Surface-Assisted Self-Assembly of a Hydrogel by Proton Diffusion

Article abstract of DOI:10.1002/anie.201806668

Controlling supramolecular growth at solid surfaces is of great importance to expand the scope of supramolecular materials. A dendritic benzene-1,3,5-tricarboxamide peptide conjugate is described in which assembly can be triggered by a pH jump. Stopped-flow kinetics and mathematical modeling provide a quantitative understanding of the nucleation, elongation, and fragmentation behavior in solution. To assemble the molecule at a solid–liquid interface, we use proton diffusion from the bulk. The latter needs to be slower than the lag phase of nucleation to progressively grow a hydrogel outwards from the surface. Our method of surface-assisted self-assembly is generally applicable to other gelators, and can be used to create structured supramolecular materials.

Full text of DOI:10.1002/anie.201806668

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Title: Surface-assisted self-assembly of a hydrogel by proton diffusion
Authors: Daniel Spitzer, Vincent Marichez, Georges Formon, Pol
Besenius, and Thomas Hermans
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806668
Angew. Chem. 10.1002/ange.201806668
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Surface-assisted self-assembly of a hydrogel by proton diffusion
Daniel Spitzer†,[a], Vincent Marichez†,[b], Georges J. M. Formon[b], Pol Besenius*,[a], Thomas M.
Hermans*,[b]
Abstract: Controlling supramolecular growth at solid surfaces is of
great importance to expand the scope of supramolecular materials.
Here we describe a dendritic benzene-1,3,5-tricarboxamide peptide
conjugate whose assembly can be triggered by a pH jump. Stopped
flow kinetics and mathematical modeling provide a quantitative
understanding of the nucleation, elongation, and fragmentation
behavior in solution. To assemble the molecule at a solid-liquid
interface, we use proton diffusion from the bulk. The latter needs to
be slower than the lag phase of nucleation in order to progressively
grow a hydrogel outwards from the surface. Our method of surface-
assisted self-assembly is generally applicable to other gelators, and
can be used to create structured supramolecular materials.
Carrière et al[26] together with Jierry[27]. Recently, controlled proton
diffusion in a microfluidic device was utilized to study the kinetics
of gelation of a pH responsive benzene-1,3,5-tricarboxamide
(BTA).[28] In line with the first philosophy, here we describe the pH-
regulated self-assembly of an amphiphilic C3-symmetrical
benzene-1,3,5-tricarboxamide peptide conjugate (BTA-1, Figure
1A), and show how surface-assisted assembly is controlled inside
microfluidic devices and from the surface of elastomer cubes.
First, we study the (cooperative) mechanism of self-assembly in
solution using stopped-flow kinetics and apply fitting procedures
using temperature and concentration dependent mathematical
models. Next, we utilize two proton releasing materials, either
agarose or poly(dimethyl siloxane), PDMS, surfaces, which have
significantly different kinetics of diffusion. To grow supramolecular
(hydrogel) structures off the surface, the proton diffusion needs to
be tuned and slow enough for nucleation to take place at the solid-
liquid interface, in order to avoid nucleation and growth in solution.
Our combined theoretical-experimental approach shows that
investigating the kinetics of supramolecular self-assembly is key
in manipulating lag times of nucleation and overall growth rates of
supramolecular polymers, with the aim to develop surface-
confined supramolecular materials. Our strategy does not require
the addition of an external catalyst and is applicable to many pH-
responsive systems for the preparation of 3D-structured gels and
surfaces.
We synthesized the dendritic peptide amphiphile BTA-1
analogously to previous methods (see SI, section 1).[29,30] BTA-1
self-assembles through hydrogen bonding, π–π stacking and
desolvation of hydrophobic amino acids into densely packed
supramolecular fibers with a diameter of 7 nm and more than 500
nm in length (Figure 1B, Figure S2). The C-terminal dendritic
carboxylic acids of the star-shaped peptide amphiphile introduces
pH-switchable properties into the molecular buildings blocks.[29] At
high pH, the monomers of BTA-1 remain molecularly dissolved
due to Coulomb repulsion of the anionic charges of the
deprotonated carboxylates. Upon lowering the pH, the
carboxylates are protonated and alleviate the repulsive term
which in turn induces a monomer to supramolecular polymer
transition. While, the isolated carboxylic acids typically have a pKa
of 4,[31] the thermodynamic driving force of supramolecular
assembly leads to a strong shift in the apparent pKa value and
transitions at a pH value of 5.6 (Figure S3). From pH-dependent
steady state circular dichroism (CD) spectroscopy experiments, it
is safe to assume that BTA-1 is fully deprotonated at pH > 6.0 and
fully protonated at pH < 5.0.
Supramolecular structures are widely found in biological systems
and in chemistry.[1] In the former, microtubules and actin filaments
have been studied intensively due to their crucial role in
controlling cell migration and/or differentiation.[2] In chemistry, in
addition to the desire to mimic natural 1D fiber for medical
applications,[3–5] synthetic supramolecular polymers are also
promising candidates for smart[6] and self-healing[7,8] materials or
even molecular electronics.[9,10] Despite tremendous progress in
controlling the size and shape of supramolecular structures by
electrostatic
interactions[11]
,
steric
hindrance[12]
or
stoichiometry,[13] spatial control of the self-assembly process is
still difficult to achieve. Up to now, only a few examples can be
found as recently reviewed by Vigier-Carrière et al.[14] Two main
approaches can be used: 1) a seed layer deposited on a surface
by adjusting the charge of the surface,[15,16] its hydrophilicity,[17] or
by directly grafting monomers to trigger further self-assembly,[18]
or 2) by localized production of monomers, followed by gelation.
The latter strategy was notably adopted by Cameron and Adams
who used an electrode to locally decrease the pH (through
oxidation of hydroquinone into 1,4-benzoquinone) thus activating
the monomers whose self-assembly is then promoted,[19] further
achieving spatiotemporal and composition control of gel formation
on electrodes.[20] Electrochemical production of protons using
patterned electrodes was also used by Payne to gain spatial
control on the self-assembly of Fmoc protected amino acids.[21]
Others, like van Esch and Eelkema could control fiber formation
and orientation by a pH gradient,[22] further resorting to surface-
confined acidic catalysis,[23] while Ulijn paved the way of surface-
confined enzyme catalysis,[24,25] further developed by Vigier-
[a]
Dr. D. Spitzer, Prof. Dr. P. Besenius
Institute of Organic Chemistry
To investigate the self-assembly mechanism of BTA-1, we
performed stopped-flow experiments, where CD intensity was
monitored immediately after performing a pH-jump. Since two
plateau regions can be identified (i.e., 100% monomer, and 100%
polymer), the latter intensity can be directly converted to the
dimensionless degree of polymerization  (Figure 1C). Note, that
we have previously studied neutral dendritic peptide amphiphiles
at great length and correlated degree of order from CD
spectroscopy with length of the 1D nanorods using electron
Johannes Gutenberg-University Mainz
Duesbergweg 10–14, 55128 Mainz (Germany)
E-mail: besenius@uni-mainz.de
Dr. V. Marichez, G. J. M. Formon, Prof. Dr. T. M. Hermans
University of Strasbourg, CNRS, ISIS UMR 7006
8 allée Gaspard Monge, 67000 Strasbourg (France)
E-mail : hermans@unistra.fr
[b]
Supporting information for this article is given via a link at the end of
the document.
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microscopy, X‐ray scattering and diffusion NMR spectroscopy.[32]
Recently, theoretical models that describe protein filament self-
assembly (e.g., amyloids) have expanded beyond the
conventional nucleation and elongation processes, and now
include for example fragmentation and secondary nucleation.[33–
S5 to S7). Given the nature of the data, i.e., unseeded
experiments, the model is dependent on the combined rate
constants 푘푝푘푛, 푘푝푘푓, and 푘푓푘푑, where 푘푝 is the elongation, 푘푑 is
the depolymerization, 푘푛 is the nucleation, and 푘푓 is the
fragmentation rate constant.[37] As discussed in Section 3C of the
SI, 푘푑 was determined to be negligible and was set to zero to
further reduce the number of free parameters. To understand the
temperature dependency of the system, the half-times 휏1/2 of the
supramolecular polymerization were plotted as a function of the
inverse of temperature and an Arrhenius-type equation was
successfully fitted to the data (Figure 1D), indicating that the
process follows Arrhenius behavior. A global fit of the model to
the variable temperature data was then performed, including a
nucleation–elongation–fragmentation mechanism and the
combined rates predicted by the Arrhenius equation (see
derivation of model in the SI, section 3A). Global minimization
(Figure 1C, solid lines) with an adjusted R2 of 0.9848, gives
37]
Knowles and co-workers have also included a temperature
dependence in these models.[38] Here, we use a modified version
of the latter in the analyses that follow.
Concentration dependent series for pH-jump induced
supramolecular polymerization were performed, first at a constant
temperature of 40 °C (Figure S7). In addition, temperatures series
(Figure 1C), at a constant monomer concentration of 80 μM were
carried out. The latter series provided better quality data, and
global fitting using a single model (see below) was possible.
The model was first individually fitted to the temperature and
concentration series, considering
a nucleation–elongation–
fragmentation mechanism (SI Sections 3B and 3C and Figures
Figure 1: BTA-1 pH-triggered self-assembly. A) Structure of BTA-1. The tricarboxylic acid moieties can be protonated and deprotonated as a function of the
pH. At high pH (pH>5.6), the monomer has 9 negative charges, and the resulting electrostatic repulsion between monomers prevents self-assembly. B) Cryo-
TEM picture of the self-assembled fibers (at pH 5). Scale bar is 200 nm. C) Temperature dependent self-assembly process of BTA-1 at pH 5. The dimensionless
degree of polymerization α is shown versus time. Circles are data points observed by stopped-flow circular dichroism and the solid lines are the results of the
global fitting of the supramolecular polymerization model including nucleation, elongation, fragmentation and Arrhenius equation to predict the rate constants.
Adjusted R2 of 0.9848. D) Half time of the polymerization as a function of the inverse of the temperature. The squares are the data points and the solid line is
the result of the fitting with an Arrhenius type equation. The good fit (adjusted R2 = 0.9916) indicates that the kinetics of the supramolecular polymerization of
the BTA-1 follows the Arrhenius law.
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activation energies of 156.7 ± 0.3 kJ mol–1 and 264.3 ± 0.2 kJ mol–
for the combined rates 푘푝푘푛 and 푘푝푘푓 , respectively. The
self-assembling at the surface forming a growing hydrogel layer
on the PDMS cube. The gel front moves at ~ 3 µm s–1, suggesting
that the proton diffusion from PDMS is rate limiting (see below).
The formed hydrogel initially looks completely uniform (at the
resolution of confocal microscopy), but after ~9 min (Figure 2,
Supporting Videos 2 and 3) signs of fiber bundling / gel
coarsening start to appear. Surprisingly, our surface-assisted self-
assembly procedure, more than providing spatial resolution,
yields bundles of fibers (imaged by electron microscopy in Figure
S10) much bigger than those observed when nucleation occurs in
solution (cf. Figure 1B). Heterogeneous nucleation from the
surface thus seems to be significantly different from
homogeneous nucleation for BTA-1 and leads to distinct
supramolecular architectures. It is known that crystal morphology
is dependent on the property of the surface where they grow
from,[41] and it has been shown that the degree of hydrophobicity
of a surface can influence the properties of the assemblies that
grow from it.[42] Therefore, the PDMS surface properties (i.e.,
hydrophobicity) could also be playing a templating effect on the
self-assembly and influencing the gel properties.
To be able to investigate the early stages of gelation at the PDMS
surface, we used a home-built microfluidic device consisting of
two 3D-printed parts that clamp a thin 100 µm PDMS membrane
(Figure 3A,B). The membrane is flanked by two perpendicular
rectangular channels (500 by 800 µm). The top channel (cf. Figure
2A) is first filled with a 160 µM BTA-1 solution at pH 7.4
(monomers), after which the flow is stopped. The bottom
(perpendicular) channel contains a continuous flow at 500 µL min-
1 of pH 4 potassium hydrogen phthalate (KHP) buffer.
1
enthalpy and entropy of activation of the combined nucleation–
elongation rate were determined to be ∆퐻푛≠,푒 = 154.1 ± 0.3 kJ mol–
and ∆푆푛≠,푒 = 310.0 ± 1.1 J mol–1 K–1 (Figures S8 and S9). Only
1
few similar temperature dependent kinetic studies exist,
especially in water. However, our enthalpy and free energy of
activation are in the same order of magnitude as compared to
other studies of this kind.[38,39]
The fact that this system fits with an Arrhenius model shows that
the process is more enthalpy than entropy driven, which is
confirmed by the Eyring plot (Figure S8). This is surprising for
supramolecular polymers in water due to the hydrophobic effect,
which has an entropic origin.[40] We therefore conclude, that in the
case of BTA-1 the self-assembly is driven by H-bonding of the
peptide side arms, confirmed by the high β-sheet content
observed in CD spectra (Figure S3A), while hydrophobic
interactions play a secondary role.[40]
To gain spatial control over the self-assembly, in terms of where
a hydrogel layer is formed, we decided to combine proton
diffusion from a solid substrate with pH-triggered BTA-1 self-
assembly in order to induce nucleation at (or close to) the solid-
liquid interface followed by hydrogel growth from the surface.
From our kinetic studies, we know that typical lag times of
nucleation at room temperature are ~100 s (see Figure 1C). One
can imagine that very fast proton diffusion is undesired if aiming
for a surface-assisted self-assembly, since the supramolecular
polymerization is not able to keep up. Indeed, when we placed 5–
10 mm3 agarose gel cubes, soaked in concentrated HCl,aq for 96
h, in a 160 µM solution of BTA-1 at pH = 7.4, the entire solution
rapidly became cloudy followed by precipitation (cf. Supporting
Movie 1). Neither supramolecular structures at the surface nor
gelation was observed. However, if 5–10 mm3 cubes of
poly(dimethyl siloxane), PDMS, soaked in concentrated HCl,aq for
96
h were used, a propagating front of supramolecular
polymerization / gelation was observed (Figure 2 and Supporting
Videos 2 and 3). After a few minutes, when the protons start to
diffuse out of the PDMS, BTA-1 monomers get activated and start
Figure 2: Surface-assisted self-assembly from a PDMS cube. Confocal microscopy of a 5 mm3 PDMS cube (screenshots of Supporting Video 2), soaked in
saturated HCl solution for 96 hours and subsequently dropped in a 160 µM BTA-1 solution at pH 7.4 (monomers). After 4 min, one can see a thin hydrogel layer
emerging from the PDMS block, followed by a propagating front of polymerization. Nile Red at 5 μM is used as a dye. The scale bar is 200 μm.
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Figure 3: Microfluidic device to control surface-assisted self-assembly. A) Side view of the microfluidic device. It consists of 2 perpendicular channels on top of
each other and separated by a 100 µm PDMS membrane. The bottom channel is filled with a pH 4 KHP buffer and the top one is filled with a 160 µM BTA-1
solution at pH 7.4 (monomers). At t=t0+t, we start the flow of the buffer channel at 500 µL min-1 while the monomer channel is at rest (i.e., no flow). The protons
start diffusing through the membrane and eventually reach the other channel, activating the monomers in solution that start growing on the membrane. The self-
assembly occurs at the intersection of the 2 channels B) Picture of the 3D-printed microfluidic device 75 by 75 by 13 mm on the microscope stage. C) Transmitted
light (left) and fluorescence image (right) of the intersection between the two channels taken after the experiment. Only the top channel shows fluorescence
intensity which indicates that the BTA-1 monomers self-assemble in response to the pH-gradient. Scale bar is 500 μm. D) 3D-reconstructed image (from a z-slice
confocal experiment) of the membrane after 2h proton diffusion. Supramolecular ~2 µm spheroids were formed at the PDMS surface. Scale bar is 10 μm. The top
left colour gradient indicates the height in the z-axis, where red is 0 and blue is 10 μm. Note that the image is elongated in the z-direction (up) due to the point
spread function. Nile Red at 5 μM is used as a dye for all these experiments.
After 5 minutes, protons start diffusing through the membrane and
the fluorescence intensity (due to the presence of solvatochromic
Nile red which intercalates in the hydrophobic domains of the
supramolecular polymers) in the channel containing the
monomers gradually increases, indicating that the self-assembly
is occurring. This is more in agreement with the water diffusion in
PDMS, which has been reported to be in the order of 10–9 m2 s–
microscopy. Similar transition from vesicles to fibers are observed
in gelators at the critical concentration.[45–47]
In conclusion, we have shown that investigating the kinetics of pH-
regulated supramolecular polymerization in water using stopped
flow experiments and fitting the data with a broadly applicable
concentration and temperature dependent mathematical model
provides access to important kinetic parameters, including the lag
time (of nucleation), and overall growth rates (here due to
elongation and fragmentation). We further utilized two synthetic
proton releasing solid substrates to grow supramolecular
(hydrogel) structures from the solid-liquid interface. In order for
surface-assisted self-assembly triggered by proton diffusion to
work, the rate of diffusion needs to be slower than the nucleation
rate, so supramolecular polymer structures form close to the
surface and can grow gradually outwards. Our approach can be
applied to many other pH-responsive (small molecule) self-
assembling systems and (hydro)gelators in order to obtain
surface functionalization and patterning. An interesting
,
1 [43] rather than proton diffusion in water, which at ~9·10–9 m2 s–1
is an order of magnitude faster.[44] After 2 hours, the experiment
was stopped and the PDMS membrane was removed and imaged
using confocal fluorescence microscopy (Figure 3D). The latter
was done to use a high magnification oil-immersion objective,
which cannot be used inside the 3D-printed microfluidic device.
Small ~2 µm assemblies were observed (Figure 3D, and middle
slice in Figure S11). It therefore seems that in the first stages of
nucleation and growth of BTA-1 starts from the latter spherical
assemblies, before growing into a more uniform hydrogel
observed on the PDMS cubes with confocal and electron
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[22] I. Ziemecka, G. J. M. Koper, A. G. L. Olive, J. H. van Esch, Soft Matter
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TMH would like to acknowledge funding from FP7-PEOPLE-
2013-CIG ‘NON-EQ-SA’ (631350), ERC-2017-STG ‘Life-Cycle’
(757910), LabEx CSC project Controlling supramolecular
assembly by “tunable anti-cooperativity”, GF received funding
from Ministère de l'Education Nationale de l'Enseignement
supérieur et de la Recherche. VM was funded by IdEx attractivité
Centrosome centering by dissipative self-organization. DS and
PB acknowledge financial support from the University of Mainz
and the Center for INnovative and Emerging MAterials (CINEMA).
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Keywords: self-assembly • supramolecular chemistry • adaptive
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10.1002/anie.201806668
Angewandte Chemie International Edition
COMMUNICATION
Table of Contents
COMMUNICATION
Hydrogel growing from a surface:
A pH-responsive dendritic benzene-
1,3,5-tricarboxamide peptide
D. Spitzer, V. Marichez, G. J. M.
Formon, P. Besenius*, T. M. Hermans*
conjugate self-assembles into 1-D
supramolecular polymers at pH < 5.6.
The system was kinetically and
mechanistically studied and modelled,
and hydrogels were grown from solid-
liquid interfaces driven by proton
diffusion.
Page No. – Page No.
Surface-assisted self-assembly of a
hydrogel by proton diffusion
This article is protected by copyright. All rights reserved.