Optimization and Characterization of a Novel Antioxidant Naringenin-Loaded Hydrogel for Encouraging Re-Epithelization in Chronic Diabetic Wounds: A Preclinical Study
Status PubMed-not-MEDLINE Language English Country United States Media electronic-ecollection
Document type Journal Article
PubMed
37779948
PubMed Central
PMC10536028
DOI
10.1021/acsomega.3c04441
Knihovny.cz E-resources
- Publication type
- Journal Article MeSH
Nonhealed wounds are one of the most dangerous side effects of type-2 diabetes, which is linked to a high frequency of bacterial infections around the globe that eventually results in amputation of limbs. The present investigation aimed to explore the drug-loaded (naringenin) hydrogel system for chronic wound healing. The hydrogel membranes comprising Na-alginate with F-127 and poly(vinyl alcohol) were developed to treat chronic wounds using the quality-by-design (QbD) approach. The optimized formulation was tested for various parameters, such as swelling, gel fraction, water vapor transition rate (WVTR), etc. In vitro evaluation indicated that a drug-loaded hydrogel displayed better tissue adhesiveness and can release drugs for a prolonged duration of 12 h. Scratch assay performed on L929 cell lines demonstrated good cell migration. The diabetic wound healing potential of the hydrogel membrane was assessed in streptozotocin-induced male Wistar rats (50 mg/kg). Higher rates of wound closure, re-epithelialization, and accumulation of collagen were seen in in vivo experiments. Histopathologic investigation correspondingly implied that the drug-loaded hydrogel could enhance dermal wound repair. The improved antimicrobial and antioxidant properties with expedited healing indicated that the drug-loaded hydrogel is a perfect dressing for chronic wounds.
See more in PubMed
Khan M. A. B.; Hashim M. J.; King J. K.; Govender R. D.; Mustafa H.; Al Kaabi J. Epidemiology of type 2 diabetes–global burden of disease and forecasted trends. J. Epidemiol. Global Health 2020, 10 (1), 107.10.2991/jegh.k.191028.001. PubMed DOI PMC
Spampinato S. F.; Caruso G. I.; De Pasquale R.; Sortino M. A.; Merlo S. The treatment of impaired wound healing in diabetes: looking among old drugs. Pharmaceuticals 2020, 13 (4), 60.10.3390/ph13040060. PubMed DOI PMC
Patel S.; Srivastava S.; Singh M. R.; Singh D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed. Pharmacother. 2019, 112, 108615.10.1016/j.biopha.2019.108615. PubMed DOI
Kujath P.; Michelsen A. Wounds–From physiology to wound dressing. Dtsch. Ärzteblatt Int. 2008, 105 (13), 239.10.3238/Farztebl.2008.0239. PubMed DOI PMC
Brumberg V.; Astrelina T.; Malivanova T.; Samoilov A. Modern wound dressings: hydrogel dressings. Biomedicines 2021, 9 (9), 1235.10.3390/biomedicines9091235. PubMed DOI PMC
Wu L.; He Y.; Mao H.; Gu Z. Bioactive hydrogels based on polysaccharides and peptides for soft tissue wound management. J. Mater. Chem. B 2022, 10, 7148–7160. 10.1039/D2TB00591C. PubMed DOI
Raina N.; Pahwa R.; Thakur V. K.; Gupta M. Polysaccharide-based hydrogels: New insights and futuristic prospects in wound healing. Int. J. Biol. Macromol. 2022, 223, 1586–1603. 10.1016/j.ijbiomac.2022.11.115. PubMed DOI
Beaumont M.; Tran R.; Vera G.; Niedrist D.; Rousset A.; Pierre R.; Shastri V. P.; Forget A. Hydrogel-forming algae polysaccharides: from seaweed to biomedical applications. Biomacromolecules 2021, 22 (3), 1027–1052. 10.1021/acs.biomac.0c01406. PubMed DOI PMC
Aderibigbe B. A.; Buyana B. Alginate in wound dressings. Pharmaceutics 2018, 10 (2), 42.10.3390/pharmaceutics10020042. PubMed DOI PMC
Shah S. A.; Sohail M.; Khan S.; Minhas M. U.; De Matas M.; Sikstone V.; Hussain Z.; Abbasi M.; Kousar M. Biopolymer-based biomaterials for accelerated diabetic wound healing: A critical review. Int. J. Biol. Macromol. 2019, 139, 975–993. 10.1016/j.ijbiomac.2019.08.007. PubMed DOI
Lee K. Y.; Mooney D. J. Alginate: properties and biomedical applications. Prog. Polym. Sci. 2012, 37 (1), 106–126. 10.1016/j.progpolymsci.2011.06.003. PubMed DOI PMC
Kamoun E. A.; Kenawy E. R.; Chen X. A review on polymeric hydrogel membranes for wound dressing applications: PVA-based hydrogel dressings. J. Adv. Res. 2017, 8 (3), 217–233. 10.1016/j.jare.2017.01.005. PubMed DOI PMC
Kant V.; Gopal A.; Kumar D.; Gopalkrishnan A.; Pathak N. N.; Kurade N. P.; Tandan S. K.; Kumar D. Topical pluronic F-127 gel application enhances cutaneous wound healing in rats. Acta Histochem. 2014, 116 (1), 5–13. 10.1016/j.acthis.2013.04.010. PubMed DOI
Raina N.; Rani R.; Pahwa R.; Gupta M. Biopolymers and treatment strategies for wound healing: an insight view. Int. J. Polym. Mater. Polym. Biomater. 2022, 71 (5), 359–375. 10.1080/00914037.2020.1838518. DOI
Salehi B.; Fokou P. V.; Sharifi-Rad M.; Zucca P.; Pezzani R.; Martins N.; Sharifi-Rad J. The therapeutic potential of naringenin: a review of clinical trials. Pharmaceuticals 2019, 12 (1), 11.10.3390/ph12010011. PubMed DOI PMC
Rauf A.; Shariati M. A.; Imran M.; Bashir K.; Khan S. A.; Mitra S.; Emran T. B.; Badalova K.; Uddin M. S.; Mubarak M. S.; Aljohani A. S.; et al. Comprehensive review on naringenin and naringin polyphenols as a potent anticancer agent. Environ. Sci. Pollut. Res. 2022, 29 (21), 31025–31041. 10.1007/s11356-022-18754-6. PubMed DOI
Yu L. X.; Amidon G.; Khan M. A.; Hoag S. W.; Polli J.; Raju G. K.; Woodcock J. Understanding pharmaceutical quality by design. AAPS J. 2014, 16, 771–783. 10.1208/s12248-014-9598-3. PubMed DOI PMC
Alavi T.; Rezvanian M.; Ahmad N.; Mohamad N.; Ng S. F. Pluronic-F127 composite film loaded with erythromycin for wound application: formulation, physicomechanical and in vitro evaluations. Drug Delivery Transl. Res. 2019, 9, 508–519. 10.1007/s13346-017-0450-z. PubMed DOI
Singh B.; Dahiya M.; Saharan V.; Ahuja N. Optimizing drug delivery systems using systematic″ design of experiments.″ Part II: retrospect and prospects. Crit. Rev. Ther. Drug Carrier Syst. 2005, 22 (3), 215–294. 10.1615/CritRevTherDrugCarrierSyst.v22.i3.10. PubMed DOI
Sharma R.; Pahwa R.; Ahuja M. Iodine-loaded poly (silicic acid) gellan nanocomposite mucoadhesive film for antibacterial application. J. Appl. Polym. Sci. 2021, 138 (2), 49679.10.1002/app.49679. DOI
Shafique M.; Sohail M.; Minhas M. U.; Khaliq T.; Kousar M.; Khan S.; Hussain Z.; Mahmood A.; Abbasi M.; Aziz H. C.; Shah S. A. Bio-functional hydrogel membranes loaded with chitosan nanoparticles for accelerated wound healing. Int. J. Biol. Macromol. 2021, 170, 207–221. 10.1016/j.ijbiomac.2020.12.157. PubMed DOI
Abbasi A. R.; Sohail M.; Minhas M. U.; Khaliq T.; Kousar M.; Khan S.; Hussain Z.; Munir A. Bioinspired Na-alginate based thermosensitive hydrogel membranes for accelerated wound healing. Int. J. Biol. Macromol. 2020, 155, 751–765. 10.1016/j.ijbiomac.2020.03.248. PubMed DOI
Pereira R.; Carvalho A.; Vaz D. C.; Gil M. H.; Mendes A.; Bártolo P. Development of novel alginate based hydrogel films for wound healing applications. Int. J. Biol. Macromol. 2013, 52, 221–230. 10.1016/j.ijbiomac.2012.09.031. PubMed DOI
Patel S.; Srivastava S.; Singh M. R.; Singh D. Preparation and optimization of chitosan-gelatin films for sustained delivery of lupeol for wound healing. Int. J. Biol. Macromol. 2018, 107, 1888–1897. 10.1016/j.ijbiomac.2017.10.056. PubMed DOI
Natarajan N.; Shashirekha V.; Noorjahan S. E.; Rameshkumar M.; Rose C.; Sastry T. P. Fibrin–chitosan–gelatin composite film: preparation and characterization. J. Macromol. Sci. A 2005, 42 (7), 945–953. 10.1081/MA-200063188. DOI
Postolović K.; Ljujić B.; Kovačević M. M.; Đorđević S.; Nikolić S.; Živanović S.; Stanić Z. Optimization, characterization, and evaluation of carrageenan/alginate/poloxamer/curcumin hydrogel film as a functional wound dressing material. Mater. Today Commun. 2022, 31, 103528.10.1016/j.mtcomm.2022.103528. DOI
Khan S.; Minhas M. U.; Ahmad M.; Sohail M. Self-assembled supramolecular thermoreversible β-cyclodextrin/ethylene glycol injectable hydrogels with difunctional Pluronic 127 as controlled delivery depot of curcumin. Development, characterization and in vitro evaluation. J. Biomater. Sci., Polym. Ed. 2018, 29 (1), 1–34. 10.1080/09205063.2017.1396707. PubMed DOI
Champeau M.; Póvoa V.; Militão L.; Cabrini F. M.; Picheth G. F.; Meneau F.; Jara C. P.; de Araujo E. P.; de Oliveira M. G. Supramolecular poly (acrylic acid)/F127 hydrogel with hydration-controlled nitric oxide release for enhancing wound healing. Acta Biomater. 2018, 74, 312–325. 10.1016/j.actbio.2018.05.025. PubMed DOI
Hwang M. R.; Kim J. O.; Lee J. H.; Kim Y. I.; Kim J. H.; Chang S. W.; Jin S. G.; Kim J. A.; Lyoo W. S.; Han S. S.; Ku S. K.; et al. Gentamicin-loaded wound dressing with polyvinyl alcohol/dextran hydrogel: gel characterization and in vivo healing evaluation. AAPS PharmSciTech 2010, 11, 1092–1113. 10.1208/s12249-010-9474-0. PubMed DOI PMC
Xu R.; Xia H.; He W.; Li Z.; Zhao J.; Liu B.; Wu J.; et al. Controlled water vapor transmission rate promotes wound-healing via wound re-epithelialization and contraction enhancement. Sci. Rep. 2016, 6 (1), 2459610.1038/srep24596. PubMed DOI PMC
Ahmed A.; Niazi M. B.; Jahan Z.; Ahmad T.; Hussain A.; Pervaiz E.; Janjua H. A.; Hussain Z. In-vitro and in-vivo study of superabsorbent PVA/Starch/g-C3N4/Ag@ TiO2 NPs hydrogel membranes for wound dressing. Eur. Polym. J. 2020, 130, 109650.10.1016/j.eurpolymj.2020.109650. DOI
Huang Y.; Dan N.; Dan W.; Zhao W. Reinforcement of polycaprolactone/chitosan with nanoclay and controlled release of curcumin for wound dressing. ACS Omega 2019, 4 (27), 22292–22301. 10.1021/acsomega.9b02217. PubMed DOI PMC
Li X.; Nan K.; Li L.; Zhang Z.; Chen H. In vivo evaluation of curcumin nanoformulation loaded methoxy poly(ethylene glycol)-graft-chitosan composite film for wound healing application. Carbohydr. Polym. 2012, 88, 84–90. 10.1016/j.carbpol.2011.11.068. DOI
Rezvanian M.; Amin M. C. I. M.; Ng S. F. Development and physicochemical characterization of alginate composite film loaded with simvastatin as a potential wound dressing. Carbohydr. Polym. 2016, 137, 295–304. 10.1016/j.carbpol.2015.10.091. PubMed DOI
Tang X.; Gu X.; Wang Y.; Chen X.; Ling J.; Yang Y. Stable antibacterial polysaccharide-based hydrogels as tissue adhesives for wound healing. RSC Adv. 2020, 10 (29), 17280–17287. 10.1039/D0RA02017F. PubMed DOI PMC
Tamahkar E.; Özkahraman B.; Süloğlu A. K.; İdil N.; Perçin I. A novel multilayer hydrogel wound dressing for antibiotic release. J. Drug Delivery Sci. Technol. 2020, 58, 101536.10.1016/j.jddst.2020.101536. DOI
Hago E. E.; Li X. Interpenetrating polymer network hydrogels based on gelatin and PVA by biocompatible approaches: synthesis and characterization. Adv. Mater. Sci. Eng. 2013, 2013, 1.10.1155/2013/328763. DOI
Gharibi R.; Shaker A.; Rezapour-Lactoee A.; Agarwal S. Antibacterial and biocompatible hydrogel dressing based on gelatin-and castor-oil-derived biocidal agent. ACS Biomater. Sci. Eng. 2021, 7 (8), 3633–3647. 10.1021/acsbiomaterials.1c00706. PubMed DOI
Rezapour-Lactoee A.; Yeganeh H.; Gharibi R.; Milan P. B. Enhanced healing of a full-thickness wound by a thermoresponsive dressing utilized for simultaneous transfer and protection of adipose-derived mesenchymal stem cells sheet. J. Mater. Sci. Mater. Med. 2020, 31, 101.10.1007/s10856-020-06433-2. PubMed DOI
Rezvanian M.; Ng S. F.; Alavi T.; Ahmad W. In-vivo evaluation of Alginate-Pectin hydrogel film loaded with Simvastatin for diabetic wound healing in Streptozotocin-induced diabetic rats. Int. J. Biol. Macromol. 2021, 171, 308–319. 10.1016/j.ijbiomac.2020.12.221. PubMed DOI
Al-Roujayee A. S. Naringenin improves the healing process of thermally-induced skin damage in rats. J. Int. Med. Res. 2017, 45 (2), 570–582. 10.1177/0300060517692483. PubMed DOI PMC
Shan S.; Zhang Y.; Wu M.; Yi B.; Wang J.; Li Q. Naringenin attenuates fibroblast activation and inflammatory response in a mechanical stretch-induced hypertrophic scar mouse model. Mol. Med. Rep. 2017, 16 (4), 4643–4649. 10.3892/mmr.2017.7209. PubMed DOI PMC
Thomas A.; Harding K.; Moore K. Alginates from wound dressings activate human macrophages to secrete tumour necrosis factor-α. Biomaterials 2000, 21, 1797–1802. 10.1016/S0142-9612(00)00072-7. PubMed DOI
Abbas M. M.; Al-Rawi N.; Abbas M. A.; Al-Khateeb I. Naringenin potentiated β-sitosterol healing effect on the scratch wound assay. Res. Pharm. Sci. 2019, 14 (6), 566.10.4103/1735-5362.272565. PubMed DOI PMC
Zhang Y.; Li M.; Wang Y.; Han F.; Shen K.; Luo L.; Li Y.; Jia Y.; Zhang J.; Cai W.; Wang K.; et al. Exosome/metformin-loaded self-healing conductive hydrogel rescues microvascular dysfunction and promotes chronic diabetic wound healing by inhibiting mitochondrial fission. Bioact. Mater. 2023, 26, 323–336. 10.1016/j.bioactmat.2023.01.020. PubMed DOI PMC
Wang C.; Liang Y.; Huang Y.; Li M.; Guo B. Porous photothermal antibacterial antioxidant dual–crosslinked cryogel based on hyaluronic acid/polydopamine for non-compressible hemostasis and infectious wound repair. J. Mater. Sci. Technol. 2022, 121, 207–219. 10.1016/j.jmst.2021.12.054. DOI
Wang K.; Dong R.; Tang J.; Li H.; Dang J.; Zhang Z.; Yu Z.; Guo B.; Yi C. Exosomes laden self-healing injectable hydrogel enhances diabetic wound healing via regulating macrophage polarization to accelerate angiogenesis. Chem. Eng. J. 2022, 430, 132664.10.1016/j.cej.2021.132664. DOI
Li D.; Chen K.; Tang H.; Hu S.; Xin L.; Jing X.; He Q.; Wang S.; Song J.; Mei L.; Cannon R. D.; et al. A Logic-Based Diagnostic and Therapeutic Hydrogel with Multistimuli Responsiveness to Orchestrate Diabetic Bone Regeneration. Adv. Mater. 2022, 34 (11), 2108430.10.1002/adma.202108430. PubMed DOI
Cao H.; Zhu J.; Zhang J.; Yang L.; Guo X.; Tian R.; Wu H.; Li Y.; Gu Z. In Situ Fabrication of Robust Polyphenolic Hydrogels for Skin Protection and Repair. Chem. Mater. 2023, 35 (5), 2191–2201. 10.1021/acs.chemmater.3c00159. DOI
Liu B.; Kong Y.; Alimi O. A.; Kuss M. A.; Tu H.; Hu W.; Rafay A.; Vikas K.; Shi W.; Lerner M.; Berry W. L.; et al. Multifunctional Microgel-Based Cream Hydrogels for Postoperative Abdominal Adhesion Prevention. ACS Nano 2023, 17 (4), 3847–3864. 10.1021/acsnano.2c12104. PubMed DOI PMC
Wen J.; Liu B.; Yuan E.; Ma Y.; Zhu Y. Preparation and physicochemical properties of the complex of naringenin with hydroxypropyl-β-cyclodextrin. Molecules 2010, 15 (6), 4401–4407. 10.3390/molecules15064401. PubMed DOI PMC
Zhao L.; Mitomo H.; Zhai M.; Yoshii F.; Nagasawa N.; Kume T. Synthesis of antibacterial PVA/CM-chitosan blend hydrogels with electron beam irradiation. Carbohydr. Polym. 2003, 53 (4), 439–446. 10.1016/S0144-8617(03)00103-6. DOI
Shahzad A.; Khan A.; Afzal Z.; Umer M. F.; Khan J.; Khan G. M. Formulation development and characterization of cefazolin nanoparticles-loaded cross-linked films of sodium alginate and pectin as wound dressings. Int. J. Biol. Macromol. 2019, 124, 255–269. 10.1016/j.ijbiomac.2018.11.090. PubMed DOI
Karolewicz B.; Gajda M.; Pluta J.; Górniak A. Dissolution study and thermal analysis of fenofibrate–Pluronic F127 solid dispersions. J. Therm. Anal. Calorim. 2016, 125, 751–757. 10.1007/s10973-015-5013-2. DOI