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 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) Types of 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 Type of synthetics Silicate based grafts Aluminum oxide Alumina ceramic bonds bind to bone in response to stress and strain Calcium phosphate 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), MONTAGE Calcium sulfate Osteoconductive only 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) DBM and Bone Growth Factors Demineralized Bone Matrix Osteoinductive and osteoconductive Contains: collagen, bone morphogenetic proteins, transforming growth factor-beta, residual calcium Does NOT contain mesenchymal precursor cells BMP TGF-B IGF-II PDGF see Rank-L and Bone Growth Factors 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 increased stem cell concentration with posterior harvesting 2% to 36% complication rate blood loss and hematoma injury to superior gluteal artery 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 two years 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 osteoinductive despite loss of some 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 solely stimulates undifferentiated perivascular mesenchymal cells to differentiate into osteoblasts through serine-threonine kinase receptors Platelet rich plasma (PRP) (like other BMPs) solely osteoinductive 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 complications higher volume blood loss and transfusion rate compared to iliac crest autologous bone grafting 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 to 1,670,000 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