Refuse to Fuse! - Cambridge Polymer Group to Fuse! The development of a nucleus pulposus replacement...

Refuse to Fuse!The development of a nucleus pulposus replacement

Biomimetic hydrogels in load-bearing applications

Gavin Braithwaite

CambridgePolymer Group, Inc.

Testing, Consultation, and Instrumentation for Polymeric Materials

Cambridge Polymer Group, 56 Roland Street, Suite 310

Boston, MA 02129

NEBEC, Brown UniversityApril 2008

Cambridge Polymer Group 2

Refuse to Fuse!†

• The development of nucleus replacement as a case history for thedevelopment of naturally inspired solutions to surgical problems

• General Outline– The spine and sources of pain– Treatment options– PVA injectable hydrogels - “Thetagels”

• Spine treatment is at a turning-point analogous to the transition from fusion to total hip replacements in the 60’s

Image: http://marbella.to/humour/jun00/evolution.jpg† apologies to the unknown source of the title of the talk



Bad backs - perspective

• Predominantly a middle-aged issue– 50% of population have degenerative changes in the cervical spine by 50

• Back pain a major impact on the economy– The number one reason for healthcare expenditure– In 1998 $90 billion was spent on back pain– Causes 100 million days of lost work per year– $26 billion in direct back pain costs in 1998

• A serious source of problems for patients– Disables 1.2 million Americans per year– Over 80% of all Americans suffer from back-pain during their life– The second most common reason for visiting the doctor– The most common cause of disability in the US for under 45’s– Are the most significant cause of absenteeism in the US

Sources:Bare Bones. 2004 Weinstein, J.N., et al., United States' Trends and Regional Variations in Lumbar Spine Surgery: 1992-2003. . Spine 2006. 31(23): p. 2707-2714Windsor, R.E. and K.P. Sullivan. Lumbosacral Discogenic Pain Syndrome. 2004 Becker, C., Spine-tingling prospects. Modern Healthcare, 2003. 33(45): p. 30-32.Neckreference.com:- Causes. 2004 .

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



General spine structure

L5

L1

T12

T1

C7

C1

Cer

vica

lTh

orac

icLu

mba

rSa

crum

Spinal Nerve

Anterior Longitudinal Ligament

Posterior Longitudinal Ligament Vertebral Body

IntervertebralDisc

Lamina

SpinousProcess

Facet

Spinal Chord

Nucleus Pulposus

• The complex structure (hard & soft tissue) of the spine imparts high load bearing properties whilst still allowing motion and cushioning

Annulus Fibrosus

End Plate

Cancellous Bone

Neural Arch

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



The intervertebral disc

• 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)

• Annulus Fibrosus– 20-30 highly oriented collagen sheets– Fiber orientation in sheets ~65-60º from vertical– Adjacent sheets alternate orientation– 65-75% water– 75-90% collagen (dry weight)– 10% proteoglycans (dry weight)

• Nucleus Pulposus– Jelly-like collagen hydrogel– 75-90% water– 25% collagen (dry weight)– 20-60% proteoglycans (dry weight)

Statistics:Bogduk, N., Clinical Anatomy of the Lumbar spine and Sacrum. 2005Iatridis, J. C., M. Weidenbaum, et al. (1996). Spine 21(10): 1174-84.Urban, J. P. G., S. Roberts, et al. (2000). American Zoology 40: 53-61.

Image: Bogduk, N., Clinical Anatomy of the Lumbar spine and Sacrum



IVD mechanics

• The hybrid structure allows flexion, rotation, cushioning and protecting function of the healthy spine

– The annulus confines and contains the nucleus– The nucleus acts to transfer compressive loads to tensile loads in the annulus– The annulus is not designed to primarily take purely compressive loads– The annulus structure is analogous to a bias (cross-ply) tire

Images: Bogduk, N., Clinical Anatomy of the Lumbar spine and Sacrumhttp://bucarotechelp.com/



What happens when you have a puncture?

• When the IVD is intact, the loads are transferred from the nucleus to the annular walls

• When the nucleus is removed, or compromised, the loads are purely compressive on the annulus walls.

• This results in annular buckling, facet loading and degeneration

Images: www.savingadvice.com



The degenerative cascade

• The IVD starts deteriorating from youth– A healthy IVD supports and articulates the spine– IVD is poorly vascularized– Poor nutrition results in cell death– Cells responsible for maintenance of

proteoglycans– Lower hydration results in changed biomechanics– Changed loading damages annulus and

increases risk of herniations– Changed loads reduce disc height – Joint becomes lax and facet joints abnormally

loaded– Changed biomechanics result in bone

remodelling, osteophyte formation and arthrosis– Deterioration also influenced by

• Lifestyle, trauma, genetics, surgery…

Images: www.spineuniverse.com



Conservative therapies

• Back pain arises from a number of sources, many of which do not need surgical intervention

• 80% of patients can be treated successfully with conservative treatment• Conservative treatments include

– Bed rest / mild pain medication / NSAID’s / Physical Therapy– Steroid injections / narcotics / muscle relaxants

• In many cases, treats the patients immediate problem, but not the source -short-term prognosis good, longer term (>2 years) less clear

0102030405060708090

100

0 6 12 24Time after surgery [months]

VAS

pain

out

com

es

Back Pain (non-surgical)Leg Pain (non-surgical)

Fritzell, P., et al., Spine, 2001. 26(23): p. 2521-2532.



Treat the symptom

• Large proportion of disc-related pain results from interaction with nerve root• Most surgical interventions are decompression of the nerve root

– 700,000 annually– Removal of herniated disc tissue (discectomy)– Removal of confining bone (laminectomy)

• Success rates high 50-90% initially– 50%-60% suffer recurring back pain, 20-30% re-suffer sciatica– After 10 years 75% suffer residual back pain, 13% severe

• Treats the symptom, not the cause• Removes material – compromise the disc and joint

Traynelis, V.C., Neurosurgical Focus, 2002. 13(2): p. Article 10.Errico, T.J., Letters to the editor New York Times 2004.

Resnick, D.K., et al., Journal of Neurosurgery: Spine, 2005. 2(6): p. 673-678. Images: http://www.eorthopod.com



Stop all movement

• Hypothesis: In more degenerated discs, pain comes from the motion – stop that and you have cured the symptom

• Fusion involves permanently fixing two vertebrae together– 320,000 fusions in the US in 2002, 90-95% operative success rates– 70-75% clinical success rates but “major” or “complete” relief from pain in only

50% of patients – “end of the road” for surgical intervention– Long-term, fusion is often no better than discectomy, or conservative therapy

0102030405060708090

100

0 6 12 24Time after surgery

VAS

pain

out

com

esBack Pain (non-surgical)Back Pain (surgical)Leg Pain (non-surgical)Leg Pain (surgical)

Image: healthlibrary.epnet.comFritzell, P., et al., Spine, 2001. 26(23): p. 2521-2532.



Restore – “Refuse to fuse”

• Spine interventional surgery at the same point as hip-surgery in the 60’s– Gold-standard is fusion – complete prevention of motion to prevent pain– New technologies will allow transition to “motion preservation”

• Total Disc Replacement (TDR)• Equivalent of the step to Total Hip Replacement

– Remove the painful region and replace with a motion segment

• Aggressive surgery• Too much motion?

DePuy Spine Charite

Images: www.spine-health.com



The treatment “gap”

• There is a set of patients currently poorly addressed by existing treatments• Aging but more active and wealthier demographics encouraging more “life-

enhancing” approaches (less invasive, more mobility, reduced pain)

Mild Moderate Severe

% o

f chr

onic

bac

k pa

in p

opul

atio

n

FusionArtificial disc

Dynamic stabilization

Conservative, non-surgical

DecompressionNucleus replacement

Annulus repair

Severity of disc degeneration



Rebuild – “Refuse to fuse – and make it easy!”

• Concept:– Rebuilding the nucleus relieves pressure on the joint– Restores biomechanics– Can be performed relatively non-invasively

• Nucleus replacement– Implantables

• Easy to design, test and validate• Questions over load bearing, longevity and expulsion• Still relatively invasive

– Injectables• Conceptually simple• Harder to test and validate• Questions concerning extrusion and longevity

RaymedicaSpinewave



Nucleus Replacement

Table:Davis, R.J. and F.P. Girardi, eds. Volume I: Fundamentals. Nucleus Arthroplasty Technology in Spinal Care. 2006, Raymedica, Inc.



The ideal candidate

• The ideal candidate nucleus replacement should be– Properties similar to the natural nucleus

• Highly hydrated• Viscoelastic• Inert• Space-filling (even end-plate load distribution)

– Surgically it should also be• Injectable• Radiopaque and/or NMR visible• Revisable• Resist Extrusion/Expulsion• Minimally invasive (as little damage to the annulus as possible)

– An injectable hydrogel



Concept



Hydrogels

• Hydrogels are two-phase systems composed of a water matrix supporting and surrounding a continuous polymer network

– conformable, tough, viscoelastic, permeable and mostly water• Polymers are initially entangled in the solvent and fill the volume as a solution• Polymer are “crosslinked” – individual chains are joined together at link points

– Chemistry, radiation, association• Water matrix is largely free to move and diffuse

– Water is a solvent for the polymer– Swells the network, imparting viscoelasticity, porosity and resilience

Scale bar: 100 nm

Image: QFDE micrograph, CPG



What material?

• Poly(vinyl alcohol) - PVA– Prepared by hydrolysis of poly(vinyl acetate)– Used industrially

• sizing in the textile industry • base gel component for cosmetics industry • as an adherent for the paper industry

– Increasing biomedical applications• opthalmic lubricant • artificial sponges • cartilage and meniscus replacement • nerve guides

– Generally considered non-toxic, blood compatible and non-degradeable

– Hydrophilic– Crystal structure similar to poly(ethylene)

• CHOH group fits into CH2 structure • Unit cell monoclinic with a=7.81 Å, b=2.52

Å (chain axis), c=5.51 Å and b=91°42’• Chains can link through hydrogen bonds

into sheets

Images: Billmeyer, F.W., Textbook of Polymer Science



Solvent driven gelation of PVA

Single Polymer Chain in solution

Cha

in E

xclu

ded

Volu

me

Solution Temperature

Tθ

Flory Interaction Parameter, 1/χ

χ θ(T, P,..)=1/2

Single Polymer Chain in solution

Cha

in E

xclu

ded

Volu

me

Gaussian distribution

Collapsed chainSwollen, distorted chain

Pol

ymer

Loc

al D

ensi

ty

Solvent “Quality”

“Bad” “Good”“Theta”

Solvent Rich

Polymer Rich

Polymer solution

20 µm

• Polymer solubility is controlled by the chemical potential• Expressed in terms of the solvent “quality”, described by the “Flory

Interaction Parameter”, χ– χ < 0.5 (good solvent) the polymer swells and dissolves– χ > 0.5 (bad solvent) the chain segments prefer to be next to each rather than

to a solvent molecule• Thus manipulation of the solvent can drive a controlled phase separation• And temperature can be used to control the crystallization

Image: ESEM CPG



Injectable PVA hydrogels

-80

-60

-40

-20

0

20

40

60

80

100

0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 20% 22% 24%

Mass percentage of ingredient [%]

Swel

l Rat

io (r

elat

ive

tohy

drat

ed) [

%]

Glycine Serine PEG 200Chondroitin NaCl Proline20K PEG PEG 400 Bovine Serum

• The balance of phase separation and crystallization governs gelation time and hydrogel structure

– Solvent Quality drives the phase separation– Temperature controls the crystallization process

• The solvent quality for PVA can be manipulated to allow injection†

– Pressure, temperature– A third ingredient – the “gellant”– 2M NaCl is a theta solvent for PVA at room temperature– Gravimetric swell ratio allows equivalent solvent activity to be determined

-80

-60

-40

-20

0

20

40

60

80

100

0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 20% 22% 24%

Mass percentage of ingredient [%]

Swel

l Rat

io (r

elat

ive

tohy

drat

ed) [

%]

PEG 200 NaCl 20K PEG PEG 4002M Salt is ~12.5% solids

Swell ratio at 2M salt is ~30%

Current gellant choice:Poly(ethylene glycol)

†Ruberti et al. “Systems and Methods for Controlling and Forming Polymer Gels” US Patent application US2004/0171740 (2004)



• Validation of injectable material as permanent device not straight forward• Biocompatibility/Toxicity

– Industry standards e.g. ISO 10993– All ingredients pharmaceutical excipients

• Mechanical properties – use is unusual for the permanent device industry– Injected

• Must gel “fast” – rheology• Must gel in vivo – no existing tests

– Confined • Need not bear loads on its own – draft standards in development• Space fill and conform• Must not extrude/expulse – no existing tests

– Viscoelastic • Modulus - unconfined compression (stress-strain)• Fatigue testing rate sensitive – draft standards in development

– Hydrated• Must recognize impact of gelation environment – no existing tests• Must measure water contents (“Equilibrium Water Content”)

• Validation of injectable material as permanent device not straight forward• Biocompatibility/Toxicity

– Industry standards e.g. ISO 10993– All ingredients pharmaceutical excipients

• Mechanical properties – use is unusual for the permanent device industry– Injected

• Must gel “fast”• Must gel in vivo

– Confined • Need not bear loads on its own• Space fill and conform• Must not extrude/expulse

– Viscoelastic • Modulus - unconfined compression (stress-strain)• Fatigue testing rate sensitive

– Hydrated• Must recognize impact of gelation environment • Must measure water contents (“Equilibrium Water Content”)

Validation as a medical device



Polymer response to solvent

• 4 cm stainless cone, TA instruments AR1000, 1% strain, 1 Hz• PVA in DI water is unstable above approximately 95 ºC, consistent with

theta temperature (Brandrup, Polymer Handbook)



Gelation time (in vitro)

• 15% PVA, 28% PEG 400 (relative to water content) is stable at >90 ºC• Predominantly elastic (G”>G’) after 50 min (this formulation)• Transition visible at ~ 50 ºC• Thermal history has some impact



Impact of environment (in vitro)

• 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)

• 5% Agar hydrogel at 40 ºC used as model for in vivo environment

FailLittle opacity

Diffuse interface

PassCompletely opaque

Sharp interface



Impact of environment (ex vivo)

• Porcine vertebral column with excess tissue removed• Denucleated using commercial tool (Hydrocision)• Bleed needle used to relieve pressure• Entire column immersed in DI water for 4 hours at 40 ºC• Hydrogel injected at 40 ºC and submerged for one day

Bleed needle

Hydrogel in 5 ml syringe

Gelled hydrogel after 1 day

Gelled hydrogel after 1 day

Dissected IVD



Injectability

• Critical for a surgical application that the material is injectable• Empirically a surgeon can exert a force of up to ~150 N• The complex gelling polymer solution is not a simple Newtonian solution,

therefore injection forces difficult to predict a priori• Injection force measurement

– Custom fixture– Standard load-frame– 16G needle and 5 ml syringe

Polyethylene standoff

500 N load cell Linear

actuator

Acrylic tube

5 mL syringe

16 gauge needle0

50

100

150

200

0 5 10 15 20Time (s)

Forc

e (N

)

PassFail



Extrusion/Expulsion

• Of serious concern is the possibility of extrusion and/or expulsion• Implanted devices intrinsically weaken the annulus

– Incision must be at least as big as the device– Incision usually sutured to allow it to heal

• Injectable devices fully fill the space– Incision can be a needle-stick– Material must not exude

Rigid container with plunger connected to load-frame. Load to 3000 N at 5 mm/min, 5 mm hole.

Orifice

Piston within acrylic sheath

0500

10001500200025003000

0 5 10 15 20Time (s)

Load

(N)

Passed ExtrusionFailed Extrusion

PASS

FAIL



Fatigue

• Fatigue testing is critical for biomedical materials– Conventional materials (PE, SS etc) have well developed techniques– Soft-solids do not– For an injectable nucleus replacement there are further problems

• Works in tandem with an “intact” annulus• (May) require hydration and fluid access• Must resist expulsion through pin-holes and orifices• Deformation is extremely complex (flexion/extension/rotation/compression/tension)

– Propose simpler model initially

Inst

ron



Confined compression fatigue

• Complete testing system and protocol under development in-house• RTV annulus based on ASTM guidance document• Porous end-plates (membrane supported by porous frit) to allow water

access• 40 ºC, 2750N ± 250N, 1Hz • Hydrogel gelled in situ,

injected through hole• Strain determined from

average displacement• Modulus determined from

displacement amplitude5 mm hole

Nucleus cavityRTV Annulus

Porous end-platesMembrane



Fatigue data

• Control “empty” nucleus with free access of water• Hydrogel formulation injected into nucleus space and allowed to gel for 1

hour• Control always presents higher creep, and stiffer dynamic modulus

– Suggest hydrogel reduces long term creep• No visual indication of hydrogel destruction

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 100000 200000 300000 400000 500000

Cycle Number

Stra

in [m

m/m

m]

ControlHydrogel

0

1

2

3

4

5

6

7

8

9

10

0 100000 200000 300000 400000 500000

Cycle Number

Mod

ulus

Mag

nitu

de [M

Pa]

E' Control E'' ControlE' Hydrogel E'' Hydrogel



Porcine proof-of-concept

• Preliminary proof-of-concept in a porcine model• Hydrogel rendered radiopaque using Barium Sulfate

Empty Nucleus cavity Nucleus cavity with hydrogelSpinal column

Syringe (end on)

Adjacent disc



Where next…

• Injectable hydrogels hold great promise for nucleus replacement strategies– Hydrated, permeable, viscoelastic– Minimally invasive, easily revised

• PVA hydrogels have a proven biomedical track record– Inert and biocompatible– Good mechanical properties– Highly hydrated

• The techniques developed by CPG yield an exceptional opportunity to use an existing material in a expanding medical indication

• But…– Developing suitable tests is non-trivial– Challenge is to find a suite of tests that are relevant to the application

• Confined deformation• Hydrated environment and material

• Next…– Long term fatigue and quantitative determination of hydrogel aging– Further in vivo safety and longevity studies



Acknowledgements

• Everyone at Cambridge Polymer Group– In particular Jason Berlin (bulk of experimental work)

• Lou Jenis at the Boston Spine Group• Questions:

– Gavin Braithwaite ([email protected])– Cambridge Polymer Group– 56 Roland Street, Suite 310– Boston. MA 02129

Refuse to Fuse! - Cambridge Polymer Group to Fuse! The development of a nucleus pulposus replacement...

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