Bone Grafting and Bone Graft Substitutes Original Author: James Krieg, MD Revision Author: David Hak, MD Last Revision May 2010

Bone Graft Function Structural support of articular fracture Tibial plateau fracture Prevent post-op collapse Void filler to prevent fracture Cyst excision Improved healing of fracture and nonunions Speed healing Fewer nonunions Bone grafts, and bone graft substitutes, are used primarily for three main purposes. One, to provide structural support, such as after elevation of a depressed tibial plateau fracture. Second, to fill a void, such as after excision of a bone cyst in an area that does not demand any structural support. Third, to improve fracture healing. Either by speeding healing or increasing the successful union rate.

Mechanisms of Bone Growth Osteoconduction Provides matrix for bone growth Osteoinduction Growth factors encourage mesenchymal cells to differentiate into osteoblastic lineages Osteogenesis Transplanted osteoblasts and periosteal cells directly produce bone

Types of Bone Grafts Autograft Allograft Bone graft substitutes Most have osteoconductive properties Osteoinductive agents rhBMP-2 (Infuse) and rhBMP-7 (OP-1)

Autogenous Bone Graft “Gold standard” Standard by which other materials are judged May provide osteoconduction, osteoinduction and osteogenesis Drawbacks Limited supply Donor site morbidity

Autogenous Bone Grafts Cancellous Cortical Free vascular transfers Bone marrow aspirate The most common form of autogenous bone graft is cancellous bone, usually harvested from either anterior or posterior iliac crests, but which also may be harvested locally such as in the proximal tibia or distal radius. Cortical bone strips may be harvested from the inner table of the pelvis. Occasionally a vascularized bone graft may be used, such ass a free fibular transfer. Another option for obtaining osteogenic cells is by bone marrow aspirate.

Cancellous Bone Grafts Three dimensional scaffold (osteoconductive) Osteocytes and stem cells (osteogenic) A small quantity of growth factors (osteoinductive) Little initial structural support Can gain support quickly as bone is formed

Cortical Bone Grafts Less biologically active than cancellous bone Less porous, less surface area, less cellular matrix Prologed time to revascularizarion Provides more structural support Can be used to span defects Vascularized cortical grafts Better structural support due to earlier incorporation Also osteogenic, osteoinductive Transported periosteum

Bone Marrow Aspirate Osteogenic Mesenchymal stem cells (osteoprogenitor cells) exist in a 1:50,000 ratio to nucleated cells in marrow aspirate Numbers decrease with advancing age Can be used in combination with an osteoconductive matrix

Autograft Harvest Cancellous Iliac crest (most common) Anterior- taken from gluteus medius pillar Posterior- taken from posterior ilium near SI joint Metaphyseal bone May offer local source for graft harvest Greater trochanter, distal femur, proximal or distal tibia, calcaneus, olecranon, distal radius, proximal humerus

Autograft Harvest Cancellous harvest technique Cortical window made with osteotomes Cancellous bone harvested with gouge or currette Can be done with trephine instrument Circular drills for dowel harvest Commercially available trephines or “harvesters” Can be a percutaneus procedure

Autograft Harvest Cortical Fibula common donor Iliac crest Avoid distal fibula to protect ankle function Preserve head to keep LCL, hamstrings intact Iliac crest Cortical or tricortical pieces can be harvested in shape to fill defect

Bone Allografts Cancellous or cortical Plentiful supply Limited infection risk (varies based on processing method) Provide osteoconductive scaffold May provide structural support

Bone Allografts Available in various forms Fresh Fresh Frozen Processing methods may vary between companies / agencies Fresh Fresh Frozen Freeze Dried

Bone Allografts Fresh Highly antigenic Limited time to test for immunogenicity or diseases Use limited to joint replacement using shape matched osteochondral allografts

Bone Allografts Fresh frozen Less antigenic Time to test for diseases Strictly regulated by FDA Preserves biomechanical properties Good for structural grafts

Bone Allografts Freeze-dried Even less antigenic Time to test for diseases Strictly regulated by FDA Can be stored at room temperature up to 5 years Mechanical properties degrade

Graft Incorporation Hematoma formation Release of cytokines and growth factors

Graft Incorporation Hematoma formation Inflammation Release of cytokines and growth factors Inflammation Development of fibrovascular tissue

Graft Incorporation Hematoma formation Inflammation Vascular ingrowth Release of cytokines and growth factors Inflammation Development of fibrovascular tissue Vascular ingrowth Often extending Haversian canals

Graft Incorporation Hematoma formation Inflammation Vascular ingrowth Release of cytokines and growth factors Inflammation Development of fibrovascular tissue Vascular ingrowth Often extending Haversian canals Focal osteoclastic resorption of graft

Graft Incorporation Hematoma formation Inflammation Vascular ingrowth Release of cytokines and growth factors Inflammation Development of fibrovascular tissue Vascular ingrowth Often extending Haversian canals Focal osteoclastic resorption of graft Intramembranous and/or endochondral bone formation on graft surfaces

Graft Incorporation Cancellous bone interface between graft and host bone

Graft Incorporation Cortical allograft strut graft placed next to cortex of host After 4 years of incorporation

Bone Graft Substitute Incorporation Partial incorporation of hydroxyapatite bone graft substitute\ Biopsy of material obtained 1 year post-op

Bone Graft Substitutes Need for bone graft alternatives has lead to development of numerous bone graft substitutes Avoid morbidity of autogenous bone graft harvest Mechanical properties vary Most offer osteoconductive properties Some provide osteoinductive properties

Bone Graft Substitutes Potential Roles Extender for autogenous bone graft Large defects Multiple level spinal fusion Enhancer To improve success of autogenous bone graft Substitute To replace autogenous bone graft

Bone Graft Substitutes Calcium phosphate Calcium sulfate Collagen based matrices Demineralized bone matrix Hydroxyapatite Tricalcium phosphate Osteoinductive proteins

Bone Graft Substitutes Resorption rates vary widely Dependant on composition Calcium sulfate - very rapid Hydroxyapatite (HA) – very, very slow Some products may be combined to optimize resorption rate Also dependant on porosity, geometry

Bone Graft Substitutes Mechanical properties vary widely Dependant on composition Calcium phosphate cement has highest compressive strength Cancellous bone compressive strength is relatively low Many substitutes have compressive strengths similar to cancellous bone All designed to be used with internal fixation

Calcium Phosphate Injectable pastes of calcium and phospate Norian SRS (Synthes/Stratec) Alpha BSM (Etex/Depuy) Callos Bone Void Filler (Skeletal Kinetics) Calcium phosphate products are an injectable paste of calcium and phosphate. Norian SRS was the first such product available and is marketed by Synthes / Stratec. Two other calcium phosphate type products are also available in the U.S.

Calcium Phosphate Injectable Very high compressive strength once hardens Some studies of its use have allowed earlier weightbearing and range of motion

Calcium Sulfate Osteoconductive void filler Low compressive strength – no structural support Rapidly resorbs May be used as a autogenous graft extender Available from numerous companies Osteoset, Calceon 6, Bone Blast, etc. Medical grade calcium sulfate is an osteoconductive void filler. It has low compressive strength so doesn’t offer structural support. Another disadvantage of the product is that it resorbs rather rapidly, perhaps more rapidly then it can be replaced by new bone. One way it which it may be used is an extender for autogenous bone graft.

Calcium Sulfate Pellets Pellet injectors Bead kits Allows addition of antibiotics Injectable May be used to augment screw purchase Calcium sulfate products are available both as pellets, bead kits, and injectable preparations. The pellets can be poured into position, but some companies also provide an injector apparatus. The bead kits allow the addition of antibiotics if desired.

Collagen Based Matrices Highly purified Type 1 bovine dermal fibrillar collagen Bone marrow is added to provide bone forming cells Collagraft (Zimmer) Collagen / HA / Tricalcium phosphate Healos (Depuy) Collagen / HA

Demineralized Bone Matrix Prepared from cadaveric human bone Acid extraction of bone leaving Collagen Noncollagenous proteins Bone growth factors BMP quantity extremely low and variable Sterilized which may decrease the availability of BMP

Demineralized Bone Matrix Available from multiple vendors in multiple preparations Gel Putty Strip Combination products with cancellous bone and other bone graft substitute products

Demineralized Bone Matrix Growth factor activity varies between tissue banks and between batches While they may offer some osteoinductive potential because of available growth factors, they mainly act as an osteoconductive agents Han B et al. J Orthop Res. 21(4):648-54, 2003. Blum B, et al. Orthopedics. 27 (1 Suppl): S161 – S165, 2004.

Coralline hydroxyapatite Produced from marine coral exoskeletons that are hydrothermically converted to hydroxyapatite, the natural mineral composition of bone Interconnected porous structure closely resembles the porosity of human cancellous bone Cancellous Bone Coralline hydroxyapatite

Hydroxyapatite Marketed as ProOsteon by Interpore Cross Available in various size blocks & granules ProOsteon 500 Very slow resorption ProOsteon 500 R Only a thin layer of HA Faster resorption

Tricalcium Phosphate Wet compressive strength slightly less than cancellous bone Available as blocks, wedges, and granules Numerous tradenames Vitoss (Orthovita) ChronOS (Synthes) Conduit (DePuy) Cellplex TCP (Wright Medical) Various Theri__ names (Therics)

Bone Morphogenetic Proteins Produced by recombinant technology Two most extensively studied and commercially available BMP-2 (Infuse) Medtronics BMP-7 (OP-1) Stryker Biotech Two bone morphogenetic proteins are commercially available. These are BMP-2,marketed by Medtronics, and BMP-7, more commonly known of osteogenic protein 1, produced by Stryker Biotech. These products are produced by recombinant technology in which large quantities of the material are produced in cell culture.

BMP-2 for Open Tibial Fractures Prospective, randomized study 450 patients All received IM nail (vast majority with UNREAMED technique) and appropriate soft tissue management Randomized to 3 treatments at time of definitive wound closure Placebo 0.75 mg/ml BMP-2/ACS 1.50 mg/ml BMP-2/ACS BMPs have been studies in several human investigations including open fractures and nonunions. BMP-2 was studied in a prospective, randomized study of 450 patients with open tibial shaft fractures treated with fracture debridement and an IM nail. At the time of definitive wound closure patients were randomized to one of three treatments placebo 0.75 mg/ml BMP-2/ACS (lower BMP dose) 1.50 mg/ml BMP-2/ACS (higher BMP dose) BESTT Study Group, et al. J Bone Joint Surg 84A: 2123, 2002.

BESTT Study Group, et al. J Bone Joint Surg 84A: 2123, 2002. Results 44% reduction in risk of nonunion/delayed union with high dose BMP-2 Significantly faster fracture healing Significantly fewer invasive interventions hardware failures infections The primary outcome measure was the proportion of patients requiring secondary intervention because of delayed union or nonunion within twelve months postoperatively. In the group treated with the higher dose BMP-2 there was a 44% reduction in risk of nonunion/delayed union Significantly faster fracture healing Significantly fewer invasive interventions Significantly fewer hardware failures and fewer infections The graph from their publication shows the placebo control groups in black representing the standard of care. The Gustilo IIIB's are on the left and the Gustilo I, II and IIIA's on the right. There is a statistically significant reduction in the number of secondary interventions in those fractures treated with the higher dose of BMP-2. BESTT Study Group, et al. J Bone Joint Surg 84A: 2123, 2002.

Indications for Bone Graft Provide mechanical support Metaphyseal impaction 27 y.o male with lateral split/depression tibial plateau fracture. Note posterolateral depression.

Indications for Bone Graft Provide mechanical support Metaphyseal impaction ORIF with allograft cancellous bone chips to fill defect and support depressed area Alternatively could use any osteoconductive substitute with similar compressive strength

Indications for Bone Graft Provide mechanical support Metaphyseal impaction 4 months s/p surgery and the graft is well incorporated.

Indications for Bone Graft Provide mechanical support Metaphyseal impaction Replace bone Cortical or segmental defect 29 y.o male with defect s/p IMN Type IIIB open tibia fracture. Gentamicin PMMA beads were used as spacers and removed.

Indications for Bone Graft Provide mechanical support Metaphyseal impaction Replace bone Cortical or segmental defect s/p bone grafting with iliac crest autograft.

Indications for Bone Graft Provide mechanical support Metaphyseal impaction Replace bone Cortical or segmental defect 14 months after injury, the fracture is healed and the nail removed.

Indications for Bone Graft Provide mechanical support Metaphyseal impaction Replace bone Cortical or segmental defect Stimulate healing Atrophic and Oligotrophic Nonunions 26 y.o. woman with established atrophic nonunion of the clavicle.

Indications for Bone Graft Provide mechanical support Metaphyseal impaction Replace bone Cortical or segmental defect Stimulate healing Atrophic and Oligotrophic Nonunions Plating with cancellous iliac crest autograft.

Indications for Bone Graft Provide mechanical support Metaphyseal impaction Replace bone Cortical or segmental defect Stimulate healing Atrophic and Oligotrophic Nonunions 6 months after surgery, she is healed and asymptomatic.

Indications for Bone Graft Provide mechanical support Metaphyseal impaction Replace bone Cortical or segmental defect Stimulate healing Nonunions Arthrodesis Failed subtalar arthrodesis

Indications for Bone Graft Provide mechanical support Metaphyseal impaction Replace bone Cortical or segmental defect Stimulate healing Nonunions Arthrodesis Repeat fusion with autogenous iliac crest.

Indications for Bone Graft Provide mechanical support Metaphyseal impaction Replace bone Cortical or segmental defect Stimulate healing Nonunions Arthrodesis 6 months after surgery, fused successfully

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