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Hyaluronic acid-based biodegradable microneedles loaded with epidermal growth factor for treatment of diabetic foot

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Abstract

Pain relief and effective methods of treating patients with diabetic foot wounds have yet to be established. Improved surgical treatment, other than suturing, and medical (drug) treatments, are required to address severe symptoms. In this study, we developed a drug delivery system using biodegradable microneedles that are suitable for delivering drugs to sensitive skin and reducing pain. First, we successfully fabricated a silicon mold using a microneedle metal master. The dimensions of the microneedle are width 200 µm × height 250 µm, as confirmed by election microscopy. A microneedle loaded with epidermal growth factor (EGF; 10 ppm) in biodegradable hyaluronic acid, prepared using a silicon mold, was also established for drug delivery. The characteristics of the EGF-loaded microneedles (MPEGF) were also confirmed using porcine back skin and polymer membranes, demonstrating a skin permeability of more than 95%. Finally, MPEGF showed a skin-healing effect and angiogenesis in vitro and ex vivo experiments. Taken together, we suggest that MPEGF may be a new treatment method for patients with diabetic feet for wound healing and blood vessel regeneration.

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References

  1. A. Ndip, L. Ebah, A. Mbako, Neuropathic diabetic foot ulcers—evidence-to-practice. Int. J. Gen. Med. 5, 129–134 (2012)

    PubMed  PubMed Central  Google Scholar 

  2. NCD Risk Factor Collaboration (NCD-RisC), Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 10027, 1513–1530 (2016)

    Google Scholar 

  3. J. Larsson, J. Apelqvist, Towards less amputations in diabetic patients. Incidence, causes, cost, treatment, and prevention—a review. Acta Orthop. Scand. 66(2), 181–192 (1995)

    Article  CAS  PubMed  Google Scholar 

  4. A.J.M. Boulton, R.W. Whitehouse. The diabetic foot. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA) (2023)

  5. D.G. Armstrong, T.W. Tan, A.J.M. Boulton, S.A. Bus, Diabetic foot ulcers: a review. JAMA 330(1), 62–75 (2023)

    Article  CAS  PubMed  Google Scholar 

  6. B.C. Oliveira, B.G.R.B. de Oliveira, G. Deutsch, F.S. Pessanha, S.R. de Castilho, Effectiveness of a synthetic human recombinant epidermal growth factor in diabetic patients wound healing: pilot, double-blind, randomized clinical controlled trial. Wound Repair Regen. 29(6), 920–926 (2021)

    Article  PubMed  Google Scholar 

  7. C. Ang, Y. Lim, Recurrent admissions for diabetic foot complications. Malays. Orthop. J. 7(2), 21–26 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  8. D.M. Bermudez, B.J. Herdrich, J. Xu, R. Lind, D.P. Beason, M.E. Mitchell, L.J. Soslowsky, K.W. Liechty, Impaired biomechanical properties of diabetic skin implications in pathogenesis of diabetic wound complications. Am. J. Pathol. 178(5), 2215–2223 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. K. Moronkeji, S. Todd, I. Dawidowska, S.D. Barrett, R. Akhtar, The role of subcutaneous tissue stiffness on microneedle performance in a representative in vitro model of skin. J. Control. Rel. 265, 102–112 (2017)

    Article  CAS  Google Scholar 

  10. T. Hou, J. Wang, W. Zhang, X. Xu, ADME evaluation in drug discovery. 7. Prediction of oral absorption by correlation and classification. J. Chem. Inf. Model. 47(1), 208–218 (2007)

    Article  CAS  PubMed  Google Scholar 

  11. J. Hassan, C. Haigh, T. Ahmed, M.J. Uddin, D.B. Das, Potential of microneedle systems for COVID-19 vaccination: current trends and challenges. Pharmaceutics 14(5), 1066 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. X. Jiang, P.B. Lillehoj, Microneedle-based skin patch for blood-free rapid diagnostic testing. Microsyst. Nanoeng. 6, 96 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. F.K. Aldawood, A. Andar, S. Desai, A comprehensive review of microneedles: types, materials, processes, characterizations and applications. Polymers (Basel) 13(16), 2815 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. J.H. Ryu, H.Y. Shin, J.G. Lee, K.S. Tae, M.S. Kim, Analysis of hyaluronic acid microneedle characteristics as its shapes. J Biomed Eng Res 39, 30–35 (2018)

    Google Scholar 

  15. M.R. Han, E.Y. Kim, Y.H. Jung, M.S. Kim, J.H. Park, Characteristics and hair growth efficacy of water dissolving micro-needles containing minoxidil regarding length of micro-needles. Polymer (Korea) 37(3), 393–398 (2013)

    Article  CAS  Google Scholar 

  16. S.K. Yun, S.J. Lee, S.S. Giri, H.J. Kim, S.G. Kim, S.W. Kim, S.J. Han, J. Kwon, W.T. Oh, S.C. Park, Vaccination of fish against Aeromonas hydrophila infections using the novel approach of transcutaneous immunization with dissolving microneedle patches in aquaculture. Fish Shellfish Immunol. 97, 34–40 (2020)

    Article  CAS  PubMed  Google Scholar 

  17. P. Wee, Z. Wang, Epidermal growth factor receptor cell proliferation signaling pathways. Cancers 9(5), 52 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  18. H. Kim, W.H. Kong, K.Y. Seong, D.K. Sung, H. Jeong, J.K. Kim, S.Y. Yang, S.K. Hahn, Hyaluronate-epidermal growth factor conjugate for skin wound healing and regeneration. Biomacromol 17(11), 3694–3705 (2016)

    Article  CAS  Google Scholar 

  19. W. Ockenga, S. Kühne, S. Bocksberger, A. Banning, R. Tikkanen, Epidermal growth factor receptor transactivation is required for mitogen-activated protein kinase activation by muscarinic acetylcholine receptors in HaCaT keratinocytes. Int. J. Mol. Sci. 15(11), 21433–21454 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  20. Y. Xu, J.J. Voorhees, G.J. Fisher, Epidermal growth factor receptor is a critical mediator of ultraviolet B irradiation-induced signal transduction in immortalized human keratinocyte HaCaT cells. Am. J. Pathol. 169(3), 823–830 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. K.H. Park, S.H. Han, J.P. Hong, S.K. Han, D.H. Lee, B.S. Kim, J.H. Ahn, J.W. Lee, Topical epidermal growth factor spray for the treatment of chronic diabetic foot ulcers: a phase III multicenter, double-blind, randomized, placebo-controlled trial. Diabetes Res. Clin. Pract. 142, 335–344 (2018)

    Article  CAS  PubMed  Google Scholar 

  22. Z. Wang, J. Luan, A. Seth, L. Liu, M. You, P. Gupta, P. Rathi, Y. Wang, S. Cao, Q. Jiang, X. Zhang, R. Gupta, Q. Zhou, J.J. Morrissey, E.L. Scheller, J.S. Rudra, S. Singamaneni, Microneedle patch for the ultrasensitive quantification of protein biomarkers in interstitial fluid. Nat. Biomed. Eng. 5, 64–76 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. S.J. Lee, J.C. Kim, Y.M. Huh, Preparation and characterization of magnetized microneedles for application in magnetic resonance molecular imaging. Polymer (Korea) 46(6), 783–792 (2022)

    Article  CAS  Google Scholar 

  24. J.A. Kim, S.C. Park, S.J. Lee, J.C. Kim, Cellulose nanofiber-reinforced dissolving microneedles for transdermal delivery of a water-soluble compound. Cellulose 29, 9881–9897 (2022)

    Article  CAS  Google Scholar 

  25. J.E. Song, S.H. Jun, S.G. Park, N.G. Kang, A semi-dissolving microneedle patch incorporating TEMPO-oxidized bacterial cellulose nanofibers for enhanced transdermal delivery. Polymers (Basel) 12, 1873 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. S.W. Yoon, K.P. Lee, D.Y. Kim, D.I. Hwang, K.J. Won, D.W. Lee, H.M. Lee, Effect of absolute from Hibiscus syriacus L. flower on wound healing in keratinocytes. Pharmacogn. Mag. 13(49), 85–89 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. S. Baek, S.H. Kwon, J.Y. Jeon, G.Y. Lee, H.S. Ju, H.J. Yun, D.J. Cho, K.P. Lee, M.H. Nam, Radotinib attenuates TGFβ -mediated pulmonary fibrosis in vitro and in vivo: exploring the potential of drug repurposing. BMC Pharmacol. Toxicol. 23(1), 93 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. J. Kim, K.P. Lee, B.S. Kim, S.J. Lee, B.S. Moon, S. Baek, Heat shock protein 90 inhibitor AUY922 attenuates platelet-derived growth factor-BB-induced migration and proliferation of vascular smooth muscle cells. Korean J. Physiol. Pharmacol. 24(3), 241–248 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. M.J. Mistilis, J.C. Joyce, E.S. Esser, I. Skountzou, R.W. Compans, A.S. Bommarius, M.R. Prausnitz, Long-term stability of influenza vaccine in a dissolving microneedle patch. Drug Deliv. Transl. Res. 7, 195–205 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. H. Räägel, A. Turley, T. Fish, J. Franson, T. Rollins, S. Campbell, M.R. Jorgensen, Medical device industry approaches for addressing sources of failing cytotoxicity scores. Biomed. Instrum. Technol. 55(2), 69–84 (2021)

    Article  PubMed  PubMed Central  Google Scholar 

  31. J. Patry, A. Tourigny, M.P. Mercier, C.E. Dionne, Outcomes and prognosis of diabetic foot ulcers treated by an interdisciplinary team in Canada. Int. Wound J. 18(2), 134–146 (2021)

    Article  PubMed  Google Scholar 

  32. S. Gibbs, A.N. Silva-Pinto, S. Murli, M. Huber, D. Hohl, M. Ponec, Epidermal growth factor and keratinocyte growth factor differentially regulate epidermal migration, growth, and differentiation. Wound Repair Regen. 8(3), 192–203 (2000)

    Article  CAS  PubMed  Google Scholar 

  33. T.J. Puccinelli, P.J. Bertics, K.S. Masters, Regulation of keratinocyte signaling and function via changes in epidermal growth factor presentation. Acta Biomater. 6(9), 3415–3425 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. M. Chang, T.T. Nguyen, Strategy for treatment of infected diabetic foot ulcers. Acc. Chem. Res. 54(5), 1080–1093 (2021)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by the Korea Basic Science Institute (C330440) and the SMTECH (S3249169, Development of patient-focused microneedle type skin closure for severe wounds).

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Author notes

  1. Suji Baek and Kang Pa Lee have contributed equally to this work.

Authors and Affiliations

  1. Research and Development Center, UMUST R&D Corporation, 84, Madeul-ro 13-gil, Dobong-gu, 01411, Seoul, Republic of Korea

    Suji Baek & Kang Pa Lee

  2. Research and Development Center, KRON Corporation, 46, Hangaul-gil 220Beon-gil, Namyang-eup, Hwaseong-si, 18260, Gyeonggi-do, Republic of Korea

    Chung Su Han

  3. Seoul Center, Korea Basic Science Institute, Seoul, 02841, Republic of Korea

    Seung Hae Kwon

  4. Process Development Laboratory, Department of Pharmaceutical Science and Engineering, Seowon University, Chungju, Chungbuk, 28674, Republic of Korea

    Seung Jun Lee

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  1. Suji Baek
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Contributions

SJB, KPL, CSH, SHK, and SJL designed the present study. CSH and SJL fabricated the microneedle patch loaded with EGF. SJB, KPL, and SHK performed the microneedle efficiency experiments. SJB, KPL, and SJL analyzed the data. SJL wrote the manuscript.

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Correspondence to Seung Jun Lee.

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Baek, S., Lee, K.P., Han, C.S. et al. Hyaluronic acid-based biodegradable microneedles loaded with epidermal growth factor for treatment of diabetic foot. Macromol. Res. 32, 13–22 (2024). https://doi.org/10.1007/s13233-023-00206-w

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  • DOI: https://doi.org/10.1007/s13233-023-00206-w

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