Massachusetts Institute of Technology Harvard Medical School Brigham and Women’s/Massachusetts General Hosp. VA Boston Healthcare System 2.79J/3.96J/BE.441/HST522J RESPONSE TO PARTICLES M. Spector, Ph.D. BIOMATERIALS-TISSUE INTERACTIONS Particles BIOMATERIAL TISSUE 10nm 100nm 1μm 10 μm 100 μm1mm 1 sec 1 day 10 days 100 days Size Scale Time Scale Strength Modulus of Elasticity Fracture mechanics Protein Adsorption Cell Response Ion Release Wear Metal corrosion Polymer degradation BONE Tissue Remodeling Cell-cell interactions ECM proteins Cytokines Eicosanoids Enzymes BIOMATERIALS-TISSUE INTERACTIONS: Tissue Response to Implant Breakdown Particles IMPLANT TISSUE RESPONSE Degradation Products/Ions Fracture Wear Metal Corrosion Polymer Degradation Degradation: Fibrous Tissue Bone Fibroblast Macrophage Osteoclast (Cell Contraction?) LOCAL AND SYSTEMIC RESPONSES SMALL PARTICLE DISEASE ? Local Component Osteolysis - particle induced focal destruction of bone around the prosthesis ? Systemic Component Lymphadenopathy PROGRESSION OF OSTEOLYSIS: “HYLAMER” CUP Image removed due to copyright considerations Why Artificial Joints Fail Image removed due to copyright considerations Spice, Byron. “Particle Disease Seen As Plague on Total Joint Replacement” Pittsburgh Post-Gazette. POLYETHYLENE WEAR PARTICLES H. McKellop, 1994 Hip Society The number of particles generated by a hip prosthesis 7 x 10 11 particles/yr. 700,000 particles/step NUMBER OF INHALED PARTICLES Avg. particle burden of urban atmosphere: 10 5 particles/liter Respired volume in man = 1 liter/min. Therefore, 10 5 particles are inhaled/min. 10% of the inhaled particles are deposited in the lungs. Therefore, 10 4 particles are deposited in the lungs per min. 5 x 10 9 particles/yr. Titanium Wear Debris Images removed due to copyright considerations Co-Cr Particles UNSTABLE PROSTHESIS Particles Motion Bone Resorption (Osteolysis) Macrophage (15-25μm) IL-1 PGE 2 Enzymes Chemoattractants MACROPHAGE RESPONSE TO MOTION AND PARTICLES BONE Osteoclast precursor cells Osteoclast Osteoblasts Polyethylene Particles Images removed due to copyright considerations OSTEOLYSIS Determinants ? Particles < 10 μm ? Movement of the prosthesis (i.e., micomotion) – deformation (strain) of tissue ROLE OF MICROMOTION IN OSTEOLYSIS ? Mechanical perturbation can provoke macrophages to release inflammatory agents that stimulate bone resorption OSTEOLYSIS: ROLE OF IMPLANT MOVEMENT Mechanical perturbation increases release of PGE 2 by (LPS-stimulated) macrophages in vitro ? Macrophages on flexible membranes ? Cyclic strains of 4.0 and 7.7% ? Release of PGE 2 was approximately twice that of the unstretched controls B.E. Grottkau, et al. Brigham & Women’s Hospital THERAPEUTIC STARTEGIES TO MANAGE SMALL PARTICLE DISEASE ? Inhibitors of inflammatory cytokines and eicosanoids – e.g., NSAIDs to reduce PGE 2 ? Gene therapy to up-regulate the synthesis of antagonists of receptors for inflammatory molecules – e.g., IL-1 receptor antagonist ? Agents to block osteoclastic bone resorption UNSTABLE PROSTHESIS Particles Motion Bone Resorption (Osteolysis) Macrophage (15-25μm) IL-1 PGE 2 Enzymes Chemoattractants MACROPHAGE RESPONSE TO PARTICLES AND MOTION BONE Osteoclast precursor cells Osteoclast Osteoblasts Canine Model for Prosthesis Loosening 6 mos. continuous treatment with Naproxen Images removed due to copyright considerations EFFECT OF NAPROXEN ON PGE 2 LEVELS IN A CANINE MODEL Naproxen In Vivo PGE 2 Treatment Period Naproxen In Vitro (Mos.) Without With 0 314±236 177±177 3 112±63 7±6 6 84±51 0 BIOLOGIC RESPONSE TO PARTICLES ? Systemic response: lymphadenopathy Drainage of Particles by the Lymphatics Image removed due to copyright considerations H. Willert, et al. SMALL PARTICLE DISEASE: LYMPHADENOPATHY ? Enlargement of the node ? Particles drained from tissue by the lymphatic system are phagocytosed by macrophages in the nodes – histiocytes derived from cells that line the sinuses of the node and macrophages derived from circulating monocytes ? Sinus histiocytosis ? No adverse clinical sequelae yet noted MIGRATION OF PARTICLES AND CELLULAR RESPONSES BLOOD VESSEL Macrophage Histiocyte Tissue- Resident, Tissue-Fixed Phagocyte Fusion Maturation M-CSF Monocyte Migration Fusion PROSTHESIS Particles >10μm Multinucleated Foreign Body Giant Cell (less active than macrophages) Bone Resorbing Agents PGE 2 , IL-1 Micromotion Particles <10μm LYMPHATIC VESSEL BONE RESORPTION Activation Particles Lymph Node Particles (PE) from the joint Lymphadenopathy Images removed due to copyright considerations BIOLOGICAL RESPONSE TO METAL DEBRIS ? Cell response to metal particles and ions BIOLOGICAL RESPONSE TO METAL DEBRIS ? Immune responses PATIENT CONCERNS ABOUT METAL DEBRIS Am I allergic to my metal implant? IMMUNE RESPONSE TO METAL IONS ? "Metal allergy" has been incriminated as the cause of failure in certain patients. ? However, results obtained to date are not definitive. IMMUNE RESPONSE TO METAL IONS K. Merritt and S.A. Brown (1985) "The incidence of metal sensitivity in the normal population is high, with up to 15% of the population sensitive to nickel and perhaps up to 25% sensitive to at least one of the common sensitizers Ni, Co, and Cr. The incidence of metal sensitivity reactions requiring premature removal of an orthopedic device is probably small (less than the incidence of infection). Clearly there are factors not yet understood that caused one patient but not another to react." CELL RESPONSE TO METAL PARTICLES ? Macrophages in vitro ? Particles of Ti alloy not toxic; Co-Cr highly toxic ? Ti induced more release of PGE 2 than Co-Cr ? Exp. to Ti increased the release of PGE 2 , IL-1, TNF, and IL-6; exp. to Co-Cr decreased release of PGE 2 and IL-6 and had little effect on IL-1 and TNF ? “release of Ti....worse than....Co-Cr” D.R. Haynes, et al., JBJS 75-A: 825 (1993) CELL RESPONSE TO METAL PARTICLES ? Bovine articular chondrocytes ? Co was toxic to cells at all conc. ? At high conc. Cr, Ti, and Ti alloy were toxic ? At high conc. all metals decreased enzyme activity ? PGE 2 increased with conc., except for Ti alloy W.J. Maloney, et al., J. Appl. Biomat. 5: 109 (1994) BIOLOGICAL RESPONSE TO METAL PARTICLES AND IONS Summary ? Metal particles and ions are released from TJR prostheses; the amounts can be reduced by careful design and manufacturing ? Cellular response to metal particles has some of the same elements as the response to particles of other materials ? No indication yet that metal particles and ions are responsible for an unusually adverse response