Motivation: In-Situ Transforming Hydrogelsonline.itp.ucsb.edu/online/cfluids02/kornfield/pdf0/...Dr. Julia Kornfield, Caltech 15 Change of capillary rise of modified PTFE tube with

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



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)



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



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



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



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



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 %



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.



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)



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).



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.



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



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



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



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.



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

Documents

Motivation: In-Situ Transforming Hydrogelsonline.itp.ucsb.edu/online/cfluids02/kornfield/pdf0/...Dr. Julia Kornfield, Caltech 15 Change of capillary rise of modified PTFE tube with