langer - biomaterials & biotechnology

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    Dr. Robert S. LangerDavid H. Koch Institute Professor

    Massachusetts Institute of Technology

    B iomater ials and biotechnology : From

    the development o f contro l led drug

    delivery systems to the foundat ion of

    t issue engineer ing

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    Anti-angiogenesis

    (Dormant Tumor)

    New Capillaries

    T A F

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    The agent to be released is a small

    molecule with a molecular weight no larger

    than a few hundred. One would not expect

    that macromolecules e.g. proteins, could be

    released because of their extremely small

    permeation rates through polymers.

    Adv. Poly. Sci., 1977

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    Days

    10 20 30 40 50 60 70 80 90 100

    %ProteinRe

    leased

    1020

    30

    40

    50

    60

    70

    80

    90

    Lysozyme

    Soybean Trypsin Inhibitor

    Alkaline Phosphatase

    Catalase

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    0

    20

    40

    60

    80

    CumulativePercen

    trelease

    0 10 20 30 40 50

    Days

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    TUMOR

    POLYMER1.5mm

    4mm

    1m

    m

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    Angiogenesis inhibitors approved for clinical useDate Approved Drug Disease

    February 2004 Avastin(Bevacizumab) Colorectal Cancer

    November 2004 Tarceva (Erlotinib) Lung Cancer

    December 2004 Macugen Macular Degeneration

    December 2005 Nexavar (Sorafenib) Kidney Cancer

    December 2005 Revlimid Myelodysplastic Syndrome

    January 2006 Sutent(Sunitinib) Gastric (GIST), Kidney Cancer

    June 2006 Lucentis Macular Degeneration

    May 2007 Torisel (CCI-779) Kidney Cancer

    November 2007 Nexavar (Sorafenib) Hepatocellular Carcinoma

    February 2008 Avastin Breast Cancer

    May 2009 Avastin Glioblastoma

    November 2010 Afinitor Giant Cell AstrocytomaApril 2011 Zactima (Vandetanib) Medullary Thyroid Cancer

    May 2011 Sutent Pancreatic Neuroendocrine Tumors

    November 2011 Eylea(Aflibercept) Macular Degeneration

    January 2012 Axitinib (AG-013736) Kidney Cancer

    July 2012 Afinitor Breast Cancer

    September 2012 Eylea (Aflibercept) Central Retinal Vein OcclusionJanuary 2013 Avastin Metastatic Colorectal Cancer

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    -20 0 20 40 60 80 100

    0

    100

    200

    300

    400

    500

    600

    Pla

    smaGlucos

    e,mg/dl

    Days

    Implant

    Treated

    Untreated

    Normal

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    PEG chains

    Biodegradable core + drugs

    Coating nanoparticles with

    polyethylene glycol (PEG)

    Gref et al, Science, 263: 1600-1603, 1994

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    Targeting

    molecule

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    Manufacture: Pre-clinical, clinical

    and commercial scale-up

    Scale up for pre-clinical,

    clinical and commercial

    development

    Current manufacturing scales

    Laboratory 1-10 gTox 500 g

    Phase 1 5 kg

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    Prototype device

    Silicon Nitride

    or Dioxide

    CathodeActive

    Substance Anode

    Silicon

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    Reservoir activation

    SEM of a reservoir

    electrode system

    before application of

    an electric potential

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    Reservoir activation

    SEMs taken after application of 1.04 volts vs. SCE in PBS

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    Single compound release

    0

    20

    30

    40

    10ReleaseRate

    Time (days)

    1 2 3 4 5 6 7

    Fluorescein (ng/min)

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    Multiple compound release

    Time (Hours)

    0

    10

    20

    30

    40

    ReleaseRa

    te

    50

    60

    10 20 30 40 50 60 70

    Fluorescein (ng/min)

    45Ca++ (5xNCi/min)

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    Clinical trial

    Chips are communicated with over a specialfrequency called the Medical Implant

    Communications Service Band, approved by both

    the FCC and the FDA.

    A patient or doctor enters a special computer code

    to administer or change the dose.

    Bidirectional communications link between the chip

    and receiver enables the upload of status

    information, including confirmation of dose delivery,

    batter life, etc.

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    Clinical trial

    8 patients

    PTH (compliance with injections is 25%)

    Small office procedure to implant

    Some pharmacokinetics (less variability)

    and Ca, PINP, CTX measures as daily

    injections

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    In vitro tissue culture

    Biodegradablepolymer scaffold

    CellsOsteoblasts

    ChondrocytesHepatocytes

    Enterocytes

    Urothelial cells

    In vivo implantation

    New

    Bone

    Cartilage

    Liver

    Intestine

    Ureter

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    Cartilage tissue engineering

    BEFORE

    cell seeding

    AFTER

    2 weeks in culture

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    System

    Modified PGA Tubes

    8 Weeks SMC Culture, then EC

    Bio-ReactorsPulsatile Radial Stress

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    Medium

    Reservoir

    Flow Direction

    Pulsatile

    Pump

    Compliance

    Chamber Magnetic Stirplate

    20 cm

    4 Bioreactors,

    Assembled in parallel

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    Characteristics

    50% Collagen

    Rupture Strengths > 2000 mg Hg

    Suture RetentionStrengths up to 90gDemonstrates Contractile Responses to

    Serotonin, endothelin-1, and

    Prostaglandin F2

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    Degradable suture material

    tied to hold both parts of theimplant together

    Oriented portion of the

    implant providing axonal

    guidance

    Inner portion of the

    implant with large

    pores seeded with

    neural stem cells

    2 mm

    4 mm

    1.5 mm

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