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. 2024 Jan 26;9(5):5854–5861. doi: 10.1021/acsomega.3c09156

Biocompatible, Injectable, and Self-Healing Poly(N-vinylpyrrolidone)/Carboxymethyl Cellulose Hydrogel for Drug Release

Zuwu Tang †, Yuqing Yang †, Yuwei Pan †, Meiqiong Yu †,§,*, Xinxing Lin †,*, Ajoy Kanti Mondal ‡,*
PMCID: PMC10851259  PMID: 38343987

Abstract

graphic file with name ao3c09156_0007.jpg

Hydrogels have drawn intensive attention as fascinating materials for biomedicine. However, fabricating hydrogels with injectable and self-healing properties remains a challenge. Herein, we reported a biocompatible poly(N-vinylpyrrolidone)/carboxymethyl cellulose (PVP/CMC) hydrogel with excellent injectable and self-healing properties. The PVP/CMC hydrogel exhibits good biocompatible, injectable, and self-healing properties. The sol–gel transition of PVP/CMC hydrogels demonstrates an outstanding self-healing behavior, and the bisected hydrogels can self-heal within 30 s. The hydrogels have a good swelling ratio, and the swelling ratio increases with increasing amount of CMC in PVP and reaches a maximum of 2850% at a 1.0:1.5 PVP and CMC ratio. In addition, the hydrogel possesses excellent drug release capacity, and its drug release rate reaches 70%. Moreover, the release of 4-aminosalicylic acid (4-ASA) in the hydrogel can be controlled by adjusting the proportion of the hydrogel. The PVP/CMC hydrogel with excellent biocompatible, injectable, and self-healing properties has great potential for applications in drug release.

1. Introduction

Hydrogels are a class of cross-linked, polymer-based, and hydrophilic three-dimensional (3D) networks comprising a large quantity of water without being dissolved,1−3 which are promising candidates in various biomedical fields, such as tissue engineering4,5 and drug delivery or release.6−9 Self-healable and injectable hydrogels have some special properties compared with conventional injectable hydrogels because they can be injected by employing force and rapid recovery to the integral hydrogel phase.10 Self-healable and injectable hydrogels can automatically recover damage and sustain their lifetime during application.11 Additionally, compared with pre-existing drug delivery hydrogel systems,12 the engineered hydrogel formulations were expected to combine the advantages of each of the components in hydrogels and to have superior integrated properties. Moreover, the self-healing and injectable hydrogels have several benefits during the application, such as avoiding the possible risks of drug diffusion to efficiently employ the drug and decreasing toxicity to normal tissues.13 Therefore, it is still a practical demand to construct a kind of hydrogel with self-healing, injectability, and biocompatibility that can be applied to biomedical applications.

Carboxymethyl cellulose (CMC), a water-soluble cellulose derivative,14 can be developed by the etherification of alkaline cellulose together with the sodium salt of monochloroacetic acid.15 CMC is one of the amplest natural polymers and has been conceived as a nearly inexhaustible origin of raw material for the increasing necessity for biocompatible materials.16 Moreover, CMC also has significant fascinating characteristics, including inexpensiveness, excellent biocompatibility, biodegradability, high stability, and low immunogenicity.17,18 As one of the promising candidates, it has been extensively utilized for preparing hydrogels, which are widely used in bioengineering and drug delivery.19−26

Poly(N-vinylpyrrolidone) (PVP), a biocompatible and biodegradable macromolecule,27 has the same properties as CMC in terms of biological views.28 Moreover, PVP possesses tertiary amide groups, which could supply different hydrogen-acceptable sites to form hydrogen bonds with hydrogen bondable species, resulting in an increase in mechanical properties.29−31 Therefore, PVP can be considered an effective alternative.32−34

In this work, our aim was to prepare a PVP/CMC hydrogel with biocompatible, injectable, and self-healing properties in the presence of N,N′-methylenebis(acrylamide) (MBA) as a cross-linker and potassium persulfate (KPS) as an initiator, which could be used for drug loading and release with 4-ASA. In comparison with pre-existing drug delivery hydrogel systems, the engineered hydrogel formulations were expected to combine the advantages of each of the above two components and to have superior integrated properties such as good morphologies, hygroscopicity, porosity, biocompatibility, injectability, and self-healing that are especially beneficial to drug loading and release. The results showed that the porosity and swelling depend on the hydrogel composition and the release behaviors depend on the pH and the hydrogel composition as well as the specific interactions among the components of the hydrogel. It was expected that PVP and CMC would be reciprocal, and the mixture could overcome the poor mechanical strength of single-component hydrogels to extend the applications of hydrogels as a promising strategy for drug delivery.

2. Experiments

2.1. Materials

Poly(N-vinylpyrrolidone) (PVP, Mw = 1,300,000), carboxymethyl cellulose (CMC, Mw = 250,000), potassium persulfate (KPS), N,N′-methylenebis(acrylamide) (MBA), 4-aminosalicylic acid (4-ASA), and phosphate-buffered saline (PBS) were purchased from Aladdin (Shanghai, China). The agents were of analytical grade and used as received. Throughout the experiments, ultrapure water with a specific resistance of 18.25 MΩ·cm was used.

2.2. Preparation of PVP/CMC Hydrogels

According to the previously reported literature,12 the PVP/CMC hydrogels with different CMC contents were manufactured as follows. At first, a 10% PVP solution and a 1% CMC solution were prepared by dissolving 1.0 g of PVP in 10 mL of water and 1.0 g of CMC in 100 mL of water, respectively. Second, a CMC solution with different CMC contents (0.5, 1.0, and 1.5 g) was added to the PVP solution, and 0.02 g of KPS and 0.05 g of MBA were then added to the PVP/CMC complex mixture, which was continuously stirred for 30 min to form a homogeneous solution. Lastly, the PVP/CMC hydrogels were prepared at 70 °C for 30 min. The hydrogels prepared using 0.5, 1.0, and 1.5 g of CMC were denoted PVP/CMC0.5, PVP/CMC1.0, and PVP/CMC1.5, respectively.

2.3. Characterization

The morphology of the PVP/CMC hydrogel was monitored by a scanning electron microscope (SEM, JEOL, JSM-5600 V, Japan) with a 10 kV acceleration voltage. Before observation, the PVP/CMC hydrogel was freeze-dried and sprayed by galvanic platinum deposition with a current of 5 mA for 90 s.

The pore size distribution of the PVP/CMC hydrogel was measured from the 77 K N2 isotherm by an ASAP 2020 (Quantachrome Ins) device.

The dynamic rheological properties of the prepared PVP/CMC hydrogel were measured by using a stress-controlled rheometer Rotational Rheometer MARS III Haake (MARS III, Germany) by frequency sweeps at angular velocities ranging from 0.1 to 10 Hz. The storage moduli (G′) and loss moduli (G″) of the hydrogel were analyzed. Then, the creep recovery performance of the PVP/CMC hydrogel was also examined by changing the amplitude of the oscillating force.

2.4. Porosity

The porosity of the PVP/CMC hydrogel was tested. The weight of the dry samples was recorded in m1. Then, a pycnometer was loaded with ultrapure water, which was recorded as m2. The hydrogel samples were put into the pycnometer, which was plunged with ultrapure water, then loaded with water, and recorded as m3. The hydrogel samples loaded with water were taken out, and the left water and the pycnometer were recorded as m4. The porosity (ε) was calculated by eq 1:35

2.4. 1

2.5. Swelling Ratio (SR)

The swelling ratio of the hydrogel is an important parameter that was evaluated by a simple calculation. At first, the dry weight of the hydrogels was measured (m0). Then, the sample was immersed in ultrapure water at different times. The weight of the swollen samples was measured (mt). The swelling ratio (SR) was calculated by following eq 2:36

2.5. 2

2.6. Drug Loading and Release

4-ASA was used as the drug model. The hydrogels were placed in a flask containing 20 mL of a 4-ASA solution at 1 mg/mL. The samples were stirred at 100 rpm at 35 °C for 24 h. The concentrations of 4-ASA in aqueous solutions were determined at definite time intervals by using a UV–vis spectrometer (Shimadzu UV3600, Japan). Figure S1 represents the standard curves of 4-ASA at pH = 2.0 and pH = 7.4. The drug loading rate was calculated by eq 3:37

2.6. 3

where Rt is the drug loading rate of the hydrogels, M0 is the mass of the drug contained in the hydrogels, and Md is the mass of the dry hydrogels.

The hydrogels containing drugs were weighed, which were added to 20 mL of water. The samples were stirred at 100 rpm at 37 °C, which was measured at certain intervals. The cumulative release rate was calculated by eq 4:

2.6. 4

where Ra represents the drug release rate of hydrogels, Mb represents the mass of the drug released from the hydrogel, and M0 represents the total mass of the drug contained in the hydrogels.

2.7. Biocompatibility Test

A biocompatibility test was performed in a CO2 atmosphere at 37 °C, where NIH-3T3 cells (SCSP-515, Stem Cell Bank, Shanghai, China) were cultured in Dulbecco’s minimum essential medium (DMEM, HyClone) bearing 10% fetal bovine serum (FBS, HyClone) and 1% antibiotic (Gibco). At first, the hydrogels were cut in a dimension of 2 × 1 × 1 mm and washed with PBS and UV-sterilized for 30 min. Afterward, the cells on the hydrogels were cultured into 96-well plates following a concentration of 105 cells/well. The cells were subsequently cultured for 1 and 5 days, and the growth of the cells was measured by applying the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (Sigma). Finally, relative cell viability was calculated by following eq 5:38

2.7. 5

where Aadhesive and Acontrol are the absorbances of cells cultured in the adhesive and in the cell culture medium, respectively.

3. Results and Discussion

3.1. Preparation and Characterization of PVP/CMC Hydrogels

The process of PVP/CMC hydrogels is depicted in Figure 1A, which were prepared with different concentrations of PVP and CMC solutions using MBA as a cross-linker and PPS as an initiator. Additionally, the interaction between PVP and CMC based on hydrogen bonds is formed. The hydroxyl and carboxyl groups in CMC are the hydrogen donors, and the tertiary amide and carbonyl groups in PVP are the hydrogen acceptors. Therefore, a cross-linking between CMC and MBA and hydrogen bonds between PVP and CMC are generated to form the PVP/CMC hydrogel.

Figure 1.

Figure 1

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(A) Preparation of the PVP/CMC hydrogel. (B) SEM image of the PVP/CMC1.0 hydrogel. The inset in (B) is the image of the pore size distribution of the PVP/CMC1.0 hydrogel. (C) Porosity of PVP/CMC hydrogels.

The PVP/CMC1.0 hydrogel was selected as an example for SEM analysis. The morphology of the PVP/CMC1.0 hydrogel is shown in Figure 1B, and the PVP/CMC1.0 hydrogel exhibited a 3D porous structure, which presented an irregular porous structure and rough surface. This is because the PVP/CMC hydrogel is frozen, the water solidifies directly into ice crystals, and the phase is separated from the PVP/CMC hydrogel. In the process of freeze-drying, a large number of ice crystals directly sublimate into water vapors. Therefore, this results in the formation of porous structures in the position of the original ice crystals. To further confirm the size of the PVP/CMC hydrogel, the Brunauer–Emmett–Teller (BET) method was used. The pore size distribution of the PVP/CMC hydrogel presents a large range of 20–210 μm with a large number of macropores (Figure 1B), indicating typical macroporous properties. These macroporous morphologies are very conducive to the diffusion of water or drug molecules into or out of the hydrogel networks.

Additionally, the porosity of the PVP/CMC hydrogel was also studied. The porosity of PVP/CMC0.5, PVP/CMC1.0, and PVP/CMC1.5 hydrogels is shown in Figure 1C. For the PVP/CMC0.5 hydrogel, the porosity is (82 ± 6)%, while for PVP/CMC1.0 and PVP/CMC1.5 hydrogels, the porosity is 85 ± 8% and 87 ± 7%, respectively. These findings clearly show that the porosity of PVP/CMC hydrogels depends on the characteristics of the chemical structure and the system feed ratio. Large porosity can increase the specific surface area of the hydrogel, which is conducive to drug adsorption. Meanwhile, drug release also depends on a porous structure with high porosity. Therefore, the PVP/CMC hydrogels are more suitable for the controlled release of drugs.

3.2. Properties of PVP/CMC Hydrogels

Before testing the self-healing properties of the PVP/CMC hydrogel, the hydrogels were cut into two separate parts with the help of a knife. Then, the separated parts of the hydrogels were put in close contact, and self-healing performances were detected at room temperature, as shown in Figure 2A. Interestingly, the two parts of separated hydrogels completely recontacted to a single hydrogel within a very short time (∼30 s) without applying any external force. This is because when a crack occurs, the hydrogen bonding breaks, and free carbonyl, amine, and carboxyl groups are exposed at the interfaces. The exposed carbonyl, amine, and carboxyl groups could reform new hydrogen bonding owing to their dynamic and reversible properties, which make the hydrogel recover from the crack. In addition, the PVP/CMC hydrogel can be smoothly extruded by a syringe, and the PVP/CMC hydrogel can be injected into an expected shape, such as “FAFU”, as demonstrated in Figure 2B. This result shows that our PVP/CMC hydrogels were injectable. The letters containing hydrogel fragments could become smooth at room temperature without any external interventions, which shows the excellent self-healing capability of the hydrogels. Thus, the self-healable and injectable PVP/CMC hydrogels are anticipated to be employed in different areas, including bioengineering and drug release.

Figure 2.

Figure 2

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(A) Self-healing procedure of the PVP/CMC1.0 hydrogel after recovery. (B) Injecting the PVP/CMC1.0 hydrogel into an FAFU shape through a syringe.

3.3. Rheological Behaviors

In order to characterize the rheological property of the PVP/CMC hydrogel, G′ and G″ of the hydrogel with different CMC contents were assessed, as demonstrated in Figure 3. The G′ curves of all PVP/CMC hydrogels exhibited plateau-like behavior (Figure 3A), indicating the rubbery plateau region of the gel network. This can be attributed to the cross-linking structure generated by CMC, PVP, and MBA. G′ of the PVP/CMC hydrogel was higher than G″, showing a gel network with elastic nature rather than viscous behavior.39 Compared to G″ at high frequency, G″ is lower at low frequency. For this reason, the PVP/CMC hydrogels may have sufficient time to relax. Additionally, with the increase in CMC content, the modulus of the hydrogel gradually increased. This is because more carboxyl and hydroxyl groups in CMC provided a greater chance to form hydrogen bonds, and the increase in the degree of cross-linking restricts the mobility of macromolecular chains.

Figure 3.

Figure 3

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(A) G′ and G″ of the PVP/CMC hydrogels. (B) G′ and G″ of PVP/CMC1.0 hydrogels under different shear stresses.

Figure 3B shows the creep recovery property of the hydrogel. The result demonstrated that when the oscillatory strain was switched from 1 to 500%, G′ of the hydrogel reduced instantly and was less than the G″. The highest G″ suggested that the hydrogel was in a quasi-liquid state. The high shear stress broke the hydrogel structure, pondering the breakage of interactions among CMC and PVP. Nevertheless, once the external strain returns to 1%, G′ and G″ of the hydrogel are instantly restored to the original gel-like state. This sol–gel conversion presented the fact that PVP/CMC hydrogels have outstanding self-healing behavior.

3.4. Swelling Behavior

The swelling property is an important indicator for evaluating the water absorption capacity of hydrogels, and the absorption and retention of a large amount of water are important features of hydrogels. Figure 4 shows the swelling curves of hydrogels of different CMC contents in ultrapure water, indicating the changes in the swelling behavior of hydrogels composed of different proportions of PVP and CMC. It can be seen from the figure that the swelling ratio of the resultant hydrogels is increased with the increase in CMC. As the proportion of CMC increases, the swelling ratio gradually increases. When the PVP and CMC ratio is 1.0:1.5, the maximum swelling ratio obtained is 2850%. This is because as the amount of CMC increases, more hydrophilic substances are added to the PVP/CMC hydrogel, leading to an increase in the swelling ratio. These results indicate that the properties of the hydrogels are directly related to the system components and the feed ratio and thus can be readily mediated by regulating the hydrogel components. It would be logical for the hydrogels to make it easier for water to diffuse into or out of their networks during the reswelling and deswelling processes.

Figure 4.

Figure 4

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Swelling ratio of the PVP/CMC hydrogels.

3.5. Biocompatibility

Because it is applied to the human body as a carrier of drugs, biocompatibility is evaluated using NIH-3T3 cells. The PVP/CMC1.0 hydrogel was selected as an example to evaluate its biocompatibility. As shown in Figure 5, a blank group is maintained as a control for comparison. Results demonstrated that after 1 day of culture, the relative cell viability is obtained at 97% for the PVP/CMC hydrogel. After 5 days of culture, the relative cell viability is 95% for the PVP/CMC hydrogel. Both of the results indicated that the cell viability is higher than 70%.40,41 Therefore, the biocompatibility tests evidenced that the prepared PVP/CMC hydrogel is nontoxic and biocompatible. It is understandable that both the biocompatible CMC and PVP lead to biocompatible hydrogels. The hydrogels may be good materials for biomedical applications.

Figure 5.

Figure 5

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Relative cell viability of the prepared PVP/CMC1.0 hydrogel.

3.6. Drug Loading and Release

Because of the outstanding physicochemical properties of hydrogels, they have been extensively investigated as potential drug delivery carriers. However, the drug release performances of the hydrogel matrices are involved in several factors, including network porosity, swelling performances, and the interactions among the drug and the polymer chains in the hydrogel network.12

4-ASA is a white or yellowish powder, which can also decompose under exposition to moisture or heat.42 It is an antibiotic used for the treatment of tuberculosis and inflammatory bowel diseases, especially in ulcerative colitis and Crohn’s disease. Additionally, 4-ASA salts have also been reported to reduce the gastrointestinal side effects associated with 4-ASA. Moreover, the amphoteric nature of the small drug molecule is highly dependent on the pH of the aqueous system. Therefore, 4-ASA was selected as a water-soluble drug model in this present work, and then its drug loading and release profiles were evaluated from PVP/CMC hydrogels in PBS buffer solutions under different pH conditions (pH = 2.0 and 7.4) at 37 °C. The schematic diagram of PVP/CMC hydrogel drug loading and release is shown in Figure 6A. With the increase in CMC content, the loading rate of the PVP/CMC hydrogels increased in the same drug solution (Figure 6B,C). This is because as the proportion of CMC is increased, more carboxyl and hydroxyl groups in the PVP/CMC hydrogels can form hydrogen bonds with the amino group in 4-ASA, resulting in an increase in the drug loading. When the CMC content is 1.0 g, the drug loading of the PVP/CMC hydrogel is 2.5 in a pH = 2.0 PBS buffer solution (Figure 6B) and 3.5 in a pH = 7.4 PBS buffer solution (Figure 6C). The drug loading of the PVP/CMC hydrogel in the pH = 7.4 PBS buffer solution was higher than that in the pH = 2.0 PBS buffer solution. This is because acidic media may inhibit the formation of hydrogen bonds between CMC and 4-ASA.

Figure 6.

Figure 6

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(A) Schematic diagram of the PVP/CMC hydrogel drug loading and releasing. The curve of the hydrogel loading with different CMC contents in PBS at (B) pH = 2.0 and (C) pH = 7.4. The curve of 4-ASA in different hydrogels’ accumulated release with time in PBS at (D) pH = 2.0 and (E) pH = 7.4.

Additionally, the drug release of the PVP/CMC hydrogels is also studied, as shown in Figure 6D,E. The PVP/CMC hydrogels in the pH = 7.4 PBS buffer solution generally have a higher drug release rate than that in the pH = 2.0 PBS buffer solution at the same time. In the pH = 2.0 PBS buffer solution, the release rate of the PVP/CMC1.5 hydrogel is only 50% (Figure 6D), while in the pH = 7.4 PBS buffer solution, the release rate can reach 70% (Figure 6E). This is because the protonation of carboxyl groups in the CMC can form the hydrophobic groups in an acidic environment, resulting in the increase of the hydrophobicity of the PVP/CMC hydrogels. The network structure of the PVP/CMC hydrogels is easy to shrink, and the mesh becomes smaller, which makes it difficult for the drug to diffuse out of the mesh. However, the contraction originating from these interactions disappears at pH 7.4 due to the presence of stronger electrostatic repulsion among more ions. As a result, PVP/CMC hydrogels have a higher drug release rate at pH = 7.4. Moreover, with the increase in the CMC content, the drug release rate also gradually increases. These results show that the PVP/CMC hydrogel has excellent drug release. Therefore, we can conclude that the loading and release of 4-ASA from PVP/CMC hydrogels are dependent on the pH and can be tuned by altering the PVP/CMC hydrogel composition appropriately.

Compared with other types of hydrogels, the drug release of the CMC/PAM/PVP semi-IPN hydrogel with a PVP content of 19.0% was 15.5% at pH 1.4 and 24.2% at pH 7.4 when theophylline was used as the model drug.12 Moreover, chitosan-5-ASA conjugates were used for colon-specific drug delivery.43 Sulfasalazine released approximately 70% of the 5-ASA load in simulated colonic fluid (pH = 7.4) containing rat colon content in 24 h, whereas the chitosan-5-ASA azoconjugates released around 25% of the drug load over the same time period. These results exhibited that the PVP/CMC hydrogels had excellent drug release.

PBS buffer solutions (pH = 2.0 and 7.4) simulate artificial gastric liquid and artificial intestinal liquid, respectively. It is proven that the drug release rate of the hydrogel in intestinal liquid is higher than that in gastric liquid, which could make the drug continue to play and prolong the drug action time. They have potential applications in the biomedical field.

4. Conclusions

In summary, we presented a biocompatible, injectable, and self-healing PVP/CMC hydrogel. The hydrogel exhibits good self-healability, injectability, and biocompatible properties. Rheological behaviors showed that the gel network of the hydrogel possessed an elastic nature rather than viscous behavior. The sol–gel transition of PVP/CMC hydrogels presented an outstanding self-healing behavior, and the bisected hydrogels could rapidly self-heal within 30 s. The hydrogels had a good swelling ratio, and the swelling ratio increased with increasing amount of CMC in PVP and reached a maximum of 2850% at a 1.0:1.5 PVP and CMC ratio. In addition, the hydrogel possesses excellent drug release; its drug release rate reaches 70%. Moreover, the release of 4-ASA from a hydrogel can be controlled by maintaining the composition of the hydrogel in a buffer solution at pH = 7.4 and 37 °C. These results indicate that our prepared hydrogel has potential applications in biomedicine.

Acknowledgments

This work was supported by the Natural Science Foundation of Fujian Province (2023J05212 and 2021J05270) and the Education and Scientific Research Project for Young and Middle-aged Teachers of Fujian Province, China (JAT220249).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c09156.

  • Standard curve of the 4-ASA solution under different conditions (PDF)

Author Contributions

Z.T. contributed to visualization, investigation, data curation, and writing—original draft preparation. Y.Y., Y.P., M.Y., and X.L. contributed to investigation and validation. A.K.M. contributed to conceptualization, validation, and writing—reviewing and editing. This manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ao3c09156_si_001.pdf (44.8KB, pdf)

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