A resistance-sensing mechanical injector for the precise delivery of liquids to target tissue

Abstract

The precision of the delivery of therapeutics to the desired injection site by syringes and hollow needles typically depends on the operator. Here, we introduce a highly sensitive, completely mechanical and cost-effective injector for targeting tissue reliably and precisely. As the operator pushes the syringe plunger, the injector senses the loss-of-resistance on encountering a softer tissue or a cavity, stops advancing the needle and delivers the payload. We demonstrate that the injector can reliably deliver liquids to the suprachoroidal space—a challenging injection site that provides access to the back of the eye—for a wide range of eye sizes, scleral thicknesses and intraocular pressures, and target sites relevant for epidural injections, subcutaneous injections and intraperitoneal access. The design of this simple and effective injector can be adapted for a broad variety of clinical applications.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The I2T2 design and its mechanism of action.
Fig. 2: The I2T2 can inject into the SCS to deliver a drug to the back of the eye.
Fig. 3: The I2T2 can inject into the SCS and achieve broad coverage despite anatomical variations.
Fig. 4: Drug injected into the SCS with the I2T2 can reach the inner tissue layers of the retina and choroid through diffusion shortly after injection.
Fig. 5: The I2T2 can be used to deliver microparticles and cells throughout the SCS.
Fig. 6: Potential utility of the I2T2 as a technology for accessing tissues and tissue compartments.

Data availability

The authors declare that all data supporting the findings of this study are available within the paper and its supplementary information.

References

  1. 1.

    Tsukuda, Y. Venipuncture nerve injuries in the upper extremity from more than 1 million procedures. J. Patient Saf. https://doi.org/10.1097/PTS.0000000000000264 (2016).

  2. 2.

    Oven, S. & Johnson, J. Radial nerve injury after venipuncture. J. Hand Microsurg. 9, 43–44 (2017).

    Article  Google Scholar 

  3. 3.

    Aders, A. & Aders, H. Anaesthetic adverse incident reports: an Australian study of 1,231 outcomes. Anaesth. Intens. Care 33, 336–344 (2005).

    CAS  Article  Google Scholar 

  4. 4.

    Magrina, J. F. Complications of laparoscopic surgery. Clin. Obstet. Gynecol. 45, 469–480 (2002).

    Article  Google Scholar 

  5. 5.

    Benzon, H. T., Huntoon, M. A. & Rathmell, J. P. Improving the safety of epidural steroid injections. J. Am. Med. Assoc. 313, 1713 (2015).

    Article  Google Scholar 

  6. 6.

    Wu, T., Zhao, W., Dong, Y., Song, H. & Li, J. Effectiveness of ultrasound-guided versus fluoroscopy or computed tomography scanning guidance in lumbar facet joint injections in adults with facet joint syndrome: a meta-analysis of controlled trials. Arch. Phys. Med. Rehabil. 97, 1558–1563 (2016).

    Article  Google Scholar 

  7. 7.

    Evansa, I., Logina, I., Vanags, I. & Borgeat, A. Ultrasound versus fluoroscopic-guided epidural steroid injections in patients with degenerative spinal diseases. Eur. J. Anaesthesiol. 32, 262–268 (2015).

    CAS  Article  Google Scholar 

  8. 8.

    Bui, J. & Bogduk, N. A systematic review of the effectiveness of CT-guided, lumbar transforaminal injection of steroids. Pain Med. 14, 1860–1865 (2013).

    Article  Google Scholar 

  9. 9.

    Whipple, T. L. in Sports Injuries 2335–2342 (Springer Berlin, 2015).

  10. 10.

    D’Agostino, M. A. & Schmidt, W. A. Ultrasound-guided injections in rheumatology: actual knowledge on efficacy and procedures. Best Pract. Res. Clin. Rheumatol. 27, 283–294 (2013).

    Article  Google Scholar 

  11. 11.

    Palmer, R. Instrumentation et technique de la coelioscopie gynécologique. Gynecol. Obstet. 46, 420–431 (1947).

    CAS  Google Scholar 

  12. 12.

    Bassett, E. K. et al. Design of a mechanical clutch-based needle-insertion device. Proc. Natl Acad. Sci. USA 106, 5540–5545 (2009).

    CAS  Article  Google Scholar 

  13. 13.

    Begg, N. D. M. Blind Transmembrane Puncture Access: Design and Development of a Novel Laparoscopic Trocar and Blade Retraction Mechanism. MSc Thesis, Massachusetts Institute of Technology (2011).

  14. 14.

    Anderson, T. A., Kang, J. W., Gubin, T., Dasari, R. R. & So, P. T. C. Raman spectroscopy differentiates each tissue from the skin to the spinal cord. Anesthesiology 125, 793–804 (2016).

    CAS  Article  Google Scholar 

  15. 15.

    Riley, E. T. & Carvalho, B. The Episure syringe: a novel loss of resistance syringe for locating the epidural space. Anesth. Analg. 105, 1164–1166 (2007).

    Article  Google Scholar 

  16. 16.

    Vilos, G. & Vilos, A. The Veress needle causes most laparoscopic injuries and should be abandoned: against: evidence indicates that the primary trocar, not the Veress, causes most serious complications. BJOG 122, 142 (2015).

    Article  Google Scholar 

  17. 17.

    Vindal, A. & Lal, P. The Veress needle causes most laparoscopic injuries and should be abandoned: for: the open technique is safer and saves time. BJOG 122, 141 (2015).

    Article  Google Scholar 

  18. 18.

    Cornette, B. & Berrevoet, F. Trocar injuries in laparoscopy: techniques, tools, and means for prevention. A systematic review of the literature. World J. Surg. 40, 2331–2341 (2016).

    Article  Google Scholar 

  19. 19.

    Gonenc, B., Taylor, R. H., Iordachita, I., Gehlbach, P. & Handa, J. Force-sensing microneedle for assisted retinal vein cannulation. In Proc. IEEE Sensors 2014 698–701 (IEEE, 2014).

  20. 20.

    Moisseiev, E., Loewenstein, A. & Yiu, G. The suprachoroidal space: from potential space to a space with potential. Clin. Ophthalmol. 10, 173–178 (2016).

    CAS  Article  Google Scholar 

  21. 21.

    Olsen, T. W. et al. Cannulation of the suprachoroidal space: a novel drug delivery methodology to the posterior segment. Am. J. Ophthalmol. 142, 777–787 (2006).

    CAS  Article  Google Scholar 

  22. 22.

    Patel, S. R., Lin, A. S. P., Edelhauser, H. F. & Prausnitz, M. R. Suprachoroidal drug delivery to the back of the eye using hollow microneedles. Pharm. Res. 28, 166–176 (2011).

    CAS  Article  Google Scholar 

  23. 23.

    Patel, S. R. et al. Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye. Investig. Ophthalmol. Vis. Sci. 53, 4433–4441 (2012).

    CAS  Article  Google Scholar 

  24. 24.

    Abarca, E. M., Salmon, J. H. & Gilger, B. C. Effect of choroidal perfusion on ocular tissue distribution after intravitreal or suprachoroidal injection in an arterially perfused ex vivo pig eye model. J. Ocul. Pharmacol. Ther. 29, 715–722 (2013).

    CAS  Article  Google Scholar 

  25. 25.

    Kadam, R. S., Williams, J., Tyagi, P., Edelhauser, H. F. & Kompella, U. B. Suprachoroidal delivery in a rabbit ex vivo eye model: influence of drug properties, regional differences in delivery, and comparison with intravitreal and intracameral routes. Mol. Vis. 19, 1198–1210 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Gilger, B. C., Abarca, E. M., Salmon, J. H. & Patel, S. Treatment of acute posterior uveitis in a porcine model by injection of triamcinolone acetonide into the suprachoroidal space using microneedles. Investig. Ophthalmol. Vis. Sci. 54, 2483–2492 (2013).

    CAS  Article  Google Scholar 

  27. 27.

    Chen, M., Li, X., Liu, J., Han, Y. & Cheng, L. Safety and pharmacodynamics of suprachoroidal injection of triamcinolone acetonide as a controlled ocular drug release model. J. Control. Release 203, 109–117 (2015).

    CAS  Article  Google Scholar 

  28. 28.

    Chiang, B. et al. Thickness and closure kinetics of the suprachoroidal space following microneedle injection of liquid formulations. Investig. Opthalmol. Vis. Sci. 58, 555–564 (2017).

    CAS  Article  Google Scholar 

  29. 29.

    Chiang, B., Venugopal, N., Edelhauser, H. F. & Prausnitz, M. R. Distribution of particles, small molecules and polymeric formulation excipients in the suprachoroidal space after microneedle injection. Exp. Eye Res. 153, 101–109 (2016).

    CAS  Article  Google Scholar 

  30. 30.

    Gu, B. et al. Real-time monitoring of suprachoroidal space (SCS) following SCS injection using ultra-high resolution optical coherence tomography in guinea pig eyes. Invest. Ophthalmol. Vis. Sci. 56, 3623–3634 (2015).

    CAS  Article  Google Scholar 

  31. 31.

    Chen, K., Rowley, A. P., Weiland, J. D. & Humayun, M. S. Elastic properties of human posterior eye. J. Biomed. Mater. Res. A 102, 2001–2007 (2014).

    Article  Google Scholar 

  32. 32.

    Peden, M. C. et al. Ab-externo AAV-mediated gene delivery to the suprachoroidal space using a 250 micron flexible microcatheter. PLoS ONE 6, e17140 (2011).

    CAS  Article  Google Scholar 

  33. 33.

    Goldstein, D. A. Achieving drug delivery via the suprachoroidal space. Retina Today July/August, 82–84 (2014).

  34. 34.

    Zhang, L. et al. Long-term therapeutic effects of mesenchymal stem cells compared to dexamethasone on recurrent experimental autoimmune uveitis of rats. Invest. Ophth. Vis. Sci. 55, 5561–5571 (2014).

    CAS  Google Scholar 

  35. 35.

    Cao, J. et al. Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration. Stem Cells 34, 367–379 (2016).

    CAS  Article  Google Scholar 

  36. 36.

    Nickla, D. L. & Wallman, J. The multifunctional choroid. Prog. Retin. Eye. Res. 29, 144–168 (2010).

    Article  Google Scholar 

  37. 37.

    Raju, J. R. & Weinberg, D. V. Accuracy and precision of intraocular injection volume. Am. J. Ophthalmol. 133, 564–566 (2002).

    Article  Google Scholar 

  38. 38.

    Muffly, M. K. et al. Small-volume injections: evaluation of volume administration deviation from intended injection volumes. Anesth. Analg. 125, 1192–1199 (2017).

    Article  Google Scholar 

  39. 39.

    Strehle, E.-M. Making the invisible visible: near-infrared spectroscopy and phlebotomy in children. Telemed. J. E. Health 16, 889–893 (2010).

    Article  Google Scholar 

  40. 40.

    VGStudio Max 2.2 (Volume Graphics GmbH); https://www.volumegraphics.com.

  41. 41.

    Computer-aided three-dimensional interactive application (CATIA) v.5 (Dassault Systèmes, 2018); https://www.3ds.com/products-services/catia/.

Download references

Acknowledgements

Funding for this research was provided by grant no. R01HL095722 to J.M.K. Animal experiments were funded through the Boston-KPro research fund to M.G.A. and A.C. We thank Y. Jung and C. P. Lin for use of the intravital microscope, H. G. Lin and Harvard’s Center for Nanoscale Systems for use of the microCT system, and K. Cormier and the Hope Babette Tang Histology Facility at the Koch Institute at MIT for performing histology sections. We also thank the Schepens Eye Research Institute’s Animal Facility, especially J. Hoadley, M. Ortega and C. Beiler for their help. We appreciate the feedback on performing SCS injections with an I2T2 from D. Vavvas, V. Satitpitakul and K. Suri, from the Massachusetts Eye and Ear Infirmary.

Author information

Affiliations

Authors

Contributions

G.D.C. M.K.S.V. and J.M.K. conceptualized and iterated the principle and design of the I2T2. G.D.C., M.K.S.V. and J.L. were responsible for study design, guided by J.M.K. G.D.C. and J.L. developed the analytical model, improved the design and performed detailed experimental studies with focus on ocular applications. G.D.C., M.G.-A., A.C. and J.L. designed and performed the in vivo experiments. B.E.M., A.S., N.L.-B., Z.T., K.M. and K.Y. provided experimental support for the experiments with cell injections in the SCS. G.D.C., M.K.S.V. and A.D. tested the device for applications other than eye. G.D.C. and J.L. were responsible for conceptual drawings and data representation. B.E.M. captured all the photographs under the supervision of G.D.C. and J.L. G.D.C. wrote the manuscript with constructive feedback and editing from J.M.K., J.L., B.E.M. and P.A.J.

Corresponding author

Correspondence to Jeffrey M. Karp.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary methods, figures, tables and video captions.

Reporting Summary

Supplementary Video 1

Ventricular access through the heart wall by using i2T2 (ex vivo model).

Supplementary Video 2

Accessing the peritoneal cavity through the abdominal wall by using i2T2 (ex vivo model).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chitnis, G.D., Verma, M.K.S., Lamazouade, J. et al. A resistance-sensing mechanical injector for the precise delivery of liquids to target tissue. Nat Biomed Eng 3, 621–631 (2019). https://doi.org/10.1038/s41551-019-0350-2

Download citation

Further reading