Poly(vinyl alcohol) hydrogels in medicine - Cambridge Polymer Group

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Poly(vinyl alcohol) hydrogels in medicine Structure and mechanics

Gavin Braithwaite

Cambridge Polymer Group, 56 Roland Street, Suite 310 Boston, MA 02129

7-17 Presentation (10/1/2010)

Poly (vinyl alcohol) • • •

First synthesized by Hermann and Haehnel in 1924 First commercialized in US by Dupont in 1939 Not polymerized directly – Vinyl acetate formed through catalyzed addition of acetic acid to acetylene – Radical polymerization to PVAc – Converted to PVA by hydrolyzation in alcohol in presence of catalyst



Conversion rates influence solubility and application

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PVA uses • • • • • • • • •

Market (2006) > 1 million metric tons Precursors - Reacted to create polyvinyl acetals Solutions - Emulsion polymerization aid and rheology modifier Fiber production - Clothing, Concrete reinforcement Paper products - Adhesives, Sizing (preparation) Barriers - Water soluble and CO2 barrier films Medicine – Sponges, Eye drops, Embolization, Nerve guides, cartilage Children’s toys - slime Sport - fishing

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PVA structure •

Solubility and mechanical properties variable – Hydrolysis rates 87-99+% – Naturally atactic but syndiotactic can be obtained – Broad range of molecular weights



Hydroxyl groups – – – –



Crystal structure similar to PE Water soluble Does not melt (decomposes) Hydrogen bonds

Biocompatible – – – –

Cells grow happily No known toxicity Not naturally degraded Generally not persistent

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Cambridge Polymer Group Billmeyer (1984)

Crosslinking of PVA •

Chemical crosslinking – Formaldehyde, Glutaraldehyde etc – Radiation



Physical crosslinking – – – – –

Hydrogen bonding between hydroxyls Mediated by water molecules Borate ion (“slime”) Formation of crystallites in water Solutions not long-term stable

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Physical Association •

Freeze-thaw process – “Cryogels” first proposed in 1971 (Peppas) – Repeated freeze-thaw cycles • Properties influenced by – Cycles, concentration, molecular weight, hydrolysis, time of freezing

– Freezing process • Liquid-liquid phase separation • Polymer-poor regions freeze first

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Cambridge Polymer Group Holloway et al. 2013

Hydrogen bonded crystals •

Hydrogen bonds form crystals – Onset ~55 °C, Peak ~70 °C, H 1-5 J/g – (solid PVA 161 J/g, Tm ~230 °C)

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Cambridge Polymer Group Holloway et al. 2013

1 FT

PVA cryogel structure •

Croygel structure driven by formation of ice crystals

200 kDa 99.9+% PVA in DI water 8 hour freeze, 8 hour thaw

– Fine pores form during melting of polymer rich regions – Structure “sharpens” with increasing freeze-thaw – Phase separation process – Hydrogen bonded “crosslinks”

Scale bar: 10 m

2 FT

5 FT

5% PVA

10% PVA

15% PVA

25% PVA

Confocal microscopy. All images and gels MGH.

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Cambridge Polymer Group Confocal Images: Jeeyoung Choi (MGH)

Gelation of PVA •

Coarseness of gel depends on – – – – –



Molecular weight Number of cycles Concentration Age Hydrolysis

Crystal junctions – Not a conventional gel – Polymer-rich “bridges”

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Cambridge Polymer Group Bercea et al. 2013

Solvent-driven gelation •• • •

• •

An entangled polymer solution a good the When the temperature is indropped solvent is stable and homogeneous hydrogen-bonded crystals can form in If the solvent quality is dropped the polymer-rich regions The solution enters an unstable condition A physical where there iscrosslinked coexistence ofhydrogel a polymer is rich and polymer poor region formed The polymer can phase separate into two concentration regions as the solvent quality changes

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Cambridge Polymer Group Image: ESEM CPG

Simulation unknown

Theta point • • •

Freeze-thaw PVA hydrogel - Swell Ratio at equilibrium in mixed solvent (measurements using CPG SRT) 0% PEG “good” solvent, 15% PEG “poor” solvent, 28% PEG “bad” solvent Solvency approximately inversely related to temperature for these systems

Theta solvent swelling line

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Cambridge Polymer Group

Thetagel structure •

Names defined as (wt% PVA-wt% PEG 400) relative to water – 200 kDa 99.9+% hydrolyzed PVA



Distinctive pore structure – Order 10 m diameter – Size and morphology depends on PVA concentration 10-28 DP

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15-28 DP

25-28 DP

12

Cambridge Polymer Group Scale bar 20 m

PVA in water •

15% PVA in DI water is essentially stable up to 93 °C 1000

100 90

80 C

80 70

100

60 50

40 C

Temp [C]

G', G" [Pa]

80 C

40

10

30

93 C

G' Cool only G'' Cool only G' Heat and cool G'' Heat and cool

89 C

20 10

1

0 0

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100 150 Time after start [min] 13

200

250

Cambridge Polymer Group Theta temperature for PVA in water is 97 °C (Polymer Handbook, Brandrup)

Effect of solvent quality • • •

15-x: 15% PVA in x% PEG in water 15% PEG behaves qualitatively the same as DI at all temperatures 28% PEG is unstable below approximately 50 °C 15-0 G* 15-0 delta

1000

15-15 G* 15-15 delta

15-28 G* 15-28 delta

100 80

G* [Pa]

70 60 100

50 40 30 20 40 ºC

Cool to 40 ºC

80 ºC

Phase angle (d) [deg]

90

10

10

0 0

20

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60 80 Time after start [min] 14

100

120

140

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Importance of temperature 15-28 (15% PVA in 28% PEG400/water) Temperature below 55 °C drives gelation

100000

100 Cooling starts

40C

60C

20C

90 80

10000

70 60 50

G* [Pa]

G* 15-28 hold at 60C G* 15-28 cool to 40C G* 15-28 hold at 20C delta 15-28 hold at 60C delta 15-28 cool to 40C delta 15-28 hold at 20C

1000

40 30

100

20 10

Phase angle (delta) [deg]

• •

0

10 0

10 20 30 40 50 60 70 80 90 100 110 120 130 140 Time after start [min]

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PVA hydrogel creep properties • • •

“Diurnal cycle” 0.5 MPa on, 0.05 MPa off Higher molecular weight implies stiffer High creep strain and poor creep recovery 1 0.9

Strain [mm/mm]

0.8 0.7 0.6 0.5 0.4 0.3

20-28 250PVA

20-28 100PVA

0.2

15-28 250PVA

15-28 100PVA

0.1

25-28 250PVA

25-28 100PVA

0 0

2

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6

8 Time [hr] 16

10

12

14

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Elastic Modulus 20%-65%* Loading Curve E 3

n=5 Elastic Modulus [MPa]

2.5

2

1.5

1

0.5

0

DP

DP

DP

10-28

15-28

25-28

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AG RSA3 AG RSA3 AG RSA3- AG RSA3PEG PEG 15-28

25-28

17

15-28

25-28

1FT

5FT

5FT

15-28

15-28

15%

Cambridge Polymer Group

Cartilage ~ 10MPa

EWC vs. max creep strain 1.000

n=3 in all cases. Scale bar 20 m

Maximum creep strain after 8 hrs at 0.5 MPa [mm/mm]

0.900

0.800

0.700

0.600

0.500 10-28 DP 15-28 DP 25-28 DP 15-28 1FT 15-28 5FT 15% 5FT 15-28 AG RSA3 15-28 AG RSA3-PEG 25-28 AG RSA3 25-28 AG RSA3-PEG

0.400

0.300

0.200

0.100

0.000 0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

EWC [mass water/mass hydrogel]

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Injecting PVA •

Phase separation not instantaneous – “window” of useful time for injections or manipulation



Allows injection of PVA hydrogel without toxic crosslinkers 1000

90 70

G* [Pa]

60 50

100

40

45 degree phase angle

30 G* 15-28 10C/min G* 15-28 30C/min delta 15-28 10C/min delta 15-28 30C/min

10 -50

-30

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-10 10 30 Time after reached 40C [min] 19

20 10

Phase angle (delta) [deg]

80

0

50 Cambridge Polymer Group

Mitral Regurgitation •

Common complication of coronary artery disease – Doubles risk of late death

• •

Heart attack results in compromised muscle Over time changes geometry of chamber – Wall thins and distorts

• • •

Deforms mitral valve tethers Results in reversed flow through valve Chronic problem, usually fatal



Current solutions inadequate – Ring annuloplasty • Invasive and complex

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Cambridge Polymer Group Work performed in collaboration with MGH under NIH 1R01HL092101-01A1

Tissue bulking •

Mitigation of Mitral Regurgitation (MR) – Inject bulking agent to displace muscle wall

Echo Transducer Apex

Biomaterial

Ischemic LV

Biomaterial PM

AO

Coapting Surface

AO

MR LA Leaflet Tenting

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Restored Leaflet Coaptation

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Cambridge Polymer Group

MR reduction in ovine model

Figure 2

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Load-bearing applications •

Applications – – – –



Spine Mosaicplasty Interpositional Devices Resurfacing

Requirements – High fatigue resistance – Good recovery – Loads over 3 kN intermittently



Thetagels (and cryogels) do not have sufficient properties – Cartilage ~ 10MPa compressive modulus – Chemical crosslinking – “Toughening” by annealing

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Toughening of thetagels – “annealing” •

Annealing of PVA gels (dehydration) changes morphology 15-28

25-28

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15-28 annealed

25-28 annealed

24



For 15-28, annealing procedure results in thicker struts and a more closed pore structure.



For 25-28, pores appear to shrink or collapse

Cambridge Polymer Group

Elastic Modulus 20%-65%* Loading Curve E 3

n=5 Elastic Modulus [MPa]

2.5

2

1.5

1

0.5

0

DP

DP

DP

10-28

15-28

25-28

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AG RSA3 AG RSA3 AG RSA3- AG RSA3PEG PEG 15-28

25-28

25

15-28

25-28

1FT

5FT

5FT

15-28

15-28

15%

Cambridge Polymer Group

Strain Recovery as a % of strain at 10 N 100 90

n=5

Recovered Strain [%]

80 70 60 50 40 30 20 10 0

DP

DP

DP

10-28

15-28

25-28

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25-28

26

15-28

25-28

1FT

5FT

5FT

15-28

15-28

15%

Cambridge Polymer Group

Total creep strain after 8 hr at 0.5 Mpa [%]

Total Creep Strain 100 n=5

90 80 70 60 50 40 30 20 10 0 DP

DP

DP

10-28

15-28

25-28

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15-28

25-28

27

AG RSA3PEG

AG RSA3PEG

1FT

5FT

5FT

15-28

25-28

15-28

15-28

15%

Cambridge Polymer Group

EWC vs. max creep strain 1.000

n=3 in all cases Maximum creep strain after 8 hrs at 0.5 MPa [mm/mm]

0.900

Scale bar 20 m

0.800

0.700

0.600

0.500 10-28 DP 15-28 DP 25-28 DP 15-28 1FT 15-28 5FT 15% 5FT 15-28 AG RSA3 15-28 AG RSA3-PEG 25-28 AG RSA3 25-28 AG RSA3-PEG

0.400

0.300

0.200

0.100

0.000 0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

EWC [mass water/mass hydrogel]

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Cambridge Polymer Group

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Cambridge Polymer Group Plot: MGH OBBL

CoF on a rheometer Spring

Annulus

Surface

1

Kavehpour and McKinley “Tribo-rheometry: from gap-dependent rheology to tribology” Tribology Letters (2004) 17(2) 327-335

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Hydrogel coefficient of friction •

CoCr against hydrogel flats 3.0 15-28 DP, CPG 15-28 AG RSA3, CPG 15-28 DP, MGH 15-28 AG RSA3, MGH

2.5

COF

2.0 1.5 1.0 0.5 0.0 0.0 2015 SCI Rideal Meeting

10.0 20.0 30.0 40.0 Nominal contact pressure [kPa] 31

50.0

Cambridge Polymer Group

Where next? •

PVA appealing – Readily available – Biocompatible – Already in use



PVA thetagels – injectable



Limited application – – – –

Poor mechanicals Tissue bulking? Degradables? Mucoadhesives?

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Functional proteins • •

Mucins - Terminal groups cysteine-rich and naturally gel-forming Lubricin (PRG4) - present in synovial fluid as lubricant

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Thiolation of PVA •

Conversion of some OH groups to thiol groups adds thiol pendant groups directly to the PVA backbone – Mercaptopropionic acid reacted with PVA – Thiol groups react with cysteine residues in proteins to form disulfide bonds

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1H NMR of TPVA •

1H NMR of converted product indicate presence of mercaptopropionic ester fragment – Degree of modification ~3%

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Molecular Weight Distribution of PVA and TPVA •

Gel Permeation Chromatography indicates a small fraction of higher molecular weight species 9

Wn (Log M) * 10-1

8

PVA

7 6 5 4 3 2

TPVA

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3

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T-PVA/Mucin reaction •

Mixing of TPVA with mucin and tracking rheology response proves molecular interactions

|n*| (Pa.s)

– Complex viscosity of TPVA (green), mucin (blue) and TPVA combined 1.000 with mucin (red) measured at 25 °C.

0.1000

0.01000 0

10.0

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30.0 time (min) 37

40.0

50.0

60.0

Cambridge Polymer Group

Synthesis of TPVA/PEGDA Hydrogels •

TPVA crosslinking with difunctional poly (ethylene glycol) – – – –

thiol-reaction forms hydrogel through Michael-Type addition reaction Thiol groups control crosslink density PEGDA chain length control molecular weight between crosslinks Physiologically benign reaction

TPVA

b

+ pH 7.4 1xPBS PEGDA

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Gelation kinetics 10000

1000

1000

100.0

100.0

10.00

10.00

1.000

1.000

0.1000

0.1000

0.01000

G'' (Pa)

G' (Pa)

10000

0.01000

1.000E-3 0

2.5

5.0

7.5 time global (min)

Polymer

1.000E-3 15.0

12.5

Temperature, °C

concentration, % [w/v]

10.0

25 °C

37 °C

Gelation

G’

G’’

Gelation

G’

G’’

time, [min]

[Pa]

[Pa]

time, [min]

[Pa]

[Pa]

3.0

23.3

803

5

4.2

3607

480

4.5

9.2

6440

133

3.0

9860

280

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Degradability •

Esters are relatively unstable bonds – hydrolyzable 60

Gel disintegration onset

40

b

Swelling, %

50

30 20 10 0 0

5

10 Time, days

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TPVA Degradation Products by GPC Analysis •

Cleaving of ester bonds yields species with TPVA and PEGDA molecular weights

Signal MV * 10

15 14 TPVA

13 12

TPVA/PEGDA Degradation products

11 PEGDA

10 3

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7 9 11 Elution Volume (mL) 41

13

15

Cambridge Polymer Group

Thank you Cambridge Polymer Group is a contract research laboratory specializing in polymers and their applications. We provide outsourced research and development, consultation and failure analysis as well as routine analytical testing and custom test and instrumentation design. Cambridge Polymer Group, Inc. 56 Roland St., Suite 310 Boston, MA 02129 (617) 629-4400 http://www.campoly.com [email protected]

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Poly(vinyl alcohol) hydrogels in medicine - Cambridge Polymer Group

Poly(vinyl alcohol) hydrogels in medicine Structure and mechanics Gavin Braithwaite Cambridge Polymer Group, 56 Roland Street, Suite 310 Boston, MA ...

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