Multipurpose heterofunctional dendritic scaffolds as crosslinkers towards functional soft hydrogels and implant adhesives in bone fracture applications

Article abstract of DOI:10.1039/c3tb21061h

Two sets of heterofunctional dendritic frameworks displaying an inversed and exact number of ene and azide groups have successfully been synthesized and post-functionalized with biorelevant molecules. Their facile scaffolding ability enabled the fabricati

Full text of DOI:10.1039/c3tb21061h

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Materials Chemistry B
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Multipurpose heterofunctional dendritic scaffolds as
crosslinkers towards functional soft hydrogels and
implant adhesives in bone fracture applications†
Cite this: J. Mater. Chem. B, 2013, 1,
6015
a
a
a
ab
Yvonne Hed, Kim Oberg, Sandra Berg, Axel Nordberg, Hans von Holstb
Received 30th July 2013
¨
Accepted 27th September 2013
a
*
and Michael Malkoch
DOI: 10.1039/c3tb21061h
www.rsc.org/MaterialsB
Two sets of heterofunctional dendritic frameworks displaying an materials for applications such as drug delivery, magnetic
inversed and exact number of ene and azide groups have successfully resonance imaging and tissue engineering.13,14 Moreover, the
been synthesized and post-functionalized with biorelevant mole- copper-free and UV initiated thiol–ene coupling (TEC) reac-
cules. Their facile scaffolding ability enabled the fabrication of soft tion, nowadays also included in the click reaction family,15 has
and azide functional dendritic hydrogels with modulus close to fueled the eld of dendrimer chemistry yielding monodisperse
muscle tissue. The dendritic scaffolds are furthermore shown to be dendrimers via both traditional and accelerated synthetic
promising primers for the development of novel bone fracture approaches.16–18 In fact, the combination of TEC and CuAAC
stabilization adhesives with shear strengths succeeding commercial click reactions enabled the construction of a 6th generation
Histroacrylꢀ.
dendrimer in 6 reaction steps exhibiting 192 functional groups
and a molecular weight close to 60 kDa.19 The modular nature
of the UV initiated TEC reaction is recognized as chemo-
selective to a wide range of functional groups and can proceed
under benign reaction conditions in aprotic as well as protic
solvents in the presence of oxygen.15 The TEC reaction, origi-
nally used in coating applications, has most recently been
explored for the preparation of hydrogels with controlled
modulus and swelling properties20,21 as well as in the presence
of biological cells at cytocompatible levels of UV light at 365
The increasing demand for multi-purpose so materials for
advanced applications has intensied the need for highly
controlled synthetic protocols of polymeric materials.1 Typi-
cally, such materials are of well-dened or even monodisperse
nature and display a dened number of several orthogonal
functional groups. The construction of these structures relies
on the use of efficient, robust and chemoselective reactions. The
click concept, as described by Sharpless and coworkers, is today
recognized as a set of reactions that fulll such criteria.2 This
concept of reliable reactions enables facile access to advanced
polymeric structures.3 For instance, the combination of
controlled polymerization techniques with copper catalyzed
azide–alkyne cycloaddition (CuAAC) has resulted in a myriad of
sophisticated macromolecules with dened functions.4–6 Het-
erofunctional dendrimers, being synthetically one of the most
challenging macromolecular scaffolds to isolate, have also been
reported via elegant click strategies.7–12
nm and 10 mW cmÀ2 22 Although efficient, most TEC networks
.
reported are neutral and prepared from two component
monomer or polymer systems of A2 and B3 with A and B being
either a thiol or an alkene functionality. However, to deliver
crosslinked networks with desired functions the design of
components that can undergo crosslinking and in parallel
carry additional functions are foreseen as highly attractive
probes.23 In this report, two sets of orthogonally functionalized
and branched scaffolds are prepared displaying a switchable
reactive group density of alkenes and primary azides. Their
dual-purpose potential was rst exploited for the development
of a small library of bioactive HFDs via the robust CuAAC
reaction. The generated scaffolds were thereaer exploited for
the fabrication of so dendritic hydrogels as well as the use as
primers in bone fracture stabilization adhesives.
Their globular conformation coupled with the exact
number of orthogonal functional groups distributed on the
dendritic framework makes these structures promising
aKTH Royal Institute of Technology, Polymer and Fiber Technology, Division of Coating
Technology, Stockholm, Sweden. E-mail: malkoch@kth.se
bKTH Royal Institute of Technology, School of Technology and Health, Division of
Neuronic Engineering, Stockholm, Sweden
Heterofunctional dendritic (HFD) scaffolds were sought out
as promising monodisperse materials that deliver an exact
number orthogonal groups.8 The accurate structural build-up
with “inverted” bifunctionality capitalized on the synthesis of
two distinctively different Trizmaꢁ-based AB2C monomers, 1
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3tb21061h
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Scheme 1 Synthesis of heterofunctional dendritic scaffolds with interchanging functional group densities of three or six reactive sites. (i) DMAP, pyridine in DCM (ii) 3
or 6, p-TSA in THF–H2O (iii) 4, DMAP, pyridine, azide anhydride (18) in DCM (iv) 7, DMAP, pyridine, 4-pentenoic anhydride in DCM (v) acetylene functional (DOPA) (16),
4-pentanoic acid or acetylene functional mannose (21), NaAsc, CuSO4, in THF–H2O.
and 2, displaying both acetonide protected hydroxyls and ene or
Satised with the purity and dual functionality of these
azide groups (see ESI†). As can be seen in Scheme 1, by scaffolds, a robust post-functionalization protocol for the
employing a divergent growth strategy from the trimethylol introduction of biorelevant groups was adopted. Notably, both
propane (TMP) core and in combination with AB2C monomers, azide and ene groups, expressed on these HFD constructs, have
two acetonide protected dendritic scaffolds with three enes 3 separately been used for the fabrication of crosslinked
(HFD(ei)-G1-e-(Ac)3-i-(ene)3) or three azides (HFD(ei)-G1-e-(Ac)3- networks.17,25,26 In this case, the benign UV initiated TEC
i-(azide)3) 6 were efficiently synthesized in gram scales. Subse- chemistry between enes and thiols was identied as a feasible
quent acidic deprotections using pTSA in THF–water solution crosslinking strategy whereas the CuAAC click reaction was
followed by mild esterication reactions with 6-azidohexanoic chosen as a synthetic route for post-functionalization purposes.
anhydride or 4-pentenoic anhydride resulted in scaffold The multiple azides were selectively reacted with acetylene
HFD(ei)-G1-e-(azide)6-i-(ene)3
5
and HFD(ei)-G1-e-(ene)6-i- functional D-mannose, 3,4-dihydroxyphenylalanine (DOPA) and
(azide)3 8 exhibiting reactive enes and azides with “inverted” carboxylic acid. All post-functionalization reactions were carried
functional group density of three and six. The reactions were out in THF–water solution and efficiently executed at room
monitored by both NMR and MALDI-ToF MS techniques. Upon temperature in the presence of a catalytic amount of copper
completion, conventional column chromatography protocols sulphate and sodium ascorbate as a copper reducing agent,
were used, resulting in HFD scaffolds isolated in overall yields Table 1. The successful conjugations were supported by MALDI-
of 40% and 53%, Table 1.
ToF and NMR. For example, Fig. 1a shows two isolated
Table 1 Library of heterofunctional dendritic scaffolds
HFD scaffold
Interior group (3)
Exterior group (6)
m/z calculated [M + Na+]
m/z obtained [M + Na+]
4
5
7
8
Ene
Ene
OH
Azide
OH
Ene
Ene
DOPA
Ene
COOH
Mannose
1012.45
1846.89
1183.55
1675.80
2549.13
3593.56
1969.91
2435.12
3156.37
1012.32
1847.03
1183.44
1675.59
2550.67
3594.67
1970.14
2435.47
3156.86
Azide
Azide
DOPA
Ene
COOH
Ene
9
10
11
12
13
Ene
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Fig. 1 MALDI-ToF and 1H-NMR analysis of HFD(ei)-G1-e-(ene)6-i-(DOPA)3 9 and
HFD(ei)-G1-e-(DOPA)6-i-(ene)3 10 with inversed functionalities. Nomenclature
used as proposed for multifunctional dendrimers where a represent the exterior
groups and i the interior groups.24
Fig. 2 (a) A schematic representation for the fabrication of a dendritic hydrogel
(b) swelling profile of the crosslinked hydrogels.
constructs based on the reaction between acetylene functional
DOPA and HFD frameworks 5 and 8. As can be seen by MALDI- through a step-growth thiol–ene fashion with a PEG 6 kDa
ToF, complete and selective reactions resulted in the formation dithiol 14 (see ESI†). The hydrogels were cured in an ethanol
of HFD(ei)-G1-e-(ene)6-i-(DOPA)3 9 and HFD(ei)-G1-e-(DOPA)6-i- solution within 10 min using 0.5 wt% of Irgacure 2959 as a
(ene)3 10 with inverted bioactive group density and molecular photoinitiator (365 nm, 9 mW cmÀ2).22 Aer solvent exchange,
weights corresponding to calculated values. The structural from EtOH to water, the water swelling capability was moni-
1
integrity was further corroborated by H-NMR, Fig. 1b.
tored, Fig. 2b. The HFD(ei)-G1-e-(azide)6-(ene)3 5 crosslinked
One driving force to construct these elegant heterofunctional hydrogels showed swelling equilibrium at 870% and a Young's
scaffolds was to conceptually assess their modular nature as modulus (E) of 21.7 Æ 2.5 kPa, which is in close vicinity of
crosslinkers that allow facile and accurate introduction of muscle tissue (8–17 kPa).33 By crosslinking the PEG 6 kDa with
additional functionalities within 3D networks. Consequently, the inverted dendritic scaffold, HFD(ei)-G1-e-(ene)6-(azide)3 8,
their scaffolding ability was evaluated towards the fabrication of exposing twice the amount of enes the Young's modulus (E) was
so and functional crosslinked hydrogels as well as novel more than doubled (42.8 Æ 2.3 kPa). Moreover, this increased
primers for increased xation of bone stabilization patches.27 functionality of the crosslinker also led to a slight decrease in
For the development of hydrogels, polyethylene glycol (PEG) equilibrium swelling to 780%.
based networks were targeted as these systems are excellent test
In another context, bone fractures near sensitive tissue, in
beds that today are used as cell culture scaffolds,28 targeted drug thin, fragmented or weak bones are of major health care
delivery29 and articial extracellular matrices (aECMs).30 concern since these cannot be optimally repaired using tradi-
Furthermore, their high water content, low immunogenicity tional methods including metal screws and plates. The frac-
and the ability to create well dened structures with tuneable tured areas are too sensitive for such harsh surgery and
physiochemical properties make these synthetic scaffolds a therefore development of more sensitive protocols is crucial.
versatile tool for the design of novel cell culture scaffolds.31 Even if metal screws and plates are well accepted as the golden
However, the inherent inertness toward protein adsorption and standard in, for instance, iatrogenic bone fractures during
lack of cell recognition sites for PEG usually requires the neurosurgical and reconstructive procedures, the demand for
introduction of additional biorelevant chemistries to provide improved standard technologies is increasing. An alternative
these materials with cell interaction capabilities. One increas- approach is to use adhesives for proper xation of fractured
ingly popular strategy for the manufacturing of PEG hydrogels bone.35,36 However, applying adhesives within the fracture area
and simultaneous introduction of such functions has been to itself has been shown to interfere with the natural bone healing
use bioorthogonal click chemistries.32 In order to demonstrate a process and also sometimes gives rise to insufficient adhesive
simple approach to bioactive hydrogels we herein fabricate area.37 To minimize the direct use of adhesives on traumatized
azide functional PEG hydrogels utilizing the pre-synthesized area, ber reinforced adhesive patch (FRAP) protocols have
dendritic scaffolds as multifunctional dendritic crosslinkers, been proposed as promising replacements.38 This topological
Fig. 2a. Two scaffolds, HFD(ei)-G1-e-(azide)6-(ene)3 5 and procedure benets from an increased adhesive-to-bone surface
HFD(ei)-G1-e-(ene)6-(azide)3 8, were exploited as crosslinkers area and additionally avoids interference with the natural bone
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healing process within the fracture site.27 A feasible developed further corroborated by the results obtained for less polar
strategy, Fig. 3a, consisted of a two component triazine-based dendritic primers with switched functionalities. In this case, the
thiol–ene glue system, with six layers of imbedded bers, that shear strength of the FRAPs for HFD(ei)-G1-e-(ene)6-i-(COOH)3
on exposure to UV (320–390 nm, 1.45 J cmÀ2) resulted in 11 containing three carboxyl groups increased to 1.8 MPa and
crosslinked FRAPs with promising bone stabilizing features.34 HFD(ei)-G1-e-(ene)6-i-(DOPA)3 9 with three DOPA groups noted
While such FRAPs were shown to be mechanically strong, their a value of 3.2 MPa. None of the dendritic primers decorated
adhesive properties were found poor towards wet bovine femur with polar groups and enes could deliver FRAPs with adhering
bones with a shear strength of 0.4 MPa, Fig. 3b. This was a strength equivalent to the commercial wound closure adhesive
consequence of poor interactions between hydrophobic Histoacrylꢁ with an excellent shear strength value of 3.8 MPa.
matrices and wet bone surfaces. To increase the interactions, Interestingly, the azide functional HFD(ei)-G1-e-(Ac)3-i-(Azide)3
phenolic primers were introduced, for instance poly- 6 in the absence of enes was found to generate FRAPs with a
(parahydroxystyrene), which greatly enhanced the adhesion of shear strength value of 2.8 MPa. Further evaluation of HFD(ei)-
FRAPs with a shear strength of 3.4 MPa.34 In this context, the G1-e-(ene)6-i-(Azide)3 8 containing an additional six enes resul-
present heterofunctionality within our dendritic scaffolds was ted in a small increase in adherence to wet bone with a value of
sought as promising primers that can efficiently bind to a wet 3.0 MPa. These results suggest that the number of available
bone surface as well as undergo covalent crosslinking with a enes plays a minor role while the presence of azides increases
triazine based FRAP system.
the shear strength to a greater extent. Finally, exploiting
As can be seen in Fig. 3b, the patch without any primer HFD(ei)-G1-e-(azide)6-(ene)3 5 with six azides and three enes as a
resulted in a shear strength of 0.4 MPa. The introduction of the primer delivered FRAPs with an excellent shear strength of
dendritic primers at 0.5 wt% in ethanol increased the shear 4.2 MPa that is 10-fold higher than those of the systems without
strength of all FRAPs. While the HFD(ei)-G1-e-(DOPA)6-i-(ene)3 any primers or 10% higher when compared to Histoacrylꢁ.34
A
10 primer with the largest number of polar and adhering potential explanation could be that the azides participate in the
phenolic groups was initially envisioned to give rise to FRAPs crosslinking process during UV exposure of the triazine matrix
with adhesive properties to wet bone, it was surprisingly found on the wet substrate. It is already established that alkyl azides
to note the lowest values of all primers with a value of 0.6 MPa. rearrange to form reactive imines and nitrogen upon irradia-
Similar low values, 0.8 MPa, were obtained for HFD(ei)-G1-e- tion39 and form intermolecular reactions of polymers40 as well
(COOH)6-i-(ene)3 12 with six polar carboxylic groups. These as participate in reactions leading to intramolecular collapsed
unexpected results are probably due to stronger cohesive forces dendrimers.8 As the imines are intrinsically reactive to them-
between the dendritic primers in comparison with the adhesive selves, it is here suggested that higher molecular weight primers
forces towards the wet bone surfaces. This hypothesis was are generated and efficiently coupled to the bone surface. High
molecular weight primers have been previously shown to
increase the shear strength of FRAPs on bovine femur bone
when compared to low molecular counterparts.34 Furthermore,
to mimic surgical conditions, the bone surfaces were wet during
FRAP fabrication. In the presence of water, the imine will react
to produce aldehydes, hydrates and/or acetals. Aldehyde groups
are known to react with amino groups in the presence of water,36
and therefore may create covalent attachment to the bone
surface. One or a combination of these reaction pathways may
be the reason for the extraordinary results obtained when using
azide functional dendritic materials as primers. It should be
noted that both the FRAP matrix and the Trizmaꢁ based
dendritic scaffolds have previously shown low cytotoxicity
towards MG63 osteoblast cells with a cell survival of 95–98%
making this multicomponent FRAP methodology a highly
feasible approach towards bone fracture stabilization
applications.34
In summary, here, we have reported the construction of a
library of heterofunctional dendritic scaffolds with clickable
azide groups and alkene groups for crosslinking purposes. The
careful synthesis of AB2C-type monomers resulted in mono-
disperse dendritic frameworks with molecular weights close to
3000 g molÀ1 with interchanging functional group number
within the architectures. Post-functionalization via CuAAC click
reaction delivered bioactive materials that were evaluated as
dendritic crosslinkers for so 3D networks as well as primers
for the fabrication of fracture stabilization bone adhesives. The
Fig. 3 (a) Illustration of the FRAP on bone (b) maximum shear strengths of the
FRAPs using the procedure described previously.34
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presence of azide groups within the primers was found to be 17 M. I. Montanez, L. M. Campos, P. Antoni, Y. Hed,
crucial for the development of highly adhering bone patches
with shear strength equivalent to the commercially available
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We thank Knut and Alice Wallenberg Foundation (Academy
Fellow Grant 2012-0196) and the Swedish Research Council (VR)
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