AAOS Comprehensive Orthopaedic Review

Section 1 - Basic Science

Chapter 12. Bone Grafting/Bone Graft Substitutes

I. Bone Grafting

A. Bone graft may be considered for a number of different applications:


1. To facilitate healing of fractures, delayed unions, or nonunions.


2. To induce fusion of osseous structures that are normally independent (

Figure 1).


3. To replace bone defects secondary to trauma, tumor, or wear.


B. Bone grafting properties—Bone grafts may be osteogenic, osteoinductive, or osteoconductive.


1. Osteogenic


a. Osteogenic graft material directly provides cells, which go on to produce bone.


b. Osteoprogenitor cells can proliferate and differentiate to osteoblasts and eventually to osteocytes. Mesenchymal stem cells have the potential to go down any differentiation route, including bone formation.


c. Because cancellous bone has a larger surface area, it has a greater potential for forming new bone than does cortical bone.


d. Bone marrow aspirate and autologous bone graft are osteogenic.


2. Osteoinductive


a. Osteoinductive graft material has factors that induce progenitor cells down a bone-forming lineage.


   *Hyun Bae, MD, or the department with which he is affiliated has received research or institutional support from Stryker, has received miscellaneous nonincome support, commercially-derived honoraria, or other nonresearch-related funding from Abbott, has received royalties from Biomet, holds stock or stock options in LDR, Spinal Restoration, and Paradigm, and is a consultant for or an employee of Stryker and Zimmer.


b. This is most commonly seen with a family of proteins known as bone morphogenetic proteins (BMPs).


3. Osteoconductive


a. Osteoconductive bone graft serves as a scaffold onto which new bone can form.


b. The three-dimensional configuration and building-block material will dictate the osteoconductive properties.


c. Demineralized bone matrices (DBMs) are osteoconductive.


[Figure 1. L4-S1 instrumented fusion with bone graft seen in the posterolateral gutters.]


Figure 2. Reparative bone healing with osteoblasts lining new trabecular bone spicules.]

II. Bone Healing

A. Bone formation involves three phases:


1. Inflammation (early)


a. Hematoma formation and inflammation occur rapidly in the early phases of bone repair.


b. Surface osteocytes may survive and are important in synthesizing new bone during this initial phase.


c. Infiltrate consists principally of small mono-nuclear cells.


d. Capillary ingrowth is initiated.


e. BMPs play an important role in inducing host mesenchymal stem cells to migrate into the repair site.


2. Reparative (middle) (Figure 2)



New bone formation takes the form of immature woven bone (soft callus).



Table 1. Characteristics of Bone Grafts and Grafting Substitutes]


Seams of osteoid surround the core of necrotic bone and form viable new bone (hard callus).


3. Remodeling (late)


a. Coupled resorption and replacement occur.


b. Remodeling is influenced by Wolff's law and is usually complete by 1 year.


B. Factors that impair bone healing


1. Motion at the site of attempted union


2. Lack of blood supply, which is generally associated with an anatomic site or stripping from injury or surgical dissection


3. Nonsteroidal anti-inflammatory drugs


4. Smoking


5. Nonapposition of bone ends

III. Bone Graft Options (Table 1)

A. Autograft is tissue transferred from one site to another in the same individual and is commonly regarded as the gold standard bone graft material.


1. Autograft is osteogenic, osteoinductive, and osteoconductive.


2. Autograft may be cortical, cancellous, or corticocancellous; this may be nonvascular or vascularized.


a. Cortical autograft has the advantage of being able to provide structural support.


b. Cancellous autograft provides less structural support but greater osteoconduction and potentially greater osteogenesis and osteoinduction.


3. The iliac crest is the most frequent autograft donor site (iliac crest bone graft [ICBG])


a. It has the potential to provide abundant cancellous and/or cortical graft.


b. Complications have been associated with ICBG in 2% to 36% of cases. These include hematoma formation, blood loss, injury to the lateral femoral cutaneous nerve or cluneal nerve, hernia formation, infection, fracture, cosmetic defects, and sometimes chronic pain at the donor site.


4. Other bone graft sources include the ribs, fibula, and tibial metaphysis. The fibula and rib are the most common potentially vascularized options considered.


B. Allograft is tissue harvested from a cadaver, processed, and then implanted into another individual of the same species.


1. Allograft is the most frequently chosen bone substitute in the United States.


2. Allograft can be cortical, cancellous, or corticocancellous.


3. Allograft lacks viable cells and therefore does not provide osteogenic properties, nor is it osteoinductive.


4. The extent of osteoconductive properties, as well as mechanical strength, depends in part on the method of graft processing (ie, fresh, frozen, or freeze-dried form) and whether it is cortical or cancellous.


5. The quoted rate of potential HIV disease transmission is 1 per million.


6. Several different types of allograft may be considered.


a. Fresh allograft


i. Rarely used because of immune response and potential disease transmission.


ii. Fresh allograft may be cleaned and processed to remove cells and reduce the host immune reaction. This has been shown to improve incorporation.


b. Frozen or freeze-dried allograft


i. Reduces immunogenicity


ii. Maintains the osteoconductive properties and potentially some limited osteoinductive capabilities


c. Demineralized bone matrix


i. DBM is allograft treated with a mild acid extraction to remove the mineral content of bone, but leaving behind the collagenous structure and noncollagenous proteins.


ii. The osteoinductive molecules are potentially preserved, but they have minimal or no osteoinductive activity.


iii. DBMs are osteoconductive and serve as a scaffold for new bone.


iv. These extracts are combined with carriers such as collagen, gelatin, hyaluronic acid, and glycerol.


v. Evidence has shown significant interproduct and interlot variability of DBM products.


7. The use of allograft has increased 15 fold over the past decade. Its increasing availability has made it possible to manufacture customized types, such as dowels, strips, chips, and powder. DBMs do not provide structural support.


8. The shelf life of fresh frozen bone stored at -20° C is 1 year; it is 5 years if stored at -70° C. The shelf life of freeze-dried bone is indefinite.


C. Collagen


1. Collagen contributes to mineral deposition, vascular ingrowth, and growth factor binding, providing a favorable environment for bone regeneration.


2. Collagen does not provide structural support and does carry immunogenic potential.


3. Collagen functions poorly alone, but it performs better when coupled with bone. It is considered a potential carrier for BMPs, DBMs, or other graft materials.


D. Bone marrow aspirate


1. Bone marrow aspirate is a potential source of osteogenic mesenchymal precursor cells.


2. It may be from the iliac crest, vertebral body, or other sources.


3. The number of cells varies depending on variables such as host age.


4. It has been suggested that the potency of marrow aspirates could be increased via selective precursor selection, centrifugation, or clonal expansion.


E. Ceramics


1. Ceramics are inorganic compounds consisting of metallic and nonmetallic elements held together by ionic or covalent bonds.


2. There are several classes of ceramic materials.


a. Hydroxyapatite (HA)


b. Beta tricalcium phosphate (β-TCP)


c. Other molecules, such as silicone (Si)


3. Alone, ceramics possess no osteogenic or osteoinductive properties, and they have variable immediate structural support secondary to resorption.


F. Bone morphogenetic proteins


1. BMPs are members of the transforming growth factor-β (TGF-β) superfamily


2. BMPs play a key role in normal development, but they also have increasingly appreciated osteoinductive potential.


3. Two recombinant human BMPs (rhBMPs) have been approved for clinical use: rhBMP-2 and rhBMP-7 (OP-1). Their FDA-approved applications are in the long bones and spine.


4. Potential adverse effects include underproduction or overproduction of bone, exuberant inflammatory responses, and early bone resorption.

IV. Other Modalities to Enhance Bone Healing

A. Electromagnetic stimulation (EMS)


1. Bone tissue has electrical potential, known as bio-electric potential.


a. The bioelectric potential is electronegative in area of growth or healing. The area returns to neutral or electropositive as healing progresses.


b. The bioelectric potential is electronegative in areas of compression and electropositive in areas of tension.


2. Direct current electrical stimulation (DCES)—Direct current delivered through implanted electrodes.


3. Pulsed electromagnetic field (PEMF)—Alternating current delivered through an external coil used intermittently during the treatment period.


4. Capacitively coupled electrical stimulation (CCES)—Current delivered between two plates that form a magnetic field and are used throughout the treatment period.


5. The mechanism of action of EMS has not been fully resolved and may be slightly different for each type of stimulation listed above.


B. Shock wave therapy


1. Shock wave therapy theoretically creates microfractures in hypertrophic nonunions, which leads to neovascularization and osteoinduction.


2. Reported results are controversial.


C. Low-intensity ultrasound also may affect bone healing.

Top Testing Facts

1. Bone grafts may be osteogenic, osteoinductive, or osteoconductive.


2. Bone healing progresses through three stages: early (inflammation), middle (reparative), and late (remodeling).


3. Bone healing may be affected by host and local factors.


4. Autograft is the gold standard bone graft material.


5. Allograft has a reported rate of potential HIV transmission of 1 per million.


6. DBMs have been shown to have significant interproduct and interlot variability. DBMs are predominantly osteoconductive.


7. Bone marrow aspirates provide potential access to osteogenic mesenchymal precursor cells.


8. Ceramics are inorganic compounds consisting of metallic and nonmetallic elements held together by ionic or covalent bonds.


9. BMPs are potent osteoinductive factors of the TGF-β superfamily.


10. Several forms of electromagnetic stimulation may facilitate bone healing.


Bauer TW, Muschler GF: Bone graft materials: An overview of the basic science. Clin Orthop Relat Res 2000;371:10-27.

Friedlaender GE, Mankin HJ, Goldberg VM (eds): Bone Grafts and Bone Graft Substitutes. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2006.

Giannoudis PV, Dinopoulos H, Tsiridis E: Bone substitutes: An update. Injury 2005;36 (Suppl 3):S20-S27.

Miclau T III, Bozic KJ, Tay B, et al: Bone injury, regeneration, and repair, in Einhorn TA, O'Keefe RJ, Buckwalter JA (eds): Orthopaedic Basic Science, ed 3. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2007, pp 331-348.

Watson JT: New horizons in orthopaedics: A rational discussion of biologics and bone graft substitutes. Mo Med 2005; 102:240-244.