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BIOMATERIALS ENT 311/4 LECTURE 7 Tissue Reaction to Biomaterials: Foreign Body Reaction Immune Response to Biomaterials Infection and Tumorigenesis of Biomaterials Prepared by: Nur Farahiyah Binti Mohammad Date: 14th August 2008 Email : [email protected] Teaching Plan Objective Describe, discuss and illustrate inflammation, wound healing, foreign body reaction, blood material interaction and tumorgenesisi. DELIVERY MODE •Lecture •Tutorial •Supplement reading LEVEL OF COMPLEXITY •Knowledge •Repetition •Application COURSE OUTCOME COVERED •Ability to explain and illustrate tissue reaction to biomaterials EFFECT OF MATERIAL ON HOST TISSUE The main cellular host response to injury are: 2.1 2.2 2.3 Inflammation Wound healing response Foreign body reaction Sequence of host reaction following implantation of medical devices or biomaterial INJURY HEMOSTASIS INFLAMMATION Acute Inflammation Chronic Inflammation PROLIFERATION PROLIFERATION (granulation tissue) (granulation tissue) REMODELLING SCAR TISSUE or FIBROUS CAPSULE DEVELOPMENT FOREIGN BODY GIANT CELL FORMATION Acute Chronic Granulation tissue The predominant cell type that present in the cellular host response 2.3 FOREIGN BODY REACTION EVENT INJURY HEMOSTASIS ACUTE INFLAMMATION CHRONIC INFLAMMATION PROLIFERATION (granulation tissue formation FOREIGN BODY GIANTCELLS FORMATION 2.3 FOREIGN BODY REACTION (FBR) DEFINITION OF FBR FBR is an inflammatory reaction evoke by the presence of foreign material in the tissues, characterized by the formation of foreign body giant cells. 2.3 FOREIGN BODY REACTION (FBR) • The foreign body reaction begins as wound healing, including stoppage of bleeding, infiltration of inflammatory cells to debride the area, and the formation of granulation tissue. • However, the persistent presence of a biomedical implant, splinter, particulates, or other foreign bodies inhibits full healing. 2.3 FOREIGN BODY REACTION (FBR) • Rather than the resorption and reconstruction that occurs in wound healing, the foreign body reaction is characterized by: – The formation of foreign body giant cells, – Encapsulation of the foreign object – Formation of granulation tissue that consist of macrophages, fibroblasts and capillaries. 2.3 FOREIGN BODY REACTION (FBR) What is it Foreign body giant cell? • Foreign body giant cells are the products formed by the fusion of monocytes and macrophage in attempt to phagocytose the material. 2.3 FOREIGN BODY REACTION (FBR) What happened? • When macrophages encounter a foreign object too large to be phagocytosed, such as an implant, it is thought that the macrophages experience “frustrated phagocytosis.” • They fuse to form larger foreign body giant cells composed of up to a few dozen individual macrophages. 2.3 FOREIGN BODY REACTION (FBR) • Giant cells secrete degradative agents such as superoxides and free radicals, causing localized damage to implants and other foreign bodies. 2.3 FOREIGN BODY REACTION (FBR) • Macrophages and foreign body giant cells tend to remain at the surface of an implant for the duration of its residence. • Encapsulation refers to the firm, generally a vascular collagen shell deposited around a foreign body, effectively isolating it from the host tissues. • This response was developed as a protective measure. 2.3 FOREIGN BODY REACTION (FBR) • Encapsulation is especially problematic for devices designed to interact with the body, such as glucose sensors. • The foreign body reaction can lead to chronic pain and device rejection and failure. 2.3 FOREIGN BODY REACTION (FBR) • The composition of the foreign body reaction determined by: – Surface properties of the biomaterials – The form of the implant – The relationship between the surface area of the biomaterial and the volume of the implant. • Example: high surface-to-volume implant such as fabrics, porous material, particulate or micro-spheres will have higher ratios of macrophages and foreign body giant cells in the implant site than smooth-surface implants. 2.3 FOREIGN BODY REACTION (FBR) G = Foreign Body Giant cell M= Macrophage F = Fibroblast Foreign body giant cell surround the foreign material Foreign material 3.0 Immune Response to Biomaterial • Function of immune system: – To defend the host against infectious organism. • The immune system protects organisms from infection with layered defenses of increasing specificity. • The layered defenses consists of: 1. Innate Immunity 2. Adaptive Immunity 3.0 Immune Response to Biomaterial INNATE IMMUNITY • Refers to generalized set of defences that do not require recognition of foreign substance. • Physical barrier: – Skin and mucosa serve as physical barriers to microbe. 3.0 Immune Response to Biomaterial • Complement system – the complement cascade provide mechanism for microbial killing. – Complement: family of plasma proteins that are activated by an enzymatic cascade. 3.0 Immune Response to Biomaterial – The end result of this cascade is the assembly of five activated protein called the membrane attack complex (MAC) in the plasma membrane of the microbes. – The proteins work together to: • trigger the recruitment of inflammatory cells. • "tag" pathogens for destruction by other cells by opsonizing, or coating, the surface of the pathogen. • disrupt the plasma membrane of an infected cell, resulting in cytolysis of the infected cell, causing the death of the pathogen. • rid the body of neutralized antigen-antibody complexes. 3.0 Immune Response to Biomaterial • Cellular barriers – Activation of phagocytic cell such as macrophage and neutrophils. – Activation of lymphocyte-natural killer cell. – These cells serve to engulf and destroy foreign particles and microbes by targeting them into intracellular lysosomes. 3.0 Immune Response to Biomaterial ADAPTIVE IMMUNITY • Has two way of defence: – Cell mediated immunity – Humoral mediated immunity • This serve to – enhance innate immunity – present specialization by focusing the immune response on specific targets with antibodies and T-cells. – Provide immunologic memory by producing a more rapid and amplified response upon repeated exposure to targets. 3.0 Immune Response to Biomaterial • Cell-mediated immunity – Has two major mechanism • Helper T-lymphocytes • Cytotoxic T-lymphocytes – Antigen-specific T-lymphocyte recognize foreign intracellular antigens on the surface of an infected macrophage. – The helper T-lymphocytes activates the infected macrophage by secreting cytokines to cause elimination of intracellular microbes by reactive oxygen and chemical species 3.0 Immune Response to Biomaterial – Some cells are not capable of eliminating intracellular microbes (like macrophage). – So, these cells killed by cytotoxic Tlymphocytes in order to illuminate the microbe. • Humoral immunity – Functions by recognition of foreign substance (antigen) by antigen-specificantibodies. – Once activated, B-lymphocytes can differentiate into plasma cells, which produced secreted, antigen-specific antibodies. – This antibodies bind to the antigen and both activate complement and promote phagocytosis by coating the foreign substance. • Conceptually, humoral immunity should be thought as a way of attacking extra cellular foreign substance. 3.0 Immune Response to Biomaterial • Main feature of Innate and Adaptive Immunity Innate Adaptive Physical/chemical barriers Skin, mucosal epithelium, antimicrobial chemicals Lymphocyte in epithelia, secreted antibodies Onset Exposure lead to immediate response Lag time between exposure and response Type of immunity Surface barrier or mucosal immunity , cell barrier Cell mediated and humoral component. Memory No immunological memory Exposure leads to immunological memory Cells Phagocytes (macrophages, neutrophils), nature killer cells, B-lymphocytes (B cell) Helper T-lymphocytes Cytotoxic T-lymphocyte (T cell) 3.0 Immune Response to Biomaterial Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are those components of an organism's body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of nonself molecules are called antigens (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response. 3.0 Immune Response to Biomaterial • Cell-mediated immunity is an immune response that does not involve antibodies or complement but rather involves the activation of macrophages, natural killer cells (NK), antigen-specific cytotoxic Tlymphocytes, and the release of various cytokines in response to an antigen. 3.0 Immune Response to Biomaterial • The Humoral Immune Response (HIR) is mediated by proteins called antibodies that are produced by B lymphocyte (B cell). • Secreted antibodies bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), which flags them for destruction. • Humoral immunity is called as such, because it involves substances found in the humours, or body fluids. 4.0 INFECTION AND TUMORIGENESIS OF BIOMATERIALS • Serious complication that can occur due to the presence of biomaterial in the body are: 4.1 Hypersensitivity 4.2 Infection 4.3 Tumorigenesis 4.1 Hypersensitivity • Also known as allergic reaction • Is undesired immune response mediated by the adaptive immune response. • Defined as unusual, excessive, or uncontrolled immune reaction. 4.2 Infection • Can occur on or surrounding any type of implant. • Characteristic of implant-associated infection: – Presence of biomaterial – Bacterial colonization of tissue – Resistance to host defence mechanisms and antibiotic therapy – Presence of multiple bacteria species – Absence of integration of the biomaterial with the host – Presence of cell damage 4.2 Infection • Stages that involved in development of implant-associated infection: 1. Attachment: bacterial attachment to the surface occurs through non-specific interaction between the pathogen and the surface. 2. Adhesion: the preliminary attachment becomes permanent as specific receptor-ligand interactions develop and nonspesific interaction remains. 4.2 Infection 3. Aggregation: the bacteria devide after firmly attaching to the surface, causing the development of biofilm (polysaccharide slime) . This biofilm protect the micro organisms from phagocytosis by neutrophils or tissue macrophages and provide a favourable environment for bacterial growth. 4. Dispersion: The bacteria travel from the colony to other areas of the body. 4.3 Tumorigenesis • Tumorigenesis is the formation of tumours. • Tumor is composed of uncontrolled proliferating cell. • Type of tumor: – Benign tumor: do not invade adjacent tissue or spread to distant site. – Malignant tumor: Do invade surrounding tissues and gain entry into lymph and blood vessels. 4.3 Tumorigenesis 2. Latency Time period varies (15-20 years for human) 1.Initiation Implantation of biomaterial = malignant transformation of DNA Due to: Chemical carcinogenesis (chemicals leached from implant) OR Foreign body carcinogenesis (mechanism unknown, may be related to surface or bulk properties of the implant or alterations in local environment. 3. Promotion Obvious tumor growth around implant 4.3 Tumorigenesis • Two main routes of malignant transformation: 1) Chemical carcinogenesis is possible near biomaterials since tumors may be caused by substance that have leached from the implant. 4.3 Tumorigenesis 2) Foreign body carcinogenesis may be related to surface or bulk properties of the implant or alterations in local environment. • Possible cause are: – Bulk chemical properties of the implant – Physiochemical surface properties of the implant – Viral contamination of the implant – Interruption of cellular communication due to the presence of the implant – Local tissue damage leading to insufficient nutrient exchange