© 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

16

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