Next we will consider inflammation and infection which is the 2nd stage of the wound healing process. Hematopoietically derived cells are involved in this process. Last time This time

Hematopoietically derived cells are involved in this process. These blood cells do the following things: Remove cellular and tissue debris Destroy foreign material such as bacteria that cause infection Secrete chemical signals that message other cells types to come to the site of injury to repair, remodel, and make new tissue Inflammation is a normal process or part of wound healing and will also occur in the vicinity of an implant. Inflammation does not imply infection, infection is contamination of the wound by bacteria, fungi, viruses etc. Infected wounds suppurate (form pus) Inflammation has 4 cardinal signs as summarized in the table on the next slide; redness, swelling, heat, pain

swelling redness heat pain

Cellular attacks on foreign materials mediated by leukocytes which come in two flavors: lymphocytic and nonlymphocytic, which are derived either from the lymphoid stem cell line or the myeloid stem cell line as shown below. Myeloid derived nonlymphocytic leukocytes or PMN’s (polymorphonucleocytes) are: Neutrophils Eosinophils Basophils Monocytes  macrophages  foreign body giant cells granulocytes There mission is to kill, consume, destroy foreign objects Eat particulate debris from biomaterials, bacteria, damaged tissues & cells

neutrophils eosinophil neutrophil monocyte

neutrophil eosinophil lymphocytes basophil

Macrophages

These nonlymphatic leuokocytes are formed in the bone marrow and circulate in the blood with the ability to enter and migrate through the tissue. There goal is seek out, kill, consume, and destroy any and all foreign objects and particulate debris from biomaterials, bacteria, damaged cells and tissue. Note their granular nature hence granulocytes. Basophils – release histamine, bradykinin, serotonin which are all chemicals That act to mobilize other cells and increase vascular permeability Eosinophils – more involved in parasitic defense and consumption of Ab-Ag Complexes Neutrophils – are mostly involved in phagocytosis, “eating” Monocytes – when activated become macrophages which enter the tissue and phagocytize foreign objects, can also fuse together to form the foreign body giant cells that are huge 80-100 microns in diameter Chemotaxis is the process by which these cells move to a site of an injury

Phagocytosis – shown in figure below involves C3b a complement component which connects the Ab binding to a particular Ag say on a bacterium to form what is called an “opsonin” which is to opsonize which means to “prepare to eat”. The phagocyte experiences a metabolic burst that increases glucose metabolism about 10x’s and oxygen consumption by 2-3 x’s resulting in the formation of highly reactive oxygen species and hydrogen peroxide

Diapedesis – shown below, endothelial cells due to presence of localized injury chemicals express cell-cell adhesion receptors causing the neutrophils to stick to the endothelium and they tend to roll along the endothelium as shown Below, then they finally stick and migrate along the surface and then diapedesis their way across the endothelial wall to the injured tissue, chemicals from the site of the injury also find their way to the bone marrow stimulating the production of more neutrophils

Tissue macrophage levels are generally low so the monocytes first have to be activated and mature to macrophages which enter the injury site much like the neutrophils but somewhat delayed in comparison to the neutrophils. Infection means colonization of the wound with microbes. The hallmark sign is pus formation or suppuration. Sustained infection leads to fibrotic capsule formation around the liquified infected region. 3 general types of infection associated with implanted medical devices: Superficial immediate infection, from skin and air bacteria, example from sutures Deep immediate infection, occurs soon after invasive procedures, usually a’ result of the translocation of skin bacteria 3. Deep late infection, occurs months or years later in areas where everything was assumed to be fine a. delay of action of bacteria from implant b. bacteria from another incident making there way to the implant and setting up their shop c. very difficult to treat but fortunately rare

Chapter 10 discusses the immune system and our interest is in how the immune system is involved in the process of inflammation and its role with respect to medical implants as well as bioartificial organs that use immunoisolation 2 types of immunity 1. innate – processes and structures of the body that naturally resist attack; the skin, stomach acid, digestion/liver, neutrophils/macrophages, fever, plasma proteins, cough; the hallmark is lack of specificity 2. acquired – mechanism that develops as a defense based on specific attacks, usually provides some memory and in many cases results in what we call “immunity”. Specificity and memory are the hallmarks of this type. The challenge though is for the immune system to distinguish between “self” and “non-self”, otherwise you get so-called autoimmune diseases; type I diabetes, lupus, multiple sclerosis etc.

2 types of acquired immunity 1. humoral immunity – based on chemicals or proteins called Ab’s, depends on B lymphocytes 2. cell-mediated immunity – results from the cytotoxic effects of lymphocytes called T lymphocytes B lymphocytes or B cells mature in the bone marrow T lymphocytes or T cells travel from the bone marrow to the thymus where they mature, go to college, or maybe they go to college and then mature, and the self-indulgent or self-reacting ones flunk out or are eliminated by some magical and mysterious process B and T cells typically like to hang out in lymphoid tissue such as the spleen, tonsils, and the lymph nodes There is also another lymphocyte called the NK lymphocyte (natural killer) which goes after things like tumor cells (Ab dependent cell-mediated cyto- toxicity or ADCC, wherein the Fab region of an Ab binds to an invader and the Fc region of the Ab binds to the NK cell)

Pathogen – is any disease causing agent Immunogen – is a molecule or a molecular feature, or a collection of molecules that can induce an immune response by the body - examples are things like bacteria, viruses, pollens (allergens), food components, drugs

Antigen (Ag) – is any substance that is specifically recognized by an immunoglobulin (antibody, Ab) or by a surface receptor of the T cell membrane - not all antigens cause an immune response, i.e. not all are immunogenic - binding site on the antigen is called an epitope or the antigenic determinant - a given antigen can have multiple epitopes

Immunoglobulins (Ig’s) are antibodies which are proteins secreted by the B lymphocytes that bind with high specificity to a given epitope on an antigen. Fab sites Fc site

Best at agglutination

Adjuvants – are substances either chemicals or particles that enhance the immune response to a given immunogen Haptens – are small molecules that by themselves are not antigens but become antigens when bound to other larger molecules, typical for small drugs, industrial chemicals, some toxins, subsequent exposure may not require binding to the larger molecule since the immune system is now primed