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Introduction
  • A material with either osteoconductive, osteoinductive, and/or osteogenic properties
    • autografts
    • allografts
    • demineralized bone matrix (DBM)
    • synthetics
    • bone morphogenetic protein (BMP)
    • stem cells
  • Epidemiology
    • incidence
      • almost 1 million bone grafting procedures performed in US each year, with a growth of almost 13% per year 
  • Indications
    • assist in healing of fractures, delayed unions, or nonunions
    • assist in arthrodeses and spinal fusions
    • replace bone defects from trauma or tumor
  • Resorption rates
    • relative resorption rates of bone graft substitutes
      • fastest to slowest
        • calcium sulfate > tricalcium phosphate > hydroxyapatite 
  • Outcomes
    • allograft retrieval
      • retrieval studies are helpful in understanding the body's response to allografts
      • 5 years after implantation, allograft articular cartilage is completely acellular - no donor or recipient chondrocytes will be present 
Properties
  • Bone graft has aspects of one or more of these three properties
    • osteoconductive 
      • material acts as a structural framework for bone growth
        • demineralized bone matrices (DBMs)
      • the various three-dimensional makeups of the material dictate the conductive properties
    • osteoinductive 
      • material contains factors that stimulate bone growth and induction of stem cells down a bone-forming lineage
        • bone morphogenetic protein (BMP) is most common from the transforming growth factor beta (TGF-B) superfamily
    • osteogenic
      • material directly provides cells that will produce bone including primitive mesenchymal stem cells, osteoblasts, and osteocytes 
        • mesenchymal stem cells can potentially differentiate down any cell line
        • osteoprogenitor cells differentiate to osteoblasts and then osteocytes
      • cancellous bone has a greater ability than cortical bone to form new bone due to its larger surface area
      • autologous bone graft (fresh autograft and bone marrow aspirate) is the only bone graft material that contains live mensenchymal precursor cells
Antigenicity
  • Allograft is a composite material and therefore has many potential antigens (cell surface glycoproteins)
    • Class I and Class II antigens on graft are recognized by host T lymphocytes and elicit an immune response
    • immunogenic cells are marrow-based, endothelium, and retinacular-activating cells
      • bone marrow cells elicit the greatest immune response
      • extracellular matrix also acts as an antigen 
        • type I collagen stimulates both humoral and cell-mediated responses
        • noncollagenous matrix (proteoglycans, osteocalcin)
    • hydroxyapatite has not been shown to elicit an immune response
      • primary rejection is cell-mediated related to the major histocompatibility complex (MHC) incompatibility
Overview
 
Types of Bone Graft
Autograft
Cancellous - Less structural support
- Greater osteoconduction
- Rapid incorporation via creeping substitution
Cortical

- Slower incorporation due to need to remodel existing Haversion canals
- Interstitial lamellae preserved
- Provides more structural support
- 25% of massive grafts sustain insufficiency fractures

Vascularized bone graft - Technically challenging with quicker union and cell preservation
- Examples include: free fibula strut graft (peroneal artery), free iliac crest (deep circumflex iliac arteries), distal radius used for scaphoid fx (1-2 intercompartmental superretinacular artery branch of radial artery)
Allograft
Fresh - Highest risk of disease transmission and immunogenicity 
- BMP preserved and therefore osteoinductive
Fresh frozen - Less immunogenicity than fresh
- BMP preserved and therefore osteoinductive
Freeze dried (croutons)
- Least immunogenic
- Least structural integrity
- BMP depleted  (purely osteoconductive)
- Lowest likelihood of viral transmission
Demineralized Bone Matrix
Grafton DBM - Osteoinductive and osteoconductive 
- Contains: collagen, bone morphogenetic proteins, transforming growth factor-beta, residual calcium
- Does NOT contain mesenchymal precursor cells
Synthetics
Silicate based grafts

 

Aluminum oxide Alumina ceramic bonds bind to bone in response to stress and strain

Calcium phosphate grafts

- Osteoconduction and osteointegration
- Biodegrade very slowly
- Highest compressive strength 
- Many prepared as ceramics (heated to fuse into crystals)
- Examples include: tricalcium phosphate, Norian (Synthes), hydroxyapatitie (tradename Collagraft by Zimmer)
Calcium sulfate

- Osteoconductive
- Quick resorption   
- Examples include: OsteoSet (Wright medical)

Coralline hydroxyapatine - Calcium carbonate skeleton is converted to calcium phosphate via a thermoexchange process (Interpore)
Calcium carbonate - Chemically unaltered marine coral
- Osteoconductive
- Examples include: Biocora (Inoteb, france)
Bone Growth Factors
BMP
TGF-B
IGF-II
PDGF

see Rank-L and Bone Growth Factors topic

 
Autograft
  • Bone graft transferred from one body site to another in the same patient
  • Indications
    • gold standard
  • Properties
    • osteogenic, osteoinductive, and osteoconductive
    • least immunogenic 
    • cortical, cancellous, or corticocancellous
    • vascular or nonvascular
  • Donor sites
    • bone marrow aspirate
      • source of osteogenic mesenchymal precursor cells
      • iliac crest and vertebral body most common sites
      • variable number of cells depending on patient age
    • iliac crest is the most common site for autograft 
      • provides both cancellous and cortical graft
      • higher complication rate with anterior versus posterior harvesting 
      • 2% to 36% complication rate
        • blood loss and hematoma
        • injury to lateral femoral cutaneous or cluneal nerves
        • hernia formation
        • infection
        • fracture
        • cosmetic defect
        • chronic pain
    • fibula and ribs are most common sources of vascularized autografts
    • tibial metaphysis
Allograft
  • Bone graft obtained from a cadaver and inserted after processing
  • Most commonly used bone substitute
  • Properties
    • osteoconductive only due to lack of viable cells
      • the degree of osteoconduction available depends on the processing method (fresh, frozen, or freeze-dried) and type of graft (cortical or cancellous)
    • cortical, cancellous, corticocancellous, and osteoarticular (tumor surgery)
  • Osteoarticular allograft
    • immunogenic
    • preserved with glycerol or dimethyl sulfoxide (DMSO)
    • cryogenically preserved (few viable chondrocytes remain)
    • tissue-matched (syngeneic) grafts decrease immunogenicity
  • Processing methods
    • debridement of soft tissue, wash with ethanol (remove live cells), gamma irradiation (sterilization)
      • dose-dependent higher doses of irradiation kills bacteria and viruses but may impair biomechanical properties
    • fresh allograft
      • cleansing and processing removes cells and decreases the immune response improving incorporation
      • indications
        • rarely used due to disease transmission and immune response of recipient
    • frozen or freeze-dried
      • reduces immunogenicity while maintaining osteoconductive properties
      • reduces osteoinductive capabilities
      • shelf life
        • one year for fresh frozen stored at -20 degrees C
        • five years for fresh frozen stored at -70 degrees C
        • indefinite for freeze-dried
Demineralized bone matrix (DBM)
  • Acidic extraction of bone matrix from allograft 
    • removes the minerals and leaves the collagenous and noncollagenous structure and proteins
  • Properties
    • osteoconductive without structural support
    • minimally osteoinductive despite preservation of osteoinductive molecules
    • interproduct and interlot variability is common
Synthetics
  • Alternative to autografts and allografts
  • Various compositions available (see summary above)
  • Made in powder, pellet, or putty form
  • Properties
    • osteoconductive only 
  • Outcomes
    • Level I evidence shows that calcium-phosphate bone substitutes allow for bone defect filling, early rehabilitation, and prevention of articular subsidence in distal radius and tibial plateau fractures
Bone morphogenetic proteins (BMP)
  • Osteoinductive properties
    • stimulates undifferentiated perivascular mesenchymal cells to differentiate into osteoblasts through serine-threonine kinase receptors
  • rhBMP-2 and rhBMP-7 are FDA-approved for application in long bones and spine
  • Complications
    • under or overproduction of bone
    • inflammatory responses
    • early bone resorption
Reamer Aspirator Irrigator
  • Provides large volume of bone graft from intramedullary source  
    • femur (most common) 
    • tibia
  • Possible iatrogenic complications
    • femoral shaft fracture due to eccentric reaming
    • insertion site pain (hip abductors)
Graft Healing
 
 Stages of Graft Healing
Stage Characteristics
1. Inflammation Necrotic debris stimulates chemotaxis
2. Osteoblast differentiation Differentiates from mesenchymal precursor cells
3. Osteoinduction Stimulation of osteoblast and osteoclast function
4. Osteoconduction Bone forms around the new scaffold
5. Remodeling Continual process for years
 
Risks & Complications 
  • Disease Transmission
    • hepatitis B
      • risk of hepatitis B disease transmission in musculoskeletal fresh-frozen allograft transplantation is 1 in 63,000
    • hepatitis C
      • risk of hepatitis C disease transmission in musculoskeletal fresh-frozen allograft transplantation is 1 in 100,000 
    • HIV
      • risk of transmission of HIV in fresh-frozen allograft bone is 1 in 1,000,000
    • allografts are tested for HIV, HBV, HCV, HTLV-1, and syphilis 
  • Serous wound drainage
    • calcium sulfate bone graft substitute associated with increased serous wound drainage 
 

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Questions (25)
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(OBQ09.175) You are planning surgery on a 54-year-old female with the tibial plateau fracture seen in figures A and B. After reduction of the joint surface you plan to fill the void with a bone-graft substitute to prevent joint collapse. Which of the following bone-graft substitutes disappears most quickly in vivo? Review Topic

QID: 2988
FIGURES:
1

Collagen-based matrices

13%

(118/892)

2

Calcium phosphate

16%

(140/892)

3

Calcium sulfate

65%

(582/892)

4

Synthetic calcium sulfate and tri-phosphate mixture

3%

(23/892)

5

Coraline hydroxyapatite

3%

(25/892)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

(OBQ06.273) Which of the following bone graft material contains live mesenchymal osteoblastic precursor cells? Review Topic

QID: 284
1

Fresh-frozen allograft bone

2%

(10/511)

2

Recombinant bone morphogenic protein

3%

(17/511)

3

Demineralized bone matrix

0%

(2/511)

4

Autologous iliac crest marrow aspirate

92%

(472/511)

5

Calcium phosphate putty

1%

(5/511)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

(OBQ06.176) Iliac crest cancellous bone graft can be harvested from either the anterior or posterior aspect of the pelvis. When comparing these two locations, harvesting from the anterior iliac crest has which of the following? Review Topic

QID: 362
1

Less severe postoperative pain at the surgical site

10%

(96/972)

2

Decreased postoperative gait abnormalities

15%

(147/972)

3

Increased complication rates as compared to posterior harvesting

55%

(537/972)

4

Decreased postoperative pain duration

7%

(72/972)

5

Increased cancellous bone graft density

12%

(116/972)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

(OBQ05.62) Which of the following groups correctly identifies serologic tests that are required by the American Association of Tissue Banks (AATB) for musculoskeletal tissue allografts? Review Topic

QID: 948
1

Cytomegalovirus, Hepatitis A, Hepatitis B, Hepatitis C, HIV, Syphillis

15%

(48/315)

2

Cytomegalovirus, Hepatitis A, Hepatitis B, Hepatitis C, HIV

23%

(73/315)

3

Hepatitis A, Hepatitis B, Hepatitis C, HIV, Syphillis

5%

(16/315)

4

Hepatitis B, Hepatitis C, HIV, Syphillis

37%

(115/315)

5

Hepatitis B, Hepatitis C, HIV

20%

(62/315)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

(OBQ11.48) Which of the following is true of both calcium phosphate and calcium sulfate? Review Topic

QID: 3471
1

They have high resistance to shear forces

5%

(80/1665)

2

They have high resistance to torsional forces

2%

(39/1665)

3

They are contraindicated in spinal fusion

7%

(111/1665)

4

They provide a scaffold for bone progenitor cells

84%

(1401/1665)

5

They are not biocompatible with stainless steel orthopedic implants

2%

(25/1665)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

(OBQ06.150) Which of the following bone graft substitutes has the fastest resorption characteristics? Review Topic

QID: 336
1

Calcium sulfate

78%

(1399/1793)

2

Tricalcium phosphate

10%

(185/1793)

3

Hydroxyapatite

6%

(109/1793)

4

Fibular allograft

1%

(19/1793)

5

Cortical iliac crest autograft

4%

(74/1793)

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

(OBQ12.266) Which of the following graft materials has the least potential to elicit an immune response? Review Topic

QID: 4626
1

Fresh irradiated corticocancellous bulk allograft

15%

(597/3865)

2

Fresh frozen fibular strut allograft

1%

(48/3865)

3

Fresh frozen Achilles tendon allograft

2%

(75/3865)

4

Fresh Achilles tendon allograft

2%

(78/3865)

5

Freeze dried cancellous bone chips

78%

(3034/3865)

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

(OBQ05.147) You are considering using a frozen allograft distal femoral condyle in your reconstruction of a massive giant-cell tumor of the knee. In counseling your patient regarding the risks of allografts, you explain that 5 years after transplantation, what percentage of donor chondrocytes will be present and viable in the allograft? Review Topic

QID: 1033
1

1-5%

13%

(57/430)

2

6-20%

14%

(59/430)

3

21-50%

12%

(51/430)

4

greater than 50%

8%

(33/430)

5

None, by 5 years the allograft cartilage will be completely acellular

53%

(227/430)

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

(OBQ11.267) A 20-year-old male is involved in motor vehicle collision and sustains a depressed tibial plateau fracture. When performing surgery, if calcium sulfate is used as the primary bone substitute void filler, an increase in which of the following outcomes may be expected as compared to autograft? Review Topic

QID: 3690
1

Increased complications due to serous drainage

58%

(1459/2514)

2

Improved clinical outcomes as shown by more rapid time to healing

4%

(105/2514)

3

Improved clinical outcomes as shown by SF-36 scores

3%

(74/2514)

4

Increased complications due to autoimmune reactions and graft rejection

2%

(57/2514)

5

Equivalent complication rates and clinical outcomes

32%

(804/2514)

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

(OBQ06.261) What is the approximate risk of transmission of HIV in fresh-frozen allograft bone? Review Topic

QID: 272
1

1 in 10,000,000

13%

(47/374)

2

1 in 1,000,000

79%

(294/374)

3

1 in 100,000

7%

(26/374)

4

1 in 50,000

1%

(4/374)

5

1 in 10,000

1%

(2/374)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

(OBQ04.274) Which of the following substances is most osteoinductive? Review Topic

QID: 1379
1

Calcium phosphate

3%

(42/1410)

2

Hydroxyapatite

4%

(57/1410)

3

Xenograft collagen sheet

3%

(43/1410)

4

Cancellous allograft

2%

(27/1410)

5

Cancellous autograft

88%

(1239/1410)

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

(OBQ10.166) Which of the following osteoconductive bone graft substitutes resorbs faster than the rate at which bone growth occurs? Review Topic

QID: 3259
1

Coralline hydroxyapatite

4%

(90/2311)

2

Collagen-based matrix with hydroxyapatitie coating

7%

(173/2311)

3

Calcium phosphate

13%

(299/2311)

4

Calcium sulfate

69%

(1600/2311)

5

Tricalcium phosphate

6%

(144/2311)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4
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