Optimization of Chitosan-PEG/ZnO Hydrogel Formulation with Pomegranate Peel Extract as an Alternative for Wound Healing

Niamul Faza Assauqi; Retno Ariadi Lusiana; Nanang Masruchin

doi:10.22146/ijc.105215

Optimization of Chitosan-PEG/ZnO Hydrogel Formulation with Pomegranate Peel Extract as an Alternative for Wound Healing

https://doi.org/10.22146/ijc.105215

Niamul Faza Assauqi⁽¹⁾, Retno Ariadi Lusiana^(2*), Nanang Masruchin⁽³⁾

(1) Department of Chemistry, Faculty of Science and Mathematics, Diponegoro University, Jl. Prof. Soedharto SH, Tembalang, Semarang 50275, Indonesia
(2) Department of Chemistry, Faculty of Science and Mathematics, Diponegoro University, Jl. Prof. Soedharto SH, Tembalang, Semarang 50275, Indonesia
(3) Research Center for Biomass and Bioproducts, National Research and Innovation Agency (BRIN), KST Soekarno, Cibinong 16911, Indonesia
(*) Corresponding Author

Abstract

A chitosan-zinc oxide (ZnO)/poly(ethylene glycol) (PEG)/pomegranate peel extract (PE) based hydrogel has been developed as a potential material to accelerate the wound healing process by controlling the drug release mechanism. ZnO nanoparticles with an average size of about 95 nm were synthesized using the coprecipitation method and then combined into chitosan/PEG composites to improve the antimicrobial properties of the hydrogels. Characterization of the hydrogels included analysis of size, morphology, elemental composition, microstructure, swelling behavior, antibacterial activity, and wound healing effectiveness. The results of the in vitro study indicated that the antibacterial activity of PE-containing hydrogel against Escherichia coli and Staphylococcus aureus decreased due to the chelation effect caused by PE addition. However, in vivo tests for 10 d showed that the PE-containing hydrogel had better wound healing ability than commercial betadine. In addition, the developed hydrogel showed high biocompatibility with excellent antibacterial activity. This study confirmed that chitosan/PEG/ZnO nanoparticle hydrogel has the potential as wound dressing materials with sustained drug release and optimal healing effectiveness.

Keywords

hydrogel; chitosan; pomegranate peel extract; ZnO; wound healing

Full Text:

Full Text PDF

References

[1] Fadhil, I.A., Aldabbagh, B.M.D., and Mahdi, W.T., 2023, Preparing chitosan hybrid nanocomposites by novel additives for wound healing, J. Polym. Compos., 11 (2), 9–23.

[2] Sharmila, G., Muthukumaran, C., Kirthika, S., Keerthana, S., Kumar, N.M., and Jeyanthi, J., 2020, Fabrication and characterization of Spinacia oleracea extract incorporated alginate/carboxymethyl cellulose microporous scaffold for bone tissue engineering, Int. J. Biol. Macromol., 156, 430–437.

[3] Siahaan, P., Sasongko, N.A., Lusiana, R.A., Prasasty, V.D., and Martoprawiro, M.A., 2021, The validation of molecular interaction among dimer chitosan with urea and creatinine using density functional theory: In application for hemodyalisis membrane, Int. J. Biol. Macromol., 168, 339–349.

[4] Lusiana, R.A., Sangkota, V.D.A., Sasongko, N.A., Santosa, S.J., and Othman, M.H.D., 2019, Chitosan based modified polymers designed to enhance membrane permeation capability, IOP Conf. Ser.: Mater. Sci. Eng., 509 (1), 012122.

[5] Lusiana, R.A., Nuryanto, R., Muna, N., Dayanti, D., Gunawan, G., Kiswandono, A.A., Annisa, R.N., Septevani, A.A., and Sasongko, N.A., 2024, High-performance sulfonated polyether sulfone/chitosan membrane on creatinine transport improved by lithium chloride, Int. J. Biol. Macromol., 261, 129784.

[6] Ghimire, S., Sarkar, P., Rigby, K., Maan, A., Mukherjee, S., Crawford, K.E., and Mukhopadhyay, K., 2021, Polymeric materials for hemostatic wound healing, Pharmaceutics, 13 (12), 2127.

[7] Masud, R.A., Islam, M.S., Haque, P., Khan, M.N.I., Shahruzzaman, M., Khan, M., Takafuji, M., and Rahman, M.M., 2020, Preparation of novel chitosan/poly (ethylene glycol)/ZnO bionanocomposite for wound healing application: Effect of gentamicin loading, Materialia, 12, 100785.

[8] Hosseini, S., Eslahi, N., and Jahanmardi, R., 2023, Self-healing nanocomposite hydrogels based on chitosan/modified polyethylene glycol/graphene, Mater. Today Commun., 37, 107417.

[9] Safitri, B., Hudiyanti, D., Laksitorini, M.D., Sasongko, N.A., and Siahaan, P., 2020, Intermolecular hydrogen bond interactions in N-carboxymethyl chitosan and nH₂O: DFT and NBO studies, AIP Conf. Proc., 2237 (1), 020081.

[10] Lusiana, R.A., Nuryanto, R., Dayanti, D., Khabibi, K., Wijayati, N., Sasongko, N.A., and Wijaya, A.R., 2023, Synthesis and characterization of chitosan/polyvinyl alcohol immersed in sodium hydroxide thin film as a heterogeneous catalyst in biodiesel production, Int. J. Biol. Macromol., 251, 126378.

[11] Lusiana, R.A., Sangkota, V.D.A., Sasongko, N.A., Gunawan, G., Wijaya, A.R., Santosa, S.J., Siswanta, D., Mudasir, M., Abidin, M.N.Z., Mansur, S., and Othman, M.H.D., 2020, Permeability improvement of polyethersulfone-polietylene glycol (PEG-PES) flat sheet type membranes by tripolyphosphate-crosslinked chitosan (TPP-CS) coating, Int. J. Biol. Macromol., 152, 633–644.

[12] Seidi, F., Khodadadi Yazdi, M., Jouyandeh, M., Dominic, M., Naeim, H., Nezhad, M.N., Bagheri, B., Habibzadeh, S., Zarrintaj, P., Saeb, M.R., and Mozafari, M., 2021, Chitosan-based blends for biomedical applications, Int. J. Biol. Macromol., 183, 1818–1850.

[13] Lusiana, R.A., Indra, A., Prasetya, N.B.A., Sasaongko, N.A., Siahaan, P., Azmiyawati, C., Wijayanti, N., Wijaya, A.R., and Othman, M.H.D., 2021, The effect of temperature, sulfonation, and PEG addition on physicochemical characteristics of PVDF membranes and its application on hemodialysis membrane, Indones. J. Chem., 21 (4), 942–953.

[14] Lusiana, R.A., Sasongko, N.A., Sangkota, V.D.A., Prasetya, N.B.A., Siahaan, P., Kiswandono, A.A., and Dzarfan, M.H., 2020, In-vitro study of polysulfone-polyethylene glycol/chitosan (PEG-PSf/CS) membranes for urea and creatinine permeation, J. Kim. Sains Apl., 8 (23), 283–289.

[15] Raina, N., Singh, A.K., and Islam, A., 2021, “Biological Implications of Polyethylene Glycol and PEGylation: Therapeutic Approaches Based on Biophysical Studies and Protein Structure-Based Drug Design Tools” in Innovations and Implementations of Computer Aided Drug Discovery Strategies in Rational Drug Design, Eds. Singh, S.K., Springer Singapore, Singapore, 273–294.

[16] Yadollahi, M., Farhoudian, S., Barkhordari, S., Gholamali, I., Farhadnejad, H., and Motasadizadeh, H., 2016, Facile synthesis of chitosan/ZnO bio-nanocomposite hydrogel beads as drug delivery systems, Int. J. Biol. Macromol., 82, 273–278.

[17] Liang, Y., He, J., and Guo, B., 2021, Functional hydrogels as wound dressing to enhance wound healing, ACS Nano, 15 (8), 12687–12722.

[18] Sulaiman, R., Ghaffar, A., Preveen, S., Ashraf, D., Tariq, I., Kinza, K., and Shakir, T., 2023, Synthesis, characterization, and biomedical applications of zinc oxide nanoparticles, BME Horiz., 1 (3), 89.

[19] Ramesh, K., Ponnusamy, J., and Periasamy, P., 2024, Synthesis of antimicrobial and antioxidant zinc oxide hydrogel for drug delivery applications, Indones. J. Chem., 24 (6), 1615–1627.

[20] Gassim, F.A.Z.G., and Makkawi, A.J.J., 2023, Anticancer Activity of Synthesized ZnO and ZnO/AgCl Nanocomposites against Five Human Cancer Cells, Indones. J. Chem., 23 (2), 333–340.

[21] Emam-Djomeh, Z., and Hajikhani, M., 2023, “Chitosan/Poly (Ethylene Glycol)/ZnO Bionanocomposite for Wound Healing Application” in Biodegradable and Environmental Applications of Bionanocomposites, Eds. Visakh, P.M., Springer International Publishing, Cham, Switzerland, 31-65.

[22] Prasad, A.S., and Bao, B., 2019, Molecular mechanisms of zinc as a pro-antioxidant mediator: Clinical therapeutic implications, Antioxidants, 8 (6), 164.

[23] Gao, X., Xu, Z., Liu, G., and Wu, J., 2021, Polyphenols as a versatile component in tissue engineering, Acta Biomater., 119, 57–74.

[24] Qahir, A., Kakar, A.U.R., Khan, N., Samiullah, S., Hakeem, A., Kamal, R., and Ur-Rehman, F., 2021, The antioxidant, antimicrobial, and clinical effects with elemental contents of pomegranate (Punica granatum) peel extracts: A review, Baghdad J. Biochem. Appl. Biol. Sci., 2 (1), 21–28.

[25] Mo, Y., Ma, J., Gao, W., Zhang, L., Li, J., Li, J., and Zang, J., 2022, Pomegranate peel as a source of bioactive compounds: A mini review on their physiological functions, Front. Nutr., 9, 887113.

[26] Saigl, Z.M., and Ahmed, A.M., 2021, Separation of rhodamine B dye from aqueous media using natural pomegranate peels, Indones. J. Chem., 21 (1), 212–224.

[27] Purwaningsih, S.Y., Pratapa, S., Triwikantoro, T., and Darminto, D., 2016, Synthesis of nano-sized ZnO particles by co-precipitation method with variation of heating time, AIP Conf. Proc., 1710 (1), 030040.

[28] Gallas, J.A., Pelozo, L.L., Oliveira, W.P., Salvador, S.L., Corona, S.M., and Souza-Gabriel, A.E., 2023, Characterization, antimicrobial activity, and antioxidant efficacy of a pomegranate peel solution against persistent root canal pathogens, Cureus, 15 (8), e43142.

[29] Safdar, M.N., Kausar, T., Jabbar, S., Mumtaz, A., Ahad, K., and Saddozai, A.A., 2017, Extraction and quantification of polyphenols from kinnow (Citrus reticulate L.) peel using ultrasound and maceration techniques, J. Food Drug Anal., 25 (3), 488–500.

[30] Lusiana, R.A., Protoningtyas, W.P., Wijaya, A.R., Siswanta, D., Mudasir, M., and Santosa, S.J., 2017, Chitosan-tripoly phosphate (CS-TPP) synthesis through cross-linking process: The effect of concentration towards membrane mechanical characteristic and urea permeation, Orient. J. Chem., 33 (6), 2913–2919.

[31] Shafiq, M., Yasin, T., Aftab Rafiq, M., and Shaista, S., 2013, Structural, thermal, and antibacterial properties of chitosan/ZnO composites, Polym. Compos., 35 (1), 79–85.

[32] Wang, L.C., Chen, X.G., Zhong, D.Y., and Xu, Q.C., 2007, Study on poly(vinyl alcohol)/carboxymethyl-chitosan blend film as local drug delivery system, J. Mater. Sci.: Mater. Med., 18 (6), 1125–1133.

[33] Bhowmik, S., Islam, J.M.M., Debnath, T., Miah, M.Y., Bhattacharjee, S., and Khan, M.A., 2017, Reinforcement of gelatin-based nanofilled polymer biocomposite by crystalline cellulose from cotton for advanced wound dressing applications, Polymers, 9 (6), 222.

[34] Rowland, M.B., Moore, P.E., Bui, C., and Correll, R.N., 2023, Assessing wound closure in mice using skin-punch biopsy, STAR Protoc., 4 (1), 101989.

[35] Patra, P., Mitra, S., Debnath, N., Pramanik, P., and Goswami, A., 2014, Ciprofloxacin conjugated zinc oxide nanoparticle: A camouflage towards multidrug resistant bacteria, Bull. Mater. Sci., 37 (2), 199–206.

[36] Babayevska, N., Przysiecka, Ł., Iatsunskyi, I., Nowaczyk, G., Jarek, M., Janiszewska, E., and Jurga, S., 2022, ZnO size and shape effect on antibacterial activity and cytotoxicity profile, Sci. Rep., 12 (1), 8148.

[37] Clogston, J.D., and Patri, A.K., 2011, Zeta potential measurement, Methods Mol. Biol., 697, 63–70.

[38] Krishnakumar, V., and Elansezhian, R., 2021, Dispersion stability of zinc oxide nanoparticles in an electroless bath with various surfactants, Mater. Today: Proc., 51, 369–373.

[39] Khorasani, M.T., Joorabloo, A., Moghaddam, A., Shamsi, H., and MansooriMoghadam, Z., 2018, Incorporation of ZnO nanoparticles into heparinised polyvinyl alcohol/chitosan hydrogels for wound dressing application, Int. J. Biol. Macromol., 114, 1203–1215.

[40] Eichholz, K.F., Freeman, F.E., Pitacco, P., Nulty, J., Ahern, D., Burdis, R., Browe, D.C., Garcia, O., Hoey, D.A., and Kelly, D.J., 2022, Scaffold microarchitecture regulates angiogenesis and the regeneration of large bone defects, Biofabrication, 14 (4), 045013.

[41] Wang, C., Feng, L., Yang, H., Xin, G., Li, W., Zheng, J., Tian, W., and Li, X., 2012, Graphene oxide stabilized polyethylene glycol for heat storage, Phys. Chem. Chem. Phys., 14 (38), 13233–13238.

[42] Safdar, M., Naqvi, S.A., Anjum, F., Pasha, I., Shahid, M., Waliullah, W., Jaskani, M.J., Khan, I.A., and Aadil, R.M., 2021, Microbial biofilm inhibition, antioxidants, and chemical fingerprints of Afghani pomegranate peel extract documented by gas chromatography–mass spectrometry and Fourier transformation infrared, J. Food Process. Preserv., 45 (7), e15657.

[43] Chamkouri, H., and Chamkouri, M., 2021, A review of hydrogels, their properties and applications in medicine, Am. J. Biomed. Sci. Res., 11 (6), 485–493.

[44] Maiz-Fernández, S., Pérez-Álvarez, L., Silván, U., Vilas-Vilela, J.L., and Lanceros-Mendez, S., 2022, Photocrosslinkable and self-healable hydrogels of chitosan and hyaluronic acid, Int. J. Biol. Macromol., 216, 291–302.

[45] Mahmud, M., Daik, R., and Adam, Z., 2018, Influence of poly(ethylene glycol) on the characteristics of γ radiation-crosslinked poly(vinyl pyrrolidone)-low molecular weight chitosan network hydrogels, Sains Malays., 47 (6), 1189–1197.

[46] Rastegari, A., Hasanshakir, F., Mohammadi, Z., Saadatpour, F., Faghihi, H., and Moraffah, F., 2023, A chitosan-based hydrogel containing zinc oxide nanoparticles as a carrier for improving antibacterial activity and controlling the release of antibiotics, Micro Nano Lett., 18 (7), e12172.

[47] Mahlaule-Glory, L.M., Mbita, Z., Ntsendwana, B., Mathipa, M.M., Mketo, N., and Hintsho-Mbita, N.C., 2019, ZnO nanoparticles via Sutherlandia frutescens plant extract: Physical and biological properties, Mater. Res. Express, 6 (8), 085006.

[48] Zhang, B., Yang, Z., Yang, S., Xu, Y., Tang, X., Mao, H., Dai, R., and Liang, X., 2024, Construction of ZnO/Cu₂O composites for enhanced antibacterial activity and analysis of antibacterial mechanism, Inorg. Chem. Commun., 162, 112182.

[49] Xue, J., Zhang, W., Wang, C., Zhu, L., and Cao, X., 2023, Preparation of nano-sized zinc oxide by adjusting the reaction system alkalinity and its antibacterial properties, Funct. Mater., 30 (4), 620–624.

[50] Jokar, F., Rahaiee, S., Zare, M., Nasiri kenari, M., and Mirzakhani, N., 2023, Bioactive wound dressing using bacterial cellulose/dextran biopolymers loaded with pomegranate peel extract: Preparation, characterization and biological properties, J. Drug Delivery Sci. Technol., 84, 104461.

[51] Sattariazar, S., Arsalani, N., and Nejad Ebrahimi, S., 2023, Biological assessment of synthesized carbon dots from polyphenol enriched extract of pomegranate peel, incorporated with Mentha piperita essential oil, Mater. Chem. Phys., 294, 126981.

[52] Savekar, P.L., Nadaf, S.J., Killedar, S.G., Kumbar, V.M., Hoskeri, J.H., Bhagwat, D.A., and Gurav, S.S., 2024, Citric acid cross-linked pomegranate peel extract-loaded pH-responsive β-cyclodextrin/carboxymethyl tapioca starch hydrogel film for diabetic wound healing, Int. J. Biol. Macromol., 274 (Pt. 1), 133366.

DOI: https://doi.org/10.22146/ijc.105215