Engineering Biomedical Materials From total joints to tissue sparing - - PowerPoint PPT Presentation

Cambridge Polymer Group, I nc.

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7-17 Presentation (10/1/2010)

Engineering Biomedical Materials

From total joints to tissue sparing

• Dr. Gavin Braithwaite

Engineering implants

• Historical device development

– Surgeon determines a need – Engineer provides design to meet primary requirements

• Often from existing materials

– Incremental improvement iterates towards success

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Biology versus engineering

• The human body is a finely tuned biomechanical structure

– Meniscus and cartilage

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Images: medicinenet.com, MMG, sensorprod.com

The human hip

• Ball-and-socket joint
• Normal gait complex motion

– rotation, flexion, extension

• Loads can be high

– Walking 3x body weight – Stumbling 9x body weight

• Critical for mobility and quality of life

Ratner et al.

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What goes wrong

• Osteoarthritis caused by loss of cartilage

– Bone-on-bone contact – 65% of patients requiring surgery

• Up to 1M replacements annually
• Success rate at 10 years post-surgery is between 90-95% typically

– Very good!

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Images: hipresurfacing.info, wikipedia

Hip replacement

• 1891 First human implant (cemented ivory)
• 1940 first metal implant
• Up until the 1960’s, hip fusion (arthrodesis) was the standard

treatment for painful hip joints

– Pain relief, but complete loss of mobility

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Images: orthogate

Engineering a solution

• Charnley (Manchester)

– Introduced articulating artificial hip joints in the 1960s

• First attempt – driven by perception of friction

– Low-lubricity

• PTFE

– Poor wear

– Small head

• Low contact area

– dislocations

• Second attempt

– Applied engineering material to surgical problem

• Polyethylene plastic cog

– Gold standard since 1960’s

Image: Wikipedia

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The next generation

• Issue: poor wear

– Good toughness, but poor resistance to wear patterns – Erosion of material and osteolysis

• Solution: crosslinking of the polymer

– HXPE – Lower wear rates

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Ionizing radiation Crosslinks (X) Scissions (X) G(X)~3G(s)

Crystalline lamellae Amorphous regions Irradiate Crosslinks Residual free radicals

8

Crosslinked UHMWPE

• 700
• 600
• 500
• 400
• 300
• 200
• 100

100 5 10 15 20 25 30 Cycles (millions) Weight Change (mg)

Highly Crosslinked 22-46 mm

Controls (γ in N2) Control 46mm head (γ in N2) 50 mg/MC

Control 32 mm (γ in air) 31mg/MC

22 mm 15mg/MC 28 mm 17mg/MC

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Material enhancements

• Issue: Radiation crosslinking generates free-radicals

– Material oxidizes – Premature embrittlement

• Solution: Crosslinking in inert atmosphere

– Prevent oxidation during processing and storage – Long-term concerns due to in vivo oxidation

Residual free radicals

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State-of-the-art – free radical suppression

• Issue: Free-radicals persist or an induced in vivo

– Require a method for removing free radicals

• Solution 1: remove free radicals

– Melt or anneal the material – Does not help in vivo

• Solution 2: absorb free radicals

– Free radical scavenger – antioxidant – D,L-α-tocopherol (Vitamin E)

• Crosslink then dope
• Blend then crosslink

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Vitamin E free radical removal

O CH3 C H3 O H CH3 CH3 CH3 CH3 CH3 CH3

α-tocopherol (Vitamin E, α-T, T-OH)

R + O2 ROO R ROO + T-OH ROOH + TO + Vitamin-E

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Evolution in properties

• Charnley

– Biocompatible – 10-15 year life when implanted corrected

• First generation (crosslinked)

– Improved wear – Oxidation issues

• Second generation (annealed and/or melted)

– Removal of crosslinking free radicals – Sterilization and in vivo radicals remain

• Third generation (free radical suppression)

– Vitamin E doping – Improved fatigue strength

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Fatigue Crack Propagation

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Next generation

• Virgin polyethylene

– crack resistant, poor wear, oxidizes

• Crosslinking

– Improves wear but sacrifices toughness

• Hybrid structure

– Surface crosslinked - Low VE – Bulk tough - High VE – Antioxidant for protection

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0.05 wt% 2 wt% 0.02 wt%

100 kGy

0.00 0.05 0.10 0.15 0.20 0.25 2 4 6 8 10 Depth (mm) Vitamin E Index No homogenization Homogenization for 16 hours

Inhomogeneous doping Spatial crosslinking Homogenize

Pin-on-disc wear testing

0.2 0.4 0.6 0.8 1 1.2 Highly cross-linked surface Low cross-linked bulk 100-kGy irradiated 100-kGy irradiated and melted Fatigue resistance (MPa m1/2) GRADIENT

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(1) (2) (3) (1) (2) (3)

(1) (2) (3) Wear surfaces 0.5 wt% 0.05 wt% 16

The success

• Total hip replacement has evolved

– 1950s simple mechanical replacement – Materials incrementally improved – Highly successful

• 20+ year implant life
• >193,000 implants per year in US

– Technology transferred

• Knee
• Shoulder
• Small joints
• Ankle
• Spine

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Image: Ratner et al.

4/19/2011

Addressing Spine pain

• In 2004 38 million Americans suffered from back pain

– Muscle – Nerves – Bone – Joint failure

• Most patients treated conservatively

– anti-inflammatories and physical therapy

• Degradation of the vertebral column more serious

– Radiculopathy, localized pain and impingement

• Annual cost for spine conditions $194 billion

– Disc disorders $2.6 billion – Lost activity accounts for 176 million days and 80-90% suffer at some point

• Treatment of the spine at same point as hip in 1960s

– Gold standard is fusion

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Image: http://www.holistix-treatments.co.uk

The human spine

• Much more complex than hip joint
• Supports the upper body

– In activity loads can be 3x body weight and up

• Protects the spinal chord

– Provides a boney tunnel through which the spinal chord runs

• Flexible

– Allows rotation/flexion/extension – Hybrid structure of disc and vertebrae

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Images: http://www.backpain-guide.com http://www.eorthopod.com

Spine biomechanics

• The Intervertebral Disc (IVD) is a unique joint

– Poorly vascularized and immune privileged – Complex structure

• ply-like periphery (Annulus Fibrosus)
• surrounds a jelly-like core (Nucleus Pulposus)
• Hybrid structure

– Annulus confines and contains nucleus – Nucleus transfers compressive loads to tensile loads in annulus – Annulus is not intended for purely compressive loads – Analogous to a bias (cross-ply) tire

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Image: Bogduk

What can go wrong

• The degenerative cascade

– The IVD starts deteriorating from youth – IVD gradually dehydrates

• Joint becomes lax
• Annulus becomes damaged
• Reduce disc height
• Facet joints abnormally loaded
• Pain

– Biomechanics change

• Bone remodelling
• Osteophyte formation
• Arthrosis

– Deterioration also influenced by

• Lifestyle, trauma, genetics, surgery…

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Images: www.spineuniverse.com

Motion Preservation

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Nucleus removal Fusion

• Removal of nucleus

– Height loss, Ligaments slacken – Abnormal loading

• 700,000 annually
• Relieves pressure on spinal chord
• Removes material – loss of height
• 50-60% early success, 20-30% later relapse
• Fusion

– No motion ,Motion/load transferred

• 300,000 annually
• Prevents motion
• 70% clinical success
• Solution: Total disc replacement

– Analogous to hip replacement – Engineering bearing – Polyethylene on metal

Bioengineering approach

• Fusion and total disc relieve symptoms by removal of pain sites

– Changes load distribution in spinal column

• Nucleus removal relieves symptoms by removing pressure

– Collapses joint

• Compromised biomechanics

– Accelerates degradation

• Need method that is

– Less invasive

• (easier surgery and shorter recovery times)

– Preserves surrounding biomechanics

• (keep functional structures)

– Restores function

• (device is biomechanically relevant)

– Revisable

• (should something go wrong)

Nucleus replacement

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Initial attempts

• First attempts implanted solid objects into disc space

– Loaded endplates (subsidence) – Large incision

• Replaced solid objects with expanding devices

– Uneven endplate loading – No load sharing – Moderately large incision

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Ideal treatment

• Physiology of the intervertebral disc requires pressurization

– Collagen and bone responds to load

• Proper load-distribution requires fully conforming

– Implies fully fills space

• Minimal incision to avoid compromising annulus

– Needle delivery

• Survival of interior of annulus may depend on solute transport

– Free diffusion of solutes

• Viscoelasticity critical for function

– hydrogel

• Injectable, space filling, hydrogel

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Performance requirements

• Injectable

– 30 cm, 3 mm catheter, <70 N force

• Hydrated

– 80% water

• Space filling

– Must transfer load evenly to endplates and annulus walls

• Viscoelastic

– Permeable – Human disc expulses water during day and reabsorbs during night

• Biocompatible

– No toxic crosslinkers or biproducts – Safe ingredients

• Resist expulsion

– Annulus compromised by surgical incision, at least

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PVA hydrogels

• Highly biocompatible
• Viscoelastic
• Pharmaceutical grade
• High molecular weights
• Freeze-thaw hydrogels

– Crystals force chains together – Thawing allows chain mobility and crystallization – Needs a freezer to manufacture – Phase separation process

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Image: Brandrup

Physics of formation

• Solvent quality driven phase separation

– Solvent control influences how chains interact

• Tertiary solvent adjusts solvent quality

– Solution temperature controls how the crosslinks form

• The balance of the two controls how the solution behaves

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Single Polymer Chain in solution Chain Excluded Volume Solution Temperature Tθ Flory Interaction Parameter, 1/χ χ θ(T, P,..)=1/2 Single Polymer Chain in solution Chain Excluded Volume Gaussian distribution Collapsed chain Swollen, distorted chain Polymer Local Density Solvent “Quality” “Bad” “Good” “Theta”

Solvent Rich Polymer Rich

Polymer solution

Animation: math.gmu.edu

20%-65%* Loading Curve E

0.5 1 1.5 2 2.5 3

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

Elastic Modulus [MPa]

Morphology of “thetagels”

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n=5

Image box approximately 60 microns

Testing

• Standard tests

– Rheology – Modulus – Morphology

• Non-standard tests

– Fatigue – In situ gelling

• Testing that is relevant to the material and environment

– No longer a conventional rigid material (steel/polyethylene) – Allow ingress/egress of fluid – Contain implant – Reflect surgical constraints

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Rheology – 15% PVA in water

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Rheology – 15% PVA with gellant

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Gelation

• In a solvent quality driven system, concentration is critical
• The hydrated environment in vivo must impact an injectable

hydrogel formulation through

– Diffusion out of active ingredients (polymer, gellant, crosslinker) – Diffusion in of water and bodily fluids (dilution)

Fail Little opacity Diffuse interface Pass Completely opaque Sharp interface

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Fatigue

• Cyclic fatigue of hydrogel

– Confining annulus model (reflects confinement in vivo) – Porous end plates (reflects partially permeable endplates) – Relevant deformation – 40 ºC, 2750N ± 250N, 1Hz

5 mm hole Nucleus cavity RTV Annulus Porous end-plates Membrane

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Fatigue

• RTV annulus acts purely elastically
• Hydrogel filled annulus

– Water loss initially – Equilibrium pressurized condition

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Formulation development

• PVA solution behavior controlled by temperature, solvent and

molecular weight

– Low temperature allows crosslinks to form – Poor solvent allows polymer to phase separate

• Solvent quality also influenced by temperature

– Higher molecular weight PVA retards chain kinetics – Higher molecular weight PEG fills less volume

• Complex parameter space

– Gelation time – Injection viscosity – Final morphology

• Mechanical properties and permeability

– Resistance to environment – Fatigue strength/fracture resistance

• Design of Experiment

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Design of Experiment

• Statistical design of experimental plan to examine relationships

between explanatory and response variables

• Systematic way of sampling the parameter space
• Prediction optimal formulations
• Limited assumptions

– removes “intuitive” experimentation

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Conclusions

• Biomedical implants started as engineering solutions to the primary

problem

– In some cases work extremely well

• Hip is an excellent example
• Gradually iterated towards one of the most successful current devices

– Weakness is that they often don’t consider impact on secondary

• Spine demonstrates the issues with a simple-minded engineering approach
• Removal of functional tissue and transfer of loads to rest of system
• New breed of materials are designed to mimic physiology

– Addresses direct cause of problem

• Prolapsed disc due to degraded nucleus

– Sympathetic to surrounding physiology

• Preserves biomechanics and nutrition

– Very complex to test and validate

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Biomaterials

• Earliest implants were generally external

– Dental

• 600 AD nacre teeth

– Wound closure

• Egyptian linen sutures

– Visual

• 1860 glass contact lenses
• Implanted materials

– Late 19th century

• Metals for bone fixation

– Early 1940s

• Plastics
• “Engineering” materials

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Free radicals cause oxidation

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0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Conventional 100kGy 100 kGy melted Fatigue crack propagation resistance

Unaged Aged

40

• Cyclic loading stresses chains

– Induces oxidation

Environmental Stress Cracking (ESC)

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0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1 2 3 4 5 6 Depth (mm) Oxidation Index (A.U.)

100kGy VitE/PE ESC Cycled 1 100kGy VitE/PE ESC Cycled 2 100kGy VitE/PE ESC Cycled 3 100kGy VitE/PE ESC Cycled 4 100kGy VitE/PE Uncycled

Vitamin-E Polyethylene 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1 2 3 4 5 6 Depth (mm) Oxidation Index (A.U.)

• Seq. Irradiate/Anneal -

Cycled

• Seq. Irradiate/Anneal -

Uncycled Sequential Irradiation and Annealing

Total disc replacement

• Relieves pain

– Like fusion, removes source of pain

• Restores motion and height

– Allows the joint to move

• Weaknesses

– Highly invasive

• Anterior surgery

– Changes adjacent segment biomechanics

• Resects ALL, removes significant stabilizing

structures

• Mobile bearing does not mimic tensile properties of

system

• Fusion or joint replacement too aggressive for

mild degeneration

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Image: spineuniverse.com

Competitive solutions

• Spine Wave

– Silk-like protein based crosslinked hydrogel – Pivotal US clinical trials

• Disc Dynamics

– Curing PCU elastomer in balloon – Cancelled US clinical trials

• Cryolife

– Crosslinked bovine serum albumin hydrogel

• Gentis

– Crosslinked Lauryl acrylate

• Sythes-Stratec

– Phase-change polyNIPAAm

• TranS1

– Curing silicone elastomer

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Solvent quality

• A function of temperature, or of chemical species

– Critical point is the “theta” point of the solution

• Any osmotically active tertiary ingredient can be used, sensitive to

chemistry and molecular weight

– PEG 200 ~25% – PEG 400 ~18% – PEG 600 ~15% – NaCl ~12% – Glycine ~12% – PEG 1000 ~10% – Chondroitin Sulfate ~ 2%

Solvent Concentration Theta Temp [°C] t-Butanol/water 32% 25 Ethanol/Water 41.5% 25 NaCl/Water 2 mol/L 25 Water

• 25

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Table: Polymer handbook

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Demographics and solutions

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Image: healthlibrary.epnet.com

http://www.eorthopod.com

• Treatment options

– Most patients can be treated conservatively – Discectomy

• 700,000 annually
• Relieves pressure on spinal chord
• Removes material – loss of height
• 50-60% early success, 20-30% later relapse

– Fusion

• 300,000 annually
• Prevents motion
• 70% clinical success but transfers loads to adjacent joints