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Biomaterials > Biomaterials Exam II Review > Flashcards

Biomaterials Exam II Review Flashcards

1
Q

Local Biomaterial–Tissue Interactions

A

Effects on material on host tissues versus the effect of the environment on the materials. Examples: infection/tumorigenesis/healing modification/fatigue & corrosion/calcification

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2
Q

Systematic Biomaterial–Tissue Interactions

A

Examples: Hypersensitivity, implant elements in the blood, lymphatic particle transport, embolization

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3
Q

Device-Associated Complications

A

Thrombosis/infection/bad healing/adverse systemic or local tissue effects and reactions

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4
Q

Provisional Matrix

A

Injury to vascular tissue leads to immediate development. Consists of fibrins, produced by activation of coagulation and thrombosis, inflammatory products, activated platelets, inflammatory and endothelial cells

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5
Q

Inflammation

A

localized protective reaction of tissue to irritation, injury or infection. Contains, neutralizes or isolates the injury. Cab be acute (first few hours) and chronic (weeks to months). Clinical signs: redness, tissue heating, swelling, and pain

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6
Q

Injury Mechanism

A

Vasodilation (redness and heating), increase in permeability leads to exudation (fluid, proteins, blood cells enter the tissue -> swelling), and kinins are released from the blood clotting cascade (pain_

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7
Q

Plasma cells

A

Platelets, RBCs, monocytes, PMNs, lymphocytes, basophils, eosinophils, etc.

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8
Q

Polymorphonuclear leukocytes (PMNs)/Granulocytes

A

Neutrophils, basophils, eosinophils

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9
Q

Basophils

A

Release histamine, heparin, bradykinin, and mediates inflammation, but is the most important in allergic reactions

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10
Q

Eosinophils

A

Less phagocytosis, attaches to and destroys parasites

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11
Q

Lymphocytes

A

T cells and B cells, apart of adaptive immunity

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12
Q

Neutrophils

A

Granular WBC that are the first line of cell defense and are generated in the bone marrow. 4-8 hours in the blood and 4-5 days in target tissue.

They can migrate via:
Rolling -> loose attraction between endothelial cell selection and proteoglycans on neutrophil
Activation -> IL-8 and MIP-1b induce confromational change in integral to have a higher affinity to Ig superfamily CAM
Arrest and adhesion
Transendothelial migration, diapedesis (passage through the walls of the capillaries)
Once they have migrated into the tissues, express high levels of receptors for future chemoattractants to find target area

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13
Q

Phagocytosis

A

Neutrophil expresses a greater number of receptors for antibody- and complement-coated foreign particles to help with their removal
Antibody on antigen connects to Fc receptor on the neutrophil, pseudopod surrounds the antigen, making a phagosome. Lysosomes merge with the phagosome, antigen is digests and exocytosis of particles occurs

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14
Q

phagosome

A

Vesicle that ingests large particles (antigens)

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15
Q

Phagolysosome

A

Fusion of a lysosome and phagosome

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16
Q

Granules

A

Contain bactericidal agents and enzymes

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17
Q

Respiratory burst

A

Glucose metabolism increases, as well as oxygen consumption. Formation of reactive oxygen and nitrogen species in intracellular granules

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18
Q

MIP-1a and MIP-1b

A

Secreted to recruit monocytes (unpolarized macrophages)

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19
Q

IL-8

A

Attracts more neutrophils

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20
Q

Monocytes

A

Polarize intro macrophages. emigrate from the vasculature and differentiate into long-lived macrophages in the tissue

Cells enlarge, intracellular organelles increase in number and complexity, cells acquire phagocytic ability, and increase soluble factor secretion occurs

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21
Q

Acute Inflammation

A

Minutes to days. Exudation of fluid and plasma proteins (edema), emigration and localization of leukocytes at the implant site. Neutrophils get there first. Macrophages dominant, with high phagocytotic abilities. For many biomaterials, they are too big to be engulfed and degraded

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22
Q

Acute inflammation mediators

A

IL-1 and TNFa promote inflammatory response (inflammatory migration, clotting) IL-6 and IL-1 are apart of the adaptive immune response

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23
Q

Acute Inflammation systemic response

A

fever

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24
Q

Termination of Acute Inflammation

A

IL-1Ra produced by the same cells. TGF-b inhibits cell activation involved in the inflammatory response. Acute -> Chronic

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25
Q

Cell types in acute vs. chronic inflammation

A

Neutrophils are high in acute but decrease rapidly in chronic, where in chronic there is a rise of macrophages/FBGCs/fibroblasts, than a later increase in fibrosis

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26
Q

In vitro inflammatory response assay

A

Leukocyte Assays:
-Adhesion -> allow the cell to attach to the testing material for a given amount of time, then rinse. Count the amount of cells that adhered, stain and image and quantify.
-Spreading -> Determine the surface area of the cells
-Migration -> Capillary test test and ring test, Boyden Chamber assay (test cells infiltration into the media of interest through a semi-permeable membrane)
-Cytokine release -> (interleukins, TNFa), using ELISA
-Cell surface markers -> using FACS or flow cytometry

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27
Q

Sandwich ELISA

A

Plate is coated with a capture antibody, add sample antigens present will bind to the capture antibody. Detecting antibody is added and binds to antigen. Enzyme-linked secondary antibody is added. Add substrate, which is converted by the enzyme to a detectable form

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28
Q

Flow cytometer

A

Technique to sort and count particles suspended in a stream of fluid, allowing multi-parametric analysis or physical and chemical characteristics, Uses scattered light to differentiate size and shape of cells and particles. Use fluorescence to detect immunochemically labelled cells or proteins. Sorted via electrostatic deflection, which employs charged plates to change the path of the cell

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29
Q

Cytotoxicity Assay

A

Use established cell lines and positive controls like PVC, gum rubber. Negative controls: high density polyethylene. 3 assays are possible:
Direct contact -> place the test sample directly in the culture, observe under microscope, live/dead stain, MTT assay. Adv: mimics clinical use, Disadv: risk of trauma due to leachable diffusion rate
Agar diffusion
Elution/extract dilution

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30
Q

Cytotoxicity

A

Cause toxic effects at the cellular level

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31
Q

Agar Diffusion Test

A

Place sample on an agar plate. The discoloration of the plate expanding from the material indicates the material presence caused cell lysis, losing the stain in the agar layer.
Adv: better concentration gradient and can test one side of a material
Disadv: Flat surface needed, limited by solubility of toxicant in agar, risk of thermal shock and water absorption from agar

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32
Q

Elution Test

A

Determine the cytotoxicity of leachable. Soak the material in MEM and apply extract media at different doses. Good to speratate extraction from testing (test the dose resins), but requires additional time and steps. A positive cytotoxic reaction is seen when the cells lack normal cytoplasmic space and are grainy (indicates high lysis rate)

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33
Q

Chronic Inflammation

A

presence of macrophages, monocytes, and lymphocytes with proliferation of blood vessels and connective tissues.

Lymphocytes are key mediators of adaptive immunity, though little is known about their inflammation response.

Macrophages: most important, releases chemotactic factors, proteases, cytokines, growth factors, etc.

Antigen presenting cells: adaptive immune reactions (B cells)

A short lived chronic response followed by granulation is normal, and persistent chronic ifnallamtion is patholgical and can be triggered by chemical, physical, motion and infection factors

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34
Q

Granulation tissue

A

Forms one day after implantation and seen for about 3-5 days after. Fibroblasts and vascular endothelial cells proliferate and begin to form granule tissues, which is the pink soft appearance on the surface of healing wounds.
Angiogenesis occurs, fibroblasts proliferate and synthesize collagen and proteoglycans, with macrophages present

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35
Q

Foreign-Body Reaction (FBR)

A

Composed of FBGCs and components of granulation tissue (macrophages, fibroblasts, capillaries)

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36
Q

Foreign body Giant Cells (FBGCs)

A

Multi-nucleated cells formed by the fusion of macrophages in an attempt to phagocytose foreign materials much larger than a single cell

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37
Q

FBR topography depends on…

A

Flat/smooth surface: 1-2 macrophage layer with fibrosis

Rough surface: mixture of macrophages and FBGCs

a higher surface to volume ratio (fabrics, porous materials, microspheres) will have higher macrophage and FBGC ratio to fibrous/granulation tissue

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38
Q

Fibrosis/Fibrous Encapsulation

A

End stage healing response, granulation tissue maturation, larger blood vessels and alignment of collagen fibers in response to local mechanical forces.

The degree if fibrous capsule formation of thickness of the capsule depends on the degree of initial implantation jury (vascular damage, amount and type of subsequent cell death), location of the implant site (low blood vessel density), microstructure of the implant (porosity), amount and composition of the small particulates produced, mechanical factors, implant shape, degradation speed, and electrical current

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39
Q

Extrusion

A

how epithelial cells remove dying or excess cells, squeezing them out without breaking their barrier

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40
Q

Encapsulation

A

The typical response to non-resorb able materials

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41
Q

Resorption

A

Resorbable material -> Faster degradation limits fibrous capsule formation, slower degradation causes capsule collaspse

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42
Q

Local Factors on Wound healing Response to Biomaterials and Implants

A

Site of implantation, blood supply infection potential

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43
Q

Systemic Factors on Wound healing Response to Biomaterials and Implants

A

Nutrition, hematologic derangements, glucocortical steroids, preexisting diseases (diabetes, infection, atherosclerosis)

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44
Q

How to achieve ideal resolution

A
  • Adjust mechanical properties (Reduce stiffness to match soft tissue)
  • anti-inflammatory therapy (coatings or local drug delivery)
  • Antibacterial treatment
  • Surface modifications (roughness/porosity, control protein adsorption, promote cell attachment)
  • Implant size/geometry (avoid sharp edges and corners
  • Minimize motion and toxic release
  • Reduce degradation (wear debris, corroded metal ions etc.)
  • Bioactive bonding (eg. bioglass)
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45
Q

In Vivo Assays: Animals

A

Use species similar in physiology and healing response to humans, start small (rodents, rabbits) then move to large (goat, dog, sheep, cow)
The implant sire should be close to application site, but can use somewhere more accessible at the start
The study should have multiple time points.

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46
Q

In Vivo Assessments

A

Histology:
- Fix (crosslink with aldehydes, precipitate with alcohols, acetone, acetic acid, add oxidizing agents such as osmium tetroxide)
- Section with cytostat or paraffin embedding & microtome. Resin embedding ultra-microtome sectioning
- Stain with IHC or H&E
- Optical or Fluorescent Imaging
- Quantify
Electron microscopy for ultra thin sections
Biochemical assays: western, RT-PCR

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47
Q

Coagulation

A

Hemostatic mechanism to arrest bleeding from injured blood vessels: vascular contraction, platelet plug, blood coagulation (thrombosis)

Similar process produces adverse effects when artificial surfaces come in contact with the blood.

Key players: coagulation proteins, platelets, and endothelial lining of the blood vessel

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48
Q

Blood coagulation

A

complex set of interdependent reactions between the surface, platelets and coagulation proteins resulting in the formation of a clot or thrombus that may undergo removal by fibrinolysis, localized process at the surface

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49
Q

RBCs in Blood Coagulation

A

Usually passive, under low shear or venous flow, they may form large proportion of the total thrombus mass.

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50
Q

WBCs in Blood Coagulation

A

Activation of complement coagulation and fibrinolytic and other enzyme system

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51
Q

Platelets in Blood Coagulation

A

Arrest bleeding through the platelet plug, stabilize this plug via catalyzing coagulation reactions (fibrin formation)

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52
Q

Platelets

A

Activate via adhesion (activate via interactions between cell surface receptors and ligands on collagen, vWF, fibrinogen, and fibronectin), adhesion to the damaged endothelial wall (Collagen) or biomaterial surface (plasma proteins)

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53
Q

Platelet activation cascade

A

Activate -> become discoid shape (irregular shape with tiny pseudopods) -> contraction of cytoskeleton proteins causes thrombin, ADP and thromboxane 2 release -> stimulates even more platelet activation -> Glycoprotein receptor GP IIb/IIIa activation causes binding to plasma proteins (fibrinogen-vWF) or platelet-platelet binding leading to aggregation -> catalyzed coagulation with Factor X activation and a membrane forms catalytic environment to turn prothrombin to thrombin

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54
Q

Coagulation Cascade Intrinsic System

A

Can be triggered by lipid flipping.

Factor XII ––(neg. charged surface contact)––> XIIa

Factor XI ––(XIIa)––> XIa

Factor IX ––(XIIa, Ca++)––> IXa
…..

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55
Q

Coagulation Cascase Extrinsic System

A

Factor VII ––> VIIa
…..

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56
Q

Coagulation Common Pathway

A

Factor X ––(IXa, Ca++, Factor VIII, platelets) ––> Xa

Prothrombin ––(Xa, Ca++, Factor V, Platelets) ––> Thrombin

Factor XIII ––(thrombin)––> XIIIa

Fribinogen monomer ––(thrombin)––> fibrin (polymer)

fibrin –––(XIIIa, Ca++)––> stable fibrin

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57
Q

Fibrin Polymerization

A

Fibrinogen + thrombin removes fibrinopeptides A and B, forming fibrin monomer which then dimerizes before polymerizing

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58
Q

Blood Clot Primary cells

A

Blood cells, platelets, fibrin clot

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59
Q

How to limit clot formation

A

Dilute blood flow, rate of clotting is fast only when the reaction is catalyzed by a surface (conversion of X to Xa, which controls prothrombin to thrombin)
Inhibit thrombin/coagulation enzymes (heparin, anti-thrombin III (ATIII) complex), thrombomodulin
Enzymes that activate coagulation factors and degrade cofactors

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60
Q

Fibrinolysis

A

Remove unwanted fibrin deposits to improve blood flow after thrombus formation to facilitate healing post-injury and inflammation

Plasminogen -> plasmin (Factor XIa, XIIa, tPA, urokinase) breaks fibrin up

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61
Q

Complications of Blood-Material Interaction

A
  • Prolonged cardiopulmonary bypass and membrane oxygenation can produce neuropenia
  • Mechanical heart valves shed emboli (detached blood clot that can travel through the bloodstream and lodges to obstruct/occlude a blood vessel) leading to stroke
  • Graft failures due to thrombosis -> ischemic and death of downstream tissue beds
  • Systemic anti-coagulant administration leads ti bleeding risk
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62
Q

Adhesion proteins in plasma for platelets

A

include fibrinogen, fibronectin, vitronectin, and von Willebrand factor

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63
Q

Platelets are ___________ to adsorbed plasma proteins, one solution is to create a ____________ surface

A

(Sensitive, non-fouling)

Receptors IIb/IIIa and Ib/IX bind to adborped proteins and mediate adhesion

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64
Q

Non fouling surface

A

Anti-adhesion surface modifications or properties

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65
Q

Role of the endothelium

Solution based on this?

A

At rest, anti-coagulative properties: glycocalyx, heparin sulfate aids ATIII to inhibit thrombin, thrombomodulin on EC surface binds to thrombin, activates protein C to inhibit coagulation. Secretes soluble chemical mediators that prevent aggregation or active plasmin, promoting fibrinolysis

Post-injury…
The glycocalyx is compromised, the now exposed ECM is reactive to plasma proteins and platelets, and in response to pro-inflammatory cytokines, the intact Ec surface may become coagulator (reduce thrombomodulin, secrete TF and vWF)

SOLUTION? drug eluting material, or dip in thrombomodulin, graft in heparin sulfate or ATIII.
Or, try endothelial cell sending, as the endothelial vessel can maintain latency for a lot longer (but this is difficult to culture and difficult to seed into the graft)

66
Q

Static BMI In vitro Assays

A

Place whole blood (non anticoagulated or anticoagulated with sodium citrate) into containers made of test material, control: glass

Measure clotting time, phenotypes of adhered platelets, mass of thrombus, amount and types of platelet release or other clotting factors

67
Q

Dynamic BMI in vitro Assays

A

Circulating heparinized or citrated blood through a tubular device made of the test materials

Measure clotting time, phenotypes of adhered platelets, mass of thrombus, amount and types of platelet release or other clotting factors

68
Q

Blood

A

Cells and Liquid

69
Q

Plasma

A

Liquid remaining after anticoagulant has been added to the blood, no cells

70
Q

Serum

A

Liquid that remains after the blood is clotting, no cells

71
Q

Natural vascular grafts

A

Use the saphenous vein, complete endothelization, symptoms can reappear, mismatch mechanical properties, and its not always feasible

72
Q

Synthetic vascular grafts

A

Porosity enhances healing, impregnate with connective tissue proteins to help with clotting, reduce blood loss through pores, stimulate tissue ingrowth/antibiotic release.

Pre-clotting.

Good in large diameter high flow, has low resistance locations

Small diameter is more challenging

73
Q

Tissue engineering for vascular grafts

A

Used when a small diameter is needed. Scaffolds with cell seeding, or a cell free scaffold that is degradable/decellularized. This however needs to achieve stable and complete endothelialization

74
Q

Vascular graft healing

A

Fibrinogen adsorption, pseudointima, smooth muscle integration and proliferation. Endothelial cell lining forms near the suture, the rest covered by pseudointima, this can be dislodged

75
Q

Basic Mechanisms of the Innate Response

A

Phagocytes encounter and ingest the microbe. They degrade by releasing ROS intermediates and proteases. Release cytokines to attract more cells to the site. Activate adaptive immune cells

76
Q

large biomaterial > phagocyte

A

Macrophages fuse to FBGC, release ROSs and proteases into environment in attempted to breakdown material

77
Q

Complement activation

A

Activation of a complement by biomaterials leads to inflammatory cell accumulation, leads to failure.

C3 adsorption -> macrophage adhesion
C3b attachment of biomaterial -> opsonize foreign objects, make them more likely to undergo phagocytosis

78
Q

Humoral Adaptive Immunity

A

Antibodies from B lymphocytes mediate. Memory B cells express membrane bound antibodies. Plasma cells produce the antibodies. B cells activate by antigen binding and a stimulatory signal from Th cells into plasma and memory

79
Q

Antigen

A

Substance that binds to antibodies/TCRs to innate acquired immune response. The site recognized by the antibody is an epitope, one antigen may have multiple epitopes

80
Q

Antibody

A

Protein secreted by B cells with high antigen specificity. 2 light, 2 heavy chains.

Fab fragment – variable portion recognized by antigen
Fc fragment – constant, recognized by phagocytes or complements

IgG, IgD, IgE, IgA, and IgM

81
Q

T lymphocyes

A

Th (helper t) provide signals and cytokines to orchestrate cellular activity

Tc (Cytotoxic t) kill selected targets. Target INTRACELLULAR pathogens

T cells cannot recognize proteins unless that have been degraded into small fragments and bound onto APCs

82
Q

Antigen presenting cells

A

Presents antigens and activate T cells. Macrophages, B cells, dendritic cells and langerhans cells

83
Q

Major Histocompatibility Complex

A

Antigen must be displayed with MHC I or II.

Different person to person. MHCs not recognized by host with elicit T cell activation, B cell antibody production -> graft destruction, failure.

Avoid via: tissue typing, immunosuppressive agents

84
Q

MHC I

A

Transmembrane glycoprotein found on all nucleated cells with B-macroglobulin. Intracellular antigens are degraded and presented with MHC1 to Tc cells

85
Q

MHCII

A

Only on APCs. Extracellular antigens ingested and presented to Th cells, activates macrophages or B cells

86
Q

Origin of Specificity/Memory

A

B cells produce antibodies specific to antigens. T cells produce TCRs. antibodies/TCRs expose to self-antigens and undergo apoptosis (self vs non self recognition)

After activated, lymphocytes rapidly divide, specific antigen population

87
Q

Immune Response to Biomaterials

A

Synthetic biomaterials -> no specific immune response, can have failure modes. Still can activate innate

Decellularized tissue or collagen-based biomaterial do not normally cause adaptive immune response. No cells = no foreign MHCs, proteins are similar.

Denatured native proteins mya have undesired immune response

88
Q

Hypersensitivity/Allergy

A

Hypersensitivity: the immune system strikes invading molecules with high intensity towards the relative amount of damage done

Allergen: foreign substance. Large foreign molecules (proteins and nucleoproteins) are strong, lipids are not

89
Q

Hapten

A

Low MW substance combining with carrier molecules to create greater immune response (synergy). Second exposure - antibodies react against happen without carrier (metal allergy, Cp, Cr, Mo. Methyl methacrylate resin, accelerators/antioxidants in latex)

90
Q

Type I Allergy

A

Plasma cells secrete IgE -> IgE binds to mast cells, basophils -> sensitization

Second exposure -> crosslink membrane bound antibodies -> mast cell degranulation (release of mediators such as histamine, vasoactive substances) -> vasodilation, smooth muscle contraction

91
Q

Type IV Allergy

A

Cell mediated, more than 12 hours (24-7). Previously sensitized T cells -> release inflammatory mediators -> tissue damage both at and away from exposure site

92
Q

Tumorigenesis

A

Neoplasia, new growth, unregulated process of excessive/uncontrolled cell proliferationTm

93
Q

ors

A

proliferating neoplastic cells and supportive stoma of connective tissue and blood vessels

94
Q

Metastasis

A

Development of secondary malignant growth distances from the primary site

95
Q

Carcinogen

A

Stimulus causing malignant transformation vs mutagenesis

96
Q

Malignant Transformation Process

A

Accumulation of genetic damage.

Imitation -> latency -> promotion

97
Q

Biomaterial Tumorigenesis

A

Tumorsassociated with clinical implants in humans are rare, hard to demonstrate causality.

Chemical carcinogens–leachable or degradation products from polymers can be carcinogens, but no evidence shows they cause tumor formation at relevant dosages

98
Q

Foreign Body Carcinogenesis

A

Small fibers: mesothelioma

For large implants, tumorigenesis and correspond directly to the extent and maturity of tissue encapsulation.

Implants with continuous surface area: more tumorigenic

Fabrics/fibers produce fewer tumors than sheets of the same materials, and powers produce almost no tumors

99
Q

Foreign Body Tumorigenesis

A

Cellular FBR -> fibrous capsule forms -> preneoplastic cells contact the surface implant during tissue reaction -> preneoplastic cell maturation and proliferation -> tumor growth

100
Q

Carcinogenicity Test

A

Should be conduced if data from other sources suggest tumor induction tendency

In vitro -> ames test

In vivo -> long term rodent study with positive and negative controls, harvest at different time points, analyze with SEM and histo

101
Q

Ames Test

A

Carcinogenicity in vitro test. Evaluate mutagenic potential, requires histidine to grow but lacks ability to biosynthesize it because of essential gene mutation

102
Q

Infection

A

Invasion by and multiplication of microorganisms

103
Q

Gram positive bacteria

A

Strong well well with telchoic acid and peptidoglycan

104
Q

Gram negative bacteria

A

LPS, can trigger the inflammatory response

105
Q

Biofilm

A

Bacterial adhesion to surface in aqueous environment, excrete glue-like substance hat anchors them to different materials surfaces.

Can be one or many species of bacteria, as well as fungi, algae, protozoa, debris, and corrosion products

Found on all failed medical devices

106
Q

Infection steps

A

Bacterial attachment (VdWs, reversible)

Bacterial adhesion (ligand-receptor binding, irreversible)

Aggregation -> biofilm formation. Change phenotypes, produce matrix, proliferate and recruit (form micro colony), mature and into thick and stable structure

Dispersion -> spreads the infection

107
Q

How do implants facilitate infection

A

Provide access to circulation and deeper tissue by damaging natural barriers against infection

Provide surfaces for bacteria to attach to

Limit phagocyte migration to infected tissue or interfere with inflammatory cell

108
Q

Factors influencing rate/extent of biofilm formation on biomaterials

A

Microorganism exposure. Microorganisms must adhere, cell attacghemtn rate depends on: number/types of cells in liquid, flow rate, physiochemical surface characteristics components in liquid altering surface properties.

Once they attach and product extracellular polysaccharides, bacteria don’t attach to the surface but to slime. Biofilm growth rate is influenced by (flow rate, nutrient composition, antimicrobial-drug concentration, and temperature)

109
Q

Biofilm control

A

non-fouling surface is effective.

Agents: antibodies, planktonic phenotype lock in (signal blockers)

Dc field, ultrasonic energy

Delivery of agents to kill planktonic (systemic injection, irrigation after installation, local release from surface)

110
Q

Sterilization Methods

A

moist heat: saturated steam, destroy metabolic/structural component of microorganisms. Good for metallic/heat resistant surgical instruments. High speed, simplicity, efficacy, and no toxicity. Bad b/c high temp, pressure degrade product/packaging materials

ETO: toxic, carcinogen, remove residue after 2-16 hours. Alkylation of amine group. High efficacy, high penetration ability, high compatibility. Bad b/c residues

Radiation: Gamma ray, ionization causes microorganism death. simple rapid effective, but high cost and can be incompatible

111
Q

In vitro infection models

A

determine if biomaterial encourages/discourages bacterial attachment. Analyze the source of infection

112
Q

Ex vivo and in vivo infection models

A

bacterial may be directly places at implant site or via injection.

Ex vivo is good for blood contact devices

Markers of infection: histo, SEM, leukocyte/lymphocyte counts in blood. Measures the amount of bacterial cell wall antibodies found in blood. presence of LPS

113
Q

Calcification

A

Formation of nodular deposits of calcium phosphate or other calcium containing compounds. Used for osteoinductive materials used for orthopedic/dental applications. undesired for non skeletal tissue replacement and devices that aren’t supposed to calcify -> mech failure

Often principle sites are dead cells and cell membrane fragments

Affect both tissue derived biomaterials and synthetic polymers

114
Q

Biological heart valve xenograft

A

Porcine aortic valve/bovine pericardium. Fix with glutaraldehyde to preserve tissue and kill cells to reduce immunogenicity

115
Q

Biological heart valve allograft

A

human cadaveric aortic or pulmonary valves with/without vascular conduits, good hemodynamics, low thromboembolic complications and low infection. Cryopreserved, low thrombosis rate. Less durable, structural damage due to tissue deterioration

116
Q

Calcification

A

Tear and stiffening (stenosis), intrinsic on cusps. Extrinsic (in thrombi or endocarditic vegetations), accelerated in youth

117
Q

Factors causing calcification

A

mechanical force -> cell death/deformation

Fixing agents like glutaldehyde, stabilize cell surface proteins

Nonviable cells lost mechanism to remove Ca++

Phosphate contains proteins on cell membrane act as a nucleation site

alkaline phosphatase on membrane promote calcification

Collagen act as a template for growth of mineral crystals

118
Q

Calcification prevention

A

Systemic treatment of local delivery of anti-calcification agents (HA formation inhibitors, bisphosphonates, trivalent metal ions from complex, calcium diffusion inhibitor, 2-amino oleic acid covalently binds to glutaldehyde, diminishes Ca++ diffusion)

Biomaterial modifications, removal of calcifiable component, addition of exogenous agents/chemical alteration
-surfactants: remove phosphate containing proteins/acidic phospholipids
-ethanol: extract lipids, alter collagen conformation, affect cusp interactions with water/lipids
-decellularization

Modification of glutaraldehyde fixation or use other cross-linking agents

119
Q

Calcification assessment in vitro

A

physiologically relevant media with chemical composition mimicking urine or blood or CSF. Static or dynamic

120
Q

Calcification assessment in vivo

A

Subcutaneous: easy access, faster calcification. Final location

121
Q

Other calcification assessments

A

Chemical assays to determine Ca or phosphate content

Sectioned and stained for Ca content

Explant analyzed by SEM, SEM-EDAX, X-ray diffraction

In situ imaging: radiography suing X-ray, microCT

122
Q

Bioelectrode Application

A

Conducts current across the interface between the body and the electronic measuring circuit. Serves as a transducer to change an ionic current into electronic current and vise versa

Recording electrodes monito electrical events in the body: ECGs, EEGs, EMGS,a nd BMI

123
Q

Stimulating electrodes

A

Transmit electrical current into the bd=ody to influence specific biological processes (cardiac pacemakers, defibrillators, deep brain stimulators, transcutaneous drug delivery), bioelectronic medicine, electrochemical biosensors

124
Q

Faradaic process

A

Charge transfer governed by faraday’s law (the amount of change occurring at the electrode-electrolyte interface is directly proportional to the current that flows through the interface. Electrodes that undergo mainly faraday processes are called charge tarsier electrodes/non-polarizable electrodes

125
Q

Polarization at the elctrode-electrolyte interface

A

the half cell potential of the electrode results in the formation of an electrical double layer, which can be considered as a capacitor

Perfectly polarizable electrodes do not undergo faraday processes (e.g., noble metal Pt, Au, stainless steel)

126
Q

Non-faradaic process

A

current flow can be passed by charging and discharging of the capacitor

127
Q

Mixed Situation (faraday)

A

Faradaic and nonfaradaic pathways of general electrode reactions. The charge transfer reaction at the surface is faraday and the diffusion and thew adsorption/desorption processes are nonfaradaic

128
Q

Faraday circuit model

A

battery-like Ehc is the half-cell potential. Rd and Cd ate impedance and polarization effects in parallel, and Rs is the series resistance associated with interface effects and due to electrolyte resistance

129
Q

Impedance Spectroscopy

A

Z(w) = V(w) / I(w) = |Z(w)|e^(iø)
|Z(w)| = [ReZ(w))^2 + ImZ(w))^2]^(1/2)

130
Q

Non-polarizable electrodes

A

Ag/AgCl

Ag <––> Ag+ + e-
Ag+ + Cl- <––> AgCl (precipitate).

Can be made by electrolytic processes or entering processes

131
Q

Skin Surface Electrodes

A

Electrode -> Gel -> epidermis ->dermis and subcutaneous layers.

Needs to overcome the stratum corneum layer

132
Q

Microelectrode assays (MEAs) for neural recording include…

A

Utah array, microwave array, Michigan probe

133
Q

Michigan Probe

A

Gold pads contacting instrumentation -> polycrystalline silicon -> gold or iridium electrode sites

134
Q

Cellular Response around inserted Neural Electrodes

A

Macrophages.microglia.astrocyte/enurons. After awhile, the astrocytes and microglia bind to the polycrystalline silicon

135
Q

Electrode modification using conductive polymers

A

3,4-ethylenedioxythiophene + A- –––(-e-)–––> PEDOT

A is proteins/peptides/anti-inflammatory neuroprotective, neurotrophic factors and neurochemicals

136
Q

PEDOT/PSS facilitate charge transfer at electrode/tissue interface

A

Low impedance. Enables high quality recording from ultra-small sites

137
Q

Stimulating electrodes

A

produce transient electric fields in their vin city to modulate electrophysiological actives.

The uniformity and precision of the e- fields are dependent on the charge density distribution created by the stimulating electrodes

138
Q

Charge injection limit

A

Maximum quantify of charge that can be injected per unit area.

Biphasic current pulse: negative then positive step function.

Voltage Response: First: instantaneous drop, -E.mc, then there is a polarization curve (V.access), monitor voltage electrode experiences, this curve is where polarization occurs.

Goes back up then over.

Etc: maximum cathodic potential, Ema: maximum anodic potential

Safe potential window (water window): -0.6–0.8V.

Q/A = Ixt/A

139
Q

Stimulation Electrodes

A

Noble metals: mostly use noble metals which undergo minimal chemical reactions (Pt is stable, inert. Pt/Ir allow is harder. Ir and iridium oxide is reversible reactivity

Non-noble metals: stainless steel or Ni/Co based alloy, susceptible to corrosion related failure

Stimulation waveforms: voltage stimulation is susceptible to complex fluctuations in comparison to current stimulation (cannot go above the safety limit)

Pulsatile current stimulation is charged delivered = current x duration

Biphasic pulses are better than monophonic pulses: minimize tissue damage by reducing the irreversible electrochemical reaction
(can be asymmetric with a higher negative side and longer, longer positive side)

140
Q

Cardiac Pacemakers

A

For patients with cardiac arrhythmias. Deliver current to myocardium via electrodes, resulting in depolarization/heart contraction. Senses intrinsic cardiac activity

Active electrode fixation to endocardium – designed to grasp the surface of the heart

Passive electrode fixation to endocardium –addition of projection tines/fins

Porous metal surface to encourage tissue ingrowth

141
Q

Stimulation threshold

A

minimum voltage required to stimulate the heart outside of the refractory period. this threshold can increase, and the battery of the pacemaker by drain as the voltage increases

142
Q

Electrode scarring

A

Inflammation results in fibrous capsule, increases the threshold. This can be reduced with improved design and a local release of corticosteroid.

Conventional actively fixable pacemaker lead electrode with a screw on the distal end versus a lead electrolyte with additional steroid eluting ring for reduced trauma

143
Q

Natural protein polymers

A

Collagen, gelatin (partially amorphous collagen), fibrin/fibrinogen, silk (silkworm/spider)

144
Q

Natural polysaccharide polymers

A

Cellulose, carboxymethylcellulose, methylcellulose, alginate, GAGs (heparin, HA, chondroitin sulfate), Chitin/chitosan

145
Q

Natural polynucleotide polymers

A

DNA, RNA

146
Q

Natural polymer polyester made by bacteria

A

PHB/PHV polyhydroxybutyrate/polyhydroxyvalerate

147
Q

Natural vs synthetic biomaterials

A

Natural has high biocompability with biological tissues.

Synethic materials usually have no immunogenicity but could produce some if there is an allergy. Natural materials might have immunogenicity

Molecular weight of natural is defined, despaired in synthetic

Few natural polyhedral processing choices compared to synthetic

Natural has low reproducibility compared to synethctic

Natural degradation is safe, synthetic may or may not be

148
Q

Collagen

A

Most abundant natural polymer. 10 different types, differ in length and carbohydrates attached.

Type I: skin/tendon/bone, 90% of collagen. in scar tissue (OA bad)
Type II: cartilage (OA good)
Type III: major component of blood vessels, also in skin and granulation tissue prior to type I formation
Type IV: component of basement membrane separating epithelial tissue from mesodermal tissue

Type I-III forms fibrils with distinct triple helical structure while type IV is non helical, no fibril formation

149
Q

Type I Collagen Structure

A

Primary structureL animo acid sequence along peptide chain (Gly-X-Y), where X and Y are often proline and hydroxyproline

Interchain crosslinks are the condensation of lysine and hydroxylysine

Secondary structure is an alpha chain

Tertiary structure is a triple helical structure held by H-bonds

Quaternary Structure (super molecular unit structure): several triple helical molecules packed in quasi-hexagonal lattice-> microfibrils->lateral and end-to-end aggression-> fibril-> collagen fiber -> bundled fibers lead to body tissue formation

more interchain crosslinks as we grow old

150
Q

Importance and Manipulation of Structural characteristics

A

2 discrete levels of structural orders: 3° and 4°

Helix heating -> random coil like gelatin and fast degradation
D-period -> platelet aggregation (thrombogenic)

Can decrease the thrombogenecity with treatment

D-period -> acetic acid (pH<4.25)-> D band disappears and helix is unchanged

151
Q

Chemical Modifications: Degradation

A

Collagenases are naturally occurring enzymes that attack the triple helix at a specific location 2/3N, 1/3C => gelatin

152
Q

Chemical Modifications: Cross-linking

A

NH2 on lysine residue can be cross-linked with dialdehydes. The crosslinking reduces degradation rates from days to weeks. Cross-linking decreases immunogenicity problems

153
Q

Chemical Modifications: enzymatic treatment

A

Cleaves telopeptide region and may reduce the immunogenicity

154
Q

Chemical Modifications: gelatinization

A

Increases the immunogenicity

155
Q

Collagen Applications

A

hemostatic devices such as gel form (water-soluble, absorb/hold within interstices many times its weight, can be applied to bleeding surfaces)

Lipid augmentation, nerve conduits, tendons/ligaments, burn treatments/skin grafts, drug delivery, heart valves

156
Q

Fibrin Gels

A

Formed from fibrinogen and thrombin. The fee structure can be modified and controlled based on Ca++ and fribinopen concentration

Amenable to inclusion of growth factors

Degraded by plasmin, degradation products are digested by inflammatory cells (applications in tissue engineering and sealent)

157
Q

Sealent

A

2-component fibrin mixture that simulates natural physiological conditions to achieve hemostasis and tissue sealing

158
Q

Hyaluronic Acid (HA)

A

Native ECM sugar, high content in epithelial, connective and neural tissue.

Linear polysaccharide with repeated units. Ranges in size

only insulated GAG.

Hyaluronan is degraded by a family of enzymes called hyaluronidases

159
Q

HA Applications

A

hydrophilic, anti-inflammatory and pro-regeneration abilities. Adhesion barrier, ophthalmology, soft-tissue implants, wound healing, surface coatings, drug delivery, cosmetic applications, OA knees

160
Q

Chitin

A

Found incrabs/shrimps/insects/worms.

Tough, strong, used in sutures and wound healing agents

161
Q

Chitosan

A

Obtained by deacetylation of chitin and is more water soluble.

Used for gene deliveries, and bandages

162
Q

Polyhydroxyalkanoates (PHAs)

A

Aliphatic polyesters naturally produced via a microbial process on sugar or lipid based medium. where they act as carbon/energy storage material in bacteria), can be thermoplastic of elastomeric materials

PHB: poly-beta-hydroxybutyrate/ PHV: polyhydroxyvalerate.

Completely bioresorbable, no toxic byproducts, solution for plastic waste issue. Being examines as biomaterial for bone repair, fixation, suture, and tissue engineering scaffolds

Biomaterials (2 decks)

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