“Biomedical Polyurethane Developed Within y pthe Custom-IMD Project”
Dr Steve RowlandsDr Steve Rowlands.
Smithers Rapra TechnologySmithers Rapra Technology.
ContentsContents
1. Introduction to the Custom IMD Project.
2. Polyurethane for a Spinal Nucleus Prosthesis.
3. Summary.
2
IntroductionCustom-IMD is a 6th Framework programme funded in part by the EU. p y
There are three main case studies within mCustom-IMD.
1. Cranio-facial bone plate prosthetic,
2 S i l l b l h i2. Spinal lumbar nucleus prosthetic,
3. Dental restoration.
3
Project OverviewProject OverviewObjective: development of the complete e-supply chain for the j pm f mp pp y frealization of custom implants and to demonstrate those through the 3 applications :
Materials development Data acquisitionAreas of work include:
Materials development
“Rapid” Manufacturing
Data acquisition
Implant designRapid Manufacturing
Biocompatibility
p g
e Supply chainwww.CustomIMD.eu
e-Supply chain
Project Overview: The NumbersProject Overview: The Numbers
Budget: € 9 8M with € 5 4M of EU funding• Budget: € 9,8M with € 5,4M of EU funding• Duration: 48 months (from 01.02.07 to 31.01.11)• Partners: 23
– RTD: 4– SME: 16SME: 16– University Hospital: 2– Centre of excellence: 1
• Countries: 7– Belgium
G S it l d– Germany -Switzerland– Netherlands -Spain– Poland -United Kingdom
5an n t K ng m
Polyurethanes for Spinal Disc RestorationRestoration
The spinal implant investigation focuses The spinal implant investigation focuses on a nucleus implant for the lumbarregion only.
Polyurethane development and Polyurethane development and Optimisation studies have been targeted for the Spinal Nucleus g pImplant.
Specific Mechanical, Chemical and Material properties were therefore Material properties were therefore required.
Why a Spinal Nucleus Implant?W y p mpDegenerative disc disease refers to a syndrome
i hi h i d di l b k i in which a compromised disc causes low back pain.
The pain is also frequently caused by simple wear and tear on the spine.
Degenerative disc disease is fairly common, and it is estimated that at least 30% of people aged is estimated that at least 30% of people aged 30-50 years old will have some degree of disc space degeneration.
Examples of Spinal Disc ProblemsExamples of Spinal Disc Problems
Polyurethane for a Spinal Nucleus ProstheticNucleus Prosthetic
Nucleus PulposusFc
Annulus fibrosis
Fc = Compressive Forcep
Kinematics of the Natural DiscIn order to reproduce physiological kinematic behaviour the following
it i t b b d
Kinematics of the Natural Disc
criteria must be observed:
6 degrees of freedom.
(3 translations and 3 rotations) Y
Allow movement without exceeding the natural range of movement.
Avoiding implant migration.
Floating centre of rotation as in the X
Z
Floating centre of rotation as in the natural spine.
Maintain disc height during 6 degrees of spinal motion
www.CustomIMD.eu
Maintain disc height during motion.
Dynamics and Endurance of the Natural Disc
The maximum expected in vivo compression load in the lumbar discs during daily activities are:
Natural Disc.during daily activities are:
Normal Standing up: 700 – 1000 NSt ndin up ith t unk fl x d 30º: 2400 NStanding up with trunk flexed 30º: 2400 NSitting: 1800 – 2700 NBending forward and lifting a 20 kg load: 4000-4200 N
Intradiscal compressive stresses (typical adult) during daily activities are:activities are
Standing: 0.2 – 1.1 MPaSitting: 0.4 – 1.5 MPaD i d i ht b i ti : t 2 5 MPDynamic and weight bearing motions: up to 2.5 MPaEstimated Young’s Modulus (from FEM models) for a nucleus is: up to 4.2 MPa( ) p
Polyurethane Material RequirementsGeneral PU ChemistryP l h i l l d
Polyurethane Material Requirements
Polyurethanes are a common commercial polymer and can possess diverse properties depending on how they are manufactured. They are characterized by containing the repeat unit:y g p
N O
O
PU’s generally have hard and soft segments. In one way, they can be considered both amides and esters of carbamic acid
NH
O
be considered both amides and esters of carbamic acid (carbamates). The repeat unit is usually synthesized by addition of an active hydrogen containing species across the carbon-nitrogen double bond of an isocyanate double bond of an isocyanate.
Isocyanate/Polyol Reaction Forming a Linear TPUa Linear TPU
A di functional isocyanate reacting with a diol will yield a linear andtherefore thermoplastic polyurethane, (TPU).
A medium Mw diol (~400-2500 Daltons) is reacted with the l l ll ldiisocyanate yielding a pre polymer as illustrated below.
2 O C N R NCO + HO OH7 0 - 9 0 o C
D i i s o c y a n a t e O l i g o - p o l y o l
OCN R NHCOO OOCNH R NCO
P r e p o l y m e r
By the reaction of the pre polymer with a chain extender such asethylene glycol, 1,4-Butane diol or a diamine, the high Mw polymer isformed.f
Typical Isocyanates for PU ManufactureManufacture
CH2 N=C=OO=C=N
Top left-1,6, hexamethylene di-isocyanate (HDI): middle-right-2, 4-Toluene isocyanate (TDI): middle-left; Isophorone diisocyanate: bottom-4,4’ methylene bis(phenyl isocyanate), MDI, and far right Hydrogenated MDI 4 4’ methylene bis(cyclohexane diisocyanate)right, Hydrogenated MDI, 4,4 methylene bis(cyclohexane diisocyanate).
Segmented PUSegmented PUThe urethane and/or urea linkages with the extender species, because of
the possibility of hydrogen bonding generate the “hard” domain or “hard the possibility of hydrogen bonding, generate the hard domain or hard segment” of the PU elastomer as illustrated below.
The high mobility of high Mw polyol chains represent the “soft segment” d th hi h l ti it f th lti PU l t Thi t t i and ensure the high elasticity of the resulting PU elastomer. This structure is
virtually cross linked by secondary (hydrogen) bonds. At higher temperatures the hydrogen bonds are destroyed and therefore at high temperatures it is possible to process the linear PU elastomers in the melt state similar to all
Hard Domain Soft Domain
possible to process the linear PU elastomers in the melt state, similar to all common thermoplastics.
CHN
HO
N CO
OH
HO
Hydrogen bonds
HO
C NN
OH
HO
C
HO
The hard and soft domains of PU elastomers
Soft Segment StructureStudies have shown that some PU elastomers (ester-based) were not
suitable for long term implantation due to poor hydrolytic stability [1] [2]
Soft Segment Structure
suitable for long term implantation due to poor hydrolytic stability.[1] [2]
The problem was thought to be addressed to some degree by the use of polyether macro diols. Polyteramethylene oxide (PTMO) macro diols being a favourite choice, but these are susceptible to oxidative degradation[3]. g
The degradation appears as surface cracking, stiffening and erosion or deterioration of the mechanical properties such as flex fatigue or deterioration of the mechanical properties such as flex fatigue resistance.
Bi d d ti l l d t l h bl t i d t Biodegradation may also lead to leachable toxic products.
Oxidative DegradationOxidative DegradationIt is likely that the biological chemical agents derived from the host implant response are oxidative and that susceptible functionalities implant response are oxidative and that susceptible functionalities such as abstractable methylene hydrogen atoms adjacent to oxygen in the PTMO macrodiol are the points of attack [4].
This theory is reinforced by the observation of enhance bio stability in the presence of antioxidants.
NH
O
O:CH
H
NH
O
O:CH
H
H O-
O CH3
+
NH OH
The siscion products may cross link to adjacent chains, therefore the TPU becomes harder and brittle, with a
+
change in Mw.
Polycarbonate Macro DiolsPolycarbonate Macro Diols
Use Polycarbonate diol as the soft segment.
Esterase Enzymic attack of the polycarbonate moiety has been y p y yreported.
However polycarbonate soft segments are thought to be the most p yattractive avenue for chronic bio stable PU implants.
The polycarbonate shows enhanced biostability over polyester p y y p yurethanes for two main reasons.
Stability of Carbonate GroupStability of Carbonate Group.(i) The polycarbonate has a pseudo π-bonding system, thus stabilising the carbonate moiety against attack as shown belowthe carbonate moiety against attack, as shown below.
O O
O O O O
The delocalised pi system for polycarbonate
(ii) H d l i f th b l i t i id t l d
The delocalised pi system for polycarbonate
(ii) Hydrolysis of the carbonyl moiety is acid catalysed.
Hydrolysis of an ester yields an alcohol and an acid, thus the reaction becomes self catalysed, whereas hydrolysis of the carbonate group yields CO2 and an alcohol, leading to slower reaction kinetics.
Stability of Carbonate Group (Cont )Stability of Carbonate Group (Cont.)
S h PU if it’ diffi lt t hi h i (50 ) • So why use PU if it’s so difficult to achieve chronic (50 yrs +) biostability?
• PU is used for it’s excellent mechanical versatility.
• The material’s bulk properties determines the specific mechanical requirements.
• The surface chemistry governs the biostability.
• Therefore modify surface to protect the vulnerable soft segment.
Self Assembling Monolayer End-Groups (SAME) (PTG)Groups (SAME)-(PTG).
Generally, a material is designed for its bulk properties but its y g p psurface chemistry is what determines the biocompatibility. SAME technology offers a solution to this problem.
SAMEs may be engineered into medical polymers during synthesis to provide a robust, built-in surface chemistry that self-assembles after device fabrication. More than one SAME may be used on a single polymer.
Therefore the bulk polymer may determine characteristics such as mechanical integrity while the SAME determines the surface bi t bilit biostability.
Self Assembling Monolayer End-Groups (SAME) (PTG) (cont )Groups (SAME)-(PTG). (cont.)
SAMEs have the advantage over self assembled monolayers (SAM) in that they are designed to covalently bond with the surface of the bulk polymer thus enabling in vivo environmental stability E g a bulk polymer, thus enabling in vivo environmental stability. E.g. a SAME-modified polycarbonate urethane using an octadecane end group.
This technology has been developed at the Polymer Technology Group (PTG) in Berkley, CA and may be one solution to long term bi st bilit /bi d bilitbiostability/biodurability.
P f PAnother way of functionalising PU in order to provide an enhanced
Reactive Processing of PUAnother way of functionalising PU in order to provide an enhanced biostable and/or functionalised surface chemistry is to react the PU in the melt with various reactive species.
Epoxide ring opening followed by a siloxane exchange reaction.
O Si(OMe)3 O SiOSiMe3
Me3SiOO 0
OSiMe3+3HOSiMe3
+3MeOH3 3MeOH
Siloxane type materials show an enhanced biostability over conventional PU, thus the above reaction will ,
facilitate a PU with enhanced biostability.B.G.Willoughby
Reactive Processing of PU (cont )Reactive Processing of PU (cont.)As mentioned earlier, device migration under normal loading is a serious issue with a spinal nucleus prostheticserious issue with a spinal nucleus prosthetic.
It was thought that an acid surface would bind the TPCU implant to the amine groups of the portentous material of the annulus fibrosis the amine groups of the portentous material of the annulus fibrosis, thus anchoring the device in place.
OH
N
OH
SCO2H
mercaptoacetic acid
1. The reaction involves the N-H of the PU therefore temperaturesgreater than the Tm of the hard
N H N
OH
+
crotonic acid
1,2-epoxy-5-hexene
o
gsegment are required.
An epoxide ring opening reaction
N
OH
CO2H
followed by either mercapto aceticacid or crotonic acid may facilitatean acid surface, as shown.
Reactive Processing of PU (cont )Reactive Processing of PU (cont.)Anhydride Ring opening reaction.2. y g p g
The reaction of interest here is that of a cyclic anhydride, where ring opening by an active-hydrogen species (HX) gives a carboxylic acid pendant group.
OO O XO
OO
+HXO O
H
The reaction with a urethane N-H can be represented as follows:
OO ONH
OYO
N
OYO
O+OO ONH
z
NO
OOH
z
Reactive Processing of PU (cont )The Gale/ Smithers Rapra mini mixer was modified to facilitate a
l d ti t PU lt t t 180 220°C
Reactive Processing of PU (cont.)
sealed reaction at PU melt temperatures, 180<>220°C.
Thermoplastic PCU synthesisAn MDI-based polycarbonate Urethane was formulated in a two stage process targeting the previously mentioned mechanical
Thermoplastic PCU synthesis
stage process targeting the previously mentioned mechanical properties required for a nucleus prosthetic device.
Stage 1.gA 3:1 pre-polymer (NCO:OH) was prepared by reacting MDI (Sigma
Aldrich; used as received) with a mixture of two Mw oligomericHexamethylene carbonate diols; Mw 650 and Mw 2000 (Sigma Aldrich; dried y ( gunder vacuum for 8 hrs) blended in a 1:1 ratio by equivalent weight.
MDI was placed in a reaction vessel under a dry nitrogen stream and held between 70-80°C The polycarbonate diol mixture was added slowly over 40 between 70-80 C. The polycarbonate diol mixture was added slowly over 40 minutes under stirring.
Stage 2.gThe pre-polymer was chain extended with Butane diol (Sigma-Aldrich,
dried under vacuum for 8 hrs), yielding an overall stoichiometry of 1:1 NCO:OH, therefore yielding a thermoplastic PCU.
Results and Discussion:Sterilisation studiesSterilisation studies
The SRT TPCU was characterised pre and post electron beam sterilisation using the following techniques:
DMTA Th l E t•DMTA: Thermal Events.•FTIR: Functional Group.F IR Funct onal Group.•Mechanical Testing: Reduction in
ti s properties on sterilisation.
•GPC: Molecular weight Changes.Changes.
DMTA Pre- and Sterilised SampleDMTA Pre- and Sterilised SamplePolyurethane PUMCC2-99
Scales Not UKAS Calibrated
1.2E+09 0.61 Hz PeakTemperature (C)=-10.9
10 Hz PeakTemperature (C)=-6.4
6.0E+08
8.0E+08
1.0E+09
Mod
ulus
(Pa)
0.3
0.4
0.5
Tan Delta Modulus 1.
Modulus 10.Tan Delta1.Tan Delta10.
Pre-Sterilisation
0.0E+00
2.0E+08
4.0E+08
-100 -50 0 50 100 150
Temperature (C)
0
0.1
0.2
PUMCC2-B99(ii) Scales Not UKAS Calibrated
1.0E+09
1.2E+09
0.5
0.6
1 Hz Peak Temperature (C)=-10.3
10 Hz Peak Temperature (C)=-5.5 e- beam sterilised.25 kG
6.0E+08
8.0E+08
Mod
ulus
(Pa)
0.3
0.4
Tan
Del
ta Modulus 1.Modulus 10.Tan Delta1.Tan Delta10.
25 kGy
0 0 00
2.0E+08
4.0E+08
M
0
0.1
0.2
0.0E+00-100 -50 0 50 100 150
Temperature (C)
0
FTIR-Golden GateFTIR Golden Gate
80
85
90
JN0006-04.Via S Rowlands. Golden gate IR of fresh cut surface of PUMCC'B-99 sample as received.HFAV25743
80
85
JN0006-04. Research Projects. Golden Gate IR of (1) PUMCC2 - B99(ii) fresh cut surface as received. BH.AV25899
55
60
65
70
75
80
ctan
ce 55
60
65
70
75
ctan
ce
30
35
40
45
50
55
%R
efle
c
30
35
40
45
50
%R
efle
cSmithers Rapra Collection time: Thu Jun 11 12:25:37 2009
20
25
30
800 1000 1200 1400 1600 1800 2000 2000 2500 3000 3500 4000 Wavenumbers (cm-1)
Smithers Rapra Collection time: Thu Jul 02 08:36:13 2009
15
20
25
800 1000 1200 1400 1600 1800 2000 2000 2500 3000 3500 4000 Wavenumbers (cm-1)
Smithers Rapra Collection time: Thu Jun 11 12:25:37 2009 Smithers Rapra Collection time: Thu Jul 02 08:36:13 2009
Pre-sterilisation Post-Sterilisation
Mechanical TestingMechanical TestingMaximum Tensile Strength (MPa)
Sample1 2 3 4 5 Median
Unsterilised PU 16.6 10.4 15.2 10.6 10.8 10.8S ili d 4 3 0 3 3 0Sterilised PU 11.1 14.1 13.0 11.5 15.3 13.0
100% Modulus (MPa)
Sample1 2 3 4 5 Median
Sample
Unsterilised PU 9.34 7.91 8.92 8.05 8.23 8.23Sterilised PU 8.10 8.30 8.20 8.20 8.30 8.20
200% Modulus (MPa)200% Modulus (MPa)
Sample1 2 3 4 5 Median
Unsterilised PU 12.34 9.38 11.38 9.62 9.91 9.91Unsterilised PU 12.34 9.38 11.38 9.62 9.91 9.91Sterilised PU 9.7 10.5 10.4 10.0 10.8 10.4
Mechanical Testing (cont.)T St th (N/ )Tear Strength (N/mm)
Sample 1 2 3 MedianUnsterilised PU 61.2 59.0 60.8 60.8
Sterilised PU 61.2 59.8 61.8 61.2
Shore A Hardness (3 second)Shore A Hardness (3 second)
Sample 1 2 3 4 5 Median
Unsterilised PU 89 80 90 90 91 90Sterilised PU 91 89 89 90 91 90
Mechanical Testing (cont.)Shore A Hardness (15 second)
1 2 3 4 5 M diSample
1 2 3 4 5 Median
Unsterilised PU 90 90 90 90 90 90Sterilised PU 90 88 89 89 90 89Sterilised PU 90 88 89 89 90 89
Unsterilised PU
Test No. Compression Modulus @ 10% Compression Modulus @ 20% (MPa) (MPa)
1 13.3 23.8
2 16.5 26.4
3 15.8 25.6
M 15 2 25 3Mean 15.2 25.3
GPC: Chromatographic Conditions for PU Investigationsfor PU Investigations
Instrument: Polymer Laboratories PL-GPC 120 with PL-AS-MT auto sampler.
Columns: PL gel guard plus 2 x mixed-B, 30 cm, 10 µm,
Solvent: N,N’-dimethyl formamide with 0.01M lithium bromide,
Flow-rate: 1.0 mL/min (nominal),
T t PL GPC 120 80°C ( i l)Temperature: PL-GPC 120: 80°C (nominal),
PL-AS-MT: 80°C (nominal),
Detector: Refractive index.
Standards: PMMAStandards: PMMA.
GPC Trace For Sterilised And Un Sterilised TPCUUn Sterilised TPCU
1 05
1.1
1. 15
1.2
MOLECULAR WEIGHT DISTRIBUTIONSPUMCC2-B99 pre-sterilisation
PUMCC2-B99 pre-sterilisation
PUMCC2-B99 (ii) Post-Sterilised
0.8
0. 85
0.9
0. 95
1
1. 05
M
PUMCC2-B99 (ii) Post-Sterilised
0.5
0. 55
0.6
0. 65
0.7
0. 75
dw/d
logM
0 2
0. 25
0.3
0. 35
0.4
0. 45
1 00 0 10 00 0 10 00 00 1 e6
0
0. 05
0.1
0. 15
0.2
Molecular Weight
SummarySummaryAn aromatic polycarbonate Urethane (PCU), of shore 90A hardness was prepared hardness was prepared.
The PCU was electron beam sterilised by Custom-IMD ypartner LasMed with a dosage of 25 kGy.
The PCU was characterised pre and post sterilisation in The PCU was characterised pre- and post sterilisation in order to determine any detrimental effects of the sterilisation technique on the PCU.
No significant changes were observed pre and post sterilisationsterilisation.
Therefore e -beam sterilisation is an appropriate sterilisation h d f h f lmethod for this type of material.
SummarySummary
S i l th i i t h i ll h ll i • Spinal prosthesis is technically challenging, PU used for it’s Bulk mechanical properties.p p
P l b t s ft s m t s d f • Polycarbonate soft segment used for enhanced biostability.
• An aromatic polycarbonate Urethane (PCU) • An aromatic polycarbonate Urethane (PCU), of shore 90A hardness was prepared.
Further InformationFurther Information
For further information on Custom IMD and the technical developments made within the project, you can access the
project training materials which are available on the project training materials, which are available on the Extended Services website. Please visit: www.customimd.eu
and click on the link to the ‘Extended Services’ webpage.
The Custom IMD project is supported by funding under the Sixth Framework Programme of the European Union.
Contract No: 026599.Contract No 026599.