Characterizing Viscoelastic Modulations in Biopolymer Hydrogels by

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Characterizing Viscoelastic Modulations in Biopolymer Hydrogels by Coherence-gated Light Scattering Jose R. Guzman-Sepulveda, Jinan Deng, Jiyu Fang, and Aristide Dogariu J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b05835 • Publication Date (Web): 04 Sep 2017 Downloaded from http://pubs.acs.org on September 5, 2017

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The Journal of Physical Chemistry

Characterizing Viscoelastic Modulations in Biopolymer Hydrogels by Coherence-gated Light Scattering

J. R. Guzman-Sepulveda,1 J. Deng2, J. Y. Fang2,* and A. Dogariu2,* 1

CREOL, The College of Optics and Photonics and 2Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32826

*Email: [email protected]; *Email: [email protected]

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ABSTRACT: pH-responsive hydrogels are of great interest for the controlled release of drugs. However, the changes in the structural and mechanical properties of hydrogels during the pH-responsive swelling/contraction process remains largely unknown. In this paper, we demonstrate that coherence-gated dynamic light scattering can be used to in situ characterize the structural dynamics of chitosan (CS) hydrogels at different pH values and show that the CS hydrogels undergo viscoelastic modulations during the swelling/contraction/recovery process induced by pH changes. The conditions for the CS hydrogels to undergo these modulations are found by continuously monitoring the nonequilibrium, long-term dynamical process. Our findings are in a close correspondence to the macroscopic observations made at time points where the CS hydrogels is at equilibrium.


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INTRODUCTION Hydrogels are three dimensional (3-D) networks formed by crosslinked hydrophilic polymers, which can contain a large amount of water.1 Due to the permeability for small molecules, hydrogels have been widely used in drug delivery systems.2 By deliberately designing the structure of hydrogels, various stimuli including temperature3, pH4, ionic strength5, and glucose6 can be used to control the release of drugs from the hydrogels. In this regard, pH-responsive swelling/contraction processes of hydrogels are particularly interesting for the controlled release of drugs because the microenvironment of tumors has different pH values, compared to normal tissues.4 A common approach to characterize the swelling/contraction kinetics of hydrogels relies on the measurement of the ratio of the weight of water adsorbed or released by the hydrogels to the weight of the dry hydrogels.7-8 Unfortunately, this indirect method cannot provide any information about the changes in the structural and mechanical properties experienced during the swelling/contraction process. Recently, we showed that coherence-gated dynamic light scattering (DLS) can be used to in situ monitor the structural changes in the swelling process of chitosan (CS) hydrogels, in which the polystyrene (PS) particles loaded in the CS hydrogels served as optical probes.9 By following the inherently non-stationary dynamics of the PS probes, we successfully measured the structural dynamics of CS hydrogels during the swelling process. It has been shown that CS hydrogels can be formed through the formation of coordination complexes between silver ions with the -OH and -NH2 groups on the CS chains.10 CS is a weak polyelectrolyte with the pKa of ~ 6.5. Thus, the swelling/contraction of the CS hydrogels can be controlled by the environmental pH. Here, we use a coherence-gated



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DLS approach to in situ characterize the temporal evolution of the local mechanical properties of CS hydrogels at different pH values, and show that the CS hydrogels undergo viscoelastic modulations during the swelling/contraction process. The conditions for the CS hydrogels to undergo the modulations are found experimentally by continuously monitoring the non-equilibrium, long-term dynamical process.

EXPERIMENTAL SECTION Materials: Chitosan (CS, low molecular weight), silver nitrate (AgNO3), acetic acid (≥ 99.7%), sodium hydroxyl solution (NaOH), and nitric acid (HNO3) were obtained from Sigma-Aldrich (St. Louis, MO). All chemicals were used without further purification. Water used in experiments was purified with Easypure II system (18.2 MΩ cm and pH 5.7). Polystyrene (PS) particles were from Thermo Fisher Scientific. They have a diameter of 102 ± 3 nm and the size distribution of < 3%, according to the manufacturer’s specifications. Preparation of CS Hydrogels: 1wt% CS solution was prepared by dissolving CS powder in 1% acetic acid solution under magnetically stirring for 4 hours. The pH of the resultant 1wt% CS solution is ~ 4.08. The preparation of CS hydrogels is as follows: 0.12 mL of 1M NaOH solution was first added into 4.8 mL 1wt% CS solution to adjust the pH of CS solution to 4.56 and 0.05 vol% PS particles were then mixed with the CS solution, followed by the addition of 1.3 mL 0.3 M AgNO3. The CS hydrogel was formed in less than 1 min.

RESULTS AND DISCUSSION


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Figure 1 shows the photography images of 1wt% CS hydrogels in an upturned glass vial at different stages of the viscoelastic modulations. The pictures were taken at time points in which the CS hydrogel is at equilibrium i.e., the process (swelling/contraction) was temporarily interrupted. Figure 1a shows the native (original) hydrogel. After the addition of 2 mL of water with pH 5.7 on the top of the native CS hydrogel, the hydrogel slowly swells. The swelling reaches equilibrium after 20 hours. The swollen hydrogel remains stable after the removal of excess water (Figure 1b). The addition of 0.5 mL HNO3 solution with pH 2.0 on the top of the swollen CS hydrogel causes the contraction of the hydrogel (Figure 1c), and results in the releasing of a small amount of water, which can be clearly seen at the bottom of the upturned glass vial. Interestingly, the released water can be swollen back to the CS hydrogel after 23 hours, leading to the hydrogel’s recovery and the corresponding increase of its height (Figure 1d).

Figure 1. Photographs of 1wt% CS hydrogels in an upturned glass vial after the swelling, contraction, and recovery processes: (a) the original hydrogel; (b) the swollen hydrogel after the addition of 2 mL water with pH 5.7 for 20 hours; (c) the contracted hydrogel after the addition of 0.5 mL HNO3 solution with pH 2.0 for 30 min; and (d) the recovered hydrogel after the addition of 0.5mL HNO3 solution with pH 2.0 for 23 hours. The arrow in (c) shows the water released from the hydrogel. 5 ACS Paragon Plus Environment


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We used a coherence-gated DLS technique to in situ monitor the structural dynamics of CS hydrogels during the swelling/contraction/recovery process. In our approach, the spatio-temporal coherence properties of the illumination in an optical-fiber-based DLS setup were structured by implementing coherence gates on a common path interferometer built around a multimode fiber (MMF).9 The MMFs used in our setup are commercially available with a standard core size of 62.5 µm and a fiber diameter of 125 µm. Singly scattered light is effectively isolated by limiting the depth from which a reference field (inherent Fresnel reflection from the end facet of the fiber) and the field back-scattered from the system can interfere. In these conditions, the power spectrum of the light intensity fluctuations, P(f), can be decomposed into multiple Lorentzian contributions in terms of the representative relaxation times. At the same time, the excitation field is made to be spatially partially coherent. Thus, an effective number of statistically independent locations is created over which the field scattered by the medium is sampled. These locations are within a so-called ‘coherence volume’ defined by the size of the fiber core and the temporal coherence length of the incident radiation. This spatial coherence gating allows proper calculation of ensemble dynamics by measuring at multiple spatial locations in parallel, and therefore prevents from non-ergodic manifestations.11 Thus, the time-averaged intensity correlation function measured, or equivalently the power spectrum of the light intensity fluctuations, can be interpreted in terms of the ensemble-averaged properties of the medium.12-13 The simultaneous implementation of spatial and temporal coherence gates, together with the heterodyne amplification of the scattered field, results in that non-equilibrium, non-ergodic long-term processes can be continuously followed over their entire duration,


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without changing neither the hardware nor the data processing, while the time-evolving structural dynamics and local mechanical properties of the medium can be retrieved.

9, 14

In addition, the large collection area of the MMF results in a high sensitivity, which in turn allows performing these measurements based only on intrinsic scattering, i.e. without the need of auxiliary scattering centers

15

, or with a very small concentration of probe

particles, as in the present study. Figure 2a shows the typical time evolution of the raw power spectra measured experimentally from 1wt% PS particle-loaded CS hydrogels during the full swellingcontraction-recovery cycle shown in Figure 1. Figure 2b is the time evolution of the power spectrum of the light intensity fluctuations within the 20 hour-swelling process. Photography images of 1wt% PS particle-loaded CS hydrogels in an upturned glass vial before and after the swelling are shown in the inset of Figure 2b. The detailed description of the swelling process at different experimental conditions i.e. polymer concentration, amount of binding sites, and particle network interactions, can be found elsewhere.9 In the experiments, the power spectra of light intensity fluctuations were recorded in the frequency range from 100 Hz to 104 Hz with a resolution of 1 Hz and integration time of 120 s (one power spectra every two minutes).



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Figure 2. a) Time evolution of the power spectrum of the light intensity fluctuations, P(f,t), measured experimentally from the PS particles embedded into a 1wt% CS hydrogel during a full swelling-contraction-recovery cycle. b) Time evolution of the power spectrum of the light intensity fluctuations within the 12 hour-swelling process. Photography images of native and swollen CS hydrogels are inset in (b). For the CS hydrogels slowly evolving in time, the long-term structural dynamics can be described with a generalized time-frequency representation (Figure 2) in terms of the evolution of the spectral content of the light intensity fluctuations:

⁄

, = ∑

⁄

with

∑ = 1

(1)

where ai and τi are the relative amplitude and the characteristic relaxation time, respectively, of each Lorentzian component used in the decomposition of the power spectrum measured. In single scattering, the mean-square displacement (MSD) of known scattering centers can be obtained directly by Fourier-transforming PSD(f), 〈∆ , 〉 = −

!

"

#$%∑ &'(− 2* ⁄+ ,

(2)

and this, in turn, can be used to estimate the frequency-dependent local viscoelasticity: 16 |/ ∗ 1| ≈

34 5

〈67 8:

9;〉1 =

with

?@A〈67 〉 ?@A

B

:9

(3)

In Equation (2), C = 4*$EF$G⁄2/IJ is the magnitude of the scattering vector, n is the refractive index of the medium (i.e. DI water), λ0 is the free-space central wavelength of the source, and θ is the scattering angle (θ = π rad for the backscattering configuration used here). The time scale t’ is defined by the frequency range, in which the power spectrum is measured, while the time scale t describes the long-term evolution. In Equation (3), kB is the Boltzmann’s constant, T is the absolute temperature, and a is the 8 ACS Paragon Plus Environment

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radius of the probe particles. The parameter α represents the instantaneous slope of the logarithmic MSD curve and takes values from 0 (elastic confinement) to 1 (viscous diffusion). The elastic / 1 = |/ ∗ 1|KLE*>1/2 and the viscous / 1 = |/ ∗ 1|EF$*>1/2 components of the local complex viscoelastic moduli can then be calculated over the entire swelling process. The estimated frequency-dependent local viscoelasticity (Equation 3) should not be strictly interpreted as the macroscopic rheological properties due to the inherent structural discontinuity around the PS particles which could also be hydrodynamically coupled to the hydrogel network.17-18 Nevertheless, a measure of local stiffness can still be obtained by combining the viscous and elastic part of the viscoelastic moduli into the figure of merit of the frequency-averaged loss tangent M̅ = 〈/ 1⁄/ 1〉9 .9, 19 Figure 3 shows the time evolution of the loss tangent for a full cycle of swelling, contraction, and recovery in which the modulation of viscoelastic properties is induced by varying pH values. The blue arrow shown in the Figure 3 indicates the time at which 2 mL water with pH 5.7 was added on the top of the 1wt% and 2wt% CS hydrogels. It can be seen in Figure 3 that the 1wt% CS hydrogel is slightly softer at the beginning and then swells to a significantly softer state as compared to the 2wt% CS hydrogel. After the swelling saturates, 0.5 mL of water with pH 2.0 was added on the top of the 1wt% and 2wt% swollen CS hydrogels at the time indicated with a red arrow in Figure 3. It is important to note that the initial and final states of these two hydrogels are similar, as indicated by the magnitude of the loss tangent. However, the 1wt% CS hydrogel undergoes an additional contraction-expansion i.e., stiffening-softening, transition. This transition would have gone unnoticed if the process had not been followed continuously



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and the measurement had been performed only at static points where the CS hydrogel is at equilibrium. This transition reveals the capability of the 1wt% CS hydrogel to undergo viscoelastic modulations. The inset in Figure 3 suggests, schematically, the changes in the mesh size of the 1wt% CS hydrogel throughout these modulations, which occur at a constant polymer mass content while the integrity of the hydrogel remains unaffected.

Figure 3. Time evolution of the loss tangent for a full swelling-recovery cycle for 1wt% and 2wt% CS hydrogels. Schematic illustrations of hydrogel network mesh sizes at different stages during the full cycle are inset. Furthermore, we study the intermediate stiffening-softening transition in swollen 1wt% CS hydrogels. Figure 4 shows the time evolution of the loss tangent for a swollen 1wt% CS hydrogel after the addition of HNO3 solution with pH 2.0 and 3.0. The time at which the HNO3 solution was added is indicated by the red arrow shown in Figure 4. Several stages of the process can be clearly identified after the addition of HNO3 solution with pH 2.0. In our experiments, the fiber sits at 7 mm below the air-gel interface. First, the


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plot of the loss tangent as a function of time shows a steady baseline measurement (from point A to B). Within this baseline measurement, one can measure the delay in the response of the 1wt% CS hydrogel (at that particular depth), ∆t0 ≈ 180 min. The 1wt% CS hydrogel then undergoes the intermediate stiffening-softening transition from point B to C with the ∆t1 ≈ 200 min, and then from C to D with ∆t2 ≈ 1,150 min. However, no sharp change in the loss tangent is observed after the addition of HNO3 solution with pH 3.0. To understand the different responses, we measured the pH at the top of the CS hydrogels. After the addition of HNO3 solution with pH 2.0, the pH of the CS hydrogel slowly increased and then reached a constant value of 4.2 after 10 min. However, it only took less than 5 min for the pH of the CS hydrogel to reach a constant value of 4.3 after the addition of HNO3 solution with pH 3.0. The fast response of CS hydrogels to HNO3 solution with pH 3.0 cannot be resolved by our experimental setup at the particular depth where the measurement was performed, leading to the apparent ‘lack of response’ in the light scattering measurements. More specifically, resolving this fast dynamics, which are localized to the proximity of the hydrogel’s surface, would require both placing the fiber closer to the hydrogel-solution interface and shortening the integration time. It has been shown that the formation of CS hydrogels from the coordination between silver ions with the -OH and -NH2 groups on the CS chains only appears in the narrow pH range from 3.74 to 7.0.20 This may explain the stiffening-softening behaviour of the 1wt% CS hydrogel after the addition of HNO3 solution with pH 2.0. At pH 2.0, CS chains are fully charged. The complexation of Ag+ ions with the NH2 groups of CS chains is cleaved, leading to the collapse of the CS hydrogels through the contraction. Over time, the pH of the CS hydrogels increases to 4.2, leading to the recovery of the gel state through the



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formation of the complexation of Ag+ ions with the NH2 groups of CS chains. The CS hydrogel reaches a steady state 23 hours after the addition of the addition of HNO3 solution with pH 2.0 (point D in figure 4). The steady state shows a softer state, as indicated by the overall increase in the loss tangent by the end of the whole process (positive ∆γ). Despite the overall increase in the loss tangent, this final state is not much different with respect to the initial one, suggesting that the CS hydrogel goes back to a similar condition after a full cycle of viscoelastic modulations. It is important to note that the different stages in Figure 4 correspond to the stages shown in Figure 1, in which the CS hydrogel is at equilibrium and the process was temporarily interrupted. For instance, the transition between points B-C in Figure 4 corresponds to the contraction (stiffening) between Figure 1b and 1c. Similarly, the transition between points C-D shown in Figure 4 corresponds to the recovery (softening) between Figure 1c and 1d by the re-absorption of the water previously released. The schematic inset in Figure 4 suggests the changes in the mesh size of the 1wt% CS hydrogel throughout the viscoelastic modulations, which occur at a constant polymer mass content while the integrity of the hydrogel remains unaffected.


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Figure 4. Time evolution of the loss tangent of swollen 1wt% CS hydrogel after the addition of water with pH 2 and pH 3 at the time indicated by the red arrow. The inset shows schematic illustrations of changes in the mesh size of the hydrogel network at different stages.

CONCLUSION In this paper, spatio-temporal coherence-gated dynamic light scattering is used to continuously monitor the non-stationary, long-term swelling/contraction/recovery process of CS hydrogels induced by the change of pH values. We show that CS hydrogels undergo viscoelastic modulations during the process. The understanding of the conditions e.g., CS concentrations and pH variations, under which hydrogels can hold viscoelastic modulations is critical for development of their applications in drug delivery and tissue engineering. This coherence-gated light scattering approach can be also applied to other soft matter scenarios involving viscoelastic transitions such as those related to long-term



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reversibility, viscoelastic hysteresis for externally triggered processes

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21-22

and self-

oscillating materials.23

Acknowledgements

Authors would like to acknowledge financial support from US National Science Foundation (CBET-1264355). JRGS gratefully acknowledges the Mexican National Council of Science and Technology (CONACyT) for its support through a partial PhD. Scholarship.


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Characterizing Viscoelastic Modulations in Biopolymer Hydrogels by

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