synthetic CANCELLOUS BONE technical monograph Presented by Barbara Blum, Ph.D.

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2 C E L L P L E X TCP synthetic CANCELLOUS BONE technical monograph Presented by Barbara Blum, Ph.D.

3 TECHNICAL MONOGRAPH CELLPLEX TCP SYNTHETIC CANCELLOUS BONE CELLPLEX TCP synthetic CANCELLOUS BONE introduction Autograft is considered the gold standard for grafting bone deficits. There is, however, significant morbidity associated with the harvest procedure. 2-4 Often the patient complains more about the harvest site than the treatment site. Additionally, a higher cost of care must be considered with an autograft harvest. 5, 6 Historically, surgeons seeking alternatives to autograft have turned to allograft for structural and /or osteoconductive bone repair uses, or as an autograft substitute. As technology advances in bone grafting, synthetic alternatives are being relied upon more frequently to augment or replace autograft and/or allograft. Specifically, surgeons are looking for a synthetic bone replacement and regenerative material that more naturally resembles cancellous bone in structure and chemical makeup. Calcium phosphate ceramics have been the target of investigation for decades due to their compositional correlation to the mineral component of natural bone. The conversion of tricalcium phosphate (TCP) into a non-stoichiometric apatite in aqueous solutions may more closely simulate the apatite structure naturally found in bone. 7 Although early studies involving calcium phosphate as a bone graft date back to 1920, continuous investigation of calcium phosphates began through studies initiated at the Battelle Memorial Institute Columbus Laboratory in Since then, studies have centered on calcium phosphate materials, including hydroxyapatite (HA) and tricalcium phosphate (TCP) as coatings, porous constructs, or solid pieces. History dictates that many factors, including the porosity and chemical composition of a biomaterial are paramount to implant behavior. 9 The chemical structure Ca 3 (PO 4 ) 2 of TCP allows for faster resorption than less reactive HA structures. Such bioactive qualities of calcium phosphates serve as the foundation for materials proven clinically effective in otologic, dental, and orthopaedic applications. 9 one

4 TECHNICAL MONOGRAPH CELLPLEX TCP SYNTHETIC CANCELLOUS BONE CELLPLEX TCP Graft is a synthetic cancellous bone replacement scaffold that integrates an interconnected porous environment for cellular infiltration with the bioactive properties of a TCP. Comprised of both -TCP and -TCP, this biphasic tricalcium phosphate ceramic has been engineered to support new bone formation through faster resorption profiles than single phase HA and -TCP graft materials and has demonstrated excellent biocompatibility and osteoconductive potential CELLPLEX TCP Synthetic Cancellous Bone - Anatomic pore size and structure - Affinity for cellular attachment 9 - Scaffold for new bone regeneration throughout the implanted matrix A patented processing technique results in a bone graft substitute resulting in key functional characteristics: Anatomically engineered pore structure - Optimal environment for cellular repopulation and differentiation - Retain infused marrow True interconnected porosity - Intimate bone growth throughout implant scaffold Tailored biphasic composition - Graft composition conducive to bone formation two

5 T E C H N I C A L M O N O G R A P H C E L L P L E X TCP S Y N T H E T I C C A N C E L L O U S B O N E technical SPECIFICATIONS These two images demonstrate MSC s (Mesenchymal Stem Cells) in intimate contact with the CELLPLEX TCP Scaffold. 1. Anatomically engineered pore structure Definitive pore size range (50-500µm, majority between µm) allows for maximum infiltration and cell seeding from bone marrow throughout the TCP scaffold Bioengineered pore structure similar to human cancellous bone, which has been reported to range between µm9 2. Interconnected porosity Mimics the trabecular structure of human cancellous bone and allows new bone regeneration throughout implant Interconnected pores provide adequate fluid flow and nutrient support FIGURE 3 Cancellous Bone FIGURE 1 30 minutes 100µm FIGURE 4 CELLPLEX TCP Synthetic Cancellous Bone FIGURE 2 3 days 100µm FIGURE 5 Competitive TCP Scanning electron microscopy (SEM) comparing the threedimensional structure of cancellous bone, CELLPLEX TCP, Graft and a competitive TCP product. CELLPLEX TCP Graft is similar to cancellous bone in pore size and interconnective structure. 100µm three

6 TECHNICAL MONOGRAPH CELLPLEX TCP SYNTHETIC CANCELLOUS BONE 3. Viable compressive strength Resistance to crushing maintains system properties Crushed matrices lose three-dimensional architecture, resulting in lower fluid retention 4. Tailored biphasic composition Biphasic tricalcium phosphate composition combines both - and -TCP capabilities to provide predictable resorption profiles CELLPLEX TCP Synthetic Cancellous Bone FIGURE 6 While not for use in an application where the implant is intrinsic to the stability to the bone, CELLPLEX TCP Graft provides a higher compressive strength than a competitive TCP, which maintains the three-dimensional scaffolding and retains fluid carrying capacity during packing. Competitive TCP Average values shown. The minimum compressive strength specification is 0.5 MPa. REVERSE-ENGINEERING AUTOGRAFT CELLPLEX TCP Graft is packaged in the INFILTRATE Marrow Infusion Chamber. Practical handling methods - Easy, effective mixing with bone marrow aspirate (BMA) - No additional components needed to aspirate and mix with BMA Increased osteogenic potential - Retained cells and cell signaling proteins in added BMA provide osteogenic potential - Three-dimensional structure maximizes osteoconductive capacity FIGURE 7 FIGURE 8 FIGURE 9 CELLPLEX TCP Graft comes packaged in the INFILTRATE Marrow Infusion Chamber with the aspiration components. Bone marrow aspiration and composite mixing is as simple as : 1) Aspirate BMA 2) Inject into chamber and allow to clot 3) Express CELLPLEX TCP/BMA biocomposite for implantation four

7 TECHNICAL MONOGRAPH CELLPLEX TCP SYNTHETIC CANCELLOUS BONE pre-clinical RESULTS SPINE Sheep Posterolateral Lumbar Fusion CELLPLEX TCP Graft was evaluated in a preliminary ovine posterolateral lumbar fusion model, and was found to perform comparable to autograft. Each animal (n=10) received both treatments. In the CELLPLEX TCP Graft sites, one strip (10cm x 5cm x 1cm) was placed on each side between the transverse processes. Autograft sites received morselized autograft harvested from the iliac crest. Animals were sacrificed at 20 weeks. FIGURE 10A Fusion and presence of new bone were determined from radiographs and computerized tomography (CT) scans by four independent observers. Motion analysis consisted of measuring flexion/ extension, lateral bending, and axial rotation in treated segments vs. intact segments. Fusion was defined as radiographic evidence of bone bridging the gap between transverse processes, and as decreased motion compared to normal controls. Bone formation and fusion were confirmed by histology of nondecalcified specimens. FIGURE 10B These images demonstrate bridging bone between the transverse processes in the CELLPLEX TCP Graft (10A) and autograft (10B) specimens at 20 weeks. RESULTS AT 20 WEEKS CELLPLEX TCP Synthetic Cancellous Bone Autograft Radiographic bone formation 9/10 sheep (90%) 7/10 (70%) Radiographic fusion rates 5/10 (50%) 3/10 (30%) CT analysis of bridging bone 1.0cm 0.5cm In this model, motion analysis demonstrated a decrease in flexion/extension, bending and rotation in treated segments when compared to a normal control, indicating fusion of motion segments. The authors concluded that CELLPLEX TCP Graft supported new bone growth and fusion as well as the gold standard autograft in the ovine posterolateral fusion model. 10 five

8 TECHNICAL MONOGRAPH CELLPLEX TCP SYNTHETIC CANCELLOUS BONE TRAUMA Segmental defects are widely regarded as a difficult healing scenario due to the nature of the defect: FIGURE 11 The diaphyseal segmental defect shown here stabilized with the external fixator and CELLPLEX TCP Graft in place. 1. These defects are typically in diaphyseal regions where vascularity is poor 2. Often a critical sized defect; i.e. bone repair is not spontaneous 3. Managing the defect space to prevent fibrous tissue infiltration is critical to healing For these reasons, utilizing a segmental defect in an animal model provides a clinically relevant measure of bone regenerative capacity for a synthetic bone replacement, such as CELLPLEX TCP Graft. A 1.0 cm defect was created in the left tibia of skeletally mature, male New Zealand White rabbits (n=12/group). 11 An external fixator was applied across each defect and the gap was filled with CELLPLEX TCP Graft cylinders (7.5 mm OD/ 3.5 mm ID x 10mm), intact tibial autograft, crushed tibial autograft, or no implant. The intact tibial autograft was used to represent an ideal cylindrical graft. Animals were sacrificed at six weeks and evaluated by radiography, torsional testing, and histology. An additional CELLPLEX TCP group was sacrificed at eight weeks. From antero-posterolateral and lateral-oblique radiographs, callus formation and adequacy of fixation was assessed by grading the density of the graft site (1=dense as adjacent cancellous bone; 5=dense as adjacent cortical bone). Torsional strength and torsional stiffness were measured by torquing implant sites at a rate of 2º/ second until failure. The intact contralateral limb was also tested, and strength and stiffness values were expressed as the ratio of values for the treated tibia vs. values for an internal (normal) control. ANOVA methods were used to determine statistical significance (p<0.05). By eight weeks, mean radiographic density of the CELLPLEX TCP Graft sites was 4.6 (vs. 5 for intact bone). At the early time point (six weeks), sites treated with CELLPLEX TCP Graft cylinders demonstrated torsional strength that actually exceeded both autograft groups, and torsional stiffness was comparable to autograft. six

9 TECHNICAL MONOGRAPH CELLPLEX TCP SYNTHETIC CANCELLOUS BONE Torsional Strength - Ratio of Experiment to Unoperated Leg (100% is equal to un-operated leg; <100% is weaker, >100% is stronger) Specimen 6 Weeks 8 Weeks P-Value of TCP implant to controls CELLPLEX TCP 171% 185.2% NA Synthetic Cancellous Bone Intact Autograft 116% = < 0.02 Crushed Autograft 114% = < Open Defect 56% = < Data not collected. Nondecalcified specimens were embedded in plastic, cut, and stained with hematoxylin and eosin (H&E), or toluidine blue. Images of three serial sections from each implant were digitized. In each section, areas of bone and implant were measured in ten regions using Scion image software. Values of all three-dimensional regions of an implant were averaged. Histomorphometry measurements indicated that a mean of 59% CELLPLEX TCP Graft implant had resorbed by six weeks, and 62% had resorbed by eight weeks. At six weeks, histological evaluation of the CELLPLEX TCP Graft sites demonstrated complete bony ingrowth with little or no unmineralized osteoid. The amount of callus indicated normal remodeling and no signs of inflammation were detected. At eight weeks, some areas of resorbed implant were replaced by osteoid FIGURE These studies indicate that CELLPLEX TCP Synthetic Cancellous Bone is a viable alternative to autogenous bone in an ovine spinal fusion model and in the repair of traumatic defects in a rabbit. 10, 11 FIGURE 12 Time 6 WEEKS. Newly woven bone in direct apposition to residual CELLPLEX TCP implant (black). seven

10 TECHNICAL MONOGRAPH CELLPLEX TCP SYNTHETIC CANCELLOUS BONE CONCLUSIONS CELLPLEX TCP Graft is a tricalcium phosphate that closely mimics human cancellous bone in anatomic pore size and structure. The material has an affinity 9 for mesenchymal stem cells and functions as an osteoconductive scaffold for new bone regeneration. Packaged in the INFILTRATE Marrow Infusion Chamber, CELLPLEX TCP Graft may be easily combined with bone marrow aspirate to offer increased osteogenic potential for demanding clinical applications. COMPREHENSIVE GRAFTING SOLUTIONS CELLPLEX TCP Synthetic Cancellous Bone supports new bone growth in a variety of clinical applications, while eliminating the morbidity associated with harvesting autologous bone. This material platform is only one of many bone grafting solutions offered by Wright in our global effort to be the principal source for today s demanding grafting needs. eight

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12 REFERENCES 1. LeGeros RZ. Properties of Osteoconductive Biomaterials: Calcium Phosphate. Clin Orthop Rel Res 2002; 305: Fernyhough JC, Schimandle JJ, Weigel MG, et. al. Chronic donor-site pain complicating bone graft harvesting from the posterior iliac crest for spinal fusion. Spine 1992; 17: Fowler BL, Dall BE, Rowe DE. Complications associated with harvesting autogenous iliac crest bone graft. Am J of Orthop 1995; Dec: Laurie SWS, Kaban LB, Mulliken JB, Murray JE. Donor-site morbidity after harvesting rib and iliac bone. Plast Reconstr Surg 1984; 73: Scranton PE. Use of bone graft substitutes in lower extremity reconstructive surgery. Foot and Ankle INT 2002; 23(8): Shors EC. Coralline bone graft substitutes. Ortho Clinics North Am 1999; 30(4): Yubao L, Xingdong Z, de Groot K. Hydrolysis and phase transition of alpha-tricalcium phosphate. Biomaterials 1997; 18: Driskell TD. Early History of Calcium Phosphate Materials and Coatings, Characterization and Performance of Calcium Phosphate Coatings for Implants, ASTM STP Emanuel Horowitz and Jack E. Parr, Eds., American Society for Testing and Materials, Philadelphia, LeGeros RZ et al. Significance of the Porosity and Physical Chemistry of Calcium Phosphate Ceramics: Biodegradation-Bioresorption. Bioceramics: material characteristics versus in vivo behavior. Ducheyne P, Lemons J, Eds., New York: NY: Academic Science, p Fredericks DC, et al. In vivo evaluation of sintered porous ceramic material for intertransverse process fusion in the sheep model. IMAST, Fredericks DC, et al. In vivo evaluation of bone substitute in a rabbit tibial defect model. OTA, Wright Medical Technology, Inc Airline Road Arlington, TN USA Wright Medical EMEA Hoogoorddreef BA Amsterdam The Netherlands Trademarks and Registered trademarks of Wright Medical Technology, Inc Wright Medical Technology, Inc. All Rights Reserved. SK