoliosis Research Society from 2004-2007 to evaluate the use of BMP and assess its associated complications. Prior to this study, BMP products had no known association with significant complications in spinal fusions. However, the authors of this study found that BMP use with anterior cervical fusion was associated with an increased incidence of complications, while the use of BMP in the thoracolumbar and posterior cervical fusions was not associated with more complications. Complications included superficial and deep infections and epidural hematomas/seromas.^[15]

On multivariate analysis for thoracolumbar and posterior cervical fusions, BMP use was not a significant predictor of complications (P = 0.334; odds ratio = 1.039; 95% confidence interval = 0.961-1.124; covariates were BMP use, patient age, revision vs primary surgery). Multivariate analysis for anterior cervical spinal fusion demonstrated that BMP use remained a significant predictor of complications (P < 0.001; odds ratio = 1.6; 95% confidence interval = 1.516-1.721), after adjusting for the effects of patient age and whether the surgery was a revision procedure. Evaluation of this and related data is ongoing.^[16]

Bansal et al studied the use of porous hydroxyapatite and β-tricalcium phosphate as a scaffold combined with bone marrow aspirate in dorsal and lumbar spinal injuries. In this study, 30 patients were followed who had unstable dorsal and lumbar spinal injuries and needed posterior stabilization and fusion. Posterior stabilization was done using pedicle screw and rod assembly, and fusion was done using hydroxyapatite and β-tricalcium phosphate mixed with bone marrow aspirate as a bone graft substitute on one side of the spine and autologous iliac crest bone graft on the other side.

Graft incorporation and fusion occurred in all patients on the bone-graft substitute side and in 29 patients on the autologous bone graft side. One patient showed lucency and breakage of the distal pedicle screw on the autologous side. According to the authors, hydroxyapatite and β-tricalcium phosphate with bone marrow aspirate is a promising alternative to autologous iliac bone graft for posterolateral spinal fusion.^[17]

An additional study performed in 2010 by Yuan et al reaffirmed that ceramic materials present a bona fide alternative to autograft and BMP therapy. The authors prepared calcium phosphate ceramics with varying physicochemical and structural characteristics to stimulate osteogenic differentiation of stem cells in vitro and bone induction in vivo. Using an animal model (sheep), the authors showed that implantation of the calcium phosphate ceramic in a large bone defect is equally efficient in healing critical-size bone defects as autologous bone grafts or BMP therapy.^[4]

Approximately 600,000 bone graft procedures are performed in the United States annually, and roughly 2.2 million such procedures are performed worldwide, grossing approximately $2.5 billion per year.^[18] Most bone graft procedures are implemented to repair bone defects stemming from a disease or a traumatic event.^[13]

Either autograft or allograft tissue is used in 90% of these procedures. The current criterion standard is to use autologous bone or autograft, in which tissue is harvested from the patient, usually from the iliac crest, or possibly from the distal femur or the proximal tibia. The graft is then placed at the injury site to allow for new bone growth. This tissue is ideal for bone grafting because it possesses all of the characteristics necessary for new bone development—namely, osteoconductivity, osteogenicity, and osteoinductivity.

Osteoconductivity refers to the situation in which the graft supports the attachment of new osteoblasts and osteoprogenitor cells, providing an interconnected structure through which new cells can migrate into and allow new vessels to form. Osteogenicity refers to the situation when the osteoblasts found at the site of new bone formation are able to produce minerals to calcify the collagen matrix, which ultimately serves as the substrate for new bone. Osteoinductivity refers to the ability of a graft to induce nondifferentiated stem cells or osteoprogenitor cells to differentiate into osteoblasts.

Harvesting the autograft requires an additional surgery at the donor site that can result in its own complications, such as inflammation, infection, and chronic pain that occasionally outlasts the pain of the original surgical procedure. Sites of bone tissue that can be harvested are also limited, thus creating a supply problem.

Allografts are alternatives to autografts and are taken from donors or cadavers, circumventing some of the shortcomings of autografts by eliminating donor-site morbidity and issues of limited supply. However, allografts also present risks; although allograft tissue is treated by various methods, including tissue freezing, freeze-drying, gamma irradiation, electron beam radiation, and ethylene oxide, the risk of disease transmission from donor to recipient is not completely removed.

Although many scientists have developed methods to help reduce the risk of disease transmission with allograft implementation, many of these methods of sterilization also results in the removal of important proteins and tissue factors that contribute to the graft’s osteoinductivity. Therefore, many tissue banks have been hesitant to implement these sterilization techniques.

Despite the benefits of autografts and allografts, the limitations of each have necessitated the pursuit of alternatives. Using the 2 basic criteria of a successful graft, osteoconduction and osteoinduction, investigators have developed several alternatives, some of which are available for clinical use and others of which are still in the developmental stage. Many of these alternatives use various materials, including natural and synthetic polymers, ceramics, and composites, whereas others have incorporated factor- and cell-based strategies that are used either alone or in combination with other materials.

Allograft-based bone graft substitutes

AlloMatrix (Wright Medical Technology, Inc) is AlloGro combined with calcium sulfate; this paste can be formed into an onlay or injected directly into a defect site. DynaGraft II (Keystone Dental) is DBM mixed with a temperature-sensitive polymer and forms a solid, putty, or injectable paste, depending on the composition. OrthoBlast is DBM mixed with the same polymer and cancellous bone chips and is also available as a putty or a paste.

Recombinant bone morphogenetic substitutes

BMP-2 and BMP-7 have been used in various clinical conditions including, nonunions, open fractures, joint fusions, aseptic bone necrosis, and critical bone defects.

Additionally, OP-1 putty has been used in spinal fusions.^[7]

Recombinant bone morphogenetic substitutes

No studies have yet to document adverse systemic effects caused by BMP-2 and BMP-7.

Autografts

Harvesting the autograft requires an additional surgery at the donor site that can result in its own complications, such as inflammation, infection, and chronic pain that occasionally outlasts the pain of the original surgical procedure. Sites of bone tissue that can be harvested are also limited, thus creating a supply problem.

Allografts

Allografts are alternatives to autografts and are taken from donors or cadavers, circumventing some of the shortcomings of autografts by eliminating donor-site morbidity and issues of limited supply. However, allografts also present risks; although allograft tissue is treated by various methods, including tissue freezing, freeze-drying, gamma irradiation, electron beam radiation, and ethylene oxide, the risk of disease transmission from donor to recipient is not completely removed.

Some have estimated that the risk of human immunodeficiency virus (HIV) transmission alone with allograft bone is 1 case in 1.6 million.^[19] In addition, one case of hepatitis B transmission and 3 cases of hepatitis C transmission have been reported with allograft tissue.^{[20, 21]} More recently, cases of bacterial transmission have been reported.^{[22, 23]}

Allograft-associated infections have been associated with various organisms and tissue types. In most of these cases, organisms are transmitted from the donor because of unrecognized infection or contamination during tissue recovery.

In 2007, a case report demonstrated the transmission of a novel strain of group A streptococci due to transplanted hemi-patellar tendon allograft to repair an anterior cruciate ligament. One day after transplantation, the patient developed pain and erythema at the surgical site and a fever of up to 39°C. Six days after the procedure, the patient underwent surgical exploration with arthrotomy of the knee and fasciotomy of the thigh. The allograft tissue was removed, and cultures of the wound aspirate, blood, and explanted tissue demonstrated growth of group A streptococci.^[24]

In 2006, Cartwright (2010) reported on cultures that revealed the waterborne bacterium Elizabethkingia meningoseptica (formerly Chryseobacterium meningosepticum) in two patients who developed allograft-associated surgical site infections. This was unusual since this was the first reported case that linked allograft infection with environmental contamination.^[25]

Other cases of bacterial transmission have been reported. In April 2000, two patients developed septic arthritis after receiving bone-tendon-bone allografts from a common donor for anterior cruciate ligament reconstruction. In November 2001, a patient died of infection caused by Clostridium sordellii as a result of graft placement.^{[22, 23]}