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Ultrasound Triggered Drug Release from Affinity-Based β-Cyclodextrin Polymers for Infection Control

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Abstract

This work demonstrates a slow, sustained drug delivery system that provides on-demand delivery bursts through the application of pulsed therapeutic ultrasound (TUS). Insoluble β-cyclodextrin-polymer (pCD) disks were loaded with a saturated antibiotic solution of rifampicin (RIF) and used for drug delivery studies. To obtain on-demand release from the implants, TUS was applied at an intensity of 1.8 W/cm2. The therapeutic efficacy of the combination treatment was assessed in bacterial culture via an in vitro Staphylococcus aureus bioluminescence assay. The results demonstrated that the application of pulsed TUS at 3 MHz and 1.8 W/cm2 to pCD implants leads to a significantly higher short-term burst in the drug release rate compared to samples not treated with TUS. The addition of TUS increased the drug release by 100% within 4 days. The pCD disk + RIF stimulated with TUS showed a comparatively higher bacterial eradication with CFU/mL of 4.277E+09, and 8.00E+08 at 1 and 24 h compared with control treated bacteria at 1.48E+10. Overall, these results suggest that the addition of pulsed TUS could be an effective technology to noninvasively expedite antibiotic release on demand at desired intervals.

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References

  1. Ahmed, M., C. L. Brace, F. T. Lee, Jr, and S. N. Goldberg. Principles of and advances in percutaneous ablation. Radiology 258(2):351–369, 2011.

    Article  Google Scholar 

  2. Alneami, A., E. G. Khalil, R. Mohsien, and A. Albeldawi. A comparison of six ultrasound stimulation types on pseudomonas aeruginosa growth in vitro. J. Biomed. Phys. Eng. 8(2):203, 2018.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. An, Y. H., and R. J. Friedman. Prevention of sepsis in total joint arthroplasty. J. Hosp. Infect. 33(2):93–108, 1996.

    Article  CAS  Google Scholar 

  4. Arciola, C. R., L. Visai, F. Testoni, S. Arciola, D. Campoccia, P. Speziale, et al. Concise survey of Staphylococcus aureus virulence factors that promote adhesion and damage to peri-implant tissues. Int J Artif Org 34(9):771–780, 2011.

    Article  CAS  Google Scholar 

  5. Bibby, D. C., N. M. Davies, and I. G. Tucker. Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems. Int. J. Pharm. 197(1–2):1–11, 2000.

    Article  CAS  Google Scholar 

  6. Busscher, H. J., and H. C. van der Mei. How do bacteria know they are on a surface and regulate their response to an adhering state? PLoS Pathog. 8(1):2012.

    Article  CAS  Google Scholar 

  7. Campoccia, D., L. Montanaro, and C. R. Arciola. The significance of infection related to orthopedic devices and issues of antibiotic resistance. Biomaterials 27(11):2331–2339, 2006.

    Article  CAS  Google Scholar 

  8. Corvec, S., M. E. Portillo, B. M. Pasticci, O. Borens, and A. Trampuz. Epidemiology and new developments in the diagnosis of prosthetic joint infection. Int. J. Artif. Org. 35(10):923–934, 2012.

    Article  Google Scholar 

  9. Cyphert, E. L., S. T. Zuckerman, J. N. Korley, and H. A. von Recum. Affinity interactions drive post-implantation drug filling, even in the presence of bacterial biofilm. Acta Biomater. 57:95–102, 2017.

    Article  CAS  Google Scholar 

  10. Del Pozo, J. L., and R. Patel. Infection associated with prosthetic joints. N. Engl. J. Med. 361(8):787–794, 2009.

    Article  Google Scholar 

  11. Epstein-Barash, H., G. Orbey, B. E. Polat, R. H. Ewoldt, J. Feshitan, R. Langer, et al. A microcomposite hydrogel for repeated on-demand ultrasound-triggered drug delivery. Biomaterials 31(19):5208–5217, 2010.

    Article  CAS  Google Scholar 

  12. Engelsman, A. F., H. C. van der Mei, R. J. Ploeg, and H. J. Busscher. The phenomenon of infection with abdominal wall reconstruction. Biomaterials 28(14):2314–2327, 2007.

    Article  CAS  Google Scholar 

  13. Falagas, M. E., S. K. Kasiakou, and L. D. Saravolatz. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin. Infect. Dis. 40(9):1333–1341, 2005.

    Article  CAS  Google Scholar 

  14. Fu, A. S., T. R. Thatiparti, G. M. Saidel, and H. A. von Recum. Experimental studies and modeling of drug release from a tunable affinity-based drug delivery platform. Ann. Biomed. Eng. 39(9):2466–2475, 2011.

    Article  Google Scholar 

  15. Gourevich, D., O. Dogadkin, A. Volovick, L. Wang, J. Gnaim, S. Cochran, et al. Ultrasound-mediated targeted drug delivery with a novel cyclodextrin-based drug carrier by mechanical and thermal mechanisms. J. Control. Release 170(3):316–324, 2013.

    Article  CAS  Google Scholar 

  16. Haugse, R., A. Langer, S.-E. Gullaksen, S. M. Sundøy, B. T. Gjertsen, S. Kotopoulis, et al. Intracellular signaling in key pathways is induced by treatment with ultrasound and microbubbles in a leukemia cell line, but not in healthy peripheral blood mononuclear cells. Pharmaceutics 11(7):319, 2019.

    Article  CAS  Google Scholar 

  17. Horsley, H., J. Owen, R. Browning, D. Carugo, J. Malone-Lee, E. Stride, et al. Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection. J. Control. Release 301:166–175, 2019.

    Article  CAS  Google Scholar 

  18. Huebsch, N., C. J. Kearney, X. Zhao, J. Kim, C. A. Cezar, Z. Suo, et al. Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy. Proc. Natl. Acad. Sci. U.S.A. 111(27):9762–9767, 2014.

    Article  CAS  Google Scholar 

  19. Humphreys, H. Surgical site infection, ultraclean ventilated operating theatres and prosthetic joint surgery: where now? J. Hosp. Infect. 81(2):71–72, 2012.

    Article  CAS  Google Scholar 

  20. Jeganathan, S., E. Budziszewski, P. Bielecki, M. C. Kolios, and A. A. Exner. In situ forming implants exposed to ultrasound enhance therapeutic efficacy in subcutaneous murine tumors. J. Control. Release 324:146–155, 2020.

    Article  CAS  Google Scholar 

  21. Juric, D., N. A. Rohner, and H. A. von Recum. Molecular imprinting of cyclodextrin supramolecular hydrogels improves drug loading and delivery. Macromol. Biosci. 19(1):1800246, 2019.

    Article  Google Scholar 

  22. Kurtz, S. M., E. Lau, H. Watson, J. K. Schmier, and J. Parvizi. Economic burden of periprosthetic joint infection in the United States. J. Arthroplasty 27(8):61–65, 2012.

    Article  Google Scholar 

  23. Kurtz, S., K. Ong, E. Lau, F. Mowat, and M. Halpern. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. JBJS 89(4):780–785, 2007.

    Article  Google Scholar 

  24. Loftsson, T., S. B. Vogensen, M. E. Brewster, and F. Konrádsdóttir. Effects of cyclodextrins on drug delivery through biological membranes. J. Pharm. Sci. 96(10):2532–2546, 2007.

    Article  CAS  Google Scholar 

  25. Montanaro, L., P. Speziale, D. Campoccia, S. Ravaioli, I. Cangini, G. Pietrocola, et al. Scenery of Staphylococcus implant infections in orthopedics. Future Microbiol. 6(11):1329–1349, 2011.

    Article  CAS  Google Scholar 

  26. Montanaro, L., F. Testoni, A. Poggi, L. Visai, P. Speziale, and C. R. Arciola. Emerging pathogenetic mechanisms of the implant-related osteomyelitis by Staphylococcus aureus. Int. J. Artif. Org. 34(9):781–788, 2011.

    Article  CAS  Google Scholar 

  27. Sesal, N. C., and Ö. Kekeç. Effects of pulsed ultrasound on Escherichia coli and Staphylococcus aureus. Trans. R. Soc. Trop. Med. Hyg. 108(6):348–353, 2014.

    Article  Google Scholar 

  28. Singh, K., J. M. Bauer, G. Y. LaChaud, J. E. Bible, and H. R. Mir. Surgical site infection in high-energy peri-articular tibia fractures with intra-wound vancomycin powder: a retrospective pilot study. J. Orthopaedics Traumatol. 16(4):287–291, 2015.

    Article  Google Scholar 

  29. Thatiparti, T. R., and H. A. von Recum. Cyclodextrin complexation for affinity-based antibiotic delivery. Macromol. Biosci. 10(1):82–90, 2010.

    Article  CAS  Google Scholar 

  30. Uçkay, I., S. Harbarth, R. Peter, D. Lew, P. Hoffmeyer, and D. Pittet. Preventing surgical site infections. Expert Rev. Anti-infective Ther. 8(6):657–670, 2010.

    Article  Google Scholar 

  31. Vertullo, C. J., M. Quick, A. Jones, and J. E. Grayson. A surgical technique using presoaked vancomycin hamstring grafts to decrease the risk of infection after anterior cruciate ligament reconstruction. Arthroscopy. 28(3):337–342, 2012.

    Article  Google Scholar 

  32. Villatte, G., C. Massard, S. Descamps, Y. Sibaud, C. Forestier, and K.-O. Awitor. Photoactive TiO2 antibacterial coating on surgical external fixation pins for clinical application. Int. J. Nanomed. 10:3367, 2015.

    Article  CAS  Google Scholar 

  33. Von Eiff, C., C. R. Arciola, L. Montanaro, K. Becker, and D. Campoccia. Emerging Staphylococcus species as new pathogens in implant infections. Int. J. Artif. Org. 29(4):360–367, 2006.

    Article  Google Scholar 

  34. Wang, N. X., and H. A. von Recum. Affinity-based drug delivery. Macromol. Biosci. 11(3):321–332, 2011.

    Article  CAS  Google Scholar 

  35. Xin, Z., G. Lin, H. Lei, T. F. Lue, and Y. Guo. Clinical applications of low-intensity pulsed ultrasound and its potential role in urology. Transl. Androl. Urol. 5(2):255–266, 2016.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Biomedical Engineering, Mahidol University, Salaya, Thailand

    Smriti Bohara & Jackrit Suthakorn

  2. Department of Radiology, Case Western Reserve University (CWRU), 10900 Euclid Avenue, Cleveland, OH, 44106-5056, USA

    Smriti Bohara, Emily Budziszewski & Agata A. Exner

  3. Department of Biomedical Engineering, Case Western Reserve University (CWRU), 10900 Euclid Avenue, Cleveland, OH, 44106-7207, USA

    Nathan Rohner, Horst A. von Recum & Agata A. Exner

Authors
  1. Smriti Bohara
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  2. Nathan Rohner
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  3. Emily Budziszewski
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  4. Jackrit Suthakorn
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  5. Horst A. von Recum
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  6. Agata A. Exner
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Correspondence to Horst A. von Recum or Agata A. Exner.

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Associate Editor Stefan M Duma oversaw the review of this article.

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Bohara, S., Rohner, N., Budziszewski, E. et al. Ultrasound Triggered Drug Release from Affinity-Based β-Cyclodextrin Polymers for Infection Control. Ann Biomed Eng 49, 2513–2521 (2021). https://doi.org/10.1007/s10439-021-02814-y

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