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Massachusetts Institute of TechnologyHarvard Medical SchoolBrigham and Women’s HospitalVA Boston Healthcare System2.79J/3.96J/20.441/HST522JCHRONIC RESPONSE TO IMPLANTS:a-Smooth Muscle Actin and LubricinM. Spector, Ph.D.InjuryVascular ResponseInflammationTissue of Labile Tissue ofand Stable Cells Permanent CellsFramework Framework (stroma) Repair: ScarIntact DestroyedRegeneration Repair: ScarWOUND HEALINGREGENERATION VERSUS REPAIRSynoviumFibroblastsMacrophagesInjuryVascular ResponseInflammationTissue of Labile Tissue ofand Stable Cells Permanent CellsFramework Framework (stroma) Repair: ScarIntact DestroyedRegeneration Repair: ScarWOUND HEALINGREGENERATION VERSUS REPAIRMacrophageMyofibroblast>ContractionSynoviocyte>LubricinI. MetchnikoffFirst identified “macrophages” and “microphages” (polymorphonuclear neutrophils, PMNs) in an organism around a foreign bodyMarius Nygaard Smith-PetersonIn 1923 a piece of glass was removed from a patient’s back; it had been there for a year. It was surrounded by a minimal amount of fibrous tissue, lined by a glistening synovial sac, containing a few drops of clear yellow fluid. J. Bone Jt. Surg., 30-B:59 (1948)Rabbit Ear ChamberWound Healing and Wound Infection (1980)IA Silver in, TK Hunt, DR Knighton, et al., Surg 90:62 (1981)Diagrams removed due to copyright restrictions.From I. Silver, in Hunt & JE Dunphynd. of Wound Management (1979)TKFuHealing Dead Space Woundvancing terial culationRabbit Ear ChamberUnfilled Dead SpaceCellular leading edgPhotos removed due to copyright restrictions.AdarcireWound: Dead SpaceMacrophagesFibroblastsImages removed due to copyright restrictions.From I. Silver, in TK Hunt & JE DunphyFund. of Wound Management (1979)Wound: Dead SpaceMacrophagesFibroblastsImages removed due to copyright restrictions.From I. Silver, in TK Hunt & JE DunphyFund. of Wound Management (1979)Do these fibroblasts contract like the myofibroblasts in a skin wound?Wound: Dead SpaceMacrophagesFibroblastsImages removed due to copyright restrictions.From I. Silver, in TK Hunt & JE DunphyFund. of Wound Management (1979)SynoviumDo these synoviocytes express lubricin like those in joint synovium?IA Silver in, TK Hunt, Wound Healing and Wound Infection (1980)Image removed due to copyright restrictions.Graph of regional oxygen tension vs. distance around the foreign body.MacrophagesFibroblastsDead SpaceSynoviumDead SpaceSynoviumDead SpaceIn addition to wounds, where else do dead spaces form in the body?SynoviumDead SpaceIn addition to wounds, where else do dead spaces form in the body?• JointsSynoviumDead SpaceIn addition to wounds, where else do dead spaces form in the body?• Joints• BursaeSynovium:Macrophage-like (Type A) and Fibroblast-like (Type B) CellsSynoviumInjuryVascular ResponseInflammationTissue of Labile Tissue ofand Stable Cells Permanent CellsFramework Framework (stroma) Repair: ScarIntact DestroyedRegeneration Repair: ScarWOUND HEALINGREGENERATION VERSUS REPAIRMacrophageMyofibroblast>ContractionSynoviocyte>LubricinACTIN ISOFORMS• b - cytoplasmic (most cells)• g - cytoplasmic (most cells)Contractile Actins• a - skeletal muscle• a - cardiac muscle• a - (vascular) smooth muscle (SMA)• g - (enteric) smooth muscleTISSUE CLASSIFICATION• Muscle Cells (contractile cells)– skeletal a-skeletal actin– cardiac a-cardiac actin– smooth muscle a- and g-smooth muscle actin• Connective Tissue Cells– “myofibroblasts” (SMA; contractile cells)*: dermal wound closure, fibrotic (scar) contractures, Dupuytren’s Disease• * G. Majno, G. Gabbiani, et al., Science, 1971FIBROBLAST BEHAVIOR IN FIBROUS TISSUE AROUND IMPLANTS• Proliferation and increased matrix synthesis of fibroblasts leads to an increase in the thickness and density of the scar tissue.• Fibroblast contraction results in scar contracture.BREAST IMPLANTS Capsular ContractureRemoved implant: viewing the outside of the fibrous capsuleCapsuleImplantInside of the fibrous capsuleImplantPhotos removed due to copyright restrictions.See http://www.implantforum.com/capsular-contracture/CAUSE OF CAPSULAR CONTRACTIONMyofibroblasts, and the regulatory protein TGF-β, were found in the contracted capsules around silicone breast implants but not in non-contracted capsules. Mature skin scar tissue did not contain TGF-β or myofibroblasts. Lossing C, and Hansson HA,Plast Reconstr Surg 91:1277 (1993)Macrophages (CD68+ cells) in a capsule with an implant duration of 9 years. * Silicone implant; (arrows) macrophages; cells of the “frontier layer” in bracket. Original magnification: 400x.D. Wolfram, J. Autoimmunity 23:81 (2004)Double staining for “heat shock protein,”* HSP60, (arrowhead) and for smooth muscle actin (arrow). Cells expressing both, yellow. The implant duration was 14 months. Original magnification: 250x.* HSP60 (heat shock protein expression, reflects the effect of mechanical or other forms of stress exerted on the implant and capsule.Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission. Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission.D. Wolfram, J. Autoimmunity 23:81 (2004)The fibrous capsules show a three-layered composition:(1) The internal layer abutting the silicone surface formed by macrophages and fibroblasts,(2) the layer of loosely arranged connective tissue including the internal vascular supply, and(3) the outer layer of dense connective tissue with the external vascular supply.Courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission.J Bone Joint Surg 2005;87A:1284White arrows: Radiolucencies due to osteolysis associated with particulate wear debris and movement of the prosthesis (loosening)• What is the make-up of the periprosthetic tissue?• Why is it so persistent?Photos removed due to copyright restrictions.Fig. 1 Kaplan-Meier survival curves with clinical and radiographic failure as the end points.Martin S. D. et.al. J Bone Joint Surg 2005:87:1284-1292Graph removed due to copyright restrictions.Fig. 3 Prevalence of radiolucent lines around the glenoid components.Martin S. D. et.al. J Bone Joint Surg 2005:87:1284-1292Graph removed due to copyright restrictions.J. Biomed. Mater. Res. (in press)Tissue was resected during revision of symptomatic, non-cemented, glenoid components of Kirschner-IIc total shoulder arthroplasty Shouldera-Smooth Muscle Actin ImmunohistochemistrySource: Funakoshi, T., M. Spector et al. J


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