Polymers in Biomedicine Introduction of Polymers ?· Polymers in Biomedicine • Introduction of Polymers…

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  • Polymers in Biomedicine Introduction of Polymers

    Polymeric Biomaterials

    Polymeric Drugs

    Polymer Drug Transporter

  • Materials that have one or more properties that can be significantly changed in a

    controlled fashion by external stimuli,

    Such as stress

    Temperature

    Moisture

    pH

    electric or magnetic fields

    Akustik sounds

    Example:

    pH-sensitive polymers are materials that change in volume when the pH of the

    surrounding medium changes

    3. Smart Biomaterials

  • Hydrogels are crosslinked network polymeric materials that are not soluble but

    can absorb large quantities of water.

    These materials are soft and rubbery in nature, resembling living tissues in their

    physical properties.

    3. Hydrogels

    http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84 http://www.youtube.com/watch?v=pxIJdjizQes&feature=related

    Many hydrogels are smart and respond to external stimuli

    https://www.youtube.com/watch?v=iBZAwhxwHX0 https://www.youtube.com/watch?v=by53LP0Yu4c

    http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?feature=endscreen&NR=1&v=TpvNEZCvk84http://www.youtube.com/watch?v=pxIJdjizQes&feature=relatedhttp://www.youtube.com/watch?v=pxIJdjizQes&feature=relatedhttp://www.youtube.com/watch?v=pxIJdjizQes&feature=relatedhttp://www.youtube.com/watch?v=pxIJdjizQes&feature=relatedhttp://www.youtube.com/watch?v=pxIJdjizQes&feature=relatedhttp://www.youtube.com/watch?v=pxIJdjizQes&feature=relatedhttp://www.youtube.com/watch?v=pxIJdjizQes&feature=relatedhttps://www.youtube.com/watch?v=iBZAwhxwHX0https://www.youtube.com/watch?v=by53LP0Yu4c

  • 12/8/2016 4

  • 3. Definition of a Hydrogel

    Water insoluble, three dimensional network of

    polymeric chains that are cross-linked by chemical or

    physical bonding

    Polymers capable of swelling substantially in aqueous

    conditions (eg. hydrophilic)

    Polymeric network in which water is dispersed

    throughout the structure

    12/8/2016 5

  • 3. Hydrogel Forming Polymers Hydrophilc Polymers

    O

    H O O H

    H O 2 C

    O

    O H O

    N H

    H O

    O

    O

    O

    H O O H

    N a O 2 C

    O

    O

    O

    O

    N H O

    n

    p o l y ( h y a l u r o n i c a c i d ) p o l y ( s o d i u m a l g i n a t e )

    n

    n

    p o l y ( e t h y l e n e g l y c o l )

    n

    p o l y ( l a c t i c a c i d )

    n

    p o l y ( N - i s o p r o p y l a c r y l a m i d e )

    Natural

    Synthetic

  • 3. Characteristics of Hydrogels

    No flow when in the steady-state

    By weight, gels are mostly liquid but behave like solids

    Absorption of large quantities of water

    1-20% up to 1000 times their dry weight

    Cross linkers within the fluid give a gel its structure

    (hardness) and contribute to stickiness (tack).

    Tissue-like bahaviour

  • 3. Hydrogels

    Highly swollen hydrogels

    Cellulose derivatives

    Poly(vinyl alcohol)

    Poly(ethylene glycol)

    Common structural features

    Many OH (or =O) groups to interact with

    Acidic environments hydrophillic swelling

    8

    O

    n

    Poly(ethylene glycol)

  • 3. Biomedical Uses for Hydrogels

    Scaffolds in tissue engineering.

    Sustained-release delivery systems

    Hydrogels that are responsive to specific molecules, such as glucose or

    antigens can be used as biosensors as well as in DDS.

    Disposable diapers where they "capture" urine, or in sanitary napkins

    Contact lenses (silicone hydrogels, polyacrylamides)

    Medical electrodes using hydrogels composed of cross linked polymers

    (polyethylene oxide, polyAMPS and polyvinylpyrrolidone)

    Lubricating surface coating used with catheters, drainage tubes and gloves

  • 3. Biomedical Uses for Hydrogels

    Breast implants

    Dressings for healing of burn or other hard-to-heal wounds. Wound gels are

    excellent for helping to create or maintain a moist environment.

    Reservoirs in topical drug delivery; particularly ionic drugs, delivered by

    iontophoresis

    Artificial tendon and cartilage

    Wound healing dressings (Vigilon, Hydron, Gelperm)

    non-antigenic, flexible wound cover

    permeable to water and metabolites

    Artificial kidney membranes

    Artificial skin

    Vocal cord replacement

    10

  • The polymer chains usually exist in the

    shape of randomly coiled molecules.

    In the absence of Na+ ions the negative

    charges on the carboxylate ions along

    the polymer chains repel each other and

    the chains tend to uncoil.

    3. Polyacrylate Hydrogel

  • Water molecules are attracted to the

    negative charges by hydrogen bonding

    The hydrogel can absorb over five

    hundred times its own weight of pure

    water but less salty water

    3. Polyacrylate Hydrogel

  • When salt is added to the hydrogel, the chains start to change their shape and water

    is lost from the gel

    3. Polyacrylate Hydrogel

  • 3. Hydrogel Swelling

    By definition, water must constitute at least 10% of the total weight (or volume)

    for a materials to be a hydrogel

    Swelling due to one or more highly electronegative atoms which results in charge

    asymmetry favoring hydrogen bonding with water

    Because of their hydrophilic nature, dry materials absorb water

    When the content of water exceeds 95% of the total weight (or volume), the

    hydrogel is said to be superabsorbant

    12/8/2016 14

  • Hydrogels containing interactive functional groups along the main polymeric chains are

    usually called smart or stimuli-responsive hydrogels.

    the polymer conformation in solution is dictated by both the polymersolvent and

    polymerpolymer interactions.

    Good solvent: polymersolvent interactions dominate and the polymer chains are

    relaxed

    Poor solvent, the polymer will aggregate due to a restricted chain movement because of

    increased polymerpolymer

    3a. Smart Hydrogels

  • 16

    3a. Hydrogel Forming Smart Polymers

    Cross-linked Polyacrylamide

    Thermally and mechanically stabile

    Not degradable

    Cross-linked PNiPAM (poly(N-isopropyl acrylamide)

    Finetuning of LCST behavior via copolymerization

    Mechanic stability

    No degradability

    Application: 2D Tissue growth

  • Synthesized in the 1950s

    Sensitive to both pH and temperature

    T> 32C, reversible lower critical solution temperature phase transition (LCST)

    Swollen hydrated state to a shrunken dehydrated state, losing about 90% of its mass.

    3D-dimensional hydrogel when crosslinked with N,N-methylene-bis-acrylamide

    (MBAm) or N,N-cystamine-bis-acrylamide (CBAm).

    PNIPAm expels its liquid contents at a temperature near that of the human body

    PNIPAm has been investigated by many researchers for possible applications in tissue

    engineering and controlled drug delivery.

    3a. Poly(N-isopropylacrylamide) PNIPAAm or PNIPAm

  • LCST = Lower Critical Solution Temperature

    3a. Poly(N-isopropylacrylamide) PNIPAAm or PNIPAm

    lower critical solution temperature (LCST) at 32C

    soluble below its LCST, but precipitates above the LCST

  • Reversible formation (below LCST) and cleavage (above LCST) of the hydrogen bonds

    between NH and C=O groups of pNIPAAm chains and the surrounding water molecules.

    Pentagonal water structure that is generated among the water molecules adjacent to the

    hydrophobic molecular groups

    Poly(N-isopropylacrylamide) PNIPAAm or PNIPAm

  • 3a. Poly(N-isopropylacrylamide) PNIPAAm or PNIPAm

  • 3a. Poly(N-isopropylacrylamide) (PNIPAAm or PNIPAm) Application: Controlling Cell Adhesion

  • 3a. Poly(N-isopropylacrylamide) (PNIPAAm or PNIPAm) Application: Controlling Size and Surface Texture

  • 3a. Poly(N-isopropylacrylamide) (PNIPAAm or PNIPAm) Application: Controlled Drug Delivery

    Slow drug release Rapid Drug Release

  • 3a. Changes in the Physical Properties of PNIPAM with External Stimuli

  • Materials exhibit shape-memory properties if they are able to fix a temporary

    shape and recover back to their remembered permanent shape when exposed

    to an external stimulus

    3b. Shape Memory Polymers

    Large deformation can be induced and recovered through

    temperature or stress changes (pseudoelasticity)

  • Shape Memory Polymers (SMP)

    Memorize a macroscopic (permanent) shape

    Fixed to a temporary and shape under specific conditions of temperature and stress

    Relax to the original, stress-free condition under thermal, electrical, or environmental

    command.

    This relaxation is associated with elastic deformation stored during prior

    manipulation

    3b. Shape Memory Polymers

  • 3b. Elastic Polymer

    Example: Rubber

  • Two distinct types of cross-linking:

    (1) nonreversible cross-link (which can be either a covalent or a physical

    cross-link) used to fix the permanent shape.

    (2) Reversible cross-link (usually in the form of a thermal transition such as

    Tg, Tm, or clearing point of a liquid crystalline material) responsible for

    holding the temporary shape

    3b. Crosslinking is Essential

    Example: Rubber

  • 29

    3b. Non-Reversible Cross-Links

    Physical and Chemical Cross Links for restoring permanent shape

  • 30

    3b. Glass State

    Liquid

    Chains move freely

    Amorphous state

    Below the critical temperature, long distance movements are frozen (transition to

    the amorphous state)

    Glass Temperature Tg

    Crystalline and semi-crystalline polymers have up to two thermal phase transitions

    (melting of the crystalline domains or glass transition)

    Glas-like, hard Rubber-like, soft

    cooling heating

  • 3b. Thermal Shape Memory Polymers

    A rubbery compound (elastomer)

    Can be amorphous thermoplastics (covalently cross-linked) with Tg below room

    temperature to allow full chain mobility- the restoring force in entropy

    Shape memory polymers morph by the glass transition or melting transition from a

    hard to a soft phase which is responsible for the shape memory effect.

    31

  • 3b. Heating/Cooling Cycle

    2002 Wiley-VCH

  • 3b. Recovery Cycle

    Strain recovery of a cross-linked, castable shape-memory polymer upon rapid

    exposure to a water bath at T = 80 C

  • (a) UV light is absorbed by the ligand complexes and converted to localized heat, which

    disrupts the phase separation;

    (b) the material can then be deformed;

    (c) removal of the light while the material is deformed allows the metal ligand complexes to

    reform and lock in the temporary shape

    (d) additional exposure to and subsequent removal of UVlight allows for a return to the

    permanent shape.

    3b. Photoactive Shape Memory Polymers

  • Applications for Shape Memory Polymers

    Intravenous cannula

    Self-adjusting orthodontic wires

    Pliable tools for small scale surgical procedures where currently metal-based shape

    memory alloys such as Nitinol are widely used.

    Minimally invasive implantation of a device in its small temporary shape which

    after activating the shape memory by e.g. temperature increase assumes its

    permanent (and mostly bulkier) shape.

  • From top to bottom:

    Knot tightened in 20 sec when heated to 40C.

    (a) A smart surgical suture self-tightening at elevated

    temperatures (left).

    (b) A thermoplastic shape-memory polymer fiber was

    programmed by stretching to about 200% at a high

    temperature and fixing the temporary shape by

    cooling.

    (c) After forming a loose knot, both ends of the suture

    were fixed.

    Temperature-induced Self-Tightening Knot

  • (a) Degradable shape-memory suture for wound

    closure

    (b) The photo series from the animal experiment

    shows (top to bottom) the shrinkage of the fiber

    while the temperature increases from 20 to 41 C.

    http://www.sciencemag.org/cgi/content/full/296/55

    73/1673

    3b. Degradable shape-memory suture for wound closure

  • 3b. Applications: Intravenous Cannula

    Pictures of the shape memory foam deploying in in vitro aneurysm model

    Foam starts in compressed form (upper left) and expands to fill 60% the

    aneurysm (lower right). The time from the laser initiation to the final image was

    approximately 10 seconds. http://cbst.ucdavis.edu/research/aneurysm-treatment

  • Aus dem Film Die Reise ins Ich 1987

    Polymer Therapeutics & Drug Delivery

  • 3. Drug Delivery

    Drug delivery ensures that a pharmacologically active substance arrives at a relevant in

    vivo location with minimal side-effects

  • 3. Time Development of Polymer Drug Delivery Vehicles

    Nano Lett. 2010, 10, 3223-3230

  • 3. Polymer Drug Delivery Vehicles

    Ideal Systemic Delivery Particle

    Non-toxic vehicle

    Non-immunogenic

    Intracellular delivery

    Specific targeting of cells & intracellular

    compartments

    Controlled stability & degradability after release

    Challenges

    Drug release profiles

    Stabilization

    Extended circulation

    Plasma protein binding

    Specific targeting

  • 3. Controlled Drug Delivery

    Controlled drug delivery

    Site-specific delivery

    Reduced side effects

    Increased bioavailabilty

    Increased therapeutic effectiveness

  • 3. Nano Plays an Important Role in the Body

  • 3. Polymer Therapeutics

    A family of new chemical entities composed of polymers (R. Duncan)

    Conjugation of drugs to polymers, nanoparticles etc. (5-100 nm)

    Greater molecular weight = longer blood circulation

    In addition: Stabilization, improved solubility

  • Nanowirkstoffe

    Nano-sized

    Different pharmakokinetics

    Higher drug loading

    Space for cell targeting groups

    More challenging degradation

    Toxic metabolites

    Approved Anti-Tumor Drug Doxorubicin

    Small molecule

    No space for attaching new functions

    3. Polymer Therapeutics

  • Approved

    Late development phases

  • 3. Size Matters - The EPR-Effect Enhanced Permeability and Retention Effect

    Peer, D, et al. Nature Nanotechnology 2007, 2, 751-760

    Duncan, R. Nature Reviews Cancer 2006, 6, 688-701

  • Peer, D, et al. Nature Nanotechnology 2007, 2, 751-760

    Duncan, R. Nature Reviews Cancer 2006, 6, 688-701

    EPR effect (passive targeting)

    Decreased systemic drug

    elimination.

    Enhanced retention of the drug-

    carrier complex in the tumor as

    compared to the blood

    (tumor : blood ratio of >2500).

    Leaky vasculature is

    characteristic of solid tumors

    and inflamed tissue and allows

    nano-sized objects to enter.

    3. Size Matters - The EPR-Effect Enhanced Permeability and Retention Effect

  • 3. Polymer Therapeutics - Architectures

  • 3. Drug Delivery Agents

  • Drug: Doxorubicin

    Chemotherapeutic against ovarian cancer

    Product name: Doxcil

    Significantly reduced cardiotoxicity of Doxorubicin

    Http://www.doxil.com

    Doxil: Liposomal Formulation of Doxorubicin (100 nm size) Approved February, 2005.

    Nanomedicine: Delivery of Doxorubicin

  • Chemotherapeutic against breast cancer

    Product name: Abraxane Approved 2005 ($134 turnover /

    year)* Drug: Paclitaxel

    Protein Nanocarriers: Serum Albumin (Abraxane)

    Http:/...

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