Skip to main content

Advertisement

Log in

Fabrication and evaluation of nanoencapsulated quercetin for wound healing application

  • Original Paper
  • Published:
Polymer Bulletin Aims and scope Submit manuscript

Abstract

Nanotechnology based platforms have gained new insights into the development of effective modes of drug delivery systems for addressing wounds and related pathologies. Drugs encapsulated in nanodimensioned materials or nanoparticles are becoming a dermatologically attractive and versatile strategy for the development of optimized pharmaceutical formulations. In the current study, we developed gel formulations of Quercetin (Q) loaded alginate (ALG)/chitosan nanoparticle (CSNP) with concentrations 0.01% and 0.075% incorporated into carbopol encoded as Q-ALG/CSNP-G1, Q-ALG/CSNP-G2, respectively, and assessed their wound healing potential when topically applied to open excision wounds on adult Wistar rats. The characterization tests confirmed Q-ALG/CSNP-G2 featured pH, spreadability, extrudability and consistency. The in vitro release profile showed that the optimized Q-ALG/CSNP-G2 released quercetin in a sustained manner of 62.51 ± 0.72% over the period of 24 h as optimally needed for the wound healing onrush covering the inflammatory and proliferative phases. The in vivo acute dermal toxicity study did not produce any overt indications of toxicity as compared with control rats. The healing time for wounds treated with quercetin was even longer than those treated with Q-ALG/CSNP-G2. Antioxidant assays (SOD, CAT, LPO, and NO) revealed enhanced free radical scavenging ability of Q-ALG/CSNP-G2 gel receiving rats, thus improving healing quality. Furthermore, the restoration of biomarkers hydroxyproline and hexosamine content significantly proved increased re-epithelialization and collagen formation. The histopathological investigations on wounds treated with drug-loaded gel demonstrated efficient healing, as evidenced by the deficit of inflammation, established fibrous tissues, well-organized fibroblasts, and blood capillaries. Combining the unique properties of controlled drug release, enhanced antioxidant and antibacterial effects, the developed Q-ALG/CSNP-G2 were topically effective and showed synergistic wound healing capabilities compared with free quercetin in Wistar albino rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Xu R, Luo G, Xia H et al (2015) Biomaterials novel bilayer wound dressing composed of silicone rubber with particular micropores enhanced wound re-epithelialization and contraction. Biomaterials 40:1–11

    Google Scholar 

  2. Raja IS, Fathima NN (2018) Gelatin-cerium oxide nanocomposite for enhanced excisional wound healing. ACS Appl Bio Mater 1:487–495

    CAS  Google Scholar 

  3. Liu H, Wang C, Li C et al (2018) A functional chitosan-based hydrogel as a wound dressing and drug delivery system in the treatment of wound healing. RSC Adv 8:7533–7549

    CAS  Google Scholar 

  4. Son YJ, Tse JW, Zhou Y et al (2019) Biomaterials and controlled release strategy for epithelial wound healing. Biomater Sci 7:4444–4471

    CAS  Google Scholar 

  5. Xia G, Liu Y, Tian M et al (2017) Nanoparticles/thermosensitive hydrogel reinforced with chitin whiskers as a wound dressing for treating chronic wounds. J Mater Chem B 5:3172–3185

    CAS  Google Scholar 

  6. Choi HJ, Thambi T, Yang YH et al (2017) AgNP and rhEGF-incorporating synergistic polyurethane foam as a dressing material for scar-free healing of diabetic wounds. RSC Adv 7:13714–13725

    CAS  Google Scholar 

  7. Bankoti K, Rameshbabu AP, Datta S et al (2017) Onion derived carbon nanodots for live cell imaging and accelerated skin wound healing. J Mater Chem B 5:6579–6592. https://doi.org/10.1039/c7tb00869d

    Article  CAS  Google Scholar 

  8. Chouhan D, Chakraborty B, Nandi SK, Mandal BB (2017) Role of non-mulberry silk fibroin in deposition and regulation of extracellular matrix towards accelerated wound healing. Acta Biomater 48:157–174

    CAS  Google Scholar 

  9. AbdEllah NH, Abd El-Aziz FEZA, Abouelmagd SA et al (2019) Spidroin in carbopol-based gel promotes wound healing in earthworm’s skin model. Drug Dev Res 80:1051–1061

    CAS  Google Scholar 

  10. Khalid A, Ullah H, Ul-Islam M et al (2017) Bacterial cellulose-TiO2 nanocomposites promote healing and tissue regeneration in burn mice model. RSC Adv 7:47662–47668

    CAS  Google Scholar 

  11. Pyun DG, Yoon HS, Chung HY et al (2015) Evaluation of AgHAP-containing polyurethane foam dressing for wound healing: synthesis, characterization, in vitro and in vivo studies. J Mater Chem B 3:7752–7763

    CAS  Google Scholar 

  12. Zhu J, Jiang G, Song G et al (2019) Incorporation of ZnO/bioactive glass nanoparticles into alginate/chitosan composite hydrogels for wound closure. ACS Appl Bio Mater 2:5042–5052

    CAS  Google Scholar 

  13. Liu M, Shen Y, Ao P et al (2014) The improvement of hemostatic and wound healing property of chitosan by halloysite nanotubes. RSC Adv 4:23540–23553

    CAS  Google Scholar 

  14. Poonguzhali R, Khaleel Basha S, Sugantha Kumari V (2018) Fabrication of asymmetric nanostarch reinforced Chitosan/PVP membrane and its evaluation as an antibacterial patch for in vivo wound healing application. Int J Biol Macromol 114:204–213

    CAS  Google Scholar 

  15. Abrigo M, McArthur SL, Kingshott P (2014) Electrospun nanofibers as dressings for chronic wound care: Advances, challenges, and future prospects. Macromol Biosci 14:772–792

    CAS  Google Scholar 

  16. Stejskalová A, Almquist BD (2017) Using biomaterials to rewire the process of wound repair. Biomater Sci 5:1421–1434

    Google Scholar 

  17. Kaur L, Jain SK, Singh K (2015) Vitamin E TPGS based nanogel for the skin targeting of high molecular weight anti-fungal drug: development and in vitro and in vivo assessment. RSC Adv 5:53671–53686

    CAS  Google Scholar 

  18. Gopalakrishnan A, Ram M, Kumawat S et al (2016) Quercetin accelerated cutaneous wound healing in rats by increasing levels of VEGF and TGF-β1. Indian J Exp Biol 54:187–195

    CAS  Google Scholar 

  19. Selvaraj S, Fathima NN (2017) Fenugreek incorporated silk fibroin nanofibers–a potential antioxidant scaffold for enhanced wound healing. ACS Appl Mater Interf 9:5916–5926. https://doi.org/10.1021/acsami.6b16306

    Article  CAS  Google Scholar 

  20. Tian R, Jin Z, Zhou L et al (2021) Quercetin attenuated myeloperoxidase-dependent HOCl generation and endothelial dysfunction in diabetic vasculature. J Agric Food Chem 69:404–413

    CAS  Google Scholar 

  21. Srinivasan P, Vijayakumar S, Kothandaraman S, Palani M (2018) Anti-diabetic activity of quercetin extracted from Phyllanthus emblica L. fruit: in silico and in vivo approaches. J Pharm Anal 8:109–118

    Google Scholar 

  22. Zhang J, Zhao L, Cheng Q et al (2018) Structurally different flavonoid subclasses attenuate high-fat and high-fructose diet induced metabolic syndrome in rats. J Agric Food Chem 66:12412–12420

    CAS  Google Scholar 

  23. Jaisinghani RN (2017) Antibacterial properties of quercetin. Microbiol Res (Pavia). https://doi.org/10.4081/mr.2017.6877

    Article  Google Scholar 

  24. Dodda D, Chhajed R, Mishra J (2014) Protective effect of quercetin against acetic acid induced inflammatory bowel disease (IBD) like symptoms in rats: possible morphological and biochemical alterations. Pharmacol Reports 66:169–173

    CAS  Google Scholar 

  25. Wu W, Li R, Li X et al (2015) Quercetin as an antiviral agent inhibits influenza a virus (IAV) entry. Viruses. https://doi.org/10.3390/v8010006

    Article  Google Scholar 

  26. Alkushi AGR, Elsawy NAM (2017) Quercetin attenuates, indomethacin-induced acute gastric ulcer in rats. Folia Morphol 76:252–261

    CAS  Google Scholar 

  27. Ravikumar N, Kavitha CN (2020) Immunomodulatory effect of Quercetin on dysregulated Th1/Th2 cytokine balance in mice with both type 1 diabetes and allergic asthma. J Appl Pharm Sci 10:80–87

    CAS  Google Scholar 

  28. Porcu EP, Cossu M, Rassu G et al (2018) Aqueous injection of quercetin: an approach for confirmation of its direct in vivo cardiovascular effects. Int J Pharm 541:224–233

    CAS  Google Scholar 

  29. Nalini T, Basha SK, Mohamed AM et al (2019) Development and characterization of alginate/chitosan nanoparticulate system for hydrophobic drug encapsulation. J Drug Deliv Sci Technol 52:65–72

    CAS  Google Scholar 

  30. Fraile M, Buratto R, Gómez B et al (2014) Enhanced delivery of quercetin by encapsulation in poloxamers by supercritical antisolvent process. Ind Eng Chem Res 53:4318–4327

    CAS  Google Scholar 

  31. Hu K, Miao L, Goodwin TJ et al (2017) Quercetin remodels the tumor microenvironment to improve the permeation, retention, and antitumor effects of nanoparticles. ACS Nano 11:4916–4925

    CAS  Google Scholar 

  32. Jain AK, Thanki K, Jain S (2013) Co-encapsulation of tamoxifen and quercetin in polymeric nanoparticles: implications on oral bioavailability, antitumor efficacy, and drug-induced toxicity. Mol Pharm 10:3459–3474

    CAS  Google Scholar 

  33. Muhammad G, Hussain MA, Amin M et al (2017) Glucuronoxylan-mediated silver nanoparticles: green synthesis, antimicrobial and wound healing applications. RSC Adv 7:42900–42908

    CAS  Google Scholar 

  34. Fayemi OE, Ekennia AC, Katata-Seru L et al (2018) Antimicrobial and wound healing properties of polyacrylonitrile-moringa extract nanofibers. ACS Omega 3:4791–4797

    CAS  Google Scholar 

  35. Xia J, Zhang H, Yu F et al (2020) Applications of polymer, composite, and coating materials super clear, porous cellulose membranes with chitosan-coated nanofibers for visualized cutaneous wound healing dressing. ACS Appl Mater Interf 12:24370–24379

    CAS  Google Scholar 

  36. Yuan H, Chen L, Hong F (2019) Biological and medical applications of materials and interfaces a biodegradable antibacterial nanocomposite based on oxidized bacterial nanocellulose for rapid hemostasis and wound healing a biodegradable antibacterial nanocomposite based on oxidized bact. ACS Appl Mater Interf 12:3382–3392

    Google Scholar 

  37. Ambrogi V, Donnadio A, Pietrella D et al (2014) Chitosan films containing mesoporous SBA-15 supported silver nanoparticles for wound dressing. J Mater Chem B 2:6054–6063

    CAS  Google Scholar 

  38. Ali IH, Khalil IA, El-Sherbiny IM (2016) Single-dose electrospun nanoparticles-in-nanofibers wound dressings with enhanced epithelialization, collagen deposition, and granulation properties. ACS Appl Mater Interf 8:14453–14469

    Google Scholar 

  39. Parani M, Lokhande G, Singh A, Gaharwar AK (2016) Engineered nanomaterials for infection control and healing acute and chronic Wounds. ACS Appl Mater Interf 8:10049–10069

    CAS  Google Scholar 

  40. Poonguzhali R, Khaleel Basha S, Sugantha Kumari V (2018) Synthesis of alginate/nanocellulose bionanocomposite for in vitro delivery of ampicillin. Polym Bull 75:4165–4173

    CAS  Google Scholar 

  41. Khaleel Basha S, Syed Muzammil M, Dhandayuthabani R, Sugantha Kumari V (2020) Polysaccharides as excipient in drug delivery system. Mater Today Proc 36:280–289

    Google Scholar 

  42. Stopilha RT, Xavier-Júnior FH, de Vasconcelos CL et al (2019) particles: bulk solids and aqueous dispersions. J Dispers Sci Technol 0:1–8

    Google Scholar 

  43. de Lima CRM, de Souza PRS, Stopilha RT et al (2018) Formation and structure of chitosan–poly(sodium methacrylate) complex nanoparticles. J Dispers Sci Technol 39:83–91

    Google Scholar 

  44. Zhong Y, Seidi F, Li C et al (2021) Antimicrobial/biocompatible hydrogels dual-reinforced by cellulose as ultrastretchable and rapid self-healing wound dressing. Biomacromol 22:1654–1663

    CAS  Google Scholar 

  45. Kesharwani P, Jain A, Srivastava AK, Keshari MK (2020) Systematic development and characterization of curcumin-loaded nanogel for topical application. Drug Dev Ind Pharm 0:1–15

    Google Scholar 

  46. Bagher Z, Ehterami A, Safdel MH et al (2020) Wound healing with alginate/chitosan hydrogel containing hesperidin in rat model. J Drug Deliv Sci Technol 55:101379

    CAS  Google Scholar 

  47. Jangdey MS, Gupta A, Saraf S (2017) Fabrication, in-vitro characterization, and enhanced in-vivo evaluation of carbopol-based nanoemulsion gel of apigenin for uv-induced skin carcinoma. Drug Deliv 24:1026–1036

    CAS  Google Scholar 

  48. Avasatthi V, Pawar H, Dora CP et al (2016) A novel nanogel formulation of methotrexate for topical treatment of psoriasis: optimization, in vitro and in vivo evaluation. Pharm Dev Technol 21:554–562

    CAS  Google Scholar 

  49. Ghosh D, Mondal S, Ramakrishna K (2019) A topical ointment formulation containing leaves extract of Aegialitis rotundifolia Roxb., accelerates excision, incision and burn wound healing in rats. Wound Med 26:100168

    Google Scholar 

  50. OECD (2017) Guidelines for the testing of chemicals, section 4, test no. 402. Acute dermal toxicity. ISSN: 20745788 (online). https://doi.org/10.1787/20745788/9789264070585

  51. Prado-Ochoa MG, Gutiérrez-Amezquita RA, Abrego-Reyes VH et al (2014) Assessment of acute oral and dermal toxicity of 2 ethyl-carbamates with activity against rhipicephalus microplus in rats. Biomed Res Int. https://doi.org/10.1155/2014/956456

    Article  Google Scholar 

  52. Moreira CF, Cassini-Vieira P, Felipetto M (2015) http://www.bio-protocol.org/e1661. 5:20–23

  53. Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474

    CAS  Google Scholar 

  54. Sinha AK (1972) Colorimetric assay of catalase. Anal Biochem 47:389–394

    CAS  Google Scholar 

  55. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    CAS  Google Scholar 

  56. Miranda KM, Espey MG, Wink DA (2001) A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide–Biol Chem 5:62–71

    CAS  Google Scholar 

  57. Woessner JF (1961) The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch Biochem Biophys 93:440–447

    CAS  Google Scholar 

  58. Dwivedi D, Dwivedi M, Malviya S, Singh V (2017) Evaluation of wound healing, anti-microbial and antioxidant potential of Pongamia pinnata in wistar rats. J Tradit Complement Med 7:79–85

    Google Scholar 

  59. Maver T, Hribernik S, Mohan T et al (2015) Functional wound dressing materials with highly tunable drug release properties. RSC Adv 5:77873–77884

    CAS  Google Scholar 

  60. B-loaded A, Ghosh S (2017) RSC Advances the treatment of visceral leishmaniasis: in vitro and in vivo approaches. RSC Adv 7:29575–29590

    Google Scholar 

  61. Yadav E, Singh D, Yadav P, Verma A (2018) Ameliorative effect of biofabricated ZnO nanoparticles of: Trianthema portulacastrum Linn. on dermal wounds via removal of oxidative stress and inflammation. RSC Adv 8:21621–21635

    CAS  Google Scholar 

  62. Li X, Wang H, Rong H et al (2015) Effect of composite SiO2@AuNPs on wound healing: in vitro and vivo studies. J Colloid Interf Sci 445:312–319

    CAS  Google Scholar 

  63. Yadav E, Singh D, Yadav P, Verma A (2017) Attenuation of dermal wounds via downregulating oxidative stress and inflammatory markers by protocatechuic acid rich n-butanol fraction of Trianthema portulacastrum Linn. in wistar albino rats. Biomed Pharmacother 96:86–97

    CAS  Google Scholar 

  64. Ahmed OAA, Badr-Eldin SM, Tawfik MK et al (2014) Design and optimization of self-nanoemulsifying delivery system to enhance quercetin hepatoprotective activity in paracetamol-induced hepatotoxicity. J Pharm Sci 103:602–612

    CAS  Google Scholar 

  65. Roy P, Amdekar S, Kumar A et al (2012) In vivo antioxidative property, antimicrobial and wound healing activity of flower extracts of Pyrostegia venusta (Ker Gawl) Miers. J Ethnopharmacol 140:186–192

    Google Scholar 

  66. Huang X, Li LD, Lyu GM et al (2018) Chitosan-coated cerium oxide nanocubes accelerate cutaneous wound healing by curtailing persistent inflammation. Inorg Chem Front 5:386–393

    CAS  Google Scholar 

  67. Vishwanath M, Patil K, Kandhare AD, Bhise SD (2012) Anti-arthritic and anti-inflammatory activity of Xanthium srtumarium L. ethanolic extract in Freund’s complete adjuvant induced arthritis. Biomed Aging Pathol 2:6–15

    Google Scholar 

  68. Kandhare AD, Alam J, Patil MVK et al (2016) Wound healing potential of naringin ointment formulation via regulating the expression of inflammatory, apoptotic and growth mediators in experimental rats. Pharm Biol 54:419–432

    CAS  Google Scholar 

  69. Goswami S, Kandhare A, Zanwar AA et al (2016) Oral L-glutamine administration attenuated cutaneous wound healing in Wistar rats. Int Wound J 13:116–124

    Google Scholar 

  70. Liang D, Lu Z, Yang H et al (2016) Novel asymmetric wettable AgNPs/chitosan wound dressing. In vitro and in vivo evaluation. ACS Appl Mater Interf 8:3958–3968

    CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Auxilium College Management and D.K.M. College, Tamil Nadu, India, for providing the necessary facilities for the laboratory work. The authors would like to acknowledge and record a deep sense of gratitude to Adhiparasakthi College of Arts and Science, Kalavai, Tamil Nadu, India, for their valuable contribution to make this research work possible.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V. Sugantha Kumari.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nalini, T., Khaleel Basha, S., Mohamed Sadiq, A. et al. Fabrication and evaluation of nanoencapsulated quercetin for wound healing application. Polym. Bull. 80, 515–540 (2023). https://doi.org/10.1007/s00289-022-04094-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00289-022-04094-5

Keywords

Navigation