Exploring thiol-yne based monomers as low cytotoxic building blocks for radical photopolymerization

Article abstract of DOI:10.1002/pola.28239

The last decade has seen a remarkable interest in the development of biocompatible monomers for the realization of patient specific medical devices by means of UV-based additive manufacturing technologies. This contribution deals with the synthesis and investigation of novel thiol-yne based monomers with a focus on their biocompatibility and also the mechanical properties in their cured state. It could be successfully shown that propargyl and but-1-yne-4-yl ether derivatives have a significant lower cytotoxicity than the corresponding (meth)acrylates with similar backbones. Together with appropriate thiol monomers, these compounds show reactivities in the range of (meth)acrylates and almost quantitative triple bond conversions. A particular highlight is the investigation of the network properties of photo cured alkynyl ether/thiol resins by means of low field solid state nuclear magnetic resonance spectroscopy. Additionally, dynamic mechanical analysis of those polymers revealed that monomers containing rigid backbones lead to moduli and glass transition temperatures (T_g's), sufficiently high for the fabrication of medical devices by UV based additive manufacturing methods.

Full text of DOI:10.1002/pola.28239

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Exploring Thiol-Yne Based Monomers as Low Cytotoxic Building Blocks
for Radical Photopolymerization
1
2
3
Andreas Oesterreicher, Santhosh Ayalur-Karunakaran, Andreas Moser,
1
1
4
3
4
Florian H. Mostegel, Matthias Edler, Petra Kaschnitz, Gerald Pinter, Gregor Trimmel,
Sandra Schl o€ gl, Thomas Griesser
2
1
1
Chair of Chemistry of Polymeric Materials & Christian Doppler Laboratory for Functional and Polymer Based Ink-Jet Inks,
University of Leoben, Otto-Gl o€ ckel-Strasse 2, Leoben, 8700, Austria
2
Polymer Competence Center Leoben GmbH, Roseggerstrasse 12, Leoben, 8700, Austria
3
Chair of Material Science and Testing of Polymers, University of Leoben, Otto-Gl o€ ckel-Strasse 2, Leoben, 8700, Austria
4
Institute for Chemistry and Technology of Materials (ICTM), NAWI Graz, University of Technology, Stremayrgasse 9, Graz, 8010,
Austria
Correspondence to: T. Griesser (E-mail: thomas.griesser@unileoben.ac.at)
Received 28 April 2016; accepted 18 July 2016; published online 00 Month 2016
DOI: 10.1002/pola.28239
ABSTRACT: The last decade has seen a remarkable interest in
the development of biocompatible monomers for the realiza-
tion of patient specific medical devices by means of UV-based
additive manufacturing technologies. This contribution deals
with the synthesis and investigation of novel thiol-yne based
monomers with a focus on their biocompatibility and also the
mechanical properties in their cured state. It could be success-
fully shown that propargyl and but-1-yne-4-yl ether derivatives
have a significant lower cytotoxicity than the corresponding
bond conversions. A particular highlight is the investigation of
the network properties of photo cured alkynyl ether/thiol resins
by means of low field solid state nuclear magnetic resonance
spectroscopy. Additionally, dynamic mechanical analysis of
those polymers revealed that monomers containing rigid back-
bones lead to moduli and glass transition temperatures (T
sufficiently high for the fabrication of medical devices by UV
based additive manufacturing methods. V
2016 Wiley Periodi-
cals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 00, 000–
00
g
’s),
C
0
(
meth)acrylates with similar backbones. Together with appro-
priate thiol monomers, these compounds show reactivities in
the range of (meth)acrylates and almost quantitative triple
KEYWORDS: low cytotoxicity; photopolymers; thiol-yne
INTRODUCTION Recent years have seen an increasing inter-
reactive diluents. One considerable drawback of this class of
chemical compounds is their comparably high irritancy and
even cytotoxicity in their uncured state. This disadvanta-
est in the development of biocompatible, UV curable mono-
1
6,7
mers for medical applications. This fact can mainly be
explained by the rapid progress in UV-based additive
manufacturing technologies (AMTs), such as stereolithogra-
phy, digital light processing, or three-dimensional (3D) ink-
jet printing, which enable fast, accurate, and individual fabri-
geous behavior can be mainly attributed to the reactivity of
the acrylate double bond toward Michael addition reactions
with amino- or thiol-groups of proteins or DNA. This fact,
together with the incomplete curing behavior of (meth)acry-
lates (double bond conversions in the range of 60%–90%
can usually be obtained) prevents their usability for medical
purposes, that is, for materials which remain in contact with
or within the human body.
8
2
cation of biocompatible structures.
Currently, monomers based on (meth)acrylates are the state-
of-the-art UV curable materials for protective and decorative
3
–5
coatings.
These building blocks are characterized by their
excellent storage stability and fast curing rates. Moreover,
the mechanical properties of the resulting polymers can easi-
ly be adjusted by the choice of different spacers in photopo-
lymerizable oligomers and by using different types of low
molecular mono-, di-, and multifunctional (meth)acrylates as
Recently, several alternative radical curable functionalities,
such as vinylcarbonates, vinylesters, and vinylcarbamates have
been introduced as interesting alternatives to (meth)acrylate
based resins providing a significant lower cytotoxicity.
However, the need of expensive reagents for the synthesis of
1
,2,9
Additional Supporting Information may be found in the online version of this article.
2016 Wiley Periodicals, Inc.
V
C
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those monomers along with their comparably low homopoly-
merization rates may explain why such resins have not
entered the market so far. In particular, compounds bearing
which are known to offer high moduli and high T ’s, lead to
g
comparably low curing rates and double bond conversions.
2
2
1
Taking those facts into account, in the present article, the
curing and cytotoxic behavior of propargyl and but-1-yne-4-
yl monomers containing butyl (C4) spacers, that is, butane-
diol dipropargyl ether (BuPE) and butanediol di-1-butinyl
ether (BuBE), were investigated and compared with the cor-
responding (meth)acrylate based compounds butanediol
dimethacrylate (BuMAc) and butanediol diacrylate (BuAc).
The network properties (cross-link density, glass transition
temperature, and storage modulus) of these thiol-yne poly-
mers were studied by solid state nuclear magnetic resonance
easily abstractable hydrogens as, for example, in oligo ethyl-
ene glycol units are far less reactive than the corresponding
acrylates. Although the addition of multifunctional thiols,
which also provide very low cytotoxicity, accelerates the cur-
ing rates of those monomers toward values of acrylates, the
Young’s modulus and the glass transition temperature are
lowered significantly. This fact can be attributed to a decrease
in the cross-link density and also to the flexibility of the com-
monly used thiol compounds, that is, mercapto propionic
9
ester derivatives, and the formed thioether bonds.
(
NMR) and dynamic mechanical analysis (DMA) measure-
In general, the addition of thiols to ene-monomers results in
reduced resin stability (shelf-life) due to occurring dark poly-
ments. Additionally, a second class of alkynyl ether based
monomers bearing rigid spacers was investigated consider-
ing reactivity and network properties after UV polymeriza-
tion. This study reveals the versatility of those monomers for
the individual and patient customized fabrication of medical
devices by UV-based additive manufacturing methods.
1
0
merization reactions. Another mentionable drawback is the
characteristic odor of thiol monomers. Due to the limited net-
work properties, thiol-ene photopolymers do not fulfill the
demands of medical applications, such as dental restoratives
1
1
or hard tissue replacements. This fundamental limitation of
the thiol-ene step growth polymerization is explained by the
fact that each ene functional group reacts only once with a
thiol, whereas in chain growth polymerization, each ene group
becomes part of a polymer chain leading to higher network
densities. Numerous approaches have been undertaken to
increase the mechanical properties of thiol-ene polymers by
using rigid ene and thiol compounds or monomers which are
EXPERIMENTAL
NMR Studies
1
13
H-NMR and C-NMR spectra were recorded on a Varian
00-NMR spectrometer operating at 399.66 and 100.5 MHz,
respectively, and were reference to Si(CH . For the acquisi-
4
)
3 4
1
tion of the H-NMR spectra a relaxation delay of 10 s and a
458 pulse were used. The NMR spectra were referenced to
solvent residual peaks according to values given in the
1
0,12–15
capable to form hydrogen bonds.
2
3
Another possibility to enhance the network properties is to
increase the network density of such photopolymers. An ele-
gant approach is to use multifunctional alkynes instead of
literature.
1
H-NMR spectra for real-time experiments were recorded on
a Varian INOVA 500 MHz spectrometer operating at 499.803
1
6–19
ene monomers.
In this so called thiol-yne polymeriza-
tion an yne functional group reacts with a thiol to form a
vinylsulfide, which can subsequently react with another thiol.
Outside of the dual reactivity that offers a significant
increase in the cross-link density, all other characteristics of
the thiol-yne photopolymerization follow the ideal click reac-
tion paradigm of thiol-ene systems. The polymerization is
highly efficient and relatively unaffected by oxygen, ensuring
the formed network being nearly ideal in homogeneity.
MHz and were referenced to Si(CH ) . A relaxation delay of
3 4
1 s and 458 pulse were used for acquisition of the H-NMR
spectra. The measurements were performed at 37 8C.
1
Low field NMR measurements were recorded on a Bruker
minispec mq20 NF series spectrometer equipped with a 0.47
1
T magnet ( H resonance frequency of 20 MHz) and a ratio
probe. The 908, 1808 pulse lengths and the receiver dead
time were 2.8, 5.7, and 9 ms, respectively. The sample was
cut into stripes, which were vertically stacked into the sam-
ple tube to fill a cylindrical volume of 8 mm diameter and
Fairbanks et al. studied systematically the relative reactiv-
ities of a range of different yne monomers revealing high
2
0
reaction rates for terminal alkynes and propargyl esters.
8
mm height. Measurements were carried out at 100 8C after
Only moderate polymerization rates were found for propar-
gylethers and internal alkynes. Cyclooctyne, methylpropar-
gylamine and ethyl propiolate do not show this bireactive
character.
an equilibration time of about 45 min. The sample was heat-
ed by dry air and the temperature regulated with a BVT3000
variable temperature controller.
DQ NMR measurements were carried out with the so-called
2
4
Very recently, Pretzel et al. investigated the cytotoxic poten-
tial of internal alkynes. It was found that besides the type of
the polymerizable moiety, also the spacer group of photo-
reactive building blocks exerts significant influence on the
5-pulse segment and the modified Baum-pines sequence.
Further details of the measurement principle are given in
25
the Supporting Information and were reviewed elsewhere.
2
,21
curing and cytotoxic behavior.
Moreover, the network
Real-Time FT-IR Measurements
properties of the cured monomers strongly depend on the
type and flexibility of the spacer. For example, monomers
containing rigid structures such as bisphenol A moieties,
Kinetic real-time FT-IR measurements were conducted on a
VERTEX 70 (Bruker, Billerica) in reflection mode with the
unit A513. About 1 mL of the resin of investigation was
2
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2
1
placed in between two CaF2 windows (8 mm diameter,
mm thickness) and illuminated with an Omnicure s1000
Lumen Dynamics, Mississauga) with 9 cm gap between the
sample and light guide (P 5 22 mW/cm at the sample sur-
face). For real-time FT-IR measurements the corresponding
monomers were mixed with 5 wt % of the photoinitiator
blend, diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide/2-
60 mm at a shear rate of 300 s . The viscosity was mea-
sured at 25 8C.
1
(
2
Cytotoxicity
The cytotoxicity experiments were conducted at Cytox biolo-
gische Sicherheitspr u€ fungen (Bayreuth, Germany) according
to ISO 10993-5:2009. For these tests mouse fibroblast cells
L929) were used. Cells were cultured for 24 h in Dulbecco’s
modified Eagle’s medium (DMEM) with added antibiotics,
(
hydroxy-2-methylpropiophenone and
amount of trimethylolpropane tris(3-mercaptopropionate)
TMPMP). The corresponding (meth)acrylates were prepared
a
stoichiometric
supplemented with 10% fetal calf serum at 37 8C in an incu-
(
bator with 5% CO . Four different concentrations of the
examined substance (dissolved in DMSO) were applied onto
the cells and incubated for 48 h at 37 8C with 5% CO . The
2
without any thiol component. For thermal post-curing the
sample was placed on a 100 8C heated plate and illuminated
stepwise with the same intensity as described above.
2
final concentration of DMSO in all cavities in the cell culture
medium was 1% (v/v). Triton X 100 was used as toxic posi-
tive control [final concentration 1% (v/v)] and the cell cul-
ture medium was used as non-toxic negative control. All
experiments were conducted four times simultaneously. After
the incubation the L929-cells were washed with phosphate
buffered saline (PBS), and after an alkaline lysis step the
protein concentration was determined via the Bradford
method. Graphical illustrations of the protein content in
dependence of the monomer concentration can be found in
the Supporting Information.
Photo-DSC
The photo-DSC experiments were performed on a NETZSCH
photo-DSC 204 F1 Phoenix. All measurements were con-
ducted at 50 8C in aluminum crucibles under nitrogen atmo-
sphere. Sample quantity was 8 mg of resin, which was
prepared in the same way as being described for real-time
FT-IR measurements [5 wt % of the photoinitiator blend,
diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide/2-hydroxy-
2-methylpropiophenone and a stoichiometric amount of
TMPMP]. The Omnicure s2000 was used as the light source
at 1 W/cm resulting in an intensity of 80 mW/cm at the
surface of the sample (range of wavelength was 250–
2
2
Materials
4
45 nm). For the determination of the reaction enthalpy and
2-Hydroxyethyl acrylate (Sigma Aldrich, 96%), 2-
hydroxyethyl methacrylate (Sigma Aldrich, 99%), ethanol-
amine hydrochloride (Sigma Aldrich, 99%), 2-(2-methoxye-
thoxy)ethanethiol (97%), 1,4-dibromobutane (Sigma Aldrich,
99%), 2-propyn-1-ol (Sigma Aldrich, 99%), 3-butyn-1-ol (Sig-
ma Aldrich, 97%), sodium hydride (Sigma Aldrich, 60% dis-
persion), tetrabutylammonium iodide (Sigma Aldrich, 98%),
bisphenol A (Sigma Aldrich, 99%), ethylene carbonate (Sig-
ma Aldrich, 99%), 3-bromo-1-propyne (Sigma Aldrich, 80 wt
tmax, the samples were illuminated twice for 10 min each
with an idle time of 2 min in between. For the analysis, the
second run was subtracted from the first one to obtain the
reaction enthalpy curve.
Sample Preparation
For the determination of the thermomechanical properties of
derived photopolymers sample specimens with 2 3 5 3
2
0 mm rectangular dimensions, respectively, were fabricated
%
in toluene), tetrachlorosilane (Sigma Aldrich, 99%), mag-
in PTFE molds. The resin samples were photocured by a
Lighthammer 6 (Fusion UV Systems) with a Hg bulb (4
passes each side, belt speed of 4 m/min, 40% light intensity,
E 5 4.7 J/cm ). The resin contained the corresponding alkyne
with a stoichiometric amount of silanetetrayltetrakis(proR-
nesium (Sigma Aldrich, 99.9%), 3-chloro-1-propene (Sigma
Aldrich, 99%), 2,2‘-azobis(2-methylpropionnitrile) (Fluka),
thioacetic acid (Sigma Aldrich, 96%), ethyl(2,4,6-trimethyl-
2
benzoyl)phenylphosphinate
diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide/2-hydroxy-
-methylpropiophenone, blend (Sigma Aldrich), pentaerythri-
tol tetra(3-mercaptopropionate) (PETMP) (Sigma Aldrich,
9%), and trimethylolpropane tri(3-mercaptopropionate)
TMPMP) (Bruno Bock Chemische Fabrik GmbH & Co. KG)
(IrgacureVR TPO-L,
BASF),
V
pane-1-thiol) and 3 wt % of the photoinitiator Irgacure
TPO-L. The T was determined at the maximum of tan delta.
2
g
9
(
Dynamic Mechanical Thermal Analysis (DMA)
The thermomechanical properties were measured in tension
mode using a DMA/SDTA 861 (Mettler Toledo) with a heat-
ing rate of 2 K/min in the temperature range from 240 8C
to 115 8C. The operating frequency was determined at 1 Hz.
For comparison of the alkyne ether formulations, the storage
modulus was evaluated at room temperature (37 8C) and the
glass transition temperature was determined at the maxi-
mum of tan delta.
were used as received. 1,4-Butanediol diacrylate (abcr
GmbH) and 1,4-butanediol dimethacrylate (abcr GmbH,
90%) have been purified by flash chromatography prior
usage. Tetra(3-mercaptopropyl)silane (TMPS) was synthe-
2
6
sized according to literature.
Synthesis
1,4-Butanediol dipropargyl Ether (BuPE)
Viscosity Measurements
In a three-neck round-bottom flask 2.4 g (100.0 mmol, 2.7
eq) sodium hydride was washed two times with n-hexane
and afterward suspended in 50 mL DMF. The mixture was
purged with nitrogen and cooled down to 210 8C in an etha-
nol cooling bath. About 5.4 g (96.3 mmol, 2.6 eq) 2-propyn-
The viscosities of the monomers were determined using an
Anton Paar rheometer (MCR-102, Graz, Austria) in a cone-
plate system setup with titanium cone (MK 22/60 mm,
0.588) with an opening angle of 0.588 and a diameter of
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1
-ol in 50 mL DMF was added dropwise over 30 min. The
DMF and refluxed at 145 8C for 3 h. The reaction mixture
was then poured into 1.5 L deionized water. The resulting
white precipitate was filtered and washed with water, with
methanol and afterward with a small amount of cold THF.
The remaining white powder was dried under vacuum at 70
8C to yield 18.0 g (65%) of BisAE.
mixture was stirred for 2 h. Eight grams of (37.1 mmol) 1,4-
dibromobutane in 50 mL DMF was added dropwise over a
time span of 30 min. The reaction mixture was kept at 0 8C
for further 3 h and quenched afterward with a saturated
ammonium chloride solution. Afterward the mixture was
extracted three times with diethyl ether and dried over
Na SO . The combined organic extracts were concentrated
under reduced pressure at elevated temperature to remove
the excess of 2-propyn-1-ol and residual DMF. The crude
product was further purified by flash column chromatogra-
phy (ethyl acetate:cyclohexane 1:10) leading to 5.3 g (yield:
1
H-NMR (d, 400 MHz, 25 8C, CDCl ): 7.15–7.13 (d, 4H,
3
2
4
ArAH); 6.83–6.81 (d, 4H, ArAH); 4.07 (t, 4H, ACH AOA);
2
3
.95 (m, 4H, ACH AOH); 1.64(s, 6H, ACH ) ppm.
2
3
13
C-NMR: (d, 100 MHz, 25 8C, CDCl
3
):156.42 (2C, ArACAO),
1
6
43.57 (2C, ArAC), 127.78 (4C, ArAC), 113.92 (4C, ArAC),
9.09 (2C, OAC), 61.53 (2C, CAOH), 41.72 (1C, CACH3),
86%) of BuPE as a transparent and colorless liquid.
1
31.02 (2C, CH ); ppm
3
H-NMR (d, 400 MHz, 25 8C, CDCl ): 4.11 (d, 4H, CH ACBC);
3
2
3
.52 (m, 4H, CH AO); 2.52 (t, 2H, CBCH); 1.66 (m, 4H,
2
2
,2-Bis[4-(2-(prop-2-yn-1-yloxy)ethoxyphenyl]propane
CH ACH AO) ppm.
2
2
(BisAEPE)
1
3
In a 250 mL three-neck round-bottom flask 0.9 g (37.9
mmol, 2.4 eq.) sodium hydride was washed with n-hexane
and afterward suspended in 30 mL DMF. The mixture was
purged with nitrogen and cooled down to 210 8C in an etha-
nol cooling bath. Five grams (15.8 mmol) of BisAE were dis-
solved in 30 mL DMF and added dropwise over 30 min. The
mixture was stirred for 1 h while the temperature was kept
around 0 8C. A solution of 4.7 g (39.5 mmol, 2.5 eq.) 3-
bromo-1-propyne in 30 mL DMF was added dropwise over a
time span of 30 min. The reaction mixture was stirred for
2 h while the mixture was allowed to reach room tempera-
ture. It was then quenched with a saturated solution of
ammonium chloride, extracted with diethyl ether and dried
over Na SO . The combined organic extracts were concen-
C-NMR: (d, 100 MHz, 25 8C, CDCl ): 79.92 (s, 2C, ACBC);
3
7
4.01 (s, 2C, ACBC); 69.68 (s, 2C, CAO); 57.93 (s, 2C,
CACBC); 26.08 (s, 2C, CACAO) ppm.
1
,4-Butanediol dibut-3-yn-1-yl Ether (BuBE)
In a 500 mL three-neck round-bottom flask 3.00 g (125
mmol, 2.5 eq.) sodium hydride was washed two times with
n-hexane and afterward suspended in 150 mL DMF. The mix-
ture was purged with nitrogen and cooled down to 210 8C
in an ethanol cooling bath. About 21.20 g 3-butyn-1-ol (300
mmol, 6 eq.) in 50 mL DMF was added dropwise over 30
min. The mixture was stirred for 2.5 h while the temperature
was kept around 0 8C. About 1.30 g tetrabutylammonium
iodide (3.5 mmol; 0.07 eq.) was added to the mixture before
a solution of 10.80 g 1,4-dibromobutane (50 mmol) in
2
4
trated under reduced pressure to receive the crude product,
which was further purified by flash column chromatography
(ethyl acetate:cyclohexane 1:3) to yield 5.4 g (87%) of
BisAEPE as a transparent, yellowish liquid.
4
0 mL DMF was added dropwise over a time span of 30
min. The reaction mixture was kept at 0 8C for 4 h and
quenched with a saturated solution ammonium chloride.
Afterward the mixture was extracted three times with
1
H-NMR (d, 400 MHz, 25 8C, CDCl ): 7.13–7.11 (d, 4H,
3
2 4
diethyl ether and dried over Na SO . The combined organic
ArAH); 6.83–6.81 (d, 4H, ArAH); 4.27 (d, 4H, CH ACBC);
2
extracts were concentrated under reduced pressure at ele-
vated temperature to remove the excess of 3-butyn-1-ol and
residual DMF. The crude product was further purified by
flash column chromatography (ethyl acetate:cyclohexane
4
.13 (t, 4H, CH AOAAr); 3.89(t, 4H, CH AO); 2.45 (t, 2H,
2
2
CBCAH); 1.63 (s, 6H, CH ) ppm.
3
13
C-NMR: (d, 100 MHz, 25 8C, CDCl
3
): 156.47 (s, 2C,
1
:20 ! 1:10) leading to 3.3 g (yield: 34%) of BuBE as a
ArACAO); 143.41 (s, 2C, ArAC); 127.69 (s, 4C, ArAC);
13.94 (s, 4C, ArAC); 79.49 (s, 2C, ACBC); 74.69 (s, 2C,
ACBC); 68.26 (s, 2C, OAC); 67.11 (s, 2C, ArAOAC); 58.53
s, 2C, CACBC); 41.68 (s, 1C, Cq.); 31.03 (s, 2C, CH ) ppm.
transparent and colorless liquid.
1
1
H-NMR (d, 400 MHz, 25 8C, CDCl ): 3.55–3.48 (m, 8H,
3
(
3
CH
2 2 2
AOACH ); 2.45 (t, 4H, CH ACBC); 1.97 (t, 2H, CBCAH);
1
.65 (m, 4H, OACH ACH ) ppm.
2
2
2,2-Bis[4-(prop-2-yn-1-Yloxy)phenyl]propane (BisAPE))
1
3
In a 250 mL three-neck round-bottom flask 1.3 g (52.6
mmol, 2.4 eq.) sodium hydride was washed with n-hexane
and afterward suspended in 50 mL DMF. The mixture was
purged with nitrogen and cooled down to 210 8C in an etha-
nol cooling bath. Five grams (21.9 mmol) of bisphenol A was
dissolved in 50 mL DMF and added dropwise over 30 min.
The mixture was stirred for 1 h while the temperature was
kept around 0 8C. A solution of 6.8 g (57.2 mmol, 2.6 eq.) 3-
bromo-1-propyne in 30 mL DMF was added dropwise over a
time span of 30 min. The reaction mixture was stirred for
C-NMR: (d, 100 MHz, 25 8C, CDCl ): 81.4 (s, 2C, ACBC); 70.7
3
(s, 2C, OAC); 69.2 (s, 2C, ACBC); 68.7 (s, 2C, CACACBC);
2
6.2 (s, 2C, CACACAC); 19.8(s, 2C, CACBC) ppm.
2
,2-Bis[4-(2-hydroxy)ethoxyphenyl]propane (BisAE)
The product was synthesized according to a modified litera-
ture procedure.
equipped with a reflux condenser 20 g (87.6 mmol) bisphe-
nol A and 17.7 g (201.5 mmol, 2.3 eq.) ethylene carbonate
were added to 24.2 g (175 mmol, 2 eq.) K CO in 300 mL
2
7
In a three-neck round-bottom flask
2
3
4
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their neighborhood, are mostly inert in the thiol Michael
3
0
reaction even under basic conditions.
The reactivity of radically polymerizable moieties toward
amino and mercapto groups under physiological conditions
1
was studied by H-NMR spectroscopy using D
2
O soluble
model compounds (as shown in Scheme 1). Taking into
Account the pH-Value (pH ꢀ 7.4) and the puffer capacity of
blood, as well as the comparably high pK value of primary
b
amines, it can be assumed that the majority of protein or
DNA related amino groups exist in their protonated state.
Considering this fact and the lower nucleophilicity of proton-
ated amines, ethanolamine hydrochloride was chosen as
model compound in the following experiments. For the
exclusion of radical mediated reactions (e.g., thiol-ene) 0.1
wt % of pyrogallol was added as radical scavenger in all
samples. Figure 1 shows the double bond conversion (DBC)
of the (meth)acrylate model compounds during storage
determined by kinetic NMR measurements at body tempera-
ture (37 8C). As expected, the acrylate, that is, HEA, shows
the highest reactivity toward both nucleophiles. While the
reaction with the mercapto group proceeds quantitatively
within several minutes, a conversion of 30% was reached
with ETAHC after 30 h.
SCHEME 1 Water soluble model compounds [HEA, 2-
hydroxyethyl acrylate; HEMA, 2-hydroxymethyl acrylate; BuOH,
3-butyne-1-ol; ETAHC, ethanolamine hydrochloride; MTE, 2-(2-
methoxyethoxy)ethanethiol] used for the evaluation of the
reactivity of unsaturated functional groups.
Detailed NMR spectra confirmed the formation of the thiol
Michael adduct, whereas the reaction with ETAHC lead to
several by-products. Presumably, the formed secondary
amine undergoes a subsequent Michael addition; further-
more, hydrolytic cleavage reactions of present ester groups
are conceivable.
2
h while the mixture was allowed to reach room tempera-
ture. It was then quenched with a saturated solution of
ammonium chloride, extracted with diethyl ether and dried
over Na SO . The combined organic extracts were concen-
2 4
trated under reduced pressure to receive the crude product,
which was further purified by flash column chromatography
In contrast, HEMA shows a significant lower reactivity in
both cases. Although it also provides full conversion in the
reaction with MTE after 19 h, no formation of the aza
Michael adduct could be observed, which can be assigned to
the higher electron density of the CAC double bond (vide
(
ethyl acetate:cyclohexane 1:5) to yield 6.1 g (92%) of
BisAPE as a transparent and yellow liquid.
1
H-NMR (d, 400 MHz, 25 8C, CDCl ): 7.17–7.15 (d, 4H,
3
ArAH); 6.89–6.87 (d, 4H, ArAH); 4.67 (d, 4H, CBCAH); 2.52
(
t, 2H, CBCAH); 1.64 (s, 6H, CH ) ppm.
3
1
3
C-NMR: (d, 100 MHz, 25 8C, CDCl ): 155.4 (s, 2C, ArAC);
3
143.9 (s, 2C, ArAC); 127.7 (s, 4C, ArAC), 114.2 (s, 4C,
ArAC); 78.8 (s, 2C, ACBC); 75.35 (s, 2C, ACBC); 55.8 (s, 2C,
OAC); 41.8 (s, 1C, Cq.); 30.9 (s, 2C, CH ) ppm.
3
RESULTS AND DISCUSSION
Reactivity of Monomer Model Compounds Under
Physiological Conditions
The cytotoxicity of state-of-the-art building blocks can be
attributed to their reactivity toward amino- or thiol-groups
8
of proteins or DNA. In general, the electron density of
unsaturated compounds, that is, the Michael acceptor, strong-
ly determines the reactivity with (hetero) Michael
2
8,29
donors.
Both facts can explain the lower cytotoxicity of
FIGURE 1 Double bond conversion (DBC) of HEA/MTE
methacrylates compared with their acrylate counterparts
due to the higher electron density induced by the additional
methyl group. Moreover, it is well reported that terminal
alkyne groups, without electron withdrawing moieties in
(
squares), HEMA/MTE (triangle), and HEA/ETAHC (circles)
under simulated physiological conditions. [Color figure can be
viewed in the online issue, which is available at wileyonlineli-
brary.com.]
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SCHEME 2 Structures of the investigated monomers.
supra). Importantly, under these conditions, the terminal
alkyne group undergoes no reaction with any of the two
Michael donors, neither with mercapto, nor with amino
hydrochloride groups.
Monomers with C4 Spacer
Besides the type of unsaturated polymerizable moiety and
its reactivity toward the thiol and aza Michael reaction, also
the group of photoreactive building blocks exerts significant
influence on the cytotoxic behavior, which is a key require-
ment for UV curable resins for biomedical applications. For
that reason the cytotoxic potential of the synthesized alkyne
ether monomers with aliphatic C4 spacer, that is, BuPE and
BuBE, was determined by in-vitro tests using mouse fibro-
blast cells (L929, ISO 10993-5:2009) and compared with the
cytotoxicity of BuAc and BuMAc. Consequently, L929 cells
were incubated in a defined media with increasing concen-
trations of the monomers for 48 h at 37 8C. The concentra-
tion at which the half of the cells remained alive compared
with the negative control (cell culture medium, see Support-
ing Information) was assessed as cell viability (EC50). The
Synthesis of Alkynyl Ether Monomers
An overview of the synthesized alkynyl ether based
monomers is given in Scheme 2. A straightforward proce-
dure for the preparation of those bifunctional ether deriv-
atives, that is, BuPE, BuBE, BisAPE, and BisAEPE,
represents the well described Williamson etherification
reaction using hydroxyl- and bromo-functionalized start-
ing compounds. For the synthesis of BisAEPE, the inter-
mediate 2,2-bis[4-(2-hydroxy)ethoxyphenyl]propane was
obtained by a reaction of bisphenol A with ethylene car-
1
2
bonate as described elsewhere.
In a first step, the
(
meth)acrylate based compounds (BuAc and BuMAc) exhibit
hydroxyl terminated bifunctional spacers were converted
with sodium hydride to the corresponding sodium alkoxy-
lates, which were subsequently reacted with propargyl
bromide to give BuPE, BisAPE, and BisAEPE in appropri-
ate yields of 86%, 92%, and 87%. This reaction strategy,
however, failed for the synthesis of the but-1-yne-4-yl
ether derivatives leading to an isomerization of the triple
bond and the formation of internal 2-ynes. Alternatively,
but-1-yne-4-nyl ether monomers could be synthesized by
the reaction of the sodium 3-butyne-1-olate with bromi-
a significant higher cytotoxicity than the alkynyl ethers BuPE
and BuBE by at least a factor of 12 (as shown in Table 1).
This finding is in good accordance with the observed inertia
of terminal alkyne groups toward the thiol and aza Michael
reaction. Thus, it could be demonstrated that alkynyl ether
derivatives are a potential alternative to common (meth)ac-
rylate based monomer systems.
Further important key factors for the fabrication of medical
devices by photolithographic AMT techniques, are the rate
and yield of photopolymerization, as both determine the
amount of leachable monomers in the build device. Besides
health considerations, residual monomers can also reduce
the network properties, that is, mechanical properties and
glass transition temperature, of the cured materials. The cur-
ing behavior of resins based on propargyl and but-1-yne-4-yl
3
1
nated bifunctional compounds as reported previously.
BuBE was obtained in moderate yields of 34% after puri-
fication by column chromatography. The synthesized
1
13
monomers were characterized by H- and C-NMR spec-
troscopy. The obtained data are in good agreement with
the proposed structures.
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TABLE 1 Cell Viability of Investigated Monomers From Cyto-
thiol-yne reaction. However, a general prediction of reactiv-
ities based on the electronic density of polymerizable groups,
as possible for the thiol-ene reaction, is problematic in case
of the thiol-yne polymerization, which was shown by Fair-
banks et al. at the example of propargyl acetate, methyl
toxicity Tests
Viability
Monomer
(EC50)/mM
2
0
propargyl amine and ethyl propiolate.
BuMAc
BuAc
<0.16
<0.16
Figure 2 (above) shows the thiol and alkyne conversions for
:1 stoichiometric reactions of BuPE/TMPMP and BuBE/
BuPE
BuBE
3
2
2
TMPMP determined by real-time FT-IR spectroscopy, con-
firming the findings in the photo-DSC measurements and
underlining the superiority of the but-1-yne-4-yl derivative
in terms of reaction rate. It has to be mentioned that each
alkyne and thiol monomer is consumed simultaneously and
at the same extend, indicating the absence of side reactions
such as the homopolymerization of vinylsulfide intermedi-
ates or the formation of stable vinylsulfide compounds.
Importantly, both alkyne based systems provide a significant
higher conversion of polymerizable groups than the curing
of the corresponding (meth)acrylates as revealed in Figure 2
(below). While the photopolymerization of BuAc and BuMAc
lead to a double bond conversion of 79% and 74% after 2
monomers containing butyl (C4) spacers and the commer-
cially available multifunctional thiol TMPMP were investigat-
ed by means of photo-DSC and FT-IR spectroscopy and
compared with the corresponding (meth)acrylate based com-
pounds BuMAc and BuAc. One important parameter, which
can be obtained by photo-DSC, is the time to reach the maxi-
mum of polymerization enthalpy (tmax) revealing information
about the curing speed of the investigated system. Alterna-
tively, real-time FT-IR spectroscopy provides detailed infor-
mation on changes in the molecular structure of the
monomers during the curing reaction, enabling the precise
monitoring of the conversion of polymerizable groups with
increasing illumination time.
2
min of illumination (P 5 22 mW/cm ), respectively, an
almost quantitative consumption of alkyne and thiol groups
were obtained for resins of BuPE/TMPMP (94%) and BuBE/
TMPMP (99%).
Although, it has been reported that propargyl ether deriva-
tives offer moderate rates of polymerization compared with
2
0
aliphatic terminal alkynes and propargyl esters, BuPE can
easily compete with the methacrylate based monomer
BuMAc which is reflected by the significant lower tmax as
depicted in Table 2. Interestingly, the but-1-yne-4-yl ether
derivative BuBE outperforms BuPE and BuMAc considerably
and reacts only slightly slower than the structurally related
aliphatic acrylate BuAc. The superiority of the but-1-yne-4-yl
ether derivative might be explained by the additional CH2
group between the alkyne and ether group reducing the
influence of the ether moiety (1I-effect) on the electronic
density of the yne triple bond. This hypothesis is supported
by the outstanding reactivity of aliphatic terminal alkynes,
which react significantly faster than propargyl ethers in the
One limitation of thiol based photopolymers can mainly be
attributed to specific characteristics of the used multifunc-
tional thiols. The predominantly applied and studied thiols
are esters of mercapto propionates and thio glycolates,
which can be explained by their facile synthesis from readily
available precursors. However, the polarity of the ester
group and its affinity to water favors water absorption
which decreases the mechanical performance by lowering
the modulus, glass transition temperature and strength, all
factors that are detrimental for medical applications such
as implants. One strategy, to overcome this limitation is to
use ester-free silane based mercaptanes providing an
appropriate curing behavior and good mechanical
TABLE 2 Summary of Materials Properties for Alkyne Monomers and Their Photocured Alkyne/Thiol Networks Including Reference
Samples (BuAc and BuMAc)
Viscosity (25 8C)/
Conversion (2 min)/
%
Monomer
mPa*s
t
max/s
a
T
g
/8C
E’ at 37 8C/MPa
FWHM/8C
b
b
b
BuVE
–
1.0
6.7
1.8
5.2
2.3
6.2
8.1
–
235 6 0
17 6 1
10 6 0
BuMAc
BuAc
4.7
4.4
4.7
6.2
949
596
74
79
50 6 38
80 6 6
1,650 6 20
1,420 6 30
–
–
a
a
a
a
a
b
b
b
BuPE
94
34 6 1
255 6 30
42 6 0
a
b
b
b
BuBE
99
36 6 0
230 6 5
34 6 1
b
b,c
b,c
b,c
b,c
b,c
BisAEPE
BisAPE
65 (98)
58 6 0
1,200 6 75
20 6 0
b
b,c
b,c
b,c
62 (92)
100 6 1
1,860 6 10
59 6 0
a
b
c
Corresponds to
a
formulation with
a
stoichiometric amount of
Corresponds to a formulation with a stoichiometric amount of TMPS.
Measured after post-curing at 100 8C.
TMPMP.
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properties, the cross-link density, together with the structure
of the polymer backbone, determines the glass transition
temperature of the network, which has to be above body
temperature for polymers intended for hard tissue engineer-
ing. There are only a few methods reported, which allow for
the investigation of the network density of photopolymers.
For several reasons some of them, for example, equilibrium
swelling, can only be applied to slightly cross-linked poly-
3
5–37
mers.
For very homogeneous networks, the cross-link
density correlates with the glass transition temperature and
1
7
the storage modulus in the rubbery state.
An alternative method to study network characteristics is
3
8,39
the DQ build-up NMR method
which gives quantitative
access to network density as well as the fraction of non-
network chains (in this case unreacted monomers, photoini-
tator or its cleavage products which are not incorporated in
the polymeric network). In simple terms, the residual dipo-
lar couplings (Dres) measured through this method are influ-
enced by the orientational anisotropy of the chains which is
in turn directly proportional to the cross-link density, that
is, the molecular weight between the network points, and
chain stiffness. The ability of this method to exclusively
access Dres, allows a quantitative description of the network,
assuming
analysis.
a physically appropriate model is used for
In this study, DQ NMR has been used to investigate and to
compare the cross-link density of a vinyl ether based thiol-
ene network with the highly cross-linked alkynyl ether net-
works. Consequently, butanediol divinylether (BuVE), BuPE,
and BuBE (in combination with TMPS) were used as model
compounds as these monomers provide a C4 backbone lead-
ing to a similar stiffness.
FIGURE 2 Real-time FT-IR measurements: Conversion of alkyne
and thiol moieties [above: BuBE (open triangle)/TMPMP (dia-
mond), BuPE (open square)/TMPMP (circle)], and the (meth)ac-
rylate groups [below: BuAc (square) and BuMAc (triangle)].
Considering that (a) the network chain length is near-
homogenous and (b) any heterogeneity appears only due to
the spin-system heterogeneity and/or the different mobility
of the two component chains between network points, an
analytical model assuming Gaussian distribution of residual
dipolar couplings with an average value Dres and its standard
deviation rres accounting for the aforementioned heterogene-
ity was used (see eq. 1).
[
Color figure can be viewed in the online issue, which is avail-
able at wileyonlinelibrary.com.]
properties in the cured state even after water storage as
2
6,32
recently demonstrated.
Consequently, formulations con-
taining the multifunctional thiol tetra(3-mercaptopropyl)si-
lane (TMPS) instead of TMPMP were used for the
characterization of the network properties. The synthesis of
TMPS has previously been described in a patent dealing
with novel biocompatible thiol-ene based materials for aug-
Analytical fitting equation assuming Gaussian distribution
8
>
:
ꢀ
ꢁ9
>
;
2
2
2
5DressDQ
>
>
>
<
exp 2 1
>
=
4
5
2
2
1 r
s
res DQ
InDQðsDQ; Dres; rresÞ50:5 12 qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
(1)
3
3
mentation of hard tissues. As shown recently, this thiol
compound offers a comparable reactivity as mercapto pro-
>
4
5
2
2
>
11 r
s
res DQ
2
6
pionic acid derivatives.
The Dres values (which relates to the cross-link density) and
the fraction of non-network chains determined for samples
BuBE/TMPS and BuPE/TMPS are given in Table 3. For com-
parison, measurements were also carried out on BuVE/TMPS
and for consistency analyzed with the same model. It should
be noted for the latter sample, however, that with rres ꢁ D
(in other words a too high standard deviation), the limits of
applicability of this fit becomes unrealistic. Therefore, the
It has to be mentioned that similar high conversions have
been reported for thiol-ene polymerization reactions of vinyl-
ethers, which are also known to provide good biocompatibil-
3
4
ity due to their electron rich double bond. However, the
comparably low cross- link densities of such thiol-ene net-
works lead to mechanical properties which are inferior com-
res
1
7
pared with thiol-yne polymers.
Besides the mechanical
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TABLE 3 Analysis of the Normalized DQ Curves Obtained for
the Different Samples at 100 8C
building blocks. This concept is commonly applied for high
performance resins such as dental restoratives or automotive
and aerospace resins; for example, 2,2-bis-[4-(2-hydroxy-3-
methacryloyloxypropoxy)phenyl]-propane) (Bis-GMA), is a
widely applied monomer in dental practice. Although the
stiff molecular structure of Bis-GMA is responsible for the
excellent mechanical properties and low polymerization
shrinkage, it also leads to an extremely high viscosity and to
Dres/2p
rres/2p % Non-Network
Sample
[kHz]
[kHz]
Chains
BuBE/TMPS
BuPE/TMPS
BuVE/TMPS
9.0
8.4
1.4
1.4
2.0
1.3
4.3
4.6
2.5
2
2
a comparably low degree of conversion.
(Gaussian distribution)
However, in these systems the gel point is reached very
quickly, which significantly reduces the mobility of the
unreacted functional monomers. An additional decrease in
curve was also analyzed with a simple two-component
Gaussian fit (see Supporting Information eq. S2).
mobility can be observed when the T exceeds the polymeri-
g
zation reaction temperature. Both effects limit the final con-
1
7
version of high viscous monomers containing rigid spacer.
The analysis (see Table 3) shows an increase in cross-link
density by about the factor of six for samples BuBE/TMPS
and BuPE/TMPS compared with sample BuVE/TMPS which
is in good accordance with the findings of Bowman and co-
workers for networks formed of bifunctional ynes and tetra-
In principle, a similar behavior can also be observed for
BisAPE/TMPS and BisAEPE/TMPS formulations as shown in
Figure 4. While these bisphenol A based monomers exhibit
curing rates in the range of BuPE, which seems to be typical
1
7
functional thiols. The fraction of non-network chains corre-
sponds to the expected amount of unbound species
(
monomer, photoinitiator, cleavage products). Further details
of the analysis and interpretation of the data for sample
BuVE/TMPS are given in Supporting Information.
Moreover, the thermo-mechanical properties, that is, the
glass transition temperature and the storage modulus in the
rubbery state, of the thiol-yne networks are significantly
higher than the BuVE network (shown in Fig. 3), which can
be directly attributed to the higher cross-link density. The
alkynyl ether/TMPS based polymers exhibit significant lower
network properties than the corresponding (meth)acrylates
BuAc and BuMAc (Table 2 and Fig. 3). While BuAc provides
a T
g
(ꢀ80 8C) well above the body temperature together
0
with an appropriate storage modulus (E 5 1420 MPa), the
glass transition temperature of BuPE/TMPS (34 8C) and
BuBE/TMPS (36 8C) is only in the range of body temperature
explaining the comparably low moduli (BuBE: E 5 230 MPa;
BuPE: E 5 260 MPa) at 37 8C. This fact can be attributed to
0
0
the rather flexible (thio)ether linkage of the thiol-yne poly-
4
0
mers. Interestingly, there is only a slight difference, in the
thermo-mechanical properties of BuBE and BuPE, despite
two additional carbon atoms per molecule.
The full width at half-maxima (FWHM) of tan delta of the
BuBE/TMPS and the BuPE/TMPS networks are approximate-
ly three times higher than the one of the BuVE/TMPS net-
work. However, this transition is still narrow compared with
chain growth networks, such as BuAc (see Fig. 3). However,
materials that offer glass transition temperatures in the
range or even below body temperature are not suitable for
hard tissue engineering.
FIGURE 3 Storage modulus and tan delta versus temperature
for the stoichiometrically balanced polymerization of BuVE/
TMPS (above), as well as BuAc (below: dashed), BuBE (below:
dotted), and BuPE/TMPS (below: solid). [Color figure can be
viewed in the online issue, which is available at wileyonlineli-
brary.com.]
Monomers Containing Rigid Spacers
One possibility to increase the network properties of photo-
polymers is to introduce rigid spacers such as biphenyl, iso-
1
2
41
42
cyanurate, bisphenol A, bisphenol S, etc., in the used
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explains the superiority of the alkynyl ether/TMPMP formu-
lation in this accelerated shelf-life tests, which represents
another important advantage of the presented thiol-yne
system.
CONCLUSIONS
This contribution deals with the development of new bio-
compatible monomers based on the thiol-yne reaction for
the fabrication of medical devices by UV-based additive
manufacturing technologies. It could be successfully shown
that propargyl and but-1-yne-4-yl ether derivatives offer a
significant lower cytotoxicity than the corresponding (meth)-
acrylates with similar backbones. Together with appropriate
thiol monomers, these compounds show reactivities in the
range of acrylates (but-1-yne-4-yl ether) and methacrylates
(
propargyl ether), respectively, and almost quantitative triple
FIGURE 4 Conversion of the alkyne monomers [BisAEPE
bond conversions. Besides the reaction behavior, also the
thermo-mechanical properties as well as the cross-link densi-
ty of photo cured samples of alkynyl ether/thiol networks
were investigated by DMA and solid state NMR and com-
pared with those of BuVE/TMPS formulations. Although the
BuPE/TMPS and BuBE/TMPS networks provide a six times
higher cross-link density and thermo-mechanical properties,
which are far above of the corresponding vinyl ether based
network (BuVE/TMPS), these polymers show glass transition
temperatures which are in the range of the body tempera-
ture. By using monomers that contain rigid bisphenol A
spacers comparably high triple bond conversions after a
post-curing step at elevated temperatures were obtained.
(
square), BisAPE (triangle)] in alkyne/TMPS formulations versus
illumination time. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
for propargyl ethers, the degree of conversion is comparably
low for BisAPE/TMPS (62%) and BisAEPE/TMPS (65%).
However, it can be shown that a post curing of BisAPE and
BisAEPE based resins above the T (in this case 100 8C were
g
chosen) significantly increases the degree of conversion of
both systems toward 92% (BisAPE) and 98% (BisAEPE),
respectively, as demonstrated in Figure 4. This behavior is
fully compatible with photolithographic AMT techniques, in
which post curing of the printed structures is commonly per-
formed, enabling the fabrication of biomedical devices with a
low content of leachable monomeric residues.
g
The derived polymers show decent storage moduli and T ’s
which seems to be sufficiently high for the fabrication of
medical devices.
As expected the networks formed of monomers with rigid
Even though, the cytotoxicity of C4 alkynyl ethers is far lower
than the one of the corresponding (meth)acrylates, the long
term toxicity of such compounds, in particular of monomers
containing bisphenol A moieties, has to be investigated in
spacers provide a significantly higher T as the correspond-
g
g
ing C4 based polymers resulting in T ’s which are well above
the body temperature as depicted in Figure 5.
In particular, bisphenol A based monomers (with TMPS as
thiol component) offer decent storage moduli (comparable to
those of the C4 (meth)acrylic monomers) making these
materials interesting for biocompatible AMT resins. Addition-
ally, the comparably low FWHM of tan delta of BisAEPE/
TMPS has to be highlighted, indicating a very homogeneous
network and also providing almost constant mechanical
properties over a long range up to 40 8C (5onset tempera-
ture of the glass transition; compare Fig. 5).
Another limiting factor of thiol based formulations is their
poor shelf-life stability preventing a broad application in the
1
0
UV curing and coating industry so far. While formulations
of BuVE/TMPMP (containing 0.5 wt % of pyrogallol and 2
wt % decylphosphonic acid as stabilizer) showed gelation
after 4 h at 50 8C storage temperature, the corresponding
thiol-yne resin, that is, BuBE/TMPMP (with the same stabi-
lizer), increased in viscosity by only 22% after 1 week of
storage under equal conditions. Presumably, the inertia of
the alkyne triple bond toward Michael addition reactions
FIGURE 5 Storage modulus and tan delta versus temperature
for stoichiometrically balanced polymerization of BisAEPE/
TMPS (solid) and BisAPE/TMPS (dashed). [Color figure can be
viewed in the online issue, which is available at wileyonlineli-
brary.com.]
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further studies. However, the almost quantitative conversion
of the investigated alkynyl ether/thiol resins significantly
reduces the migration of potential harmful compounds to a
level which cannot be reached by (meth)acrylate monomers.
15 S. Parker, R. Reit, H. Abitz, G. Ellson, K. Yang, B. Lund, W.
E. Voit, Macromol. Rapid Commun. 2016, 37, 1027–1032.
1
1
6 A. B. Lowe, Polymer 2014, 55, 5517–5549.
7 B. D. Fairbanks, T. F. Scott, C. J. Kloxin, K. S. Anseth, C. N.
Bowman, Macromolecules 2009, 42, 211–217.
This study reveals the versatility of this class of monomers
paving the way toward the individual and patient specific
fabrication of medical devices by UV-based additive
manufacturing methods.
18 J. W. Chan, J. Shin, C. E. Hoyle, C. N. Bowman, A. B. Lowe,
Macromolecules 2010, 43, 4937–4942.
1
2
9 J. W. Chan, H. Zhou, C. E. Hoyle, A. B. Lowe, Chem. Mater.
009, 21, 1579–1585.
2
0 B. D. Fairbanks, E. A. Sims, K. S. Anseth, C. N. Bowman,
Macromolecules 2010, 43, 4113–4119.
1 D. Pretzel, B. Sandmann, M. Hartlieb, J. Vitz, S. H o€ lzer, N.
Fritz, N. Moszner, U. S. Schubert, J. Polym. Sci., Part a: Polym.
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2
ACKNOWLEDGMENTS
Financial support by the Christian Doppler Research Associa-
tion, the Austrian Federal Ministry of Science, Research and
Economy (BMWFW), and Durst Phototechnik GmbH is grateful-
ly acknowledged. Part of the research work of this paper was
performed at the Polymer Competence Center Leoben GmbH
22 F. Goncalves, Y. Kawano, C. Pfeifer, J. W. Stansbury, R. R.
Braga, Eur. J. Oral Sci. 2009, 117, 442–446.
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PCCL, Austria) within the framework of the COMET-program
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