Post on 25-Aug-2020
© 2014 TissueGen 1
TISSUEGEN PROPRIETARY
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IFAI Specialty Fabrics Expo and Advanced Textiles Expo
Latest Advancement in
Extrusion Technology for
Drug Delivery Applications
Dr. Kevin Nelson, PhD
CSO, TissueGen
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Overview
• Drug delivery from fiber
• Fiber manufacturing methods
• Novel extrusion method for drug loading
– Drugs
– Polymers
– Release studies
• Medical applications
• Commercial availability
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Implantable Drug Delivery
• Advantages
• Slow sustained release
• Avoid high toxic levels
• May be site specific
• Patient compliance
• Many Formats
• Gels
• Nanoparticles
• Microspheres
• Fibers
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Advantages of Fibers
• Mechanically strong
• Remain in place
• Readily explanted
• Highly uniform diameter and drug concentration
• Slower release than spheres of same diameter
• Coatings and complex geometries
• Readily mass produced
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Fiber Manufacturing Methods
• Melt Extrusion
• High temperature melt and high shear stress
• Relatively low cost
• Limited drugs due to process
• Electrospinning
• Non-woven sheets, filters, and membranes not individual fibers
• Harsh organic solvents
• Wider range of drugs
• Wet Extrusion
• Extremely strong fibers
• Harsh organic solvents
• Widest range of drugs including pharmaceuticals and
biologically-derived agents
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Wet Extrusion
• Developed in 1850’s
• Polymer solution
• Coagulating bath
• Harsh organic solvents
• Fiber drawn (stretched)
• Low shear stress
• Room temperature
“Technique Paper for Wet-Spinning Poly(L-lactic acid) and Poly(DL-lactide-co-
glycolide) Monofilament Fibers.” Tissue Engineering 9(6): 1323-30 (2003)
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Solvent Issue for Drug Loading
• Harsh organic solvents
• Very few drugs can survive extrusion
• Must remove residual solvents from fiber
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The Solution is the Solution
• Drug loading process
• Isolation
• Excipients
• Create protective bubble for drug within harsh solvent bath
• Extrude drug-loaded polymer
• Post-process to remove residual solvents
• Enables loading broadest range of drugs
• Pharmaceuticals
• Biologically-derived agents
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• Broad water solubility
• Hydrophobic
• Hydrophilic
• Broad molecular weight
• Antibiotics
• Antimicrobials
• Cancer remediation
Pharmaceuticals
(Note bubble size proportional to amount loaded - mean 1.36ug/mm^2)
0
200
400
600
800
1000
1200
1400
1600
-3 -2 -1 0 1 2 3 4 5 6
logP value
Mo
lec
ula
r W
eig
ht
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• Proteins
• BDNF
• GDNF
• NGF
• VEGF
• BSA
• Collagen
• Lysozyme
• Matrigel
• Fab fragment of IgG
• DNA
• -galactosidase adenovirus)
Biologically-derived Agents
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Polymers
• Polymer requirements
• Both solvent and non-solvent must exist
• Combination of solvent and non-solvent must be miscible
• Synthetic biodegradable polymers
• Poly(L-lactic acid) (“PLLA”)
• Poly(D,L-lactic acid) (“PDLLA”)
• Poly(lactic acid-co-glycolic acid) (“PLGA”)
• Poly(p-dioxanone) (“PDO" also referred to as “PDS”)
• Blends with poly(-caprolactone) (“PCL”)
• Biopolymers
• Chitosan and chitosan/alginate blends
• Silk and silk blended with synthetic polymers
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• Diverse formats
• Hollow
• Gel-filled core
• Core sheath
• Over-the-wire
• Multi-lumen
• Broad range of sizes
• Circular monofilament
(~10 um to 1 mm diameter)
• Ribbon fiber
(0.1 mm x 1 mm shown)
Fiber Conformations
Hollow
Core Sheath
Cross Section of Ribbon Fiber
Gel-Filled Core
Over-the-Wire
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• Directs cells to migrate
through specified
pathways.
• Guided by concentration
gradient introduced by
continuously variable
pitched coil
Coil Delivery Format
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Release vs. Time
0
20
40
60
0 2 4 6 8 10 12 14
Time (weeks)
Cum
ula
tive
% R
ele
ase PLLA 10
PLGA 5
PLGA 10
PLLA 5
Tunable Drug Delivery
Mw Degradation
0
20000
40000
60000
80000
0 2 4 6 8 10 12 14
Time (weeks)
Avg
. M
ol. W
eig
ht
(Da
)
PLLA 10
PLGA 10
20 mm
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7 weeks 6 months
Intr
acell
ula
r R
eti
na
l S
orb
ito
l L
ev
el
(nm
ol/
g)
0
200
400
600
800
1000
1200
Control gp
non treated
treated
• Monofiliment fiber loaded with Aldose
Reductase Inhibitor (ARI)
• ARI blocks conversion of glucose to
sorbitol—potential cause of blindness
in diabetic patients
• One eye of diabetic rats implanted
with ARI fiber compared with
untreated eye in same animal and
age-matched, normal healthy rats
• Single dose over 6 months resulted
in 5-fold reduction of diabetic state
indicators
• Demonstrated potential diabetic
retinopathy treatment
ARI Loaded Fiber
In Vivo Animal Study
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0
0.5
1
1.5
2
2.5
0 20 40 60 80 100
Eq
uiv
ale
nt
Pro
tein
Rele
ased
(m
g)
Time (Days)
Cumulative Protein Release(BSA mass equivalent)
• Bi-component fiber loaded with
Matrigel
• Matrigel resembles the complex
extracellular environment found in
many human tissues
• BSA used for calibration curve
• Cumulative release over 80 days
• Demonstrated linear protein
release from fiber over extended
period
Matrigel® Loaded Fiber
In Vitro Release Assay
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DRG Axons Responding to
Coil Concentration Gradient
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Phase Contrast
NGF Loaded Fiber
PC-12 Cell Assay
Frame A
Control (no NGF)
Frames B and C
PC12 differentiation
in presence of
NGF loaded fiber
(500ng/ml)
A B
C
• Monofiliment fiber loaded with Nerve
Growth Factor (NGF)
• PC-12 cells sprout neurites in
presence of biologically active NGF
• 5 cm and 10 cm samples of NGF
loaded fiber in 96-well plate with PC-
12 cells
• Demonstrated dose response
Fiber length Avg. cell size
5 cm 96.13 um
10 cm 120.93 um
Control (no fiber) 15.09 um
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Medical Applications
• Advanced drug delivery• Retinal delivery
• Solid tumor remediation
• Nerve regeneration• Long peripheral gaps
• Spinal cord injury repair
• Tissue engineering• Premature cell differentiation
• Small diameter vascular grafts
• Medical textiles• Hernia mesh
• Pouches and slings
• Tendon and ligament repair
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Summary
• Drug delivery from fiber
• Fiber manufacturing methods
• Novel extrusion method for drug loading
– Drugs
– Polymers
– Release studies
• Medical applications