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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