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BY 4.0 license Open Access Published by De Gruyter Open Access November 6, 2023

Metal gel particles loaded with epidermal cell growth factor promote skin wound repair mechanism by regulating miRNA

  • Yanfeng Bian EMAIL logo , Shizhou Liu , Jing Huang and Tianlong Ma
From the journal Open Chemistry


Skin wounds are prone to fungal infections and may threaten patients’ lives in severe cases. However, conventional treatment protocols rarely promote skin wound repair by modulating microRNA (miRNA). A novel binuclear cobalt(ii) complex with the chemical formula [Co2(MBBA)2(HPT)2(H2O)2]·2H2O (1) was synthesized through the reaction of 2-(4-methylbenzoyl) benzoic acid and 3-(pyridin-2-yl)-1H-1,2,4-triazole in the presence of 3,4-pyridine dicarboxylic acid as the template reagent. With natural polysaccharide hyaluronic acid and carboxymethyl chitosan as raw material, based on the chemical synthesis of epidermal cell growth factor for the load of metal gel particles, the microstructure and skin wound healing effect were studied. Molecular docking simulation showed that neither the carboxyl nor triazole group formed binding interactions with the active sites on proteins. Instead, the carbonyl group interacted with the active sites through hydrogen bonding. This study not only provides an effective solution to promote skin wound repair by modulating miRNAs but also provides useful ideas for synthesizing organometallic ligand-based hydrogels and their applications in biomedical fields.

1 Introduction

As the body’s largest organ, the skin has a vital barrier protection function [1]. The proliferative phase is a critical period for the healing of skin wounds, and the re-epithelialization process of the epidermis during this period acts as an essential player in restoring the integrity of damaged skin. The most important part of re-epithelialization is the migration of keratin-forming cells to complete the wound coverage, and the migration process cannot be separated from the cytoskeleton changes. Rho GTPase family is a pivotal protein in the modulation of the cytoskeleton, and its members, Rho A, Rac l, and Cdc42, regulate actin stress fibers, lamellar pseudopods, and filamentous pseudopods, respectively [2,3]. MicroRNAs (miRNAs), a class of non-coded small RNAs, are essential in the skin wound healing process [4].

Transition metal complexes with organic ligands and inorganic metal ions are of interest not only due to their structural versatility but also for their diverse applications, such as antimicrobial and antitumor activity, luminescent characteristics, insulin mimetic activity, DNA-binding characteristics, magnetism, catalytic activity, and gas uptake [515]. The activities and architectural diversity of metal–organic complexes depend strongly on the metal atoms and organic ligands employed and the reaction mechanism for acquiring the complexes [1618]. Therefore, the rational design of organic ligands and the choice of appropriate metal ions are pivotal in achieving coordination complexes with required characteristics [1921]. The triazole heterocyclic compound 1,2,4-triazole is an ideal organic bridging ligand that can be used in constructing coordination polymer materials. Most of its complexes have novel structures and high chemical and thermal stability and are used in selective absorption, magnetism, catalysis, luminescence, DNA binding, and bacteriostatic and anticellular activity [2225]. Cobalt is an intriguing biological element as its biological action is concentrated in the active center of vitamin B12, which modulates DNA synthesis indirectly [26]. Furthermore, at least eight cobalt-dependent proteins were detected. Cobalt is one of the components of the coenzyme vitamin B12, which is available as a vitamin supplement. The bioactivity of cobalt complexes was reported for the first time in 1952. From that time, numerous biologically active cobalt complexes have been reported, among which the most highly structurally characterized cobalt complexes possess antiproliferative, antitumor, antifungal, and antibacterial activities [27,28,29,30].

Hydrogels, whose physical properties are similar to the extracellular matrix, have good biocompatibility and efficient drug loading and release ability [31,32] and have been widely favored by researchers [33,34,35]. Hydrogel materials based on natural polysaccharides can be produced with various cross-linking approaches for various biologic clinical applications, such as wound healing and delivery of drugs or other bioactive factors [36,37]. In recent years, epidermal growth factor (EGF) has been utilized in the development and application of wound repair. EGF has been reported to stimulate the growth and proliferation of a variety of cells [38]. EGF can actively bind to specific receptors on the cell membrane near the wound, thus activating protease, accelerating the production of protein, promoting skin and mucous membrane wound healing and activating scar contraction, controlling the growth of skin deformity, and rapidly repairing the wound [39,40]. Therefore, applying EGF in hydrogels for clinical wound repair has a broad application prospect.

In this study, a novel binuclear cobalt(ii) complex was synthesized. The 1’s structure was identified with XRD, IR spectrum, and EA. Hyaluronic acid (HA) and carboxymethyl chitosan (CMCS) gel particles loaded with epidermal cytokines were successfully prepared by chemical synthesis, and their microstructure and skin wound healing effects were investigated (Scheme 1). HaCaT cells were treated with gel particles of growing concentration. Our results showed that the gel particles enhanced the cell viability. In addition, the gel particles significantly suppressed miR-200b/c levels to induce Rac1 high expression. Compared with molecular dynamics simulation, molecular docking simulation provides an efficient way for sampling local binding interactions between ligands and active sites on target proteins. Therefore, we conducted a molecular docking simulation to investigate the possible activity of a Co complex.

Scheme 1 
               Illustration of healing skin wounds with metal gel particles loaded with epidermal cell growth factor.
Scheme 1

Illustration of healing skin wounds with metal gel particles loaded with epidermal cell growth factor.

2 Experimental

2.1 Materials and physical methods

Materials were sourced from commercial suppliers, and no further purification was required for usage, except where otherwise stated. On a Nicolet Impact 410 FTIR spectrometer (from 400 to 4,000 cm−1), IR spectra were recorded with KBr particles. EA (N, H, and C) were conducted by applying a Perkin Elmer 2400 analyzer. Utilizing the JASCO V-730 UV–vis spectrophotometer (Jasco, Tokyo, Japan), the steady-state absorption along with other electronic bands was recorded. The fluorescence of the powder samples was determined through an RF-5301PC spectrofluorometer utilizing a xenon arc lamp as the light source. Samples’ microstructures were characterized through a field emission scanning electron microscope (FE-SEMS4800, Hitachi). Fluorescence data were measured on a Hitachi F4600 fluorescence spectrophotometer. The testing conditions involved exciting the solid sample powder with a 340 nm excitation wavelength and collecting fluorescence data from 300 to 500 nm.

2.2 Preparation and characterization of [Co2(MBBA)2(HPT)2(H2O)2]·2H2O

A mixture synthesized from 0.1 mmol and 30 mg Co(NO3)2·6H2O, 0.2 mmol and 48.0 mg 2-(4-methylbenzoyl) benzoic acid (MBBA), 14.6 mg and 0.1 mmol 3-(pyridin-2-yl)-1H-1,2,4-triazole (HPT), and 0.2 mmol and 33.4 mg 3,4-pyridine dicarboxylic acid (PDA) was solubilized in a hydrothermal vessel containing mixed solvent (25 mL, water and methanol 4:1, v/v). The pH of the resulting mixture was changed to 6.5 by the addition of ammonium hydroxide, and the reaction was maintained at 433 K for 3 days and thereafter cooled down to RT at a 10 K/h rate. 1’s pink crystals appropriate for XRD were gathered in a yield of 50.4% calculated with HPT. Anal. Calcd. (%) for C44H40Co2N8O10 (958.70): N, 11.58; H, 4.17; C, 54.60. Found (%): N, 11.61; H, 4.18; C, 54.43.

X-ray data were taken from an Oxford Xcalibur E diffractometer, and strength data were examined with CrysAlisPro software and later transformed into HKL files. The establishment and refinement of initial structural models were conducted through the SHELXS program with a direct approach as well as the SHELXL-2014 program with a least-squares approach. Entire non-H atoms were blended with anisotropic parameters, and the AFIX command was employed to fix the entire H-atom geometry to the C-atoms. 1’s refinement details together with its crystallographic parameters are displayed in Table 1.

Table 1

1’s refinement details together with its crystallographic parameters

Empirical formula C44H40Co2N8O10
Formula weight 958.70
Temperature (K) 296.15
Crystal system Monoclinic
Space group P21/c
a (Å) 14.5640(10)
b (Å) 8.6320(13)
c (Å) 18.2490(12)
α (°) 90
β (°) 116.596(4)
γ (°) 90
Volume (Å3) 2051.4(4)
Z 2
ρ calc (g/cm3) 1.552
μ/mm−1 0.881
Data/restraints/parameters 3603/0/296
Goodness-of-fit on F 2 0.858
Final R indexes [I ≥ 2σ(I)] R 1 a = 0.0517, ω R 2 b = 0.0834
Final R indexes [all data] R 1 = 0.1178, ωR 2 = 0.0940
Largest diff. peak/hole/e Å−3 0.83/−0.40

a R 1 = Σ||F o| – |F c||/Σ|F o|. b wR 2 = |Σw(|F o|2 – |F c|2)|/Σ|w(F o)2|1/2, where w = 1/[2(F o 2) + (aP)2 + bP]. P = (F o 2 + 2F c 2)/3.

2.3 Preparation and characterization for metal gel particles loaded with epidermal cell growth factor

First, the Co(ii)-based coordination polymer was ultrasound impregnated in a solution of 2 mg/ml of EGF for 20 min and dried to prepare the drug complex. The EDC/NHS solution was added to 1 wt% HA solution and quickly stirred at RT. Subsequently, the drug complex was added to a solution of CMCS at a concentration of 5 wt%. CMCS solution and HA solution were incorporated into the mold in a volume ratio of 1:1. After the chemical cross-linking was completed, the metal gel particles loaded with epidermal cell growth factor could be prepared by washing with deionized water.

The gel particles were cut before testing, then freeze-dried and sprayed with gold. The sample’s microscopic morphology was visualized with an SEM.

2.4 CCK-8 assay

HaCaT cells were cultured at a 104 cells/well density into 96-well plates with DMEM (100 μL) with 10% fetal bovine serum. Cells were cultivated at 37°C in a CO2 incubator for 1 day. Various concentrations of hydrogels (5, 10, 20, 50, and 100 mM) were added to plates. Incubate the plates in the incubator for 48 h. Subsequently, in each well of the plate, CCK8 solution (10 μL) was added. The plate was subsequently cultured in an incubator for 4 h. The OD values at 450 nm were measured using a microplate reader (ThermoFisher, USA).

2.5 Realtime PCR

Cellular RNA was separated from HaCaT cells using the RNA simple Total RNA Extraction Kit (Tiangen, China). cDNA was acquired via TIAN Script II M-MLV RTase kit (Tiangen, China) following the protocols of the manufacturer. Levels of relative mRNA were determined on an ABI 7500 Realtime PCR system (ABI, USA) utilizing a SuperReal PreMix Plus (SYBR Green) kit. The amplification program included an initial denaturation at 95℃ for 15 min, 40 cycles of 95℃ for 10 s, and 60℃ for 30 s. The calculation of relative mRNA expression was implemented with a 2–∆∆Ct approach with U6 and GAPDH as internal controls for miR-200b/c and Rac1, respectively.

2.6 Simulation details

The C-terminal structural domain of the RNA polymerase (αCTD) is responsible for transcribing genomic information. Such a feature makes it an excellent candidate as a probe for diseases. Thus, it was applied as the target protein for examining the bio-activity of the Co complexes. The αCTD structure was acquired from the protein data bank with a PDB ID of 2MAX [41]. The downloaded structure contained 15 conformations, and the second conformation was subtracted and used directly because the side chain of the second conformation was close to the active cavity. The grid box that covered the active cavity was placed at X, Y, and Z coordinates of 14.1, 22.2, and −7.178 Å, respectively. Given that the active cavity in 2MAX was small, 40 points were used for each direction, and the spaces between them were 0.375 Å. The Co complex contained two ligands: one containing carboxyl and carbonyl groups and the other containing a triazole group. To explore the influence of Co ions on the different functional groups, we separated the Co complex into two fragments, which were allowed to rotate during the molecular docking simulation. The first fragment had five rotatable dihedrals, and the second only had one rotatable dihedral. For both fragments, 50 trials were conducted utilizing a Lamarckian genetic algorithm. AutoDock 4 was adopted for molecular docking simulations, which were visualized via PyMOL 2.3.

3 Results and discussion

3.1 Structural characterization

We used MBBA and HPT as the main ligands and 2,3-pyridinedicarboxylic acid as an auxiliary ligand to react with Co(ii) ions to obtain complexes with novel structures. However, 2,3-pyridine-dicarboxylic acid failed to participate in the coordination. We attempted to prepare complex 1 without using 2,3-pyridine-dicarboxylic acid. Unknown powders were obtained under the same reaction conditions. Complex 1 is a binuclear complex in the P21/c space group. As presented in Figure 1a, complex 1 consisted of two Co(ii) ions, two HPT molecules, two MBBA−1 anions, and two coordinated water molecules. The whole molecule had a symmetric dinuclear structure, where two cobalt atoms were linked to two K2:N1:N2-3-(pyridin-2-yl)-1,2,4-triazole molecules and formed a stable six-membered ring structure. Each Co(ii) coordinates to three O atoms: O(3) and O(2) atoms come from the MBBA anion, and O(7) atoms derived from the water molecule, as well as three N atoms: N(4) atoms come from the pyridine ring, and N(2) and N(1) atoms derived from the triazole ring in each HPT molecule, creating twisted octahedral coordination. The angles and length of bond around Co(ii) were 52.83° (11)–176.12° (14) and 1.955 (2)–2.290 (5) Å, respectively. The Co–N bond length varied from 1.975 to 2.049 Å, with an average of 2.000 Å. These values were approximate to those of similar Co(ii) complexes. The coordination mode of the carboxylate group was bidentate, and the average Co–O (carboxyl) distance was 1.955 (2) and 2.748 Å. Notably, a fundamental binuclear unit Co2(MBBA)2(HPT)2(H2O)2 was composed of two MBBA−1 anions, two molecules of HPT, two Co ions, two coordinated, and two free molecules of water. In addition, one six-membered ring was composed of N(1), N(2), Co(1), N(1 A), N(2 A), and Co(1) atoms, and one five-membered ring consisted of Co(1), N(1), N(2), C(17), and C(18) atoms. In the six-membered ring, the Co(1)···Co(1A) of 3.993 Å had a normal range. Moreover, as shown in Figure 1b, the shortest distance between the aromatic cycles of the MBBA−1 group was 3.847 Å, which was longer than 3.700 Å, indicating that no ππ stacking interaction occurred between the aromatic cycles. The adjacent structures were further connected to each other via H-bond interactions.

Figure 1 
                  (a) 1’s molecular structure. (b) H-bond interactions between neighboring structures.
Figure 1

(a) 1’s molecular structure. (b) H-bond interactions between neighboring structures.

Complex 1 dispersed in methanol (MeOH), so we measured its UV–vis absorption data in a stock solution. Co(ii) complex displayed characteristic electronic transitions at 344, 269, and 230 nm, which were very similar to those of HPT ligands (346, 270, and 230 nm). Figure 2a presents the electronic energy spectrum of the Co(ii) complex and the HPT ligand. The electronic bands at 269 and 230 nm for the Co(ii) complex can be ascribed to the π → π* and n → π* transitions of the azomethine, while the optical band at 344 nm was assigned to the electronic transition within the ligand. The 1’s emission spectra in the solid state were examined at RT (Figure 2b). At 412 nm (λ ex = 330 nm), the emission bands were detectable. The fluorescence emissions may be a π–π* transition within the ligand, as the free HPT ligand has similar wide emissions at 450 nm from the 340 nm excitation wavelength. Compared to the HPT ligand, the 1’s emission band was blue shifted by 38 nm. Such a shift was ascribed to coordination interactions between the ligand and the metal atoms. These emission bands can be separately ascribed to the charge transfer between the ligand and the metal.

Figure 2 
                  (a) UV–vis spectrum of the HPT ligand and 1. (b) Fluorescence of the HPT ligand and 1 in solid state at RT.
Figure 2

(a) UV–vis spectrum of the HPT ligand and 1. (b) Fluorescence of the HPT ligand and 1 in solid state at RT.

3.2 Micromorphology of the drug complex and hydrogels

The microstructure of the drug complex obtained by ultrasonic immersion and drying of the Co complex in a solution of EGF is shown in Figure 3a, and its surface exhibits rough and uneven characteristics due to drug loading. Hydrogels are three-dimensional networks formed by chemical or physical cross-linking of hydrophilic polymer chains. Hydrogels have a controlled porous structure that allows them to easily carry multiple drugs and migrate to given sites for release. The morphology of freeze-dried hydrogel was observed by a scanning electron microscope. As shown in Figure 3, the hydrogels showed a three-dimensional mesh structure with excellent permeability between pores. The hydrogels had good porosity with a pore size distribution of 422.90 ± 2.56 μm, which facilitated the exchange of nutrients and metabolites and also contributed to the increased drug loading.

Figure 3 
                  (a) Microstructure of complex 1. Microstructure (b) and pore size distribution (c) of HA/CMCS hydrogels.
Figure 3

(a) Microstructure of complex 1. Microstructure (b) and pore size distribution (c) of HA/CMCS hydrogels.

3.3 Hydrogels enhanced cell viability of HaCaT cells

To verify whether the hydrogels has cell proliferation-promoting activity in keratin-forming cells, HaCaT cells were treated by hydrogel with growing concentrations for 2 day. The cell viability of HaCaT cells was determined by the CCK-8 assay. Figure 4 shows no evident differences between control and low-dose hydrogels groups (5 and 10 mM). However, the medium and high-dose hydrogels groups significantly upregulated the cellular activity, indicating that hydrogels augmented HaCaT cell viability in a dose-dependent manner.

Figure 4 
                  The effects of hydrogels on the cell viability of HaCaT were measured.
Figure 4

The effects of hydrogels on the cell viability of HaCaT were measured.

3.4 Hydrogels significantly suppressed miR-200b/c and increased Rac1 expressions

To further validate the mechanism of hydrogels-promoted skin wound healing, we examined the major miRNAs and regulatory proteins that affect skin wound healing. As shown in Figure 5a and b, after hydrogel treatment for 48 h, the levels of miR-200c and miR-200b were remarkably decreased compared to the control group. Specifically, it decreases from 1 to 0.65 and 0.70, respectively. However, Rac1 expression showed a dose-dependent increase with increasing hydrogel concentration, demonstrating that hydrogels enhanced Rac1 expression by downregulating the levels of miR-200c and miR-200b.

Figure 5 
                  The effects of hydrogels on the levels of miR-200b (a), miR-200c (b), and Rac 1 (c) were determined by real-time PCR. * expressed P < 0.05, and ** expressed P < 0.01.
Figure 5

The effects of hydrogels on the levels of miR-200b (a), miR-200c (b), and Rac 1 (c) were determined by real-time PCR. * expressed P < 0.05, and ** expressed P < 0.01.

3.5 Molecular docking

A widely used target protein for investigating biological activities, αCTD is responsible for transcribing genomic information, and its principal role is to recruit RNA polymerase to a variety of promoters [31]. The mechanisms underlying the regulation of transcription changed significantly, although the bacteria exerted limited influence on αCTD. Such behavior improved the sensitivity of the signaling effect of αCTD. The binding conformations for two fragments that revealed the minimum binding affinity energy are presented in Figure 6. The estimated affinity energy values were −7.75 kcal/mol (a) and −5.12 kcal/mol (b).

Figure 6 
                  Binding conformations for two fragments that exhibit the lowest binding affinity energies and the estimated inhibition constants are 2.1 (a) and 176.6 (b) μM, respectively. The carbonyl oxygen interacts with the active residue GLN-326.
Figure 6

Binding conformations for two fragments that exhibit the lowest binding affinity energies and the estimated inhibition constants are 2.1 (a) and 176.6 (b) μM, respectively. The carbonyl oxygen interacts with the active residue GLN-326.

Figure 6a shows that carbonyl oxygen interacted with the active residue GLN-326 through hydrogen bonding. The corresponding hydrogen bond length was about 2.4 Å. However, all the polar atoms on the carboxyl group only bound with Co ions and did not interact with surrounding active residues. By contrast, as shown in Figure 6b, the triazole group interacted only with the target protein through electrostatic interaction. Therefore, the carbonyl group was responsible for the biological activity observed in the experiment above.

4 Conclusion

Altogether, we have synthesized a new binuclear cobalt(ii) complex through the reaction of MBBA and HPT in the presence of 3,4-pyridine dicarboxylic acid as the template reagent. 1’s structure was identified with XRD. Metal gel particles loaded with EGF were formed via a chemical synthesis approach. The results of SEM revealed that the gel presented a three-dimensional porous network structure with interconnected holes and good porosity. Treatment of HaCaT cells with various concentrations of gel particles. It increased HaCaT cell viability and downregulated the levels of miR-200c and miR-200b to enhance Rac 1 high expression. The findings of molecular docking simulations suggested that neither the carboxyl group nor the triazole group formed a binding interaction with an active site on the protein. Instead, the carbonyl group was responsible for the observed biological activity.

  1. Funding information: Authors state no financial support.

  2. Author contributions: Yanfeng Bian and Shizhou Liu synthesized and characterized the compounds; Jing Huang and Tianlong Ma performed other experiments.

  3. Conflict of interest: There is no conflict of interest regarding the publication of this paper.

  4. Ethical approval: Research experiments conducted in this article with animals or humans were approved by the Ethical Committee and responsible authorities of our research organization(s) following all guidelines, regulations, legal, and ethical standards as required for humans or animals.

  5. Data availability statement: The data used to support the findings of this study are included within the article.


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Received: 2023-07-21
Revised: 2023-08-28
Accepted: 2023-09-24
Published Online: 2023-11-06

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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