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