Bone graft substitutes

Calcium phosphate cements (injectable cement)

Coralline hydroxyapatite

Derived from the calcium carbonate of sea coral.

The pore structure of coralline calcium phosphate produced by certain species is similar to human cancellous bone, making it a suitable material for an osteoconductive substitute for bone graft.

The pore size required for bone ingrowth varies from 100 to 500 μm.

Coralline bone substitutes may be natural or manufactured. In the natural form the calcium carbonate skeleton is harvested directly from the natural habitat, cleaned and sterilised.

The manufactured form is coralline hydroxyapatite, which is converted from natural coralline calcium carbonate by substitution of the carbonate components with phosphates.

The material is commercially available and is marketed with mean pore sizes of 200 or 500 μm.

It has a high compressive strength but is brittle with low tensile strength.
Main disadvantages

Variable strength
Variable rates of resorption.

More recently, coralline hydroxyapatite has been used as a carrier for some growth factors. In a canine model, it has been used as a carrier for BMP with success and in a rabbit model as a carrier for transforming growth factors and fibroblast growth factors.

Calcium sulphate

Plaster-of-Paris

It is perhaps the oldest osteoconductive material available with reports of it being used to fill bony defects in the last century.

Main disadvantages

The chemical reaction during setting results in a very variable crystalline structure, with consequent inconsistency in the material properties of the final product.
It resorbs very rapidly at a rate which may exceed the capacity of surrounding bone to regenerate.

At present, it has been superseded by more reliable osteoconductive materials.

It may still have a future role as a carrier for bone morphogenetic proteins.

Ceramics

When naturally occurring mineral salts are subjected to very high temperatures in a process known as sintering, highly crystalline materials termed ceramics are produced.

Ceramics are brittle and have poor tensile strength, making their primary clinical application one of filling contained bone defects or restoring areas of bone loss resulting from a fracture such as an articular fracture with joint depression.

Calcium phosphate biomaterials should be placed in intact bone or rigidly stabilized bone in order to protect the ceramic from shear stresses, and they should be tightly packed into the adjacent host bone to maximize ingrowth.

Their structure is quite distinct from the poorly crystalline configuration of normal bone and for this reason they are only resorbed very slowly.

The most popular materials have been tricalcium phosphate and the derived ceramic, hydroxyapatite.

The latter is a biocompatible ceramic which is produced in a high-temperature reaction
and is a highly crystalline form of calcium phosphate.

It is very stable and resorbs very slowly.

Coralline hydroxyapatite, was one of the first ceramics to be used as an osteoconductive material.

The main drawbacks of ceramics are the slow resorption and the difficulty in developing a material with favourable handling characteristics which is easy to use clinically.
The use of ceramic hydroxyapatite in the management of fractures has been more limited. Itokazu et al found that in 17 patients with fractures of the tibial plateau, the
material was safe with no evidence of post-traumatic arthritis at a mean follow-up of two years and six months.

The poor bioresorbability and difficulties with the handling of ceramics have stimulated work to develop materials which resemble the mineral phase of bone more closely. This has led to the development of calcium phosphate cements (see injectable cement).

Product	Company	Type	Form
Collagraft	Zimmer	Bovine collagen, hydroxyapatite, and tricalcium phosphate;	Granular and strip forms
Pro Osteon	Interpore	Cross Coralline hydroxyapatite	Granules,blocks; 200, 500, and R forms
Osteoset	Wright Medical Technology	Calcium sulfate	Pellets
Allomatrix	Wright Medical Technology	Demineralized human bone matrix in an Osteoset medium
NovaBone	USBiomaterials	Bioactive glass (SiO2 and minerals)
Endobon	Biomet	Hydroxyapatite (bovine)	Cancellous bone blocks
Vitoss	Orthovita	Ultraporous beta-tricalcium phosphate
SRS	Norian	Calcium phosphate (carbonated apatite)	Injectable cement

Table - Calcium-Based Bone-Graft Substitutes

Pro Osteon®

Synthesized by removing the protein and replacing the calcium carbonate of sea coral with hydroxyapatite.

Pro Osteon has interconnecting pores that allow ingrowth of blood vessels, fibrous tissue, and bone. Pro Osteon has a compressive strength similar to that of cancellous bone, but has very low tensile strength. Although relatively brittle at the time of implantation, the material gains strength as bone apposition and ingrowth progress.

Indicated for use in filling bony voids or gaps of the skeletal system.

If used for metaphyseal fracture defects, it is to be used in conjunction with rigid internal fixation.

Pro Osteon is available as blocks that can be machined into different shapes or as smaller granules.

Endobon®

A different macroporous hydroxyapatite product derived from cancellous bovine bone.

Used as a bone graft substitute or as a carrier for autologous bone marrow cells.

Hydroxyapatite can be applied as a coating to the surface of implants by plasma spray or precipitation techniques.

Blocks, granules, and coatings of high hydroxyapatite content and high crystallinity can be dissolved in the acidic pH created by osteoclasts, but are relatively stable at neutral pH and usually resorbed very slowly in vivo.

Tricalcium phosphate is a random porous ceramic that undergoes partial conversion to hydroxyapatite once it is implanted into the body.

Tricalcium phosphate is more porous and is resorbed faster than hydroxyapatite, making it mechanically weaker in compression.

After conversion, the hydroxyapatite is resorbed slowly and, therefore, large segments of hydroxyapatite remain in place for years.

Because tricalcium phosphate has an unpredictable biodegradation profile, it has not been popular as a bone-graft substitute. However, Bucholz et al. showed that tricalcium phosphate is effective for filling bone defects resulting from trauma, benign tumors, and cysts.
Coralline hydroxyapatite is processed by a hydrothermal exchange method that converts the coral calcium phosphate to crystalline hydroxyapatite with pore diameters between 200 and 500 µm and in a structure very similar to that of human trabecular bone. Bucholz et al. reported that the clinical performances of autologous cancellous bone graft and coralline hydroxyapatite are equivalent when the substances are used to fill bone voids resulting from articular surface depression in tibial plateau fractures. Other studies have demonstrated successful healing of cortical defects greater than one-third of the diaphyseal circumference of long-bone fractures, although the results are less predictable than those following treatment of metaphyseal fractures. To avoid donor site morbidity, I occasionally use coralline hydroxyapatite granules or blocks of various size, depending on the size of the defect, to fill metaphyseal defects after reduction of depressed articular segments. A contraindication to the use of this material is a joint surface defect that would allow the grafting material to migrate into the joint. In these cases, I prefer to use autologous or allograft cancellous bone, which is more adhesive to itself and to the surrounding metaphyseal bone.

Another ceramic bone-graft substitute currently in clinical use is a calcium-collagen graft material. This osteoconductive composite of hydroxyapatite, tricalcium phosphate, and Type-I and III collagen is mixed with autologous bone marrow to provide osteoprogenitor cells and other growth factors. The composite does not provide structural support, but it serves as an effective bone-graft substitute or bone-graft expander to augment acute fracture-healing. Chapman et al. performed a prospective, randomized comparison of autologous iliac crest bone graft and calcium-collagen graft material in the treatment of acute long-bone fractures with both bone-grafting (<30 cm3 volume required) and internal or external fixation. The authors observed no differences between the two groups with regard to the union rate or functional measures, and they concluded that calcium-collagen graft material with autologous bone marrow can be used instead of autologous bone graft for patients who have an acute traumatic defect of a long bone. There is no scientific evidence that calcium-collagen graft materials can effectively substitute for autologous bone graft to stimulate healing of nonunions. This material with autologous bone marrow is recommended as a replacement for autologous bone graft for acute long-bone fractures with enough comminution or cortical bone loss to require bone-grafting when internal or external fixation is planned. It is not recommended using it to fill metaphyseal bone defects resulting from articular fractures because it does not offer structural support. Finally, it is not recommend it for the treatment of nonunions except in the role of a bone-graft expander when the supply of autologous bone graft is limited.
Calcium sulfate graft material with a patented crystalline structure described as an alphahemihydrate acts primarily as an osteoconductive bone-void filler that completely resorbs as newly formed bone remodels and restores anatomic features and structural properties. Potential uses of calcium sulfate graft material include the filling of cysts, bone cavities, and segmental bone defects; expansion of grafts used for spinal fusion; and filling of bone-graft harvest sites. Currently, very limited information is available on the use of this material in humans; no published controlled studies are available.

Injectable calcium phosphate fillers

One such material, Skeletal Repair System (SRS; Norian, Cupertino, California) is an injectable paste of inorganic calcium and phosphate that hardens within minutes, forming a carbonated apatite of low crystallinity and small grain size similar to that found in the mineral phase of bone. After twelve hours, this material hardens to form dahlite with a compressive strength of 55 MPa, and, because of its crystalline structure, it can eventually be resorbed and replaced by host bone. This material may be useful as a bone-graft substitute to augment cast treatment or internal fixation of impacted metaphyseal fractures. However, while a multicenter study showed that patients treated with injectable calcium phosphate and cast immobilization had earlier functional return than patients treated with cast immobilization or external fixation alone, the advantage diminished by three months and no advantage was detectable after one year.

Potential applications of injectable calcium phosphate include:

Distal radius
Hip
Spine
Calcaneal
Tibial plateau
Other extra-articular metaphyseal fractures at risk for hardware failure or redisplacement under compressive loads. Scal outcomes.

(for more detail see injectable cements)

Bioactive Glass

Several variations of glass beads called Bioglass (USBiomaterials, Alachua, Florida) are currently being developed, and one formulation (PerioGlas) has been approved in the United States for periodontal use. The beads are composed of silica (45%), calcium oxide (24.5%), disodium oxide (24.5%), and pyrophosphate (6%). When implanted, they bind to collagen, growth factors, and fibrin to form a porous matrix to allow infiltration of osteogenic cells.

The matrix provides some compressive strength, but it does not provide structural support.

Hydroxyapatite blocks, granules, or coatings

Hydroxyapatite is an osteoconductive calcium phosphate that can be prepared as granules, blocks, or coatings on implants.

Hydroxyapatite can be applied as a coating to the surface of implants by plasma spray or precipitation techniques.

Hydroxyapatite coatings are thought to enhance early bone apposition and fixation.

Resorbable calcium containing blocks, granules and composites

Although hydroxyapatite is osteoconductive, its slow rate of resorption is interpreted by some as a limitation in certain clinical applications. Calcium sulfate readily dissolves at neutral pH in vivo and serves as a source of calcium ions that become incorporated in bone. It dissolves too rapidly to act as an osteoconductive matrix, but calcium sulfate preparations are reported to be effective in filling unloaded skeletal defects.

Osteoset®

Many investigators are developing osteoconductive materials with solubilities intermediate between hydroxyapatite and calcium sulfate.

For example:

Pro Osteon-R

This is a macroporous calcium-containing material similar to Pro Osteon except that the hydrothermal exchange process has been terminated before completion, such that the outer 2 to 10 μm is composed of hydroxyapatite, whereas the remaining material is calcium carbonate. Once the thin shell of hydroxyapatite is resorbed, the calcium carbonate dissolves relatively rapidly.

Calcium phosphates other than hydroxyapatite also have been advocated for use in bone voids.

For example, granules composed of a mixture of hydroxyapatite and tricalcium phosphate, are osteoconductive and undergo dissolution or resorption more rapidly than sintered hydroxyapatites.

Collagraft®

Hydroxyapatite and tricalcium phosphate granules, available with a bovine collagen carrier for all indications where autogenous or allogenic bone graft is required. When mixed with autogenous bone marrow, it is indicated for use in acute long bone fractures that are fixed internally or externally, and traumatic osseous defects smaller than 30 cm³.

Vitoss®

A macroporous formulation of tricalcium phosphate, is osteoconductive and completely resorbable, for use as a filler of voids that are not intrinsic to the stability of the bony structure.

Calcium phosphates also can be precipitated under conditions that favour the development of a carbonated mineral with very low crystalline order similar to bone mineral (dahllite).

This type of mineral can be adapted for use as an injectable cement, or precipitated onto cross-linked bovine collagen to form a composite for use as a bone graft substitute or carrier for bone marrow cells

Healos®

Autograft substitute in spinal applications; currently it is available only for investigational use in the United States.

References

Keating, J. F.; McQueen, M. M. SUBSTITUTES FOR AUTOLOGOUS BONE GRAFT IN ORTHOPAEDIC TRAUMA. Journal of Bone & Joint Surgery - British Volume. 83-B(1):3-8, January 2001.

Christopher G. Finkemeier; CURRENT CONCEPTS REVIEW: Bone-Grafting and Bone-Graft Substitutes; JBJS (A), Mar 2002; 84: 454 - 464.