The inflammatory process and immune reactions associated with implant use

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1 The inflammatory process and immune reactions associated with implant use Professor Peter A Revell Implant Biology Research Biomaterials and Tissue Engineering Division Eastman Dental Institute London WC1X 8LD prevell@eastman.ucl.ac.uk

2 WHENEVER a foreign material, organisms or cells are introduced into the body, inflammatory and immunological reactions take place Consider:- venesection and injections surgical implants infections blood transfusion organ transplantation

3 WHENEVER a foreign material, organisms or cells are introduced into the body, inflammatory and immunological reactions take place Consider:- venesection and injections surgical implants infections blood transfusion organ transplantation

4 Use of implants in bone Orthopaedics - joint replacement - fracture fixation - screws, nails, wires Dentistry - dental implants

5 When a joint is replaced, large pieces of foreign materials are placed in wounds created in bone by drilling, gouging and sawing The healing process takes place in the continued presence of the foreign body which cannot, of course, be removed by any natural process

6 Inflammation occurs when any foreign material is introduced into the body may be acute ( and transient) with resolution and healing may be chronic, when the noxious stimulus persists

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8 Resolution and healing inflammation resolves completely if damaging stimulus is removed OR healing with or without fibrous scarring may become chronic, when the noxious stimulus persists

9 Chronic Inflammation typically shows the presence of macrophages and lymphocytes is accompanied by the development of an immune response

10 Fibrous tissue and new bone formation Lymphocytes, macrophages and multinucleate giant cells (MNGC) T & B cells, plasma cells

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12 Healing with fibrous tissue IMPLANT BONE

13 Macrophages and multinucleate giant cells (MNGC) are found -on biomaterial surfaces -in relation to debris

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16 Development of osteolysis

17 Material properties difference Micromovement Wear debris & inflammation Aseptic loosening and osteolysis

18 At implantation

19 At implantation

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23 Professor Peter A Revell Osteoarticular Research Department of Histopathology Royal Free Campus Royal Free & University College Medical School LONDON NW3 2PF Large particles in giant cells

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30 Particles can get down between the implant and bone carried by this fluid in continuity with the joint There is gradual accumulation of particles deeper down between the implant and the bone. This is accompanied by an inflammatory cellular response which gives rise to bone loss - so called osteolysis

31 Osteolysis

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34 Macrophages & MNGCs - ACTIVATED, expressing HLA-class II, cell surface epitopes, integrins (CD11a,b,c) (Revell & Jellie 1998; Curtis 2002) CD11b α M / β 2

35 Human macrophage in tissue culture

36 INTEGRIN Focal Adhesion Kinase

37 Macrophages and foreign body multinucleate giant cells make cytokines, chemical mediators, which influence their own behaviour and that of other cells

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41 IL 1, IL 6, TNF are proinflammatory cytokines which perpetuate the inflammatory process. They have been shown in studies from various centres to be present in cells of the interface membrane and to be produced by macrophages on culture with particles.

42 Activated macrophages & MNGCs Implant GM-CSF Bone

43 Macrophages, giant cells and cytokines TGFα, GM-CSF and M-CSF are responsible for promoting the formation of giant cells

44 Proinflammatory Osteoclastogenic

45 Removal of bone by osteoclasts

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49 Lymphocytes are present

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51 Immune reactions ave specificity ( antibody - antigen ) nvolve B lymphocytes and plasma cells which make antibodies OR nvolve T lymphocytes which on stimulation produce chemical mediators

52 An immune reaction is aimed at a particular target

53 An immune reaction is aimed at a particular target BUT there may be collateral damage HYPERSENSITIVITY REACTIONS

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55 Mast cells and antibodies Antibodies Antibodies Cell mediated, T lymphocytes

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57 Clinical evidence for hypersensitivity reactions in relation to implanted biomaterials

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59 Metal sensitivity in patients with orthopaedic implants Hallab, Merritt, Jacobs (2001) J Bone Jt Surg 83A The prevalence of dermal sensitivity in patients with a joint replacement device, particularly those with a failed implant, is substantially higher than that in the general population

60 THE ROLE OF LYMPHOCYTES Passive role? Bystanders? (Agins et al,1988; Lombardi et al, 1989; Santavirta et al, 1990,1991) Active role? Immune process? (Lalor & Revell, 1991;Weyand et al, 1998; Hercus & Revell, 2001; Bainbridge et al, 2001)

61 (Lalor & Revell,1991; Revell et al,1997; Al Saffar & Revell,1999; Weyand et al,1998)

62 6 to 16 per cent of cells 6 to 16 per cent of cells (Hercus, 2005)

63 T lymphocytes having immune memory CD 45 RO positive staining (Revell & Al-Saffar, 1994)

64 ( Revell & Jellie, 1998 )

65 Ki 67

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67 T H : T C / S = 7.2 : 1

68 Determine which sub-type of T helper lymphocyte is involved in the immunological process Th 1 cells Th 2 cells Cell mediated immunity Humoural immunity Macrophages & natural B lymphocytes & killer (NK) cells plasma cells

69 Helper T cell polarisation Th1 > Th2 (Weyand et al,1998; Hercus & Revell, 2001; Hercus, Saeed & Revell, 2002; Hercus, 2005) No Th1 predominance (Arora et al, 2003)

70 Helper T cell polarisation Multiplex PCR (Hercus)

71 Helper T cell polarisation Cytokine profile Th1 cell Th2 cell IL-2, IL-12 & IFN-γ IL-4, IL-5 & IL-10 Th1 > Th2 Contact sensitisation process

72 T lymphocytes in the interface tissues in known nickel sensitivity

73 CD45Ro positive lymphocytes

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79 Bainbridge, Revell & Al-Saffar (2001) J Biomed Mater Res 54, 328

80 Bainbridge, Revell & Al-Saffar (2001) J Biomed Mater Res 54, 328 Antigen presenting cells

81 Macrophages and lymphocytes Macrophages and lymphocytes

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85 E selectin P selectin E-selectin mediates T cell adhesion to endothelial cells and migration in skin contact hypersensitivity (Norris et al, 1991; de Vries et al, 1997) Other adhesion molecules are also present (Revell et al, 1997; McFarlane & Revell, 2004)

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91 Functional studies

92 Western blot of IL15 protein prior to deglycosylation: A rhuil15, B-E interface samples Western blot of IL15 protein after degycosylation: A rhuil15, B-D interface samples

93 Lymphocytes and the IL2 receptor Macrophages and the IL15 receptor

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95 Ki 67

96 CD40 Ro Macrophages and lymphocytes

97 Interleukin 15 is able to sustain the proliferation and survival of T lymphocytes In coculture experiments T lymphocytes are sustained by U937 macrophages phagocytosing particles (Saeed, Damien and Revell, 2002a)

98 Submicron sized particles can be isolated from perimplant tissues and characterised Phagocytosis of these particles activates macrophages which produce cytokines Some of these are pro-inflammatory, others promote giant cell formation

99 The inflammatory response to the persistence of these particles gives rise to bone loss and implant loosening Activated lymphocytes are present in large numbers in some cases Immune sensitisation may be present in response to some metals

100 Evidence of sensitisation is provided by:- activated and proliferating T lymphocytes T cells sustained by IL15 T helper cell predominance and T H1 > T H2 T memory cells presence of P- and E-selectins on vessels evidence for antigen presentation

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