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Dual-responsive Carboxymethyl Cellulose/Dopamine/Cystamine

Hydrogels Driven by Dynamic Metal-Ligand and Redox Linkages for
Controllable Release of Agrochemical<!–<ForCover>Guo T, Wang W,
Song J, Jin Y, Xiao H, Dual-responsive Carboxymethyl
Cellulose/Dopamine/Cystamine Hydrogels Driven by Dynamic
Metal-Ligand and Redox Linkages for Controllable Release of
Agrochemical, Carbohydrate Polymers, doi:
10.1016/j.carbpol.2020.117188</ForCover>–>

Tianyu Guo, Wang Wangxia, Junlong Song, Yongcan Jin, Huining

Xiao

PII: S0144-8617(20)31361-8
DOI: https://doi.org/10.1016/j.carbpol.2020.117188
Reference: CARP 117188

To appear in: Carbohydrate Polymers

Received Date: 20 July 2020

Revised Date: 14 September 2020
Accepted Date: 2 October 2020

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Dual-responsive Carboxymethyl Cellulose/Dopamine/Cystamine Hydrogels Driven by

Dynamic Metal-Ligand and Redox Linkages for Controllable Release of Agrochemical

Tianyu Guo1,3, Wangxia Wang1,2,3, Junlong Song1, Yongcan Jin1*jinyongcan@njfu.edu.cn,

Huining Xiao3*hxiao@unb.ca

1
Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources,

Nanjing Forestry University, Nanjing 210037, China

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2
School of Chemistry and Chemical Engineering, Yancheng Institute of Technology,

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Yancheng 224001, China
3
Department of Chemical Engineering, University of New Brunswick, Fredericton, E3B

5A3, NB, Canada

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*Corresponding authors
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(JY), (HX), Tel: +86 (25) 85428569; Fax: +86 (25) 85428569c

Highlights
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• Dual responsive hydrogels via disulfide and metal-catechol bonds were fabricated.

• Hydrogels displayed reversible sol-gel transitions with either pH or redox changes.

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• Release of agrochemicals can be further promoted under co-triggered conditions.

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• The results of FEM simulation are consistent with those detected in the hydrogels.

Abstract

The utilization of agrochemicals in crop production is often inefficient due to lack of

appropriate carriers, raising in the significant concerns of ecological environment and public

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health. To enhance the efficiency of agrochemical delivery, a novel cellulose-based hydrogel

was constructed in this work by cross-linking dopamine (DA)-modified carboxymethyl

cellulose (CMC) with cystamine (CYS) in the presence of Fe3+ ions. The hydrogels displayed

reversible sol-gel transitions upon exposure to stimulation of changes in pH and redox, leading

to the controllable release of model agrochemical (6-benzyladenine). Compared with single-

triggered condition, the hydrogel doubled the cumulative release when co-triggered by pH and

redox. The dynamic metal/catechol complexation and disulfide bonding coexist in the hydrogel

networks, enabling occurrence of dynamic reaction under a variety of environmental conditions.

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The finite element method (FEM) was employed to simulate the hydrogel to provide a

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theoretical insight into the tested drug delivery. Benefitting from the reversibly cross-linked

networks and the excellent biodegradability of the hydrogels, we anticipate that this dual-
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responsive, polysaccharide-based hydrogel will offer diverse applications to reach the full

potential in sustainable advancement of crop production.

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Keywords: pH-responsive, redox-responsive, agrochemical, carboxymethyl cellulose,

hydrogel, controlled release

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Scheme 1. The gelation and release mechanisms of dual-responsive DACMC-CYS-Fe

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hydrogels

1. Introduction

The rapid development of agricultural technologies, for example making the best of

fertilizers and pesticides, has allowed food production to satisfy the population growth.(Foley

et al., 2011) However, it is technically inefficient for conventional fertilizers to delivery

prospective nutrients to crops, which makes vast fertilizers release to the growing environment

of the crops. With conventional methods, only about 45% of N-based and 20% of P-based

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fertilizers are effectively absorbed and utilized by crops, which means a large amount of these

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fertilizers are released into the soil.(Jan Willem Erisman, 2008) Undoubtedly, it can bring about

a list of environmental and ecological destruction, for instance, land eutrophication and
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groundwater pollution, having negative impacts on the ecological environment, economic

investments, and public health.(Urso & Gilbertson, 2018) Hence, exploring an excellent
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alternative to overcome the above-mentioned problems, not only can it immensely increase the
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yields of crops but also dramatically lighten the burden on the environment.

Hydrogels, which display a reversible sol-gel transformation in response to the

environment variations, become promising prospects in biosensing, biomedical applications as

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well as tissue engineering.(Lu, Aimetti, Langer, & Gu, 2016; Qu et al., 2020; Yuan, Lin, Qian,

& Shen, 2019) Besides, owing to hydrogels’ great capacity to store great much water in their
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three-dimensional (3D) network structure, they have attracted enormous interest in

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agrochemical release. Particularly, stimuli-responsive hydrogels, due to their unique gel-to-

liquid(SCHILD, 1992; D. Yang et al., 2014) or gel-to-solid(W.-H. Chen et al., 2018; Dai, Ravi,

& Tam, 2008) phase transitions in response to external triggers, have attracted much attention.

As a result, the dual- or multi-responsive systems(Cao & Wang, 2016) can be constructed by

connecting various functional groups, such as N,N’-bis(acryloyl)cystamine cross-linked

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cellulose hydrogels with pH-, thermo-, and redox-response,(Gong et al., 2016; Shang et al.,

2017) glutaraldehyde cross-linked carboxymethyl chitosan hydrogels with magnetic field-,

thermo-, and pH-response,(Dutta, Samanta, & Dhara, 2016) and dansyl-grafted polyacrylamide

hydrogels with pH- and thermal-response.(Rodkate & Rutnakornpituk, 2016)

Despite many investigations of redox- and pH-responsive hydrogels in drug carriers, few

attempts have shown that stimuli-responsive hydrogels are able to controlled- release

agrochemicals using both redox- and pH-response. In order to tackle the environmental

problems caused by excessive use of agrochemicals, controlled-release technology has been

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considered as an effective solution to improve efficiency in the use of agrochemicals.

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Compared with the traditional agrochemical formulations, the controlled release strategy

allows the application of agrochemicals at a lower total dosage while continuously maintaining
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the concentration at an effective level during the growing season. Previous research indicated

that the poor aeration and low oxygen content in paddy soil promoted the generation of a
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number of reductive substances, especially the reductive sulfur, due to the decomposition of
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organic matter. In addition, H2S is also generated from the reductive sulfur due to the lower

soil pH in paddy field, which leading to a negative influence on the growth of crop considerably

(Kögel-Knabner et al., 2010). Interestingly, reductive substances in soil is able to provide a

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conductive environment to trigger hydrogels to release agrochemicals, so that it can balance

the redox potential (Eh) of soil and markedly promote crop production, which is one of the
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main contributions from the modified hydrogels in this work.

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A versatile strategy consisting of changing the chemical moieties or metal coordination

complexes to facilitate dynamic non-covalent crosslinking provides the desired properties in

the agrochemical release of hydrogels.(Ryu, Hong, & Lee, 2015) It can stabilize and modulate

gel properties between mechanical strength and agrochemical release.(Pang, Gao, Feng, Wang,

& Wang, 2019) Based on our previous work on the controlled release of agrochemicals in terms

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of redox responsivity,(Hou, Li, Pan, Jin, & Xiao, 2018; Hou, Pan, Xiao, & Liu, 2019; Xue,

Mou, & Xiao, 2017) we proposed, for the first time, the cellulose-based dual-responsive

hydrogels of the controlled-release of agrochemicals that can be triggered by two different

triggers, e.g., pH and redox. Herein, we explore the potential of catechol-functionalized

biobased material to engineer pH and redox sensitive hydrogels by taking advantage of metal-

catechol coordination.

Cellulose-based materials, the stimulus-responsive hydrogels in particular, have attracted

substantial research interest due to their unique properties in response to external

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stimulus.(Dutta et al., 2016; Huo, Yuan, Tao, & Wei, 2014; Jin et al., 2016; X. Yang et al., 2017)

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Coupled with stimulus-responsive properties, nanofibrillated cellulose (NFC) nanofibrils have

acted as novel drug carriers or gene vectors, benefiting tissue engineering and wound healing,
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and enabling significant advances in healthcare. However, compared to extensive research on

NFC for medical application, the research targeting on the agriculture application is
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considerably inadequate, particularly for those associated with smart behaviour or controlled
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release.(Akalin & Pulat, 2019; Huynh, Sharma, Sosnowska, D'Souza, & Kutner, 2015; Pang et

al., 2019)

In this work, to meet the requirement related to more efficient and precise controlled
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release of agrochemicals, dual responsive hydrogels were designed by cross-linking of

carboxymethyl cellulose (CMC) with dopamine (DA) and cystamine (CYS) to form a 3D
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network named DACMC-CYS-Fe, as illustrated in Scheme 1. Meanwhile agrochemicals were

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accommodated inside the network to prevent from wasting of agrochemicals. As a common

member of cytokinins, 6-benzyladenine (6-BA) is one of the most commonly used plant

hormones to promote seed germination and nursery trees. (Ren, Zhang, Dong, Liu, & Zhao,

2018; D. Wang, Pajerowska-Mukhtar, Culler, & Dong, 2007) It was selected as model

agrochemical for precisely controlled release in this work. The swelling and sol-gel transition

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behaviour of the prepared hydrogels in water and sucrose aqueous solution, as well as the

controlled release behaviour of 6-BA from the hydrogels, were systematically investigated in

the presence of HCl and dithiothreitol (DTT). Furthermore, the visualization study of the

interaction between a model agrochemical (6-BA) and hydrogel based on independent gradient

model (IGM) further revealed the multiple weak effects in this hydrogel system.

2. Experimental

2.1 Materials

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Sodium carboxymethylcellulose (CMC, Mw = 700,000 g mol-1, degree of substitution (DS) =

0.9, Aldrich, USA), dopamine (DA, 98%, 189.6 g mol-1), N-hydroxysuccinimide (NHS), 1-(3-

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dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 6-benzyladenine (6-BA),
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dithiothreitol (DTT) were purchased from Sigma Aldrich (Milwaukee, USA). Cystamine

dihydrochloride (CYS·2HCl), ferric chloride hexahydrate (FeCl3·6H2O), hydrogen peroxide

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(H2O2, 30 wt%), Tris base (98%), hydrochloric acid solution (1 mol L-1) and phosphate buffer
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saline (PBS, pH = 3.0, 5.0, 6.0 and 7.0) were obtained from Alfa Aesar (Oakville, Canada).

Other chemicals were purchased from Nanjing Chemical Reagent Co., Ltd. (Nanjing, China).
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2.2 Preparation of DACMC-CYS complex

The DA-grafted CMC (DACMC) solution was prepared via the coupling with EDC and NHS
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as described in our previous work. (Guo et al., 2019) In short, 1-Ethyl-3-(3-

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(dimethylamino)propyl)carbodiimide hydrochloride (EDC, 5.0 mmol) was first added to 100

g of 1 wt% CMC solution and magnetically stirred at 60 °C for 1 h. N-hydroxysuccinimide

(NHS, 5.0 mmol) and dopamine hydrochloride (DA, 5.0 mmol) were then added and stirred at

22 °C under nitrogen atmosphere for 24 h. After removing unreacted agents via dialysis, the

resulting DA-grafted CMC solution was lyophilized overnight. To prepare the CMC-based

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redox responsive hydrogel, 1 g of DACMC was dissolved in 93 mL of PBS solution (pH = 6)

with vigorous stirring; 194 mg EDC (1 mmol) and 116 mg NHS (1 mmol) were added into the

solution. Then, 5 mL of PBS solution (pH = 6) containing 226 mg CYS·2HCl cross linker was

mixed with above-mentioned solution to obtain the CMC functionalized polymer (DACMC-

CYS). After mixing for 2 min, the mixture was laid for 1 h at room temperature. Then, the

resulting transparent viscous solution was dialyzed (Mw cutoff 3000) for five days against

Milli-Q water and lyophilized overnight.

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2.3 Preparation of DACMC-CYS-Fe hydrogel and agrochemical loading

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The CMC functionalized polymer (DACMC-CYS, 20 mg) was dissolved in 1 mL of water,

followed by slowly adding 0.015 mmol of FeCl3 into the DACMC-CYS solution under stirring.
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Finally, the mixture was transferred into a sealed vial and kept at room temperature for 24 h,

giving rise to a brown CMC-based hydrogel (DACMC-CYS-Fe). The loading of agrochemicals

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(500 ppm solution of 6-BA) was conducted with adding CYS simultaneously prior to gelation
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using a pre-loading method to initiate the nitrocatedchol-Fe complexation and disulfide

bonding network.
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2.4 Entrapment efficiency and loading capacity

Entrapment efficiency (EN%) of DACMC-CYS-Fe loaded with 6-BA was determined by

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monitoring the cumulative release in release experiment directly. After the hydrogel was
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swollen completely, the concentration of 6-BA in the solution was determined by a UV-visible

spectrometer (Genesys 10-s, Thermo Electron Corporation). The entrapment efficiency (EN%)

and loading capacity (LC%) were calculated by Eqs. 1 and 2

𝐶0 −𝐶𝑡
𝐸𝑁% = × 100% (1)
𝐶0

𝐶0 −𝐶𝑡
𝐿𝐶% = × 100% (2)
𝑚𝑑
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where C0 and Ct are the initial and equilibrium concentrations of 6-BA in solution, and md is

the weight of xerogel in release experiment.

2.5 Gel content and swelling tests

Approximately 0.3 g of dried hydrogel was soaked in 500 mL of DI water at room temperature
for 48 h. The remaining hydrogel was filtered and dried at 105°C for 24 h and weighed. The
gel content was calculated using the following equation,(Akalin & Pulat, 2018)
𝑊
Gel content = × 100%
𝑊0

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where W is the weight of the dried gel after soaking, and W0 refers to the initial weight of the

dried hydrogel before soaking.

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Gravimetric analysis was used to measure the swelling properties of the hydrogels.(Ellman,

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1959) Specifically, the freeze-dried hydrogels (or xerogel) were immersed in deionized water

or sucrose solution at 25 °C for 120 h to reach swelling equilibrium; before weighting on an

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analytical balance, excess water on the surface of hydrogel was wiped away by the filter paper.

The weights of dried and swollen gel were measured by analytical balance and the swelling
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ratio was calculated by Eq. 3

𝑊𝑠 −𝑊𝑑
𝑆𝑤𝑒𝑙𝑙𝑖𝑛𝑔 𝑅𝑎𝑡𝑖𝑜 = × 100% (3)
𝑊𝑑
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where Wd and Ws are the weights of dried and swollen gel, respectively.
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2.6 Redox responsive behaviours

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The redox responsive behaviours were characterized with the unloaded hydrogels as-prepared

above. Firstly, 1.0 mL of the mixed reactant with DACMC was transferred to vial after the

addition of CYS. After the solution was no longer flowing, the hydrogel was treated with

reductive DTT solution (1 μL, 0.05 mM, dissolved in pH = 8 PBS solution) at room temperature

and kept dark for 1 h. For the regeneration of hydrogel, the solution of last step was treated

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with an oxidizing agent H2O2 (2 μL, 30 wt%). During those periods, the transition time and

experimental phenomena were recorded.

2.7 Determination of thiol group contents

The thiol group content of hydrogels was quantified using an Ellman’s test(Ellman, 1959).

Briefly, 0.1 g of disjunct hydrogel (pre-treated by dialysis and lyophilization) were dispersed

in 10 mL of Tris-HCl solution (0.25 mol L-1 of Tris base with pH adjusted to 8.3 by HCl) and

then mixed with 10 mL of Ellman’s reagent (0.04 g of DTNB dissolved in 1 L of Tris-HCl

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solution). The UV adsorption was recorded at 412 nm after reaction for 10 min. The standard

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curve was established by recording the UV adsorption of a series of standard solutions of

cysteine; and the unmodified CMC was served as a control.

2.8 Preparation of simulated soil leachate

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As an important condition for redox responsiveness, the redox potential of the flooded paddy
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field is from 100 to -300 mV(Kludze, 1993). Maximum of 50 mM DTT solution, also the

frequently-used concentration in the research of drug release, was prepared for simulating the

reducing environment of flooded soil leachate. The redox potential of simulated soil leachate
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was -190 mV which is similar to the natural environment.

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2.9 Agrochemical release

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To demonstrate the agrochemical release, the hydrogels pre-loaded with 6-BA were immersed

in 50 mL of simulated soil leachate with various concentrations of DTT (i.e., blank, 10 mM,

30 mM, 50 mM DTT) in PBS solution at pH=8 in dark. The concentrations of 6-BA were

dynamically measured using a UV-visible spectrometer at a wavelength of 272 nm. Kinetics of

6-BA release was investigated by fitting the release data with various empirical kinetic models.

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2.10 Characterization

Scanning electron microscopy (SEM) analysis (JEOL JSM-6400 SEM instrument, Japan) was

conducted on freeze-dried samples to reveal the microstructures of hydrogel networks in energy

dispersive spectroscopy (EDS) mode. The chemical bonds and functional groups of redox-

responsive hydrogel were characterized with Fourier transform infrared spectroscopy (FT-IR)

using a NEXUS 470 spectrophotometer, (Nicolet Thermo Instruments, Canada) after being

grinded with KBr. The solid state 13C NMR spectra were recorded on a Bruker Advance DSX

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NMR spectrometer with a 4 mm magic angle spinning (MAS) probe at a spinning frequency

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of 100.64 MHz. The cross-linking kinetics was analyzed using an HAAKE MARS III

rheometer (Thermo Scientific) with the plate-plate geometry. X-ray photoelectron

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spectroscopy (XPS) measurements were taken on a Kratos X-ray photoelectron spectrometer

(AXIS Ultra DLD, Shimadzu, UK) using a monochromatic Al Ka X-ray source. The thermal
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stabilities of CMC, DACMC, DACMC-CYS, and DACMC-CYS-Fe were tested using a
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simultaneous thermal analyzer (TG 209F1, Netzsch, Germany) from 50 to 600 °C with a

heating rate of 30 °C min-1 in an O2 environment.

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3. Results and discussion

3.1 Characterization of DACMC-CYS-Fe

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The morphology of DACMC-CYS-Fe hydrogels was characterized using a scanning electron

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microscope (SEM) (Figures 1a and 1b). A clear porous structure could be observed in the
DACMC-CYS-Fe hydrogel, which is crucial for agrochemical loading and mass transferring
during release. Namely, agrochemicals are adsorbed or embedded by the grid cavities of the
hydrogel, which facilitates a high loading capacity and stability. Water in farmland carrying
reductants tends to penetrate into the hydrogel grids or pores via filtration under the
circumstances of agricultural application, and the reduction process can be carried out more

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efficiently.(Hou et al., 2019) The successful covalent conjugation of dopamine (DA) and
cystamine (CYS) onto CMC (1 wt%) was obtained using a carbodiimide activation technique
in a dilute aqueous solution. The results from SEM-EDS mapping of sulfur (Figure 1c)
indicated the presence of sulfur in the DACMC-CYS-Fe with relatively uniform distribution.
The covalent bonding was confirmed from FT-IR spectra shown in Figure 1d. Compared the
spectrum of DACMC with that of CMC, the amide bond formation between the carboxyl group
on CMC and the amine group of DA is evidenced by the detection of N-H bending vibration at
1522 cm-1 after DA conjugation.(Guo et al., 2019) As the CYS added, the carbonyl peak at
1708 cm-1 was partially replaced by enamine peak at 1640 cm-1. The FT-IR spectrum of

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DACMC-CYS contain new peaks at 1640 cm-1 and 1570 cm-1 which could be attributed to the
stretching of the enamine bonds.(Sanchez-Sanchez, Fulton, & Pomposo, 2014) Meanwhile, a

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new band appeared at 950 cm-1, which was assigned to the C-S stretching of CYS. After loading
of Fe3+ ions, three changes in functional groups in DACMC-CYS spectrum were observed. The
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foremost alteration is the weakening of DACMC-CYS peak at 1708 cm−1, which is due to the
complexation of the carboxylate groups of CMC coordinated with Fe3+ cations. The second
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change is the decrease in the absorption band at 1223 cm-1, suggesting the involvement of C-
OH in catechol of DA with Fe3+ coordination.(Hussain et al., 2018) The third change is the
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disappearing of the peaks in 1058 to 1073 cm-1 region, implying that the oxygen in ether linkage
and -OH in hydroxyethyl groups of DACMC-CYS coordinates complexation with Fe3+
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cations.(Basta, Hosny, El-Saied, & Hadi, 1996) Moreover, Fe3+ ions presence in the DACMC-
CYS-Fe hydrogel was confirmed by SEM-EDS (Figure S1) by the appearance of characteristic
signals of Fe at 6.40 eV. Fe content in the sample was 0.61 wt%, as quantified by SEM-EDS.
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Therefore, it can be said that metal-catechol coordination was successfully achieved.

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Figure 1. SEM images of the cross-sectional morphology of freeze-dried hydrogels (a, b);

SEM-EDS mapping of sulfur (c), scale bars = 100 μm; FT-IR spectra of CMC, DACMC,
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DACMC-CYS and DACMC-CYS-Fe hydrogels (d); Redox-responsive behaviour of CMC
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hydrogels: formed hydrogel (e); hydrogel after adding 0.05 mM DTT (f); regenerated gel after

adding 30% 2 μL of H2O2 (g).

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Solid-state MAS C NMR spectrum of DACMC-CYS was recorded for detecting the
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graft of DA, CYS on CMC (Figure 2). Noticeable peaks related to the carbon atoms (C1-C6)

of ordered structure of CMC macromolecule appeared between 60-110 ppm. The peaks at
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102.9, 81.8 and 61.6 ppm were attributed to the C1, C4 and C6 atoms, respectively. After the

conjugation of CMC with both DA and CYS, new signals were detected at the chemical shifts
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of 35.5, 41.4, 118, 129, and 145.1 ppm. The assignments of carbon signals, as shown in Figure

2, indicate that the target product of DACMC-CYS was formed after reaction. The peak at 177

ppm corresponding to the carboxyl carbon of CMC (C8) was overlapped by the peak at 174.9

ppm corresponding to -CONH in DACMC-CYS, implying that the CMC was partially grafted

with DA and CYS. Solid-state MAS 1H NMR spectrum of DACMC (Figure S2) showed that
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the signals at 3.5 and 1.4 ppm from -NCH2- and the backbone of CMC, respectively.(Dutta et

al., 2016; Hou et al., 2018) All results proved that DACMC-CYS was successfully synthesized.

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Figure 2. Solid-state MAS 13C NMR spectra of DACMC-CYS
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XPS wide scan spectra of DACMC, DACMC-CYS and DACMC-CYS-Fe hydrogels are
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shown in Figure 3. Four intense peaks, i.e., O 1s, N 1s, C 1s, and S 2p, were observed in the

XPS patterns of DACMC-CYS and DACMC-CYS-Fe hydrogels. Apparently, the N 1s peaks

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appeared in both hydrogels, suggesting the presence of C-N bond (Figures 3b and S3). The S

2p peaks appeared in the DACMC-CYS and DACMC-CYS-Fe hydrogels, suggesting the

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presence of C-S bond (Figure 3d). Peaks with binding energies of 284.6, 285.4, 286.5, 288.6,

and 290.6 eV exhibited in the C 1s core-level spectrum of DACMC (Figure 3b), were
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attributed to the presence of carbon-containing groups, such as C-C/C=C, C-N, C-O, O-C-O,

and NH-C=O.(Guo et al., 2019) The C 1s core-level spectrum of DACMC-CYS (Figure 3d)

was curved and fitted to 284.4 eV for C-C species, 285 eV for C-N species, 286.1 eV for C-O

species, 287.8 eV for O-C-O/NH-C=O, and 285.7 eV for C-S species, respectively. The C-S

peak component was associated with the CYS species of DACMC-CYS, suggesting the
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successful connection of CYS to CMC. The S 2p core-level spectrum of DACMC-CYS is

shown in Figure 3c, a main peak around 164.4 eV and a minor peak around 163.5 eV are

assigned to S2p3/2 and S2p1/2 of thiophene S, respectively.(Dong et al., 2013) Overall, the data of

XPS analysis clearly demonstrated that DA and CYS were successfully bonded to CMC, thus

strengthening the structure of DACMC-CYS-Fe hydrogel.

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Figure 3. Wide scan XPS spectra of DACMC-CYS-Fe, DACMC-CYS, and DACMC (a), C 1s

core-level spectra of DACMC (b) and DACMC-CYS (d), and S 2p core-level spectra of
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DACMC-CYS (c).

The stability of hydrogels significantly influences the transportation, distribution, and

release of agrochemicals. Compared with NaCl aqueous solution which is usually used in

human tissue, sucrose aqueous solution is more suitable for the release environment of
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hydrogel carriers in plants. The osmosis of plant cell fluid depends on the cell types.

In plant tissue culture, 58-234 mmol L-1 of sucrose solution (i.e., 2-8%) is usually added

for providing nutrition and maintaining osmotic pressure.(Hou et al., 2019) In this work, the

swelling test of DACMC-CYS-Fe hydrogels was carried out in deionized water, acid solution,

and 300 mmol L-1 of sucrose solution to characterize the stability of hydrogels in two different

osmotic-pressure environments. As shown in Table 1, after the hydrogels were completely

swollen in pure water, the swelling ratio of the hydrogels increased with increasing the content

of CYS and FeCl3. When the content of CYS increased from 0.1 to 0.2 mmol L-1, the swelling

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ratio of DACMC-CYS-Fe hydrogel decreased from 636% to 540%, while the swelling ratio

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for DACMC was 984%. This is probably due to the fact that the more disulfide bonds were

present, the denser and tighter microstructure was formed, leading to less capillary spaces in
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the hydrogel.(F. Wang et al., 2019) Moreover, the swelling ratio of DACMC-CYS-Fe-5 was

lower than those of DACMC-CYS-Fe-2 and DACMC-CYS-Fe-4. High crosslinking density in

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DACMC-CYS-Fe-5 results in dense gel structures that reduce the swelling ratio, restrict the
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repulsion force between chains, and slow permeation of the medium.

The swelling properties of the hydrogel are important when it is used under weakly acidic

conditions. In this case, the swelling ratios of hydrogel at pH 3 and pH 5 were determined with
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the same method as mentioned above. As illustrated in Figure S6, all the hydrogels displayed

excellent responses at pH 5. Since CMC has carboxylic acid groups (COO−), at higher pH
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values, e.g., higher than the pKa of carboxylic groups (pKa ~4.5), the carboxylic acid groups
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become deprotonated and the electrostatic repulsive forces between negatively charged sites

(COO−) bring about enhancement in swelling.(Mahdavinia, Etemadi, & Soleymani, 2015)

When immersing the hydrogels in water at a lower pH (pH=3), because the protonation of

carboxylate anions takes place, repulsive forces between carboxylate anions disappear and

consequently swelling values are decreased.(Akar, Altinisik, & Seki, 2012) However, the

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significant pH jump would cause catechol to undergo a spontaneous cross-linking via bis-

and/or tris-dopa-Fe3+ complexes.(Holten-Andersen et al., 2011). Thus, the swelling capacity of

hydrogel beads in the current systems is governed by anionic carboxylate groups and the

catechol-Fe3+ complex among DACMC.

The swelling ratios decreased when the concentration of sucrose increased to 300 mmol

L-1, which is attributable to the change of the osmotic pressure between gel phase and solution

phase caused by the protonation of hydrogel, giving a difference in counterion concertation

described by the Gibbs-Donnan effect.(S. Wang, Zhang, Tan, Liu, & Shi, 2011) It is also noted

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that minimum swelling ratio of the DACMC-CYS-Fe hydrogels was 280%, suggesting that the

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swelling ratio of hydrogels can be maintained steadily in plant cell isotonic solution, which is

beneficial for keeping the consistent performance of hydrogels in plants and high-salinity

soils.(Gan et al., 2019)

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Table 1. CYS, FeCl3, thiol bond content, swelling ratio, and gel content of DACMC and
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DACMC-CYS-Fe gels

Thiol
CYS FeCl3 Swelling ratio (%) in Gel
bond
Sample (mmol (mmol content
content Sucrose Acid
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mL-1) mL-1) Water (%)

(mmol g-1) solution pH=5 pH=3
DACMC 0 0 0 984 686 910 780 29
DACMC-CYS-Fe-1 0 0.015 0 743 528 820 642 40
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DACMC-CYS-Fe-2 0.1 0.015 0.75 636 413 691 534 42

DACMC-CYS-Fe-3 0.2 0.015 0.78 540 339 580 403 43
DACMC-CYS-Fe-4 0.1 0 0.75 826 570 757 704 33
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DACMC-CYS-Fe-5 0.1 0.03 0.75 413 280 545 387 48

3.2 Rheological behaviours of DACMC-CYS-Fe hydrogels

Hydrogels generally exhibit both viscous- and elastic-like behaviours or viscoelasticity under

various conditions during gelation, characterized by G’ (storage modulus) and G” (loss

modulus) values.(Bian et al., 2018) To understand the gelation process and the influence of
16
Fe3+ ions on the viscoelastic behaviour of hydrogels, the changes in the G’ and G’’ of DACMC-

CYS-Fe hydrogels over the ω (angular frequency) of 0-10 rad s-1 are illustrated in Figures 4a

and 4b. The modulus curve of all DACMC-CYS-Fe hydrogels exhibited elastic-like behaviour

(G’’<G’) at both low and high frequencies, and the rubbery zone can be shown within the

accessible ω window. Furthermore, these hydrogels showed the G’ values of 131.8, 51.5, and

413.5 Pa at ω = 1 rad s-1, respectively for DACMC-CYS-Fe-2, DACMC-CYS-Fe-4, and

DACMC-CYS-Fe-5, indicating the incorporation of Fe3+ ions enhanced the elasticity and

stiffness of the hydrogel. Figure 4c shows the rheometric properties of different states of

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DACMC-CYS-Fe-2. The hydrogel in state I reveals high stiffness (storage modulus G’ = 131.8

Pa and loss modulus G’’ = 39.0 Pa), which is consistent with the result of its cross-linking by

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the DA and CYS interactions with CMC (curves a and a’). The redox-triggered reduction of
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the disulfide bonds to the thiol groups dissociates the CMC macromolecular linkages and yields

the quasi-liquid state II (G’ = 9.5 Pa and G’’ = 1.4 Pa), curves b and b’. Furthermore, the thiol
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sites regenerate the state I by oxidation. The redox-triggered stiffness transitions of the
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hydrogel between states I and II, upon the cyclic oxidation and reduction between disulfide

sites and thiol sites, are fully reversible for five times (Figure 4d). It is clear that the stiffness

of the as-prepared hydrogel can be switched using a programmed sequence of redox triggers.
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The redox-responsiveness of DACMC-CYS-Fe hydrogels associated with rheological

behaviours shown in Figure 4d is consistent with those detailed in Figures 1e-g. The mixture
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of DACMC and CYS was a homogeneous solution initially and gelated after standing for 60
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min (Figure 1e). The hydrogel, was decomposed into sol by adding DTT as reductant (Figure

1f), and regenerated again by adding H2O2 as oxidant (Figure 1g). Each cycle was carried out

three times for demonstrating the reversibility. The mechanism of redox process is illustrated

in Figure 4e.

17
 of
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Figure 4. Angular frequency (ω) dependence of storage modulus G’ (a) and loss modulus G”
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(b) for DACMC-CYS-Fe hydrogels measured at shear strain = 10%; rheometric measurements
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corresponding to the redox-stimulated transition of the DACMC-CYS-Fe-2 hydrogel in state I

to quasi-liquid state II (c); cyclic G’ and G’’ changes stimulated at ω = 1 rad s-1 by the reversible
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redox-triggered transitions between states I and II of DACMC-CYS-Fe-2 (d); Schematic

formation and disassembly of the DACMC-CYS-Fe hydrogel, cooperatively cross-linked by

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DA and CYS interactions with CMC (e).

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3.3 Loading capacity of agrochemicals in DACMC-CYS-Fe hydrogel

The entrapment efficiency (EN%) and loading capacity (LC%) of DACMC-CYS-Fe hydrogels

were also investigated, using 6-BA as model agrochemical, to characterize their loading

performance. The pH range for loading 6-BA on DACMC-CYS-Fe was from 6 to 12. The

control sample (DACMC) was prepared by mixing DA-grafted CMC without adding CYS for

18
disulfide cross-linking. Compared with DACMC, DACMC-CYS-Fe hydrogel improved both

loading capacity and entrapment efficiency significantly (Figure 5). In neutral media, the EN%

and LC% of the hydrogels increased from 49.8% and 2.1% to 96.0% and 4.1%, respectively.

With cross-linking of CYS, more branches in DACMC-CYS-Fe hydrogel networks firmly

adsorb and immobilize 6-BA without changing its chemical property owing to their similar

polarity. This is one of the key features distinguishing our hydrogels from other carrier systems

reported elsewhere,(L. Chen et al., 2018) apart from dual-responsiveness.

In alkaline condition, EN% and LC% of DACMC hydrogels decrease, while the

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performance of DACMC-CYS-Fe is less affected, because the hydrophobic benzyl groups

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reduce its solubility in water. However, due to the presence of imidazole rings, the N-H of

imidazole is acidic and can be deprotonated by OH– in alkali medium. Such interaction allows
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6-BA to dissolve readily in alkaline solutions. On the other hand, due to the fact that the loading

of 6-BA in the hydrogels is mainly driven by non-covalent bonding interactions, e.g., hydrogen
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bonding, van der Waals, pi-pi stacking (see the results obtained from the independent gradient
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model shown in Figures S7, S8 and S9). EN% and LC% are insensitive to pH variation. Though

the loading is slightly lowered at pH 10, which might be attributed to the repulsion between

the negative charges of imidazole and carboxyl groups in DACMC-CYS-Fe. Overall,

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DACMC-CYS-Fe demonstrated the appropriate capacity in accommodating or capturing 6-BA.

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Figure 5. Entrapment efficiency (EN%) and loading capacity (LC%) of DACMC and

DACMC-CYS-Fe-2 hydrogels.

3.4 In vitro pH- and DTT-triggered release behaviours of 6-BA from the hydrogels

In this work, the as-prepared hydrogels contain both disulfide and catechol bonds, matching

the functions of redox-(Fukino, Yamagishi, & Aida, 2017) and pH-responsive,(Sanchez-

Sanchez et al., 2014) respectively. The relationship between cumulative release and time at

various pH values and DTT concentrations is summarized in Figure 6. As expected, the release

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of 6-BA was promoted remarkably by adding HCl and DTT. Therefore, the formation of

hydrogel and the load of agrochemical can be combined into “one-step” process. Most of the

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6-BA was captured simultaneously as the occurring of CMC chain crosslinking; and embedded
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in the 3D network of hydrogel over the gelation process. Part of 6-BA molecules was attached

on the carrier with weak forces (e.g., Van der Waals and electrostatic interaction). As a result,
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30.9% of loaded 6-BA was released by diffusion after 12 h in neutral environment (Figure 6a).
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While pH decreased to 5.5, the accumulative release amount of 6-BA from the hydrogels

increased significantly owing to the dynamic breakage and conjunction of catechol/Fe3+

complexation (physical gels). At pH 3, 6-BA was released completely after 6 h with the
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dissolution of hydrogels (85% released in the first 4 h). Meanwhile, DTT solutions for

simulating the in vivo environment also accelerated the release of 6-BA obviously at both pH
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5 and 7 (Figure 6b).

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In addition, at pH 5, the cumulative release rate of the samples was obviously redox-

dependent; DACMC-CYS-Fe exhibited much faster 6-BA release at 50 mM DTT than at 30

mM. With the increasing of DTT concentration from 10 to 50 mM, the duration for 6-BA to be

fully released from hydrogels were reduced from 12 to 6 h. The result indicates that the release

of 6-BA (chemical gels) was promoted by the disassembly of hydrogels induced by the

20
cleavage of disulfide bonds. In comparison with single-trigger conditions (pH 5 or 50 mM),

DACMC-CYS-Fe hydrogels in 50 mM + pH 5 doubled the amount of cumulative release,

suggesting that the release rate of 6-BA from DACMC-CYS-Fe can be highly enhanced under

co-triggered conditions. These results demonstrate that the release of 6-BA from the hydrogel

is controllable and efficient which meets the target delivery capacities with less harmful effects

on non-targeted parts. The dual-responsive hydrogels with the unique architectures developed

in this work facilitate the controlled release of 6-BA triggered by redox (DTT-triggered) and

pH (acid-triggered) changes, which is more flexible and controllable than single-responsive

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carriers.

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Interestingly, such an effect was also reported by Li et al.(Li, Deng, Fu, & Li, 2009) in an

anti-corrosion system, in which the increase of acid concentration resulted in decreasing

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inhibition efficiency of 6-BA on the corrosion of steel. Despite the different applications

involved, the effect of pH on the formation of Fe2+-6-BA complex is consistent with the finding
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in this work, i.e., lowering pH or increasing acid concentration increased the cumulative release
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of 6-BA from DACMC-CYS-Fe-2 hydrogel.

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21
 of
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-p
re
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Figure 6. Cumulative release of DACMC-CYS-Fe-2 at different pH values (a), and DTT

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concentrations (b). Modeling results of dynamic drug release at pH 5 and 7 as well as various

DDT dosages (c); and volume fraction of drug changing over position (d) in different cases of
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pH values and DTT concentrations. FEM simulation of the release behaviour of DACMC-

CYS-Fe-2 hydrogel (e-g).

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The adsorption kinetics of DACMC-CYS-Fe-2 hydrogel was investigated in terms of the

dynamic release curves at pH = 5, 7 and pH = 5 + 30 mM DTT. The fitting parameters of the

five kinetic models are listed in Table 2. The profile of 6-BA released from hydrogels fits the

kinetic model of diffusion-erosion (D-E) best, and the goodness of fit (R2) was greater than
22
 0.996. The D-E model can be applied to present the Fick diffusion process affected by carrier

erosion, whereas the Kopcha model is the exceptional case of the D-E model with the last two

terms ignored.(Hou et al., 2018) The rapid release of 6-BA at the initial stage is dominated by

the Fick diffusion of 6-BA on the carrier surface. Then, 6-BA released at a relatively stable rate

under the dual-action of diffusion path growth and hydrogel erosion. Moreover, by comparing

the values of ka/kb, it can be concluded that the erosion effect in alkali media has a less impact

on the release of 6-BA than that in acid one.

Table 2. Parameters of release models

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pH = 5
Equation pH = 7
0 30 mM DTT

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Higuchi R2 kH R2 kH R2 kH
Qt = kHt0.5 0.933 1.334 0.634 2.65 0.846 4.384
Korsmeyer-Peppas
Qt = kKPtn
R2
0.942
kKP
2.170
n
0.120
R2
0.953
-pkKP
12.880
n
0.238
R2
0.980
kKP
14.766
n
0.297
Kopcha R2 A B R2 A B R2 A B
re
Qt = At0.5+Bt 0.962 1.842 -0.024 0.990 5.198 -0.120 0.994 7.277 -0.136
Makoid-Banakar R2 kMB n R2 kMB n R2 kMB n
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Qt = kMBtne(-ct) 0.995 0.456 0.788 0.996 7.385 0.385 0.999 9.964 0.397
c c c
0.001 7.466e-4 4.476e-4
Diffusion-erosion R2 ka kb R2 ka kb R2 ka kb
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Qt = kat0.5+kbt+ kct2+ kdt3 0.998 0.367 0.139 0.999 5.939 -0.188 0.996 8.167 -0.236
kc kd kc kd kc kd
-2.826e-4 1.800e-7 7.127e-5 -1.496e-8 1.772e-4 1.158e-7
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To further explore the agrochemical release, it is pivotal to utilize the finite element
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method (FEM) simulation to provide a theoretical insight into the tested drug delivery. As

shown in Figure 6c, the results from numerical simulation display that the agrochemical release

volume ratio in pH = 5 is more than that in pH = 7, ulteriorly indicating that the efficiency of

agrochemical release is negatively corrected with pH. We also simulated agrochemical release

with the addition of DTT. The results corresponding to the samples with the addition of the

23
content of DTT are highest among these three curves, which confirm the DTT effect on

hydrogel networks (Figure 6c). Besides, no matter how hydrogel networks initially distribute

in the matrix, the agrochemical volume fraction between adjacent spatial points exhibits the

trend of narrowing with the incremental time (Figure 6d). At the beginning of agrochemical

delivery, the agrochemical volume fraction is equal nearly to the original results due to the

incremental speed of agrochemical delivery extending the passage of agrochemical release.

However, the agrochemical volume fraction rapidly decreases to zero because the

concentration of agrochemicals is dilute at the margin of the agrochemical delivery range.

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Figures 6e-g depict the three-dimensional (3D) volume fraction contours of agrochemical

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release, in which they vividly demonstrate a close association between the amount of

agrochemical released and the networks of the hydrogel matrix under different conditions. The
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effective control release could ensure their targeted delivery to specific sites. Moreover,

nonlinear finite element modeling simulation (Figure S10) exhibits that the simulated
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agrochemical release behaviour is coincident with that detected in the DACMC-CYS-Fe
lP

hydrogels. What’s more, the shape profiles closely resemble the experimental one and,

qualitatively on the basis of the data available; the contours of the water mass fraction seem to

describe well the hydration level of DACMC-CYS-Fe hydrogels.

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4. Conclusion
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A novel cellulose-based hydrogel was constructed successfully by cross-linking dopamine

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(DA)-modified carboxymethyl cellulose (CMC) and cystamine (CYS). The dynamic

metal/catechol complexation and disulfide bonding coexist in the hydrogel networks, enabling

the occurrence of dynamic interaction under a variety of conditions. In view of the G’ and G’’

values of different hydrogels, it can be concluded that all hydrogel matrices are soft materials

with moderate stiffness. The hydrogels displayed reversible sol-gel transitions when exposed

24
to either pH or redox changes or both, leading to the controllable release of model

agrochemicals, i.e., 6-BA (6-benzyladenine). In comparison with single-trigger conditions (pH

5 or 50 mM DTT), the hydrogel in pH 5 buffer containing 50 mM DTT doubled the amount of

cumulative release, suggesting the release of 6-BA from hydrogel can be promoted under co-

triggered conditions. Attributing to the reversibly cross-linked networks and superior

biodegradability as well as biocompatibility, the efficient and sustainable cellulose-based

hydrogel developed in this work might offer diverse applications in both agricultural and

biomedical fields.

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Credit author statement
Tianyu Guo: Conceptualization, Methodology, Investigation, Writing - Original Draft
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Wangxia Wang: Methodology, Investigation, Formal analysis
Junlong Song: Formal analysis, Writing - Reviewing & Editing
Yongcan Jin: Methodology, Supervision, Writing - Reviewing & Editing
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Huining Xiao: Methodology, Supervision, Writing - Reviewing & Editing
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Conflicts of interest

There are no conflicts to declare.

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Acknowledgements

This work is supported by the National Natural Science Foundation of China (Grant No.
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31730106, 31770623), China Scholarships Council, the Doctorate Fellowship Foundation of

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Nanjing Forestry University, Natural Science Foundation of Jiangsu Province (No.

BK20181052) and NSERC Canada. We thank technician Dr. Huihua Min in the Advanced

Analysis Test Center at Nanjing Forestry University for technical assistance. We also

acknowledge Dr. Ulrike Werner-Zwanziger at the Chemistry Department at Dalhousie

University for the acquisition and evaluation of solid-NMR data.

25
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