Langer - Biomaterials & Biotechnology
Transcript of 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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