Skip to main content

Advertisement

Log in

Microinfusion Using Hollow Microneedles

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Purpose

The aim of the study is to determine the effect of experimental parameters on microinfusion through hollow microneedles into skin to optimize drug delivery protocols and identify rate-limiting barriers to flow.

Methods

Glass microneedles were inserted to a depth of 720–1080 μm into human cadaver skin to microinfuse sulforhodamine solution at constant pressure. Flow rate was determined as a function of experimental parameters, such as microneedle insertion and retraction distance, infusion pressure, microneedle tip geometry, presence of hyaluronidase, and time.

Results

Single microneedles inserted into skin without retraction were able to infuse sulforhodamine solution into the skin at flow rates of 15–96 μl/h. Partial retraction of microneedles increased flow rate up to 11.6-fold. Infusion flow rate was also increased by greater insertion depth, larger infusion pressure, use of a beveled microneedle tip, and the presence of hyaluronidase such that flow rates ranging from 21 to 1130 μl/h were achieved. These effects can be explained by removing or overcoming the large flow resistance imposed by dense dermal tissue, compressed during microneedle insertion, which blocks flow from the needle tip.

Conclusions

By partially retracting microneedles after insertion and other methods to overcome flow resistance of dense dermal tissue, protocols can be designed for hollow microneedles to microinfuse fluid at therapeutically relevant rates.

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.

Institutional subscriptions

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. I. Findley G. Chamberlain (1999) ArticleTitleABC of labour care: relief of pain Br. Med. J. 318 927–930 Occurrence Handle1:STN:280:DyaK1M3jtVGjsQ%3D%3D

    CAS  Google Scholar 

  2. A. J. Fox D. J. Rowbotham (1999) ArticleTitleRecent advances: anaesthesia Br. Med. J. 319 557–560 Occurrence Handle1:CAS:528:DyaK1MXmtVGkt70%3D

    CAS  Google Scholar 

  3. C. Pasero (2002) ArticleTitleSubcutaneous opioid infusion Am. J. Nurs. 102 61–62

    Google Scholar 

  4. B. W. Bode H. T. Sabbah T. M. Gross L. P. Fredrickson P. C. Davidson (2002) ArticleTitleDiabetes management in the new millennium using insulin pump therapy Diabetes/Metab. Res. Rev. 18 S14–S20 Occurrence Handle1:CAS:528:DC%2BD38XjvVansrg%3D

    CAS  Google Scholar 

  5. M. J. Lenhard G. D. Reeves (2001) ArticleTitleContinuous subcutaneous insulin infusion: a comprehensive review of insulin pump therapy Arch. Intern. Med. 161 2293–2300 Occurrence Handle10.1001/archinte.161.19.2293 Occurrence Handle1:CAS:528:DC%2BD3MXot1GlsbY%3D Occurrence Handle11606144

    Article  CAS  PubMed  Google Scholar 

  6. J. L. Colquitt C. Green M. K. Sidhu D. Hartwell N. Waugh (2004) ArticleTitleClinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes Health Technol. Assess. 8 1–202

    Google Scholar 

  7. A. Liebl (2002) ArticleTitleChallenges in optimal metabolic control of diabetes Diabetes/Metab. Res. Rev. 18 S36–S41

    Google Scholar 

  8. D. E. Moulin J. H. Kreeft (1991) ArticleTitleComparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain Lancet 337 465–468 Occurrence Handle10.1016/0140-6736(91)93401-T Occurrence Handle1:STN:280:By6C38vpslA%3D Occurrence Handle1704089

    Article  CAS  PubMed  Google Scholar 

  9. E. Meehan Y. Gross D. Davidson M. Martin I. Tsals (1997) ArticleTitleA microinfusor device for the delivery of therapeutic levels of peptides and macromolecules J. Control. Release 46 107–116 Occurrence Handle10.1016/S0168-3659(96)01608-2 Occurrence Handle1:CAS:528:DyaK2sXhtlyhsLg%3D

    Article  CAS  Google Scholar 

  10. P. M. Lynch J. Butler D. Huerta I. Tsals D. Davidson S. Hamm (2000) ArticleTitleA pharmacokinetic and tolerability evaluation of two continuous subcutaneous infusion systems compared to an oral controlled-release morphine J. Pain Symptom Manage. 19 348–356 Occurrence Handle10.1016/S0885-3924(00)00130-5

    Article  Google Scholar 

  11. R. Jolanki L. Kanerva T. Estlander M.-L. Henriks-Eckerman R. Suhonen (2001) ArticleTitleAllergic contact dermatitis from phenoxyethoxy ethylacrylates in optical fiber coating, and glue in an insulin pump set Contact Dermatitis 45 36–37 Occurrence Handle10.1034/j.1600-0536.2001.045001036.x Occurrence Handle1:STN:280:DC%2BD3MvgsVWmsA%3D%3D Occurrence Handle11422266

    Article  CAS  PubMed  Google Scholar 

  12. S. Henry D. V. McAllister M. G. Allen M. R. Prausnitz (1998) ArticleTitleMicrofabricated microneedles: a novel approach to transdermal drug delivery J. Pharm. Sci. 87 922–925 Occurrence Handle10.1021/js980042+ Occurrence Handle1:CAS:528:DyaK1cXkvVGktrw%3D Occurrence Handle9687334

    Article  CAS  PubMed  Google Scholar 

  13. D. V. McAllister P. M. Wang S. P. Davis J.-H. Park P. J. Canatella M. G. Allen M. R. Prausnitz (2003) ArticleTitleMicrofabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies Proc. Natl. Acad. Sci. USA 100 13755–13760 Occurrence Handle10.1073/pnas.2331316100 Occurrence Handle1:CAS:528:DC%2BD3sXpsFGisrw%3D Occurrence Handle14623977

    Article  CAS  PubMed  Google Scholar 

  14. F. Chabri K. Bouris T. Jones D. Barrow A. Hann C. Allender K. Brain J. Birchall (2004) ArticleTitleMicrofabricated silicon microneedles for nonviral cutaneous gene delivery Br. J. Dermatol. 150 869–877 Occurrence Handle10.1111/j.1365-2133.2004.05921.x Occurrence Handle1:CAS:528:DC%2BD2cXlt1Kgurk%3D Occurrence Handle15149498

    Article  CAS  PubMed  Google Scholar 

  15. W. Martanto S. P. Davis N. R. Holiday J. Wang H. S. Gill M. R. Prausnitz (2004) ArticleTitleTransdermal delivery of insulin using microneedles in vivo Pharm. Res. 21 947–952 Occurrence Handle10.1023/B:PHAM.0000029282.44140.2e Occurrence Handle1:CAS:528:DC%2BD2cXktlykurw%3D Occurrence Handle15212158

    Article  CAS  PubMed  Google Scholar 

  16. W. Lin M. Cormier A. Samiee A. Griffin B. Johnson C. L. Teng G. E. Hardee P. E. Daddona (2001) ArticleTitleTransdermal delivery of antisense oligonucleotides with microprojection patch (Macroflux) technology Pharm. Res. 18 1789–1793 Occurrence Handle10.1023/A:1013395102049 Occurrence Handle1:CAS:528:DC%2BD38XhvVamsQ%3D%3D Occurrence Handle11785702

    Article  CAS  PubMed  Google Scholar 

  17. M. Cormier P. E. Daddona (2003) Macroflux technology for transdermal delivery of therapeutic proteins and vaccines M. J. Rathbone J. Hadgraft M. S. Roberts (Eds) Modified-Release Drug Delivery Technology Marcel Dekker New York, NY 589–598

    Google Scholar 

  18. M. Cormier B. Johnson M. Ameri K. Nyam L. Libiran D. D. Zhang P. Daddona (2004) ArticleTitleTransdermal delivery of desmopressin using a coated microneedle array patch system J. Control. Release 97 503–511 Occurrence Handle10.1016/j.jconrel.2004.04.003 Occurrence Handle1:CAS:528:DC%2BD2cXkvF2itLs%3D Occurrence Handle15212882

    Article  CAS  PubMed  Google Scholar 

  19. J. A. Matriano M. Cormier J. Johnson W. A. Young M. Buttery K. Nyam P. E. Daddona (2002) ArticleTitleMacroflux microprojection array patch technology: a new and efficient approach for intracutaneous immunization Pharm. Res. 19 63–70 Occurrence Handle10.1023/A:1013607400040 Occurrence Handle1:CAS:528:DC%2BD38XhtVSmsbg%3D Occurrence Handle11837701

    Article  CAS  PubMed  Google Scholar 

  20. J. A. Mikszta J. B. Alarcon J. M. Brittingham D. E. Sutter R. J. Pettis N. G. Harvey (2002) ArticleTitleImproved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery Nat. Med. 8 415–419 Occurrence Handle10.1038/nm0402-415 Occurrence Handle1:CAS:528:DC%2BD38XivVGls7k%3D Occurrence Handle11927950

    Article  CAS  PubMed  Google Scholar 

  21. J. A. Mikszta V. J. Sullivan C. Dean A. M. Waterston J. B. Alarcon J. P. Dekker SuffixIII J. M. Brittingham J. Huang C. R. Hwang M. Ferriter G. Jiang K. Mar K. U. Saikh B. G. Stiles C. J. Roy R. G. Ulrich N. G. Harvey (2005) ArticleTitleProtective immunization against inhalational anthrax: a comparison of minimally invasive delivery platforms J. Infect. Dis. 191 278–288 Occurrence Handle10.1086/426865 Occurrence Handle1:CAS:528:DC%2BD2MXhtFCqt7k%3D Occurrence Handle15609239

    Article  CAS  PubMed  Google Scholar 

  22. S. Kaushik A. H. Hord D. D. Denson D. V. McAllister S. Smitra M. G. Allen M. R. Prausnitz (2001) ArticleTitleLack of pain associated with microfabricated microneedles Anesth. Analg. 92 502–504 Occurrence Handle1:STN:280:DC%2BD3M7ktFCqtA%3D%3D Occurrence Handle11159258

    CAS  PubMed  Google Scholar 

  23. D. V. McAllister M. G. Allen M. R. Prausnitz (2000) ArticleTitleMicrofabricated microneedles for gene and drug delivery Annu. Rev. Biomed. Eng. 2 289–313 Occurrence Handle10.1146/annurev.bioeng.2.1.289 Occurrence Handle1:CAS:528:DC%2BD3cXnsVaktbw%3D Occurrence Handle11701514

    Article  CAS  PubMed  Google Scholar 

  24. M. L. Reed W.-K. Lye (2004) ArticleTitleMicrosystems for drug and gene delivery Proc. IEEE 92 56–75 Occurrence Handle10.1109/JPROC.2003.820542 Occurrence Handle1:CAS:528:DC%2BD2cXht1eks7g%3D

    Article  CAS  Google Scholar 

  25. H. J. G. E. Gardeniers R. Luttge E. J. W. Berenschot M. J. Boer Particlede S. Y. Yeshurun M. Hefetz R. Oever Particlevan't A. Berg Particlevan den (2003) ArticleTitleSilicon micromachined hollow microneedles for transdermal liquid transport J. MEMS 12 855–862

    Google Scholar 

  26. J. Chen K. D. Wise J. F. Hetke S. C. Bledsoe SuffixJr (1997) ArticleTitleA multichannel neural probe for selective chemical delivery at the cellular level IEEE Trans. Biomed. Eng. 44 760–769 Occurrence Handle1:STN:280:ByiA1MfotVA%3D Occurrence Handle9254989

    CAS  PubMed  Google Scholar 

  27. B. Stoeber D. Liepmann (2002) Design, fabrication, and testing of a MEMS Syringe, Proceedings of Solid-State Sensor and Actuator Workshop Transducers Research Foundation Hilton Head Island, SC, USA

    Google Scholar 

  28. S. P. Davis W. Martanto M. G. Allen M. R. Prausnitz (2005) ArticleTitleHollow metal microneedles for insulin delivery to diabetic rats IEEE Trans. Biomed. Eng. 52 909–915 Occurrence Handle15887540

    PubMed  Google Scholar 

  29. W. H. Smart K. Subramanian (2000) ArticleTitleThe use of silicon microfabrication technology in painless blood glucose monitoring Diabetes Technol. Ther. 2 549–559 Occurrence Handle10.1089/15209150050501961 Occurrence Handle1:STN:280:DC%2BD3MvhvF2htg%3D%3D Occurrence Handle11469618

    Article  CAS  PubMed  Google Scholar 

  30. P. M. Wang, M. Cornwell, J. Hill, and M. R. Prausnitz. Precise microinjection into skin using hollow microneedles. (submitted)

  31. P. M. Wang M. Cornwell M. R. Prausnitz (2005) ArticleTitleMinimally invasive extraction of dermal interstitial fluid for glucose monitoring using microneedles Diabetes Technol. Ther. 7 131–141 Occurrence Handle10.1089/dia.2005.7.131 Occurrence Handle1:CAS:528:DC%2BD2MXhs12qs70%3D Occurrence Handle15738711

    Article  CAS  PubMed  Google Scholar 

  32. J. D. Bancroft M. Gamble (2002) Theory and Practice of Histological Techniques Churchill Livingstone New York, NY

    Google Scholar 

  33. R. W. Fox A. T. McDonald (1998) Introduction to Fluid Mechanics Wiley New York, NY

    Google Scholar 

  34. X.-Y. Zhang J. Luck M. W. Dewhirst F. Yuan (2000) ArticleTitleInterstitial hydraulic conductivity in a fibrosarcoma Am. J. Physiol. Heart Circ. Physiol. 279 H2726–H2734 Occurrence Handle1:CAS:528:DC%2BD3cXptFSmurY%3D Occurrence Handle11087227

    CAS  PubMed  Google Scholar 

  35. S. McGuire F. Yuan (2001) ArticleTitleQuantitative analysis of intratumoral infusion of color molecules Am. J. Physiol. Heart Circ. Physiol. 281 H715–H721 Occurrence Handle1:CAS:528:DC%2BD3MXmtVClsLo%3D Occurrence Handle11454575

    CAS  PubMed  Google Scholar 

  36. G. Kreil (1995) ArticleTitleHyaluronidases—a group of neglected enzymes Protein Sci. 4 1666–1669 Occurrence Handle1:CAS:528:DyaK2MXos1Sgtbs%3D Occurrence Handle8528065 Occurrence Handle10.1002/pro.5560040902

    Article  CAS  PubMed  Google Scholar 

  37. E. Bruera C. M. Neumann E. Pituskin K. Calder J. Hanson (1999) ArticleTitleA randomized controlled trial of local injections of hyaluronidase versus placebo in cancer patients receiving subcutaneous hydration Ann. Oncol. 10 1255–1258 Occurrence Handle1:STN:280:DC%2BD3c%2Flt1Oqtg%3D%3D Occurrence Handle10586347

    CAS  PubMed  Google Scholar 

  38. K. Meyer (1971) Hyaluronidases P. D. Boyer (Eds) The Enzymes, Vol. 5 Academic Press New York, NY 307–320

    Google Scholar 

  39. Hyaluronidase (Vitrase)-ISTA. Drugs R&D 4:194–197 (2003).

  40. W. Martanto M. K. Smith S. M. Baisch E. A. Costner M. R. Prausnitz (2005) ArticleTitleFluid dynamics in conically tapered microneedles AIChE J. 51 1599–1607 Occurrence Handle10.1002/aic.10424 Occurrence Handle1:CAS:528:DC%2BD2MXkvV2isr8%3D

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Tracey Couse, Harvinder Gill, Daniel Hallow, Bradley Parker, and Vladimir Zarnitsyn for helpful technical discussions. This work was supported in part by the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mark R. Prausnitz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martanto, W., Moore, J.S., Kashlan, O. et al. Microinfusion Using Hollow Microneedles. Pharm Res 23, 104–113 (2006). https://doi.org/10.1007/s11095-005-8498-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-005-8498-8

Key Words

Navigation