Motivation: In-Situ Transforming Hydrogelsonline.itp.ucsb.edu/online/cfluids02/kornfield/pdf0/...Dr....

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 1

Giyoong TaeJulia A. Kornfield

Chemical Engineering, California Institute of Technology

Jeffrey A. HubbellBiomedical Engineering, Swiss Federal Institute of Technology

Jyotsana LalIPNS, Argonne National Laboratory

Diethelm JohansmannMPI-Polymerforschung

Phase Behavior, Rheology, Erosion Kinetics and Biomedical Applications of

Fluoroalkyl-Ended PEGs

Motivation: In-Situ Transforming Hydrogels

Proteins or Cells

1) Delivery Carrier: Immobilization of cells or controlled release of proteins

2) Soft Structural Support orBarrier for Adhesion Prevention

solubilization

to

t1

t2

Applications Erosion typeSurface vs. Bulk

desired

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 2

Associative polymers

● With att racting groups

● Physical junctions : electrostatic hydrogen bonding hydrophobic

● Model system : End-group modified polymer in good solvent

Topo logy of Associative Network for “ Single Phase” Systems

superloops

superbridges

infinite clusters

C > CMC

C > C*

Increasing concentration(Annable, ‘93)

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 3

Phase Behavior of End-Associating Polymers

sol weak physical gel

single phase solution

Conc.

(stickiness)-1

two phases

Phase behavior governed by• attraction due to exchange entropy:

increases with aggregation number of core Nagg• repulsion due to excluded volume interaction:independent of chain length N

(Semenov, ‘95; Russel and coworkers, ‘98-’99)

Structure-Property Relations & Materials Design

● Phase behavior ● Rheology ● Erosion behavior ● Triggered solidification

● Midblock type & length● Hydrophobe type & length

● Midblock: PEG - why? biocompatible- length ∅ mesh size of gel

● Hydrophobe: fluoroalkyl, Rf

- why? hydrophobic and biocompatible- length ∅ strength of aggregation

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 4

Materials and Phase Behavior

type of equilibrium composition equilibrium compositionSample behavior in water (wt %) in PBS (wt %)

Cgel.eq. Csol.eq. Cgel.eq. Csol.eq.

20KC8 1 phase 20KC10 1 phase

10KC8 2 phase 6.5±0.2 0.075±0.005 7.8±0.2 0.055±0.00210KC10 2 phase 6.8±0.7 0.019±0.008 8.1±0.7 0.011±0.003

6KC6 2 phase 9.5±0.5 0.066±0.006 10.5±0.6 0.038±0.0026KC8 2 phase 11.0±0.3 0.042±0.007 12.5±0.3 0.017±0.001

6KC10 insoluble

Csol.eq.

Cgel.eq.

at 25 oC

H-C-N H

N-C-

=O

=O

Fluoroalkyl (Rf) :-(CH2)2-CnF2n+1

PEGIPDU (linker):

Dynamic moduli of “ single phase” species (20KC10)

101

102

103

104

105

G*

(Pa)

0.1 1 10 100 1000ωaT (rad/s) To = 25

oC

G' G"17 wt %12 wt %

5 wt %

25 oC 17 oC 9 oC 1 oC

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 5

103

104

105

Go (

Pa)

0.1 1 10 100

C (wt %)

3.0

2.5

2.0

1.5

1.0

0.5

τ (s)

302010

C (wt %)

Concentration dependence of Go and τ for “ single phase” species (20KC10)

2.1

Dynamic moduli of the equilibrium gels of species that show sol-gel coexistence

100

101

102

103

104

G' (

Pa)

0.01 0.1 1 10 100

ω (rad/s)

6KC810KC810KC10

100

101

102

103

104

G"

(Pa)

0.01 0.1 1 10 100

ω (rad/s)

6KC810KC810KC10

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 6

Nearly single relaxation behavior at Cgel,eq. (10KC10)

101

102

103

104

G*

(Pa)

0.01 0.1 1 10 100

ω (rad/s)

G'G"

1.0

0.5

0.010

-4x

G"

(Pa)

1.00.5

10-4

x G' (Pa)

Exp. Datasingle relaxation(m=0.5)m=0.49 with Gî=(GíGo-Gí2)m

Literature on Rheologyof Alkyl-ended “ Single Phase” Systems

η

C

log(η)

.log(γ)

G’

G”

log(ω)

log(G*)

C*

Go

η (or τ)

log(1/T)

G”

G’

τ

CC*1/τ

PEG

CnH2n+1

H2O

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 7

End-Dissociation Time and Apparent “ Effective Fraction” of Chains in the Gel

0.01

0.1

1

10

τ e.d

. (s)

1 10 100

CM1/2

(wt.fractn.)(g/mol)1/2

6KC8 10KC8 10KC10 20KC10

2.5

2.0

1.5

1.0

0.5

0.0

Go /

nkT

30252015105

C (wt %)

6KC8 10KC8 10KC10 20KC10

two phasesystemsshow Go > nkT

similar to other single phasesystems

}

}

Formation o f a new plateau at C > Cgel,eq.(10KC8)

C ♠ Cgel.eq.

} C > Cgel.eq.; new plateauat low freq.

1/τe.d.

end-group dissociation

Go: high freq. plateau

100

101

102

103

104

G*

(Pa)

0.1 1 10 100

ω (rad/s)

G' G"8 wt %

12 wt % 17 wt %

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 8

SANS (10KC8 at 25 oC)Aggregation number

Ordering Transition in the Gel Phase

0.01

0.1

1

I/φ (

cm-1

)

0.012 3 4 5 6 7 8 9

0.12

q (A-1

)

8 wt %12 wt %17 wt %

Species (wt %) Nagg

6KC8 (15) 32±4

10KC8 ( 8) 32±410KC8 (12) 32±4 10KC8 (17) 34±4

10KC10 (12) 50±6

20KC10 (12) 51±9

5KmC8 (0.5) 28 ±4

5KmC10 (0.5) 48 ±5

Implications for Theory

● Rheology of single-phase systems: » Annable’s could be improved by

better description of bridge:loop and inclusion of micelle-micelle repulsion

● Phase behavior:» Aggregation number is not the

primary determinant of the phase behavior as Semenov and Russelassume; deeper understanding of the effect of chain length on micelle-micelle repulsion is needed.

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 9

Polymer matrix erosion

Surface(heterogenous) vs. Bulk(homogeneous) erosion

desired for the controlled release

to

t1

t2

solubilization

Dissolution characteristics of polymer matrix by SPR in a flow system

Light

GlassMetalPolymerMatrix

Prism

water

θ

Reflected intensity

θθc θo

With increasing D or n

τ1 τ2 τ3

64

62

60

58Res

onan

ce A

ngle

(°)

403020100

Time (hr)

-dry-high n

-swollen-low n

-constant n∴ cons. c

10KC8 film (.55 µm, dried state)

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 10

Erosion Rates Correlate with Phase Behavior

phase composition dissolution rateSample behavior (wt %) (mg/cm2/hr)

5K-M-C10 lyotropic gel 12.8 0.201 20KC10 single phase 10.0 0.168

6KC8 sol-gel coex. 11.0 3.33 x 10-4

10KC8 sol-gel coex. 6.5 1.67 x 10-3

10KC10 sol-gel coex. 6.8 too slow to measureby SPR

Summary of Gel Properties in the Sol-Gel Coexistence Regime

● Mechanical properties (modulus, viscosity) can be controlled by the manipulation of hydrophilic and hydrophobic parts.

● Erosion of the matrix is achieved from the surface (heterogeneous type).

● Dissolution rates are much slower (~10-3 times) than systems with no phase separation.

● Dissolution is an activated process governed by end group length (10KC10 vs. 10KC8).

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 11

Sol-Gel Transition with Water-Miscible, Bio-Tolerable Organic Solvent

(N-methyl pyrrolidone (NMP))

Conc. solution in NMP (Injectible)

Gel

NMP diffusion-out& water absorption

Viscosity change at 37 oCafter exposing 50 % 10KC8 in NMPto water reservoir.

For initial thickness d ~ 1.5 mmtransition occurs within 10 min.

time (min)

1

10

100

1000

1 10 100 1000 10000

Initial Value

η *(ω

∅0)

(Pa

sec)

Human growth hormone (hGH)

● A single-chain polypeptide of 191 AAs with 2 disulfide bonds. M.W. ~ 22 KD

● Synthesized and secreted into storage granules as dimerwith 2 Zn2+ ions and then released from the anterior pituitary.

● Deficiency prevents normal growth, so the recombinant form (rhGH) is used to treat hGH deficient children.

● Current clinical administration : daily injections for several years => need for sustained release systems.

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 12

Release of hGH from In-Situ Forming Hydrogels of PEG with Fluorocarbon Ends

Protein precipitate

● The equilibrium gel phase of PEG modified with fluorocarbon ends shows slow, surface erosion.

● Injectible state by dissolving in NMP.

● Gelation after injection by diffusion of NMP out and water in.

● Sustained release of protein through the hydrogel.

Release experiment protocol for NMP formulation

• Dissolve PEG-Rf in NMP.

• Add protein powder (protein:PEG-Rf :NMP = 1:10:10).

• Inject the suspension into PBS

• Collect the supernatant at intervals and refill.

• Measure total protein concentration. Protein precipitate

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 13

hGH-Zn release from injectible NMP formulation 6KC8 at 37 oC to PBS buffer, thickness of gel at eq. ~ 0.25 cm

initial gel state of 1 :10:10 (weight) of hGH:Polymer:NMP

exchange of NMP for water

hGH standard

gel prepared by:1.0

0.8

0.6

0.4

0.2

0.0

Am

ount

Rel

ased

(%

)

3020100

t1/2 (hr1/2)

100x10-3

50

0

Abs

. at 2

20 n

m (

arb.

)

1614

t (min)

day2 : 6 : 9 :

Blood response to foreign materials

FOREIGN SURFACEFlowing blood

PROTEIN ADSORPTIONHigher flow rate; arterial

Lower flow rate; venous

PLATELET AGGREGATION(WHITE THROMBOSIS)

FIBRIN FORMATION+

PLATELET AGGREGATION+

TRAPPED RED CELLS(RED THROMBOSIS)

Ref.; Hoffman, A.S., Polymeric Materials and Artificial Organs, 1984, p.27

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 14

Rf-PEGs as surface-modifying materials for PTFE

• Rf-PEGs with long enough Rf showed slow (6KC8, 10KC8, 10KC10) or no (6KC10) erosion. → Adsorbed Rf-PEGs on PTFE can give a long-lasting surface-modifying coating.

• Suggests easy route to PEG surface layer on teflon:• 1.Immerse PTFE part in a solution of Rf-PEG in ethanol (1 wt %). • 2. Remove to leave a viscous liquid film on the surface, and • 3. immerse in water to induce association of the Rf groups with each

other and the PTFE surface.

• Observe that PTFE surface is hydrophilic after adsorption.

Capillarity of small PTFE tube

(a) Before Coating (Bare PTFE); Capillary Depression (Non-Wetting)

(b) After Coating; Capillary Rise (Wetting)

Direction of Tube Movementh

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 15

Change of capillary rise of modified PTFE tube with time under flow

(I.D =1.35 mm,varying shear rate (sec-1))

10KC10 6KC10

1 10 1000

4

8

12

16

20

Ca

pill

ary

ris

e (

mm

)

time (hr)

τw (Pa) 0.03 0.6 1.2

1 10 1000

4

8

12

16

20

Ca

pill

ary

ris

e (

mm

)

time (hr)

τw (Pa) 0.03 1.2 2.0

Results for PTFE modification

• Surface adsorption of Rf-PEGs onto PTFE effectively modifies the surface from being hydrophobic to hydrophilic.

• Capillary rise method is a sensitive tool to monitor the change in the surface properties of a narrow tube.

• Stability of this physisorption under flow correlates with the phase behavior and erosion rate of the bulk state of Rf-PEGs. In particular, an Rf-PEG that is insoluble in water provides the most stable modification.

Flow and Fracture of Transient Networks (ITP Complex Fluids Program 4/04/02)

Dr. Julia Kornfield, Caltech 16

Acknowledgment

● Thio E. Hogen-Esch (Synthesis) Chemistry, USC

● Diethelm Johannsmann (SPR characterization) MPI for Polymer Research, Germany

● Jyotsana Lal (SANS)Argonne National Lab, USA

● Ministry of Education, Korea Government