Using to Characterize Flow and Viscoelastic Properties of , Adhesives and Biopolymers

Tianhong Terri Chen PhD Senior Applications Scientist TA Instruments – Waters LLC

TAINSTRUMENTS.COM Outline

 Basics in Rheology Theory

 TA Instruments and DMAs  Instrumentation  Test methodologies

 Rheological Applications in Biopolymer and Biomedical  Hydrogels and creams  Adhesives  Drug capsules  for medical devices

TAINSTRUMENTS.COM Rheology: An Introduction

TAINSTRUMENTS.COM Rheology: An Introduction

Rheology: The study of the relationship between a and

Deformation F = F(x); F ≠ F(v) Purely Elastic

Most Deformation + Flow Viscoelastic

Flow F = F(v); F ≠ F(x) Purely Viscous

Stress Stress = Modulus = Strain Shear rate

TAINSTRUMENTS.COM What does a do?

 Rheometer – an instrument that measures both viscosity and of , semi- and solids

 It can provide information about the material’s:  Viscosity - defined as a material’s resistance to flow deformation and is a function of shear rate or stress, with time and temperature dependence

 Viscoelasticity – is a property of a material that exhibits both viscous and elastic character. Measurements of G’, G”, tan δ with respect to time, temperature, frequency and stress/strain are important for characterization.

TAINSTRUMENTS.COM Who Will Need Help with Rheology Analysis?

Food Personal Care Pharmaceutical

Polymers Adhesives & coating Automotive

Aerospace

Bio-medical devices Asphalt TAINSTRUMENTS.COM TA Instruments Rheometers and DMAs

 TA Rotational Rheometers  ARES-G2 and ARES (Strain Control – SMT)  DHR or AR (Stress Control – CMT)

 TA DMAs  RSA-G2 and RSA (Strain Control – SMT)  DMA Q800 (Stress Control – CMT)

TAINSTRUMENTS.COM Rotational Rheometers at TA

ARES G2 DHR

Controlled Strain Controlled Stress Dual Head Single Head SMT CMT

TAINSTRUMENTS.COM Geometry Options

Concentric Cone and Parallel Torsion Cylinders Plate Plate Rectangular

Very Low Very Low Very Low Solids to Medium to High Viscosity Viscosity Viscosity to Soft Solids Water to Steel

TAINSTRUMENTS.COM DMAs from TA Instruments

RSA G2 Q800 ARES G2 and DHR

Controlled Strain Controlled Stress DMA mode SMT CMT (oscillation)

TAINSTRUMENTS.COM DMA Clamps

Submersible Submersible S/D Cantilever Tension-Film Shear-Sandwich Compression 3 Pt Bend

Submersible 3-Point Tension-Fiber Compression Tension

TAINSTRUMENTS.COM ElectroForce Load Frames

ElectroForce 3300 ElectroForce 3510 ElectroForce 3500 Floor Standing (7500 N) (15000 N) ElectroForce 3300 (3000 N) (3000 N) ElectroForce 3200 (450 N) ElectroForce 5500 ElectroForce 3100 (200 N) (22 N)

Frequency to Interchangeable to 300 Hz 15kN Fixtures

TAINSTRUMENTS.COM Common Rheological Experimental Methods

TAINSTRUMENTS.COM Flow Experiments

 What flow measures o Viscosity

 “lack of slipperiness,” resistance to flow

 The viscosity of water at room temperature is 1cP

Type of flow measurements on rheometer o Viscosity vs. time

 Viscosity at single shear rate/stress

 Time dependence ( or Rheopexy) o Viscosity vs. or rate

 Newtonian

 , shear thickening,

 stress o Viscosity vs. temperature

TAINSTRUMENTS.COM Flow Behaviors

TAINSTRUMENTS.COM Information from a Flow Curve

What shear rate? 4) Chewing, swallowing 5) Dip coating 1) Sedimentation 6) Mixing, stirring 2) Leveling, Sagging 7) Pipe flow 3) Draining under gravity η

log 8) Spraying and brushing 9) Rubbing 10) Milling pigments 11) High Speed coating

4 5 6 8 9 1 2 3 7 10 11

1.00E-5 1.00E-4 1.00E-3 0.0100 0.100 1.00 10.00 100.00 1000.00 1.00E4 1.00E5 1.00E6

shear rate (1/s)

TAINSTRUMENTS.COM Dynamic Oscillatory Tests

Phase angle δ Strain, ε

Stress, σ*

Dynamic stress applied sinusoidally User-defined Stress or Strain amplitude and frequency

TAINSTRUMENTS.COM Viscoelastic Parameters

The Modulus: Measure of materials overall ∗ = ∗ resistance to deformation. The Elastic (Storage) Modulus: Measure of ∗ of material. The ability of the G = cos δ material to store energy.

The Viscous (loss) Modulus: ∗ G" = sin δ The ability of the material to dissipate energy. Energy lost as heat. Tan delta (phase angle): " tan δ = Measure of material damping - such as vibration or sound damping. G* The triangle relationship G"

Phase angle δ

G' TAINSTRUMENTS.COM Understanding Oscillation Experiments

 What oscillation measures? oViscoelastic properties (G’/E’, G”/E”, tan δ)

 Approach to Oscillation Experimentation oStress and Strain Sweep

• Measure linear viscoelastic region

• Yield stress, stability oTime Sweep

• Stability and structure recovery

• Curing o Frequency Sweep

• Measure

• Compare viscoelasticity of different formulations oTemperature Ramp

• Measure transition,

• Temperature operation range of a material

TAINSTRUMENTS.COM Rheology Applications in Biopolymers & Biomedical Materials

TAINSTRUMENTS.COM Purpose of a Rheological Measurement

Three main reasons for rheological testing:

• Characterization Structure-property relationship. MW, MWD, branching, state of flocculation, etc.

• Process performance Formulation stability, processing temperatures, extrusion, blow molding, pumping, leveling, etc.

• End product properties Mechanical strength, and sub-ambient transition temperatures, dimensional stability, settling stability, etc.

TAINSTRUMENTS.COM Hydrogels and Creams

• Hydrogels and creams are soft matters that contain high level of such as water or oil • Hydrogels and creams are used in a wide variety of applications including tissue , wound patch, drug delivery, contact lenses and superabsorbent materials • Rheology can provide key information on formation and gel strength on different formulations

TAINSTRUMENTS.COM Natural Polymer: Hyaluronic Acid

• Hyaluronic acid is a natural , which is commonly used in pharmaceutical, biomedical and personal care • Rheology can evaluate the visco-elastic properties as function of concentration, ionic strength, Mw, degree of crosslinking, formulations etc.

TAINSTRUMENTS.COM Hyaluronic Acid :

• Hyaluronic acid gels are used as lubricating agent during abdominal surgeries to prevent and also for join lubrication, wound healing etc. • Rheology can monitor HA gelation and evaluate the gel strength

TAINSTRUMENTS.COM Gels: Gelatin Gelation vs. Temperature

 Thermal reversible gelatin gels: o Measure gelation and gel melt

TAINSTRUMENTS.COM Gelatin Gel Strength at Different Concentration

• A dynamic frequency sweep test can be used to compare gel strength at applications temperature

TAINSTRUMENTS.COM Gelatin/Chitosan Conjugation

• Use enzymatic approach to covalently graft gelatin to chitosan

• The conjugate exhibits interesting Tyrosine mechanical properties • Applications as biomedical adhesives

Chen et al. Biopolymers, Vol. 64, 292-302 (2002)

TAINSTRUMENTS.COM Vesicle-Biopolymer Gels

• Attach n-dodecyl tails to Chitosan backbone to obtain an associating biopolymer (HM-Chitosan) • HM-Chitosan mixed with vesicle solution leads to a gel formation • This showed strong elasticity HM-Chitosan behavior and has potential applications in biomedical control release

Chen T; Raghavan SR et al, Langmuir, 21, 26-33 (2005)

TAINSTRUMENTS.COM Contact Lens Visco-elasticity

• Compare frequency dependency of contact lens elasticity

0.3500 " t = 0.3000 Vendor A

0.2500

0.2000 Vendor B

tan(delta) 0.1500

0.1000

0.05000

0 1.000 10.00 100.0 ang. frequency (rad/s)

TAINSTRUMENTS.COM Creams/Lotions: Stability Testing

Stability, phase separation of a cosmetic cream

1E+06

l G' Ap G'' emulsion A l G' emulsion Bp G'' emulsion B 1E+05

l l l l l l l l l l l l l 1E+04 l p p p lp p ' ' ' ' l' 'p 'p 'p 'p 'p 'p l l

Moduli [Pa] G'' & G' l l l l 1E+03 0 1 2 3 4 5 6 7 8 910 strain [%]

TAINSTRUMENTS.COM High Temperature Performance of Lotions

A: Hydrating Lotion B: UV Protection C: Generic Brand

o 10 3  G‘ for A decreases at 37 C  G‘ for B withstands higher temperature =>used at 10 2 2 higher temperature

hydrating beauty lotion δ same lotion with UV protection conditions (beach) generic hydrating lotion 1  10 G‘ for lotion C increases

Loss tan before dropping; tan δ decreases => phase ModulusG' [Pa] 0 10 0 separation for lotion C  Tan δ for A & B increases above 37 oC=> wax crystals 0 10 20 30 40 50 60 melt and lower the modulus Temperature T [°C]

Ming L. Yao; Jayesh C. Patel Appl. Rheol. 11 ,2,83 (2001)

TAINSTRUMENTS.COM Low Temperature Performance of Lotions

0.8

7 6 10 w/o emulsion 10 o/w emulsion: G' G' 10 6 G" 0.6 G" 5 tand δ 10 10 5

0.4 δ 10 4 tan 10 4 3 Modulus [Pa] G' 10 0.2 Modulus G', G" [Pa] Modulus G" G',

Modulus G’, G” [Pa] G” G’, Modulus 2 10 3 10 -8 oC 0.0 -30 -20 -10 0 10 20 30 -100 -80 -60 -40 -20 0 20 40 60 80 100 Temperature T [ oC] Temperature T [ oC]

 In an o/w emulsion the point of water is depressed due to the dispersed oil phase. Cooling below the freezing point has a major effect on temperature stability  In an w/o emulsion, the dispersed water droplets freeze, but not the matrix. These do not have a sharp freezing point

R.Brummer Rheology essentials of Springer ISBN: 3-540-25553-2

TAINSTRUMENTS.COM Emulsion Temperature Stability

• Cycle temperature to evaluate temperature stability of emulsions

V. André, N. Willenbacher, H. Debus, L. Börger, P. Fernandez, T. Frechen, J. Rieger. Prediction of Emulsion Stability: Facts and Myth . Cosmetics and Toiletries Manufacture Worldwide

TAINSTRUMENTS.COM Lotions: Coefficient of Friction

Application window

37°C, 3 N load Transpore

TAINSTRUMENTS.COM Biomedical Adhesives

• Adhesives are used in biomedical device assembly; hard tissue or attachments (e.g. dentistry or wound closure) • Rheology helps to guide adhesive process • Rheology measurements can correlate to the tack and peel performance of the finial products

35 TAINSTRUMENTS.COM Bio-adhesives Test Methodologies

TAINSTRUMENTS.COM Adhesive Tack Testing

• Experimental: 8mm parallel plate, Axial tensile at 0.1mm/sec

Crosslinked PSA: Non-Crosslinked PSA: Adhesive failure Cohesive failure

TAINSTRUMENTS.COM Adhesive 180 Degree Peel Test

• The SER geometry on a rheometer can perform peel test at 180 degree angel.

http://www.xpansioninstruments.com/results_peel.htm

TAINSTRUMENTS.COM Adhesive Temperature Ramp

• Most popular test in adhesive industry • The measurement results correlate to the performance of a PSA with temperature

• Glass transition: Tg = 16.3 °C

• G crossover: Tx = 75.9 °C

• Dahlquist temperature: Td = 11.6 °C

• Plateau modulus G’p = 7694 Pa

TAINSTRUMENTS.COM Adhesive: Tack and Peel Performance

• A dynamic frequency sweep test results can correlates to tack and peel performance

Tack and Peel performance of a PSA

good tack and peel Bad tack and peel

10 4

peel

10 3

Storage Modulus [Pa] G' Modulus Storage tack

0.1 1 10 Frequency ω [rad/s]

TAINSTRUMENTS.COM Dental Adhesive UV Curing

• Dental materials cure under blue light

1.000E9

1.000E8

1.000E7

1.000E6

|G*| (Pa) 1.000E5 Formulation #1 10000 Formulation #2 Formulation #3 1000 Formulation #4 Formulation #5

100.0 10.000 20.000 30.000 40.000 50.000 60.000 70.000 80.000 time (s)

TAINSTRUMENTS.COM Adhesive Curing Shrinkage

• Adhesive curing shrinkage will cause fractures in process

• Using rheometer + UV curing accessory, we can quantitatively monitor the shrinking during curing or the dimension shrinkage

Monitor force buildup Monitor dimension/gap change

TAINSTRUMENTS.COM Drug Capsules

•Drug capsules are typically made from gelatin or polysaccharide such as (HPMC) •Rheology and DMA can help to investigate the optimum capsule process conditions and also evaluate the capsule properties with a controlled temperature and humidity

TAINSTRUMENTS.COM Gelatin Capsule: Mechanical Strength vs. Temperature and Humidity

• A dynamic temperature or humidity ramp experiment can help evaluate the mechanical properties (stability) of gelatin capsules at different storage conditions (temperature and humidity).

5000 100 25°C

4000 400 80 50°C 37°C 3000 300 60

2000 200 40 Loss Modulus (MPa) Relative Humidity (%) Storage Modulus (MPa)

1000 100 20 ––––––– T25C-RAMP RH.001 – – – – T37C-RAMP RH.001 ––––– · T50C-RAMP RH.001 0 0 30 40 50 60 70 80 90 Time (min) Universal V4.7A TA Instruments TAINSTRUMENTS.COM Water Soluble - HPMC

• Hydroxypropyl methylcellulose (HPMC) • Soluble in cold water, insoluble in hot water. Gelation temperature and gel strength depending on the ratio of HP/MC and degree of substitution • Cellulose based drug capsules

TAINSTRUMENTS.COM HPMC Gelation Mechanism

• Thermal reversible gel • Transition from intra-molecular interaction to inter-molecular interaction

10000 10000 HPMC Temp Ramp Capsule manufacturing process – a hot pin dipped 1000 1000 into a cold solution

Gelation T = 60.5 °C (Pa) '' G G': 8.190 Pa 100.0 100.0 G' (Pa)

10.00 10.00

1.000 1.000 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 temperature (°C)

TAINSTRUMENTS.COM Polymers – Medical Devices

• Polymers are used as medical devices such as hips and knees joints, sutures, stents, and facial prostheses etc.

• Rheology helps to guide Application Polymer Used process conditions and Knee, Hip, & Shoulder Ultrahigh molecular weight evaluate end product Joints (UHMWPE) Finger Joints performance Sutures Polylactic and Polyglycolic acid, Tracheal Tubes Silicone, Acrylic, Nylon Heart Pacemaker Acetal, Polyethylene, Polyurethane Blood Vessels Polyester, PVC, Polytetrafluoroethylene, Gastrointestinal Segments Nylon, PVC, Facial Prostheses Polydimethyl siloxane, Polyurethane, PVC Bone Polymethyl methacrylate

47 TAINSTRUMENTS.COM Polylactic Acid (PLA)

• Polylactic acid (PLA) and its composite materials are FDA approved synthetic degradable polymers. It shows many good characteristic features:  Biocompatibility  Biodegradability  Good process ability  Low cost • PLA has been widely used in many biomedical applications such as  Orthopedics  Drug carriers  Stents  Tissue engineering  Antimicrobial agents

TAINSTRUMENTS.COM What Rheology Can Help?

• Rheology helps to investigate processing conditions (e.g. temperature and shear). Polymer processing technologies including extrusion, injection molding and blow molding.

• Rheology provides quantitative evaluation on the end unit performance of PLA based products. Such as influence of Mw, plasticizers, stabilizers, pigments and fillers etc.

TAINSTRUMENTS.COM Idealized Flow Curve – Polymer Melts

Power Law Region

First Newtonian Plateau

η0 = Zero Shear Viscosity 3.4 η0 = K x MW Extend Range ηη with Time- Temperature log log Superposition (TTS) Measure in Flow Mode & Cox-Merz

Extend Range Second Newtonian with Oscillation Plateau & Cox-Merz

Molecular Structure Compression Molding Extrusion Blow and Injection Molding

1.00E-5 1.00E-4 1.00E-3 0.0100 0.100 1.00 10.00 100.00 1000.00 1.00E4 1.00E5 shear rate (1/s)

TAINSTRUMENTS.COM PLA Melt Flow Processing Temperature

• DSC Indicates PLA melt at 170°C. The extrusion process temperature needs to be greater than Tm (melt) but lower than Td (decomposition).

• After melt, extrusion temperature may need to be adjusted to reach ideal shear viscosity

R. Al-Itry et al. / Polymer Degradation and Stability 97 (2012) 1898e1914

TAINSTRUMENTS.COM PLA Melt Temp Ramp Test on a Rheometer

• A dynamic temperature ramp test on rheometer can help to investigate appropriate extrusion temperature and also cooling conditions

10 8

10 7

10 6 Heating 10 5

10 4

10 3 Cooling 10 2 Heating

10 1 80 100 120 140 160 180 200 Temperature (°C)

TAINSTRUMENTS.COM PLA End Product Performance-Fast Cooling

• PLA fast cooling after extrusion

TAINSTRUMENTS.COM PLA End Product Performance-Slow Cooling

• PLA slow cooling after extrusion

TAINSTRUMENTS.COM PLA – Compare Different Process Conditions

10 10 3.5

PLA Slow Cooling PLA Fast Cooling 3.0

10 9 2.5

2.0

10 8

1.5

1.0 10 7

0.5

10 6 0.0 20 40 60 80 100 120 140 160 Temperature (°C)

TAINSTRUMENTS.COM Summary

• Rheology is a powerful tool for investigating viscosity and viscoelastic properties of biopolymer materials and biomedical devices

• Materials evaluated by rheological techniques can be either liquids, semi-solids, gels, or solids. The viscoelastic properties can be monitored as a function of time, temperature, frequency, shear rate and shear stress

• The rheological measurement information can be used for  and product development  Trouble shooting manufacturing problems  General QC analysis, distinguish batch to batch variation

TAINSTRUMENTS.COM Agenda

•9 - 10:15am: Thermal analysis and stability of •10:15-10:30am: Break •10:30-noon: Using rheology to characterize flow and viscoelastic properties of hydrogels, adhesives and biopolymers •12-1pm: Lunch •1-2:15pm: Mechanical testing of medical devices •2:15-2:30 - break •2:30-3:15pm: Mechanical testing of engineered tissues and biomaterials •3:15-4pm – Q&A with TA Instruments Applications Engineers

57 TAINSTRUMENTS.COM Thank you for your attention!

TAINSTRUMENTS.COM