Any material of natural or of synthetic origin that comes in contact with tissue,

blood or biological fluids, and intended for use in medicine including prosthetic,

diagnostic, therapeutic or storage application.

• The ability of a material to perform with an appropriate host response in a specific application.

• A general term meaning that a biomaterial, device or construct can be brought into direct contact with living tissue without:

o Causing a harmful tissue reaction (persistent pain, swelling or tissue necrosis) or without causing a systemic toxic reaction; or having tumorigenic potential that could compromise device function or the life and health of the patient.

• Opinion: it is an important concept in this course because we are dealing with material that will be implanted or at least come in contact with body fluids and therefore, we have to understand the implication of contacting these material to the body and if the body will react adversely to the material causing inflammation and etc. risk/benefit ratio

• Biological response (foreign body response)
• Definition: a description of the molecular and cellular event that follow contact with biological fluids or tissues whether in vitro or in vivo from initial contact to the eventual culmination of the response
• Biocompatibility
• Definition: The ability of a material to perform with an appropriate host response in a specific application.
• Difference (opinion): Biological response is how the body reacts to the material whereas biocompatibility is the ability of the material to elicit favorable response (not have bad reactions) in the body

• Class I devices: crutches, bedpans, tongue depressors, adhesive bandage
• Minimal invasiveness, does not contact the user internally
• Class II devices: hearing aids, blood pumps, catheters, contact lens, electrodes
• Higher degree of invasiveness and risk, but relatively short duration
• Class III devices: cardiac pacemakers, intrauterine devices, intraocular lenses, heart valves, orthopedic implants
• Considerably more invasive and can pose immense risk to the user-implants

• The ability of a material to perform with an appropriate host response in a specific application
• Opinion: it is a necessary consideration in manufacturing medical devices because biomedical devices will come in contact with biological tissues and fluids and therefore, it would be crucial to not have negative effects arising from the contact. Otherwise, it could lead to potentially lethal complications. Biocompatibility of a material varies with the position in the body which it comes into contact with and also the physical condition of the material also changes the biocompatibility

• Direct contact with the bodily tissues or fluids
• Leachables
• Wear particles or debris
• Degradation products

Differentiate between the different types of biomaterials;

Ceramics

Metals

Polymers (synthetic and natural)

Composites

• Ceramics- Inorganic compounds that contain metallic and non metallic elements
• Metals- closely packed crystal structures
• Polymers(synthetic and natural)-small repeating units strung together in long chains
• Composites- combination of the other 3

• Medical devices are not monolithic devices because they are not made up of only one type of material instead they are composites of different types of material depending on the application of the device.
• Eg. An LVAD-made up of polymer, metal

• Ceramic is an inorganic compound that contains metallic and non metallic elements, for which inter-atomic bonding is ionic or covalent, and which are generally formed at high temperatures
• Eg: artificial hip, knee prostheses, spinal fusion devices, dental crowns, bridges implants and caps, inner eat and cochlear implants, drug delivery devices 

• Metals have closely packed crystal structures, metals and metal alloys are valuable due to the type of bonding they possess. They can be used to make load bearing implants as well as internal fixation devices used for orthopedic applications as well as dental implants
• Medical tubing, stents, catheters

• Synthetic and natural polymers
• Types: Thermosets and thermoplastics, elastomers, hydrogels, polyelectrolytes, natural, biodegradable
• Have repeating structure
• Medical plastics market: thermoplastics dominates market with little under 50% of the market
• Eg: syringes, labware, tubing, blood bags, gloves, trays, catheters, thermometers

• Definition: applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function
• Two methods
• Synthetic scaffolding
• Personalized reconstruction

• Inertness: Not readily reactive with other elements; forming few or no chemical compounds. Having no pharmacologic or therapeutic action.
• Bioactivity: having an effect on a living organism

• Processable (manufacturability)
• Packaging (combined with other materials)
• Sterilizable
• Storage
• Biocompatible
• Economical

• Contain amorphous and crystalline regions
• Made up meric units
• Has a backbone with repeating meric units
• Basic make up: carbon and hydrogen
• Can have other elements
• Oxygen, chlorine, fluorine, nitrogen, silicon, phosphorous, and sulfur
• Can be elongated more than ceramics or metals
• Encompasses almost everything that is not metal or inorganic

 What were three themes discussed by James Andersen in his article “the future of biomedical materials”? 

·         1950-1975 – bioMATERIALS            inert          “off the shelf”

·         1975-2000 – BIOMATERIALS

·         2000-          - BIOmaterials                         bioactive         “designed”

·         Hydrophilic molecules are molecules that are attracted to water particles and can transiently bond with water

·         Hydrophobic molecules are molecules that repel water particles

·         Substances that can be broken down into innocuous products by living organisms (microorganisms)

Describe how the microstructure of a biomaterial influences design decisions of engineers in the biomedical device industry.

·         Microstructure dictates the physical properties of materials such as the strength, toughness, ductility, hardness, corrosion resistance, behavior at different temperatures, wear resistance. These propertied influence the behavior of the material in biomedical application

·         Engineers have to take into account the microstructure of a material to understand the effects it would have a component of a device and to understand the properties of a material when used a composite with other materials 

Understand the fundamental nomenclature of polymeric structure;

Small, repeating units strung together in long chains, Some contain only 1 C and 1 H, basic makeup is C and H, but other elements can be involved, PVC-chlorine, Nylon-Nitrogen, Teflon-fluorine, polyester/polycarbonate-oxygen

Understand what is meant by the term polymer “conformation”;

·         Conformation-refers to order that arises from the rotation of molecules about the single bonds.  Since different conformations represent varying distances between the atoms or groups rotating about the bond, and these distances determine the amount and type of interaction between adjacent atoms or groups, different conformation may represent different potential energies of the molecule.

 What is meant by the term polyelectrolyte;

polyelectrolyte: polymers whose repeating units have an electrolyte group, dissociate in aqueous solutions, polymers are charged, 

Strength of intermolecular forces and their sum over long polymer chains, molecular weight and entanglement, crystallinity and cross linking

Provide two examples of different types of polymerization reactions;

·         Condensation polymerization: 2 monomers react to form a comvalent bond, usually with the elimination of a small molecule (such as: water), EX: Nylon and PET

·         Addition polymerization: unsaturated monomers, react through stages of initiation, propagation, and termination to give the final polymer product.  Initiators can be free radicals, cations, anions, or stereospecific catalysts – in opens the double bond, presenting another initiation site, EX: PVC, PE, PMMA

·         A condensation reaction is a chemical reaction in which two molecules or moieties (functional groups) combine to form one single molecule, together with the loss of a small molecule.  The word "condensation" suggests a process in which something is lost; for reactions a small molecule is lost.  

·         Uniform polymer, A polymer composed of molecules uniform with respect to relative molecular mass and constitution, characterized by particles of uniform size in a dispersed phase- natural polymers

·         natural: include plant materials such as cellulose, natural rubber, animal materials, long-chain molecules that consist of a large number of small repating units; these polymers have polydiversity = 1

·         synthetic: the chemistry of the repeat units differs from the small molecules that were used in the original synthesis procedures, resulting from either a loss of unsaturation or the elimination of a small molecule; these polymers have polydiversity <1

·         of, relating to, characterized by, or characterized as particles of varied sizes in the dispersed phase of a disperse system, the ratio of Mw to Mn, measures the breadth of the molecular weight distribution

List several ways to experimentally determine a polymers molecular weight;

·         An interface is the boundary between two adjacent bulk phases. We only recognize three specific boundaries as surfaces interfaces: (solid and gas; solid and liquid; liquid and vapor) 

Surfaces are not smooth.  They have many microscopic defects that dictate how that surface will react with the materials it comes in contact with.  They exhibit remarkable heterogeneity in their structure. Their characteristics are highly dependent on which material they are made of: ceramics, metals, polymers or composites, for each will manifest different properties. The surface chemistry will differ; some are Polar, others Apolar.  Certain surfaces have a charge on them and will attract charged particles, others are highly inert and do not interact with the surrounding materials. 

The surface’s morphology or physical character is dependant on its material. Some materials are smooth while others are highly abrasive.  Smooth will tend to repel other materials as there is not place to which they can adhere.  There are stepped and diffusing surfaces.

They follow the order of polymers and non-polymers, those orders being amorphous, crystalline, and semi crystalline and in different phases of these.  Finally, the surface depends on what conditions it was produced in

·         ESCA: 10-250 Ao

·         SIMS: 10 Ao – 1 µm

·         CAs: 3-20 Ao

·         STM: 5 Ao

Describe the working principle of ESCA

·         X-rays induce the emission of electrons of characteristic energy

·         Sends in xrays that release photoelectrons through photoelectric effect. The measured energy of electrons tells you which atom is came from. 

·         Penetration depth of incoming beam

·         Ability of leaving ‘particle’ to escape with useful info

Name two techniques for examining surface roughness.

• Contact methods: involve dragging a measurement stylus across the surface; these instruments include profilometers.
• Non-contact methods: include interferometry, confocal microscopy, electrical capacitance and electron microscopy.

Describe structural features of proteins that affect their adsorption to surfaces 

·         Protein  passivation

·         Protein resistant

http://www.springerlink.com/content/f87479p82701m347/

(I couldn’t open entire of this article at home but I think that it will help in describing the features.)

Is protein adsorption energetically favorable?

·         Yes, rapid adsorption kinetics (text book pg. 240)

·         No, it is irreversible. (slide 6, lecture week 4)

What is the effect of water as a solvent during protein adsorption?

·         A biological response can create the Coagulation mechanism and platelet activation to occur.  This will cause inflammation and the cells will form fiborous tissue around the implant.

·         photolithographic techniques developed for microelectronics—patterning of biomaterial surfaces, ex: plasma-deposited films patterned using a photoresist lift-off method

·         Microcontact printing—a rubber stamp is made of the pattern that is desired on the biomaterial.

Ion-beam etching

Describe the effect of PEO grafted chains on protein adsorption. Describe what is meant by the term wound healing continuum;

·         Surface grafted poly (ethylene oxide) (PEO) chains are known to minimize protein adsorption and platelet adhesion.

·         EO grafted surfaces showed a surface PEO concentration dependent activation of the complement system. This is thought to be due to the hydroxyl functional group on PEO chains.

·         Wound healing continuum:

            Initiation by mechanical injury/damage to vasculature

·         Blood coagulation-clot formation

·         Platelet activation and degranulation

·         Inflammation-edema

·         Removal of damaged matrix and necrotic cell components

·         Cell proliferation and recruitment including endothelial, epithelial, stromal and inflammatory cells

·         Continued removal of matrix

·         Angiogenesis

·         Matrix synthesis and deposition

·         Epithelialization and wound contraction

·         Decrease in cellularity-apoptotic pathway

·         Tissue remodeling-elastin synthesis

·         vascular constriction. This limits the flow of blood to the area of injury.

·         platelets become activated by thrombin and aggregate at the site of injury, forming a temporary, loose platelet plug. The protein fibrinogen is primarily responsible for stimulating platelet clumping. Platelets clump by binding to collagen that becomes exposed following rupture of the endothelial lining of vessels. Upon activation, platelets release ADP and TXA2 (which activate additional platelets), serotonin, phospholipids, lipoproteins, and other proteins important for the coagulation cascade. In addition to induced secretion, activated platelets change their shape to accommodate the formation of the plug.

·         To insure stability of the initially loose platelet plug, a fibrin mesh (also called the clot) forms and entraps the plug.

Finally, the clot must be dissolved in order for normal blood flow to resume following tissue repair. The dissolution of the clot occurs through the action of plasmin. 

·Homopolymer-a single monomer is polymerized into a macromolecule

·Heteropolymer-made from two or more monomers

·Vinyl polymer-contain a c-c double bond

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Understand how to represent various common polymers by representing the meric unit in chemical shorthand and known the common abbreviation for the following polymers: polyethylene

polypropylene

polystyrene

polyvinylchloridepolytetraflouroethylene 

polyacrylic acid

poly(methylmethacrylate)

poly(vinylacetate)

poly(vinylidene dichloride)

Poly(ethylene oxide)

poly(caprolactam)

poly(hexamethylene adipamide)

poly(ethylene terephthalate)

poly(carbonate);

poly(dimethylsiloxane)

poly(methyl styrene);

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polyethylene (PE);

polypropylene (PP),

polystyrene (PS),

polyvinylchloride (PVC); polytetraflouroethylene (PTFE),

polyacrylic acid (PAA); poly(methylmethacrylate) (PMMA); poly(vinylacetate) (PVAc);

poly(vinylidene dichloride) (PVDF); Poly(ethylene oxide) (PEO);

poly(caprolactam) (nylon);  poly(hexamethylene adipamide) (Nylon 6,6); poly(ethylene terephthalate) (PET); poly(carbonate);

poly(dimethylsiloxane) (PDMS); and poly(methyl styrene);

What is meant by the term, polymer “backbone”   

covalent intramolecular bonding, usually made of carbons

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Be able to provide a sketch of the randon coil model of polymer structure and describe its relevance.

There are 2 domains – crystalline: (chains are close together and more density), and amorphous: (chains are twisted, far apart, and less density)

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What does the starting material look like for producing styrene?

polystyrene is made from the aromatic monomer styrene (vinyl benzene) 

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In general terms, how does increases in polymer molecular weight affect mechanical and chemical properties;

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Draw a graph of the general relationship of increasing molecular weight on stiffness and strength (can you explain the relationship at the level of polymer chain interaction);

 I think as the MW increases the polymer becomes more stiff, the chains are aligning, 

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How does number average molecular weight differ from weight average molecular weight;

Number average molecular weight: is the first moment of the molecular weight distribution and is an average over the number of molecules

Weight average molecular weight: the second moment of the molecular weight distribution and is an average over the weight of each polymer chain.

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Summarize the strong and weak intermolecular forces

Intermolecular forces: The short-range attractive forces operating between the particles that makes up the units of a liquid or a solid substance. Solids have strong intermolecular forces.

Liquids have intermediate intermolecular forces. Gases have extremely weak intermolecular forces.

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Describe how TOF SIMS works

Principle: Ion bombardment sputters secondary ions from the surface

Detail: A pulse of ions bombards the specimen and sputters it. This produces a cloud of atoms and molecules among which are some ionized. The ionized particles of one polarity, atomic and molecular secondary ions, are accelerated into a reflectron type spectrometer. They travel two meters through a tube to arrive at an ion detection and counting system. However, because they all depart from the sample at the same time and were subject to the same accelerating voltage, the lighter ones arrive at the detection system before the heavier ones. The "Time-of-Flight" of an ion is proportional to the square root of its mass, so that all the different masses are separated during the flight and can be detected individually.

The next pulse of primary ions cannot start until the secondary ions of the first pulse have cleared the analyzer. Otherwise the slower heavy ions of the first pulse are overtaken by the faster light ions of the second pulse. However the time interval between consecutive pulses can be used for other activities, such as sputtering and charge neutralization.

Ion images are produced by scanning the primary beam over the sample surface and recording the number of ion as a function of the position. Since all ions are detected, the images of all the ions are detected in parallel. The bombarding ions also produce secondary electrons, which are detected to give secondary electron images. The spatial resolution of the images depends largely upon the diameter of the pulse of primary ions. The ion image resolution is better than 100 nm and the SEM image resolution better than 60 nm.

The sputtering of all the secondary ions should happen simultaneously so that the spectral resolution is not degraded. This requires the primary ion pulse to be short as possible. Pulsing is achieved by rapid deflection of the primary ion beam, and a device called a buncher is introduced into the primary ion column, compressing the pulse duration to less than 1 ns.

The TOF analyzer is vertically mounted. The extracted ions travel upwards to an ion mirror where they are reflected downwards to the detection system. This allows for easy compensation of the energy spread of the sputtered species (time focusing).

The detection system is a combination of a channel plate, scintillator and photomultiplier, combined with a very fast electronic counting system. 

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What initiates the inflammatory response?

·         The Compliment system is responsible for the activation of the inflammation and immune related functions:

o    Soluble signals – cleaved fragments act as signaling molecules to enhance and regulate inflammation

·         Mediators of Inflammation are: C5a, C3a, and C4a

·         Bind to complement receptors on mast cells triggering release of histamine

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How does platelet degranulation influence wound healing

When there is damage to the wall of the blood vessel, platelets adhere to the exposed collagen, begin undergoing a conformational change, and release platelet factors that aggregate into a loose plug creating temporary hemostasis. 

·This secretion of platelet granules recruits other platelets and catalyzes the coagulation cascade – leads to the formation of fibrin

o Types of Alpha granules:

·Serotonin, thromboxane A2,ADP, and epinephrine (causes vasoconstriction)

  ·Growth factors (Platelet derived growth factor (PDGF)

       ·Fibronectin, von Willebron Factor

       ·TGF-b

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Provide a diagrammatic description of the complement system

How does the complement cascade differ from the coagulation cascade

·         1) Coagulation Cascade—involves ~12 proteins

·         2) Complement Alternative Pathway—involves >20 proteins

·         The coagulation cascade: clot formation

o    Initiated by damage to the wall of the endothelium

o    Enzyme mediated

o    Ca++

o    Amplification

o    Positive Feedback

·         The Compliment Cascade: Immune system response - helps clear pathogens from an organism

o    Opsonization: Enhancement of phagocytosis (by coating with C3b)

o    Cytolysis: Attack complex C5-C9 causes a loss of cellular contents through a transmembrane channel of a microbial plasma membrane

o    Inflammation: Increase of blood vessel permeability and chemotatic attraction of phagocytes

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·         activation pathway (formerly known as the intrinsic pathway), and the tissue factor pathway (formerly known as the extrinsic pathway), which lead to fibrin formation.

The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin.

What are serine proteases and what role do they play in the wound healing;

·         Serine proteases or serine endopeptidases (newer name) are proteases (enzymes that cut peptide bonds in proteins) in which one of the amino acids at the active site is serine.
An enzyme that cuts a peptide bond in an amino acid sequence in which on of the amino acids at the active site is serine. 

·         Plasmin, Thrombin, Factor X, and Factor IX, are all serine proteases that play a role in the wound healing process by helping in the clotting process.  

What is meant by the term “platelet activation”;

When platelets adhere to collagen fibers in the subendothelium, a series of morphologic and functional changes. This occurance is known as activation. Though not fully understood, platelet activation involves changes to platelet metabolic biochemistry, shape, surface receptors, and membrane phospholipid orientation. Substances that induce platelet activation are called agonists. Each agonist attaches to a specific receptor on the platelet, causing a series of reactions inside of the platelet. One of the biochemical changes that occurs within the platelet is an increase in internal calcium levels. During platelet activation, the glycoprotein IIb/IIIa is activated. The binding site for adhesive proteins appears shortly after activation with an agonist. It provides a site to which fibrinogen and von Willebrand factor will bind. Activation also causes a change in the membrane surface. This change enables fibrin-forming proteins (coagulation factors) to bind to the membrane.²

Describe what is meant by the final common pathway;

·         the steps in the mechanism of coagulation from the activation of factor X through the conversion of fibrinogen to fibrin.

·         A device implantation (implantation of a biomaterial) changes the sequence or cascade of events that follow a wound or injury:

o    Normal wound healing follows:

·         Injury

·         Hemostasis

·         Acute Inflammation

·         Granulation tissue

·         Mature extracellular matrix

·         Wound contraction (Scar formation)

o    Device implantation follows:

·         Injury

·         Hemostasis

·         Acute Inflammation

·         Granulation tissue

·         Fibrous encapsulation

·         Chronic Inflammation

·         Foreign Body Giant Cell formation

·         Cellular necrosis

Calcification

The provisional extracellular matrix (ECM) is different in composition from the

ECM in normal tissue and includes fibronectin, collagen, glycosaminoglycans, and

proteoglycans. Its main components are fibronectin and hyaluronan, which create a

very hydrated matrix and facilitate cell migration. It is the maxrix formed in wound

healing.

What are the major cytokines released by platelets and how do they affect the wound healing process?

·         The cytokines are the signaling molecules that are used for cellular communication – platelets adhere and release α-granule contents - see previous question for types of alpha-granules that are secreted by platelets

·         These cytokines recruit other resting platelets, help with vasoconstriction, and stimulate fibroblast proliferation

·         TGF-b: A chemoattractant for monocytes and fibroblasts

o    Pro-fibrogenic

o    stimulates fibroblast proliferation

o    Stimulates fibroblasts to secrete matrix (collagen, fibronectin, and glycosaminoglycans) and therefore aids in the development of wound strength

o    Stimulates angiogenesis (new blood vessel development)

(chemotactic and /or mitogenic agents for leukocytes, endothelial cells and fibroblasts);

·         Macrophages come from monocytes, which are a type of White Blood Cell.

o    3-8 % of WBC’s;

o    Sites of infection or inflammation;

o    Phagocytosis-bound antibodies and complement coated materials (opsonisation);

o    Vacuolization; proteolysis

o    Derived from monocytes-bone marrow-hematopoietic stem cells;

o    Monocyte count-monocytosis-chronic inflammation.

·         Angiogenesis – new blood vessel formation

Stimulated by TGF-b (released from platelets adhering to exposed collagen from a wound)

·         Fibroblasts grow and form a new, provisional extracellular matrix (ECM) by excreting collagen and fibronectin and glycosaminoglycans(component of connective tissue) – They synthesize, maintain and provide the structural framework

·         Complement: blood-materials interactions and protein adsorption

o    making bacteria more susceptible to phagocytosis

o    directly lysing some bacteria and foreign cells

o    producing chemotactic substances

o    increasing vascular permeability

o    causing smooth muscle contraction promoting mast cell degranulation

·         Compliment Cascade

o    A complex cascade involving approximately 30 glycoproteins present in serum as well as cell surface receptors

o    A summary of the general features of the compliment cascade:

·         AMPLIFICATION: (zymogen cascade)

·         SOLID-STATE: increases local protein concentration

·         SOLUBLE SIGNALS: cleaved fragments act as signaling molecules to enhance and regulate inflammation

·         MULTIPLE INHIBITORS: host cells contain numerous complement inhibitors, inhibitors also present in circulating serum (Serpins)

Cellular- actual cells that come in and respond neutrophills, macrophages

Humoral-antibody tagging side of immune system

·         C1q                                                      Binding to Ag/Antibody Complexes

·         C1r, C1s, C2b, Bd, D, MASP1,2          Activation Enzymes

·         C4b, C3b, MBP                                   Membrane-binding opsonins

·         C5a, C3b, C4a                                     Mediators of inflammation

·         C5b, C6, C7, C8, C9                            Membrane attack

·         CR1, CR2, CR3, CR4, C1qR               Compliment receptors

C1INH, C4bp, CR1, MCP, DAF, H, I, P, CD59           Compliment-regulatory proteins