bone graft substitutes

PRESENTER: DR. SUSHIL PAUDEL

Bone Graft Substitutes

Definition

Bone substitutes are natural, synthetic or composite materials used to fill bone defects and promote bone healing

Purpose

To provide:

Linkage

Splintage

and

Promote osteogenesis

Linkage

Fill bony defects/cavities

Replace crushed bone

Arthrodesis

Splintage

Non unions

Arthrodesis

Why do we need them???

2.2 million graft procedures done yearly

9 out of 10 involve use of Auto/Allografts

Estimated cost about $2.5 billion per year

Properties of an ideal bone graft

Osteoconductive matrix

Osteogenic cells

Osteoinductive proteins

Osteoconductive matrix

Acts as a scaffold which supports osteoblasts and progenitor cells

Provides integrated porous structure through which new cells can migrate and new vessels can form

Osteogenic cells

Includes osteoblasts and osteoblastic precursors

Capable of forming new bone in proper environment

Osteoinductive proteins

Stimulate and support mitogenesis of undifferentiated cells into osteoblastic cells

Bone graft substitutes have one or more of these three properties

Autografts Harvested from the patient

Cancellous, vascularized cortical, non vascularized cortical and autogeneous bone marrow grafts

Commonly taken from iliac crests

Advantages

No immune reaction

All three properties present

Disadvantages

Requires additional surgery

Limited quantity

Non availability for further surgery

Increased morbidity Infection Chronic pain Cosmetic

Allografts

Alternative to autografts

Taken from donors or cadavers

Advantages

Eliminates donor site morbidity

Tackles issue of limited supply

Disadvantages

Immune reaction

Risk of infection

Disease transmission

Reduced osteoinductivity and osteogenecity

Ethical issues

FUELLED THE QUEST FOR NEW ALTERNATIVES

BONE GRAFT SUBSTITUTES

Disadvantages of allo/autografts

Classification

Laurencin et al, proposed a classification system of material based groups

Includes: Allograft based Factor based Cell based Ceramic based Polymer based

Allograft based

Includes allograft bone used alone or in combination with other material

Available as Demineralized bone matrix, and other forms as an autograft, Eg- corticocancellous grafts etc.

Dimineralized bone matrix

Has osteoconductive and osteoinductive properties

Does not provide structural support

Very good for filling bone defects and cavities

Biological activity - proteins and growth factors present in the extracellular matrix

Prepared by a standard process- Urist et al, modified by Reddi and huggins

Pulverized allogenic bone (74-420 micrometer)

Demineralization in 0.5N HCL for 3 hours

Extra acid rinsed- sterile water, ethanol and ethyl ether

Uses

Excellent for contained stable defects Eg- cysts and cavities

Have been used for non unions and acute bone defects *

Also been used to enhance arthrodesis Eg- spine etc.**

• *tiedmann et al, Orthopedics 1995:18 1153-8

• **Urist MR et al, Clin. Orthop. 1981;154:97-113

DBM is available in various forms as

Freeze dried powder Crushed granules, chips Paste Gels

mixture of DBM with autologous bone marrow has also been used as injection*

* Connolly JF, Clin. Orthop. 1995;313:8-18

Product Company Type

Grafton DBM Osteotech DBM as gel, flex, putty

Dynagraft Gensci Reg. Process

DBM

Orthoblast DO DBM+ allograft cancellous bone

Osteofil Sofamor Danek

DBM+gelatin carrier+ water

Opteform Exactech Compacted corticocancellous bone chips with same material as osteofil

DBX Synthes DBM as putty, paste

Disadvantages

Infection

Disease transmission

Variable potency- multiple donors, manufacture processes

No RCT has been done comparing its efficacy

Factor based Involves natural or

recombinant factors

Factors responsible for differentiation of progenitor cells and regulation of activity

Mechanism of action based mostly on activation of protein kinases

Combined and simultaneous activity of various factors-controlled resorption and formation of bone

Factor+ Receptor on cell surface

Activation of protein kinases

Transcription of mRNA Proteins

Regulation of cell activity

include TGF-beta, insulinlike growth factors I and II, PDGF, FGF, and BMPs

Mostly in research phase

Recombinant BMP2 as INFUSE bone graft

Brief history of rhBMP2

1965- Urist et al, isolated a group of proteins they called BMPs

2002- FDA approved rhBMP2 for use in lumbar spine fusion with LT-CAGER device

2004-FDA approved use of rhBMP2 in open tibial fractures

rhBMP2/ACS+allograft V/S autogeneous bone graft in diaphyseal

tibial fractures

Study by Jones AL et al

30 patients with diaphyseal tibial fractures with cortical bone loss

Mean length of defect-4 cm

Divided in 2 groups

Short musculoskeletal function assessment administered before and after surgery

10 in autograft group, 13 in rhBMP2 group showed healing

Significantly less blood loss in rhBMP2 group

Comparative improvement in SMFA in both groups

Jones AL et al J Bone Joint Surgery AM 2006 Jul;88(2):1431-41

Contraindications to rhBMP2

Hypersensitivity to rhBMP2 or bovine collagen type I

In vicinity of resected tumor

Patients with active malignancy or patients undergoing treatment

Skeletally immature patient

Pregnant women

Patients with active infection at operative site

Cell based

Based on in vitro differentiation of mesenchymal stem cells to osteoblastic lineage

Various additives- dexamethasone, ascorbic acid, b-glycerophosphate

Addition of factors- TGF-beta, BMP2, BMP4, BMP7

They have been used alongwith ceramics

Proposed to be used in bone repair prosthetic setting

Ceramic based About 60 % bone substitutes

involve ceramics- alone or in combination

Eg- Calcium sulfate Calcium phosphate Bioactive glass

Primary inorganic component of bone is calcium hydroxyapatite

Property of OSTEOINTEGRATION- newly formed mineralized tissue forms intimate bond with implant material

Ideal ceramic

Chemical structure to promote bone healing

Replaced by native bone

Mechanically strong to provide stability

Calcium phosphate biomaterials

Mainly used as osteoconductive matrix

Polycrystalline structure

Crystals of highly oxidised material fused by sintering

Brittle substance with poor tensile strength

Used for filling contained bone defects and areas of bone loss

Placed in rigidly stabilized bone or intact bone- to avoid shear stress on biomaterial

Tightly pack in adjacent host bone to maximize ingrowth

Available as porous/non porous blocks or porous granules

Tri calcium phosphate

It is a porous ceramic

Converts partly to hydroxyapatite in the body

More porous and faster rate of resorption than hydroxyapatite mechanically weaker in compression

Unpredictable Biodegradation profile not popular

May be used for filling bone defects- trauma, benign tumors, cysts

Coralline hydroxyapatite Processed by hydrothermal

exchange

Converts coral calcium carbonate to crystalline hydroxyapatite

Pore diameter 200-500 micrometer

Structure very similar to human trabecular bone

Contraindication to use- joint surface defect, material may enter joint

Study show equivalent result with coralline hydroxyapatite and autologous bone graft-tibial plateau fractures*

Results less predictable on management of metaphyseal fractures

* Bucholz RW clin orthop. 1989;240:53-62

Calcium collagen graft material

Osteoconductive composite of hydroxyapatite calcium phosphate type I and III collagen autologous bone marrow

Does not provide structural support

Effective bone substitute/ bone graft expander

Good for use in acute long bone cortical fractures

No scientific evidence of benefit in management of non-unions

Not recommended for use in metaphyseal bone defects due to articular fractures as provides no structural support

Calcium sulfate graft material

Alphahemihydrate crystalline structure

May be used as a bone void filler

Completely resorbs as new bone remodels to fill defect

Potential uses- filling defects including segmental defects, exapanding grafts as in spinal fusion

May be used to fill bone graft harvest sites

Very limited information available regarding use in humans

No published control studies available

Injectable calcium phosphate-SRS Norian

Injectable paste of inorganic calcium phosphate

Hardens quickly to carbonated apatite of low crystallinity similar to found in mineral phase of bone

Within 12 hours, crystallises to Dahlite, which can be resorbed and replaced by host bone

Useful to augment cast treatment or internal fixation of impacted metaphyseal fractures

Studies have been done in cases of impacted extra articular distal end radius fractures with good results

Jupiter et al. J Orthop Trauma 1997;11:110-6Kopylov et al. J Hand Surg [Br]. 1996;21:768-71Kopylov et al. Acta Orthop Scand 1999;70;1-5

Norian SRS in radial osteotomies

study by Logano calderon et al

Retrospective analysis of 6 elderly patients with corrective radial osteotomies

Fixed with angular stable implants+ Norian SRS

All osteotomies healed

Post op DASH-28 points, Modified Mayo score-68

Logan calderon et al J Hand Surg[Am] 2007 sep;32(7):976-83

Norian SRS in knee replacement

Study by Mangotti A et al

Used Norian SRS as substitute of bone graft for tibial bone defects in TKR

3 unicompartmental TKR, 2 revision TKR, 1 hinged knee prosthesis

No poor results, improved knee scores, no evidence of post op deformity

Mangotti A et al Arch Orthop Trauma Surg.2006 Nov:126(9):594-8

Other uses: hip spine calcaneal other metaphyseal fractures

At risk of implant failure or redisplacment due to load

Bio active glass

Variation of glass beads

Composed of silica, calcium oxide, disodium oxide and peroxide

They bind to collagen, growth factors and fibrin to form a matrix

Provides compressive strength but not structural support

Polymer based group

Can be divided into natural/synthetic

Further divided into biodegradable/non biodegradable

Eg:

Healoss(DePuy)- natural polymer based group polymer-ceramic composite collagen coated with

hydroxapatite used in spinal fusions

Cortoss: injectable, resin based product for application to load bearing sites

Rhakoss (orthovita, inc.): Resin composite available in various forms for spinal fusion

Composite grafts

Rationale most of the graft substitutes are only

osteoconductive

Cinolti G et al J Bone Joint Surg Br. 2004 Jan;86(1):135-42

“Osteoconductive material alone do not give effective fusion as autologous graft”

4 groups underwent Posterolateral lumbar arthrodesis

I- Porous ceramic+mesenchymal cells

II-Ceramic+bone marrow

III-Ceramic alone

IV-Autogeneous bone marrow alone

Rate of fusion was much higher in I, II, IV as compared to III

Boden SD et al Spine.1999 feb 15;24(4):320-7

“ Coralline Hydroxyapatite+osteoinductive bone proteins give better results in Posterolateral lumbar arthrodesis than autograft or bone marrow extracts alone”

Kai T et al. Spine 2003 aug 1;28(15):1653-8

5 groups of rabbits underwent lumbar intervertebral spinal fusion

I- sham operation

II-Porous calcium phosphate ceramic alone

III-autogeneous iliac crest

IV- ceramic + bone marrow stromal derived osteoblasts

V- Ceramic + bone marrow stromal derived osteoblasts + rhBMP2

I-0%

II-50%

III-66.7% successful spinal fusion

IV-100%

V-100%

Size of fusion mass and stiffness of fusion segments-greatest in group V

Conclusions:

rhBMP2 addition may reinforce biomechanical stiffness for spinal fusion segments

Porous calcium ceramics should not be used alone

Choice of graft

What is the expectation? Structure/bone forming function

Availability of graft?

Recipient bed?

Cost?

Remember!!! Stable fixation is required for use of most grafts

New concept

Concept of tissue engineering

Application of biologic, chemical and engineering

principles

repair, restoration and regeneration of tissues

using biomaterials, cells and factors