Synthetic Corneal Onlay and Inlays: Learnings Applicable to

Keratoprostheses

Synthetic Corneal Onlay and Inlays: Learnings Applicable to

Keratoprostheses

Tim Hughes and Vision CRC Corneal Onlay TeamCSIRO, Molecular and Health Technologies, Clayton, Victoria, Australia

Vision CRC, Kensington, New South Wales, Australia

tim.hughes@csiro.au

Vision CRC Corneal OnlayVision CRC Corneal Onlay

POD 54

LM histology POD 92

0

1

2

3

5

CLI

NIC

AL

SCO

RE

Overgrowth kinetics good

Epithelial coverage of lenticules0 = no epithelium3 = 75% of surface covered4 = 100% of surface covered5 = “full thickness” covering 100%

4

DAYS 200 3010

• Onlay glued to basement membrane• Fast overgrowth of polymer in superficial

keratotomy model

Evans et al., IOVS, 2002

• Stratified epithelium over lenticule, normal BM, MV, HDs

• Anterior stroma healthy – keratocytes present

• No capsule formation around lenticule

• No inflammatory response –inert foreign body response

• Polymer biostable, transparent

Mishka Day 742

Xie et al., IOVS 2006

Vision CRC Corneal InlayVision CRC Corneal Inlay

12 months

Corneal Implants Essential PropertiesCorneal Implants Essential Properties

Physical PropertiesPermeable

Optical transparencyMechanical properties

similar to corneaDimensional stability

Sterilisable

Biological Properties Biostability

BiocompatibilityEpithelializing Devices

Surface supports cell attachment/tissue migration

15 nm pores

Epithelium requires Nutrient FluxEpithelium requires Nutrient Flux

• Nutrient flux > 100nm Track etched membrane• Control pore size and distribution

Sweeney et al., IOVS 1998100 nm pores

Clinical toleranceClinical intolerance

Central Ulcer 10 days post implantation

Porous PolymersPorous Polymers

• UV Photo-polymerisation of microemulsions

• Polymer forms around solvent phase

• Generates IPN with continuous porestructure

Pore Distribution and Haze Pore Distribution and Haze

0

10

20

30

40

50

60

70

80

90

13 to50

50 to100

100 to150

150 to200

200 to300

300to400

400 to500

500 to600

600 to700

700 to800

800 toto 900

900 to1000

1000 to1100

1100 to1200

1200plus

Pore Diameter Range (nm)

% O

bjec

ts

1049TH019 13.8% Haze

1049TH017 5.3% Haze

1049TH017 5.3% Haze 1049TH019 13.8% Haze

Optical Clarity: IsorefractivityOptical Clarity: Isorefractivity

Non porous dry Porous dry

Porous wetorous dry

• PFPE has R.I. similar to tear film

Edge of lens

Edge of lens

Edge of lens

Non porous wet

Mechanical PropertiesMechanical Properties

• Balance between matching corneal mechanical properties and ensuring device is easy for manipulation by surgeons

• Soft and elastic • Low modulus• Sufficient tensile strength

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

10 20 30 40 50 60Y

oung

s M

odul

us

(MP

a)% Water Content (w/w)

BiostabilityBiostability

•Biostability requires an inert polymer • Hydrolytically, oxidative and enzymatically stable• Typically synthetic not biological

•Dimensional stability for stable vision

C O

O

C R

O

O

OO R

O C C

OH

R

C C

OH

R

NH

poly(anhydrides) minutes

poly(ortho esters) hours

poly(esters) weeks-years

polyamides 106 years

Pellethane 80A Ovine 3m

Non porous PFPE Ovine 3m

Incr

easi

ng b

iost

abili

ty

BiocompatibilityBiocompatibility

• Non cytotoxic• No inflammation• Inert foreign body response• Low residual extractables

0

20

40

60

80

100

120

100.00050.00025.00012.5006.2503.1251.5630.7810.3910+E0.000

Dibutyltin dilaurateZCON 0.5Darocur 1173

Concentration[μg/ml]

%Cell viability

VERY CYTOTOXIC

MILDY CYTOTOXIC

NOT CYTOTOXIC

MTT

Inlay D180

HUMAN BASEMENT MEMBRANETEM, AFM and SEM data:pore size 92 ± 34 nminterpore 159 ± 72 nmpore area 15% total area

Tissue Migration / Cell AttachmentTissue Migration / Cell Attachment

Requires:• Suitable topography (AFM, stereo SEM)• Suitable surface chemistry (surface charge, hydrophilicity /hydrophobicity)

-20

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14 16

Zwitterion Concentration

Perc

enta

ge o

f TC

PS

BCEp Cell Attachment

BCEp Tissue Outgrowth

Chan et al, Biomaterials 2006Abrams et al, 2000

Surface ModificationSurface Modification

• Enhance biological response• Apply biological or synthetic

coating• Wet chemistry• Layer by layer• Plasma deposition

TCPS PFPE

Prol

ifera

tion

Inde

x

PFPE+ Collagen

0.00

2.00

4.00

6.00

8.00

10.00

ManufacturableManufacturable

• Manufacturable process• Sterilizable device (autoclave, gamma, E.O.?)

Can we do it better?Can we do it better?

• High throughput synthesis (Eric J. Amis, NIST)

• High throughput screening• Rational design (Angelova and Hunkeler 1999)

• Computer modelling • Experimental design

Chemspeed Autoplant A100TMNIST web site

Gradient of poly(L-lactic acid) morphology

ConclusionsConclusions

• Successful devices require materials specifically designed for the application by taking the following into account:

• Device’s purpose

• Biological factors

• The optimum material may have a balance of essential properties

• Complex problem best tackled with multidisciplinary teams

Vision CRC Corneal Onlay Team

Angela RuffellAnn DaltonAnne UnderwoodAntti VannasArthur HoBarbara BorjarskiBrien HoldenBronwyn LaycockDan O’LearyDanelle BeatieDebbie SweeneyDenise LawlerElspeth McLachlanGail McFarland

John RamshawJohn WilkieKlaus SchindhelmKeith McLeanLavinia TalianaMarijan FilipicMeg EvansMichele MadiganMichelle JenkinsMinas CoroneoMirella FabbriNicola KapoPaul EricksonRobyn Lawler

Gerrit BeumerGordon MeijsGrace ChanGraham Johnson Hans GriesserHanying ChengHassan ChaoukHeather St JohnHelen FittonHelmut ThissenIndrani PereraJack SteeleJenny LanJim Bates

Ron ChatelierRoss O’DellSamantha MayerSarah TaylorSimon ToutTherese PhamTim HughesTony XieTracey DaviesWarren KnowerXiaojuan HaoXuan NguyenZoran Vasic