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Mechanics of controlled release of insulin entrapped in polyacrylic acid gels via variable electrical stimuli

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Abstract

Controlled release insulin delivery systems possess multiple advantages over conventional ones, including maintaining desired blood glucose levels for prolonged periods and minimizing complications due to insulin overdose. Compared to other controlled-release mechanisms, electro-responsive polymers present the advantages of high controllability and ability to be coupled with microelectronics. This paper reports the possibility of using electro-responsive polyacrylic acid (PAA) and polymethacrylic acid (PMA) hydrogels for controlled delivery of insulin using intermittent electrical signals via matrix deformation. PAA hydrogels showed very good electrical responsivity under both constant and step current inputs, releasing up to 80% of protein at 10 V stimulus, compared to 20% release in the absence of stimulus. Analysis of spatial variation under electrical stimuli suggested that release of protein is a combined effect of deformation of the hydrogel and electrophoresis of protein molecules. Binding interaction analysis revealed that insulin entrapment is largely due to hydrogen bonding between the polymer matrix and insulin, and flooding the matrix with electrical charge likely disrupts the attractive forces that kept protein in place helping the release of the proteins. Understanding the molecular interactions affecting insulin retention and release mechanisms of PAA hydrogels is useful for developing and optimizing hydrogel-based controlled drug release systems.

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References

  1. Global Report on Diabetes. 2016, World Health Organization.

  2. Ravaine V, Ancla C, Catargi B. Chemically controlled closed-loop insulin delivery. J Control Release. 2008;132(1):2–11.

    Article  CAS  PubMed  Google Scholar 

  3. Sonksen P, Sonksen J. Insulin: understanding its action in health and disease. Br J Anaesth. 2000;85(1):69–79.

    Article  CAS  PubMed  Google Scholar 

  4. Fonte P, Araújo F, Reis S, Sarmento B. Oral insulin delivery: how far are we? J Diabetes Sci Technol. 2013;7(2):520–31.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wong CY, Martinez J, Dass CR. Oral delivery of insulin for treatment of diabetes: status quo, challenges and opportunities. J Pharm Pharmacol. 2016;68(9):1093–108.

    Article  CAS  PubMed  Google Scholar 

  6. Shah RB, Patel M, Maahs DM, Shah VN. Insulin delivery methods: past, present and future. Int J Pharm Investig. 2016;6(1):1–9.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Al-Tabakha MM, Arida AI. Recent challenges in insulin delivery systems: a review. Indian J Pharm Sci. 2008;70(3):278–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gupta P, Vermani K, Garg S. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov Today. 2002;7(10):569–79.

    Article  CAS  PubMed  Google Scholar 

  9. Priya James H, John R, Alex A, Anoop KR. Smart polymers for the controlled delivery of drugs – a concise overview. Acta Pharm Sin B. 2014;4(2):120–7.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bawa P, Pillay V, Choonara YE, du Toit LC. Stimuli-responsive polymers and their applications in drug delivery. Biomed Mater. 2009;4(2):022001.

    Article  PubMed  Google Scholar 

  11. Renard E, Place J, Cantwell M, Chevassus H, Palerm CC. Closed-loop insulin delivery using a subcutaneous glucose sensor and intraperitoneal insulin delivery feasibility study testing a new model for the artificial pancreas. Diabetes Care. 2010;33(1):121–7.

    Article  CAS  PubMed  Google Scholar 

  12. Zhao P, Liu Y, Xiao L, Deng H, du Y, Shi X. Electrochemical deposition to construct a nature inspired multilayer chitosan/layered double hydroxides hybrid gel for stimuli responsive release of protein. J Mater Chem B. 2015;3(38):7577–84.

    Article  CAS  PubMed  Google Scholar 

  13. Zhao W, Zhang H, He Q, Li Y, Gu J, Li L, et al. A glucose-responsive controlled release of insulin system based on enzyme multilayers-coated mesoporous silica particles. Chem Commun. 2011;47(33):9459–61.

    Article  CAS  Google Scholar 

  14. Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev. 2001;53(3):321–39.

    Article  CAS  PubMed  Google Scholar 

  15. Peppas NA, et al. Hydrogels in pharmaceutical formulations. Eur J Pharm Biopharm. 2000;50(1):27–46.

    Article  CAS  PubMed  Google Scholar 

  16. Siegel, R.A., et al. Novel swelling/shrinking behaviors of glucose-binding hydrogels and their potential use in a microfluidic insulin delivery system. In Macromolecular Symposia. 2004. Wiley Online Library.

  17. Uchiyama T, Kiritoshi Y, Watanabe J, Ishihara K. Degradation of phospholipid polymer hydrogel by hydrogen peroxide aiming at insulin release device. Biomaterials. 2003;24(28):5183–90.

    Article  CAS  PubMed  Google Scholar 

  18. Hosseini-Nassab N, Samanta D, Abdolazimi Y, Annes JP, Zare RN. Electrically controlled release of insulin using polypyrrole nanoparticles. Nanoscale. 2017;9(1):143–9.

    Article  CAS  PubMed  Google Scholar 

  19. Gu Z, Dang TT, Ma M, Tang BC, Cheng H, Jiang S, et al. Glucose-responsive microgels integrated with enzyme nanocapsules for closed-loop insulin delivery. ACS Nano. 2013;7(8):6758–66.

    Article  CAS  PubMed  Google Scholar 

  20. Roy D, Cambre JN, Sumerlin BS. Future perspectives and recent advances in stimuli-responsive materials. Prog Polym Sci. 2010;35(1–2):278–301.

    Article  CAS  Google Scholar 

  21. Ma R, Shi L. Phenylboronic acid-based glucose-responsive polymeric nanoparticles: synthesis and applications in drug delivery. Polym Chem. 2014;5(5):1503–18.

    Article  CAS  Google Scholar 

  22. Matsumoto A, Miyahara Y. ‘Borono-lectin’based engineering as a versatile platform for biomedical applications. Sci Technol Adv Mater. 2018;19(1):18–30.

    Article  CAS  PubMed  Google Scholar 

  23. Kim SY, Lee YM. Drug release behavior of electrical responsive poly (vinyl alcohol)/poly (acrylic acid) IPN hydrogels under an electric stimulus. J Appl Polym Sci. 1999;74(7):1752–61.

    Article  CAS  Google Scholar 

  24. Murdan S. Electro-responsive drug delivery from hydrogels. J Control Release. 2003;92(1):1–17.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang K, Wu XY. Temperature and pH-responsive polymeric composite membranes for controlled delivery of proteins and peptides. Biomaterials. 2004;25(22):5281–91.

    Article  CAS  PubMed  Google Scholar 

  26. Indermun S, Choonara YE, Kumar P, du Toit LC, Modi G, Luttge R, et al. An interfacially plasticized electro-responsive hydrogel for transdermal electro-activated and modulated (TEAM) drug delivery. Int J Pharm. 2014;462(1):52–65.

    Article  CAS  PubMed  Google Scholar 

  27. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem. 2010;31(2):455–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Timofeev V, et al. X-ray investigation of gene-engineered human insulin crystallized from a solution containing polysialic acid. Acta Crystallogr Sect F: Struct Biol Cryst Commun. 2010;66(3):259–63.

    Article  CAS  Google Scholar 

  29. Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(1):33–8.

    Article  CAS  PubMed  Google Scholar 

  30. Kulkarni RV, Setty CM, Sa B. Polyacrylamide-g-alginate-based electrically responsive hydrogel for drug delivery application: synthesis, characterization, and formulation development. J Appl Polym Sci. 2010;115(2):1180–8.

    Article  CAS  Google Scholar 

  31. Yun J, Im JS, Lee YS, Kim HI. Electro-responsive transdermal drug delivery behavior of PVA/PAA/MWCNT nanofibers. Eur Polym J. 2011;47(10):1893–902.

    Article  CAS  Google Scholar 

  32. Garland MJ, Singh TRR, Woolfson AD, Donnelly RF. Electrically enhanced solute permeation across poly(ethylene glycol)–crosslinked poly(methyl vinyl ether-co-maleic acid) hydrogels: effect of hydrogel crosslink density and ionic conductivity. Int J Pharm. 2011;406(1–2):91–8.

    Article  CAS  PubMed  Google Scholar 

  33. Servant A, Bussy C, al-Jamal K, Kostarelos K. Design, engineering and structural integrity of electro-responsive carbon nanotube- based hydrogels for pulsatile drug release. J Mater Chem B. 2013;1(36):4593–600.

    Article  CAS  PubMed  Google Scholar 

  34. Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010;67(3):217–23.

    CAS  PubMed  Google Scholar 

  35. Gouda, R., H. Baishya, and Z. Qing, Application of mathematical models in drug release kinetics of carbidopa and levodopa ER tablets. J Dev Drugs, 2017. 6(02).

  36. Higuchi T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci. 1963;52(12):1145–9.

    Article  CAS  PubMed  Google Scholar 

  37. Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15(1):25–35.

    Article  CAS  Google Scholar 

  38. Ritger PL, Peppas NA. A simple equation for description of solute release I. Fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Control Release. 1987;5(1):23–36.

    Article  CAS  Google Scholar 

  39. Kryscio DR, Shi Y, Ren P, Peppas NA. Molecular docking simulations for macromolecularly imprinted polymers. Ind Eng Chem Res. 2011;50(24):13877–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pan J, Xue X, Wang J, Xie H, Wu Z. Recognition property and preparation of Staphylococcus aureus protein A-imprinted polyacrylamide polymers by inverse-phase suspension and bulk polymerization. Polymer. 2009;50(11):2365–72.

    Article  CAS  Google Scholar 

  41. Qin P, Liu R, Pan X, Fang X, Mou Y. Impact of carbon chain length on binding of Perfluoroalkyl acids to bovine serum albumin determined by spectroscopic methods. J Agric Food Chem. 2010;58(9):5561–7.

    Article  CAS  PubMed  Google Scholar 

  42. Sulatha MS, Natarajan U. Origin of the difference in structural behavior of poly(acrylic acid) and poly(methacrylic acid) in aqueous solution discerned by explicit-solvent explicit-ion MD simulations. Ind Eng Chem Res. 2011;50(21):11785–96.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors also acknowledge the contribution of Dr. Michael Pendleton at Microscopy and Imaging Center, Texas A&M University in operating the scanning electron microscope.

Funding

This work was supported by a grant (CBET 1511303) provided by the National Science Foundation.

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Authors and Affiliations

  1. Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX, USA

    Samavath Mallawarachchi, Aishwarya Mahadevan, Varun Gejji & Sandun Fernando

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  1. Samavath Mallawarachchi
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  2. Aishwarya Mahadevan
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  3. Varun Gejji
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  4. Sandun Fernando
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Correspondence to Sandun Fernando.

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Mallawarachchi, S., Mahadevan, A., Gejji, V. et al. Mechanics of controlled release of insulin entrapped in polyacrylic acid gels via variable electrical stimuli. Drug Deliv. and Transl. Res. 9, 783–794 (2019). https://doi.org/10.1007/s13346-019-00620-7

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