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
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