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Research Article
BIOENGINEERING

Biocompatible near-infrared quantum dots delivered to the skin by microneedle patches record vaccination

Science Translational Medicine
18 Dec 2019
Vol 11, Issue 523

On the record

Vaccines prevent disease and save lives; however, lack of standardized immunization recordkeeping makes it challenging to track vaccine coverage across the world. McHugh et al. developed dissolvable microneedles that deliver patterns of near-infrared light-emitting microparticles to the skin. Particle patterns are invisible to the eye but can be imaged using modified smartphones. By codelivering a vaccine, the pattern of particles in the skin could serve as an on-person vaccination record. Patterns were detected 9 months after intradermal delivery of microparticles in rats, and codelivery of inactivated poliovirus led to protective antibody production. Discrete microneedle-delivered microparticle patterns in porcine and pigmented human skin were identifiable using semiautomated machine learning. These results demonstrate proof of concept for intradermal on-person vaccination recordkeeping.

Abstract

Accurate medical recordkeeping is a major challenge in many low-resource settings where well-maintained centralized databases do not exist, contributing to 1.5 million vaccine-preventable deaths annually. Here, we present an approach to encode medical history on a patient using the spatial distribution of biocompatible, near-infrared quantum dots (NIR QDs) in the dermis. QDs are invisible to the naked eye yet detectable when exposed to NIR light. QDs with a copper indium selenide core and aluminum-doped zinc sulfide shell were tuned to emit in the NIR spectrum by controlling stoichiometry and shelling time. The formulation showing the greatest resistance to photobleaching after simulated sunlight exposure (5-year equivalence) through pigmented human skin was encapsulated in microparticles for use in vivo. In parallel, microneedle geometry was optimized in silico and validated ex vivo using porcine and synthetic human skin. QD-containing microparticles were then embedded in dissolvable microneedles and administered to rats with or without a vaccine. Longitudinal in vivo imaging using a smartphone adapted to detect NIR light demonstrated that microneedle-delivered QD patterns remained bright and could be accurately identified using a machine learning algorithm 9 months after application. In addition, codelivery with inactivated poliovirus vaccine produced neutralizing antibody titers above the threshold considered protective. These findings suggest that intradermal QDs can be used to reliably encode information and can be delivered with a vaccine, which may be particularly valuable in the developing world and open up new avenues for decentralized data storage and biosensing.

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Supplementary Material

Summary

Materials and Methods
Fig. S1. Optical properties of organic dyes.
Fig. S2. Evolution of fluorescence emission properties with shelling time.
Fig. S3. Fluorescence lifetime characterization of the S10C QD series.
Fig. S4. Composition and physical properties of S10C5H QDs.
Fig. S5. pH stability of PMMA-encapsulated QDs.
Fig. S6. Finite element analysis of mechanical forces on microneedles.
Fig. S7. Optimization of microneedle geometry using finite element analysis.
Fig. S8. Machine learning training and validation.
Table S1. Spectral characterization of custom QD formulations.
Table S2. Multiexponential fitting parameters for photoluminescence decay curves.
Movie S1. Intradermal administration and imaging of encapsulated QDs.
Data file S1. Individual subject-level data.
References (5462)

Resources

File (aay7162_data_file_s1.xlsx)
File (aay7162_movie_s1.mp4)
File (aay7162_sm.pdf)

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Computer code associated with Biocompatible near-infrared quantum dots delivered to the skin by microneedle patches to record vaccination; doi.org/10.5281/zenodo.3571386.

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Science Translational Medicine
Volume 11 | Issue 523
December 2019

Submission history

Received: 20 July 2019
Accepted: 27 November 2019

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Acknowledgments

We acknowledge W. H. Gates, D. Hartman, S. Hershenson, S. Kern, B. Nikolic, K. Owen, L. Shackelton, C. Karp, and D. Robinson for their guidance; R. T. Bronson for pathology expertise; and the MIT Department of Comparative Medicine for advice. We thank W. Weldon and his laboratory at the U.S. Centers for Disease Control and Prevention for performing neutralizing antibody titer studies, the Koch Institute Swanson Biotechnology Center for technical support, specifically the Hope Babette Tang (1983) Histology Facility and the Peterson (1957) Nanotechnology Materials Core Facility as well as the Harvard University Center for Nanoscale Systems, and W.M. Keck Microscopy Facility at the Whitehead Institute. Funding: This work was funded by the Bill & Melinda Gates Foundation grant OPP 1150646. Fellowship support for K.J.M. was provided by an NIH Ruth L. Kirschstein National Research Service Award (F32EB022416). L.J. thanks the Youth Innovation Promotion Association CAS (2018042), National Natural Science Foundation of China (81671755), and China Scholarship Council (201604910444) for financial support. This work was supported in part by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute. This work was performed in part at the Harvard University Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI), which is supported by the National Science Foundation under NSF award no. 1541959. Author contributions: K.J.M., R.L., A.J., L.W., and P.A.W. devised the concept. K.J.M., L.J., R.L., and A.J. designed the experiments and wrote the manuscript. L.J. designed and synthesized QDs. L.J., H.S.N.J., C.F.P., and J.Y. performed optical characterization and analysis. M.G.B. and M.G. oversaw QD synthesis and analysis. L.J., H.S.N.J., and W.T. performed QD encapsulation. M.S. performed the computational modeling simulations. K.J.M., S.Y.S., and M.C. designed and fabricated microneedles. K.J.M., S.Y.S., C.F.P., F.L., M.P., N.P., and A.K. designed the smartphone optics. K.J.M., L.J., H.S.N.J., S.Y.S., S.Y.T., T.G., J.C., J.L.S., and M.T. performed the in vitro experiments. K.J.M., S.Y.S., and M.C. performed the ex vivo studies. K.J.M., S.Y.S., M.C., S.R., and S.T. performed the in vivo experiments and corresponding analysis. M.S. and D.V. developed the machine learning algorithm. Competing interests: A patent application entitled “Microneedle tattoo patches and use thereof” describing the approach presented here was filed by K.J.M., L.J., S.Y.S., H.S.N.J., A.J., and R.L. (US 62/558,172). R.L. discloses potential competing interests in the below link: www.dropbox.com/s/yc3xqb5s8s94v7x/Rev%20Langer%20COI.pdf?dl=0. Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. Computer code archive is publicly accessible: doi.org/10.5281/zenodo.3571386.

Authors

Affiliations

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Present address: Department of Bioengineering, Rice University, Houston, TX 77005, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Bei Yi Jie 2, Zhong Guan Cun, Beijing 100190, China.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Morteza Sarmadi
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Department of Mechanical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Hapuarachchige Surangi N. Jayawardena https://orcid.org/0000-0001-5866-9346
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Present address: Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA.
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Global Good, Intellectual Ventures Laboratory, 14360 SE Eastgate Way, Bellevue, WA 98007, USA.
Sviatlana Rose
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Stephany Y. Tzeng
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Present address: School of Medicine, Johns Hopkins University, 733 N. Broadway, Baltimore, MD 21205, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Daniel Vlasic
Independent consultant, 119 Kendall Rd, Lexington, MA 02421, USA (https://people.csail.mit.edu/drdaniel/).
Global Good, Intellectual Ventures Laboratory, 14360 SE Eastgate Way, Bellevue, WA 98007, USA.
Global Good, Intellectual Ventures Laboratory, 14360 SE Eastgate Way, Bellevue, WA 98007, USA.
Global Good, Intellectual Ventures Laboratory, 14360 SE Eastgate Way, Bellevue, WA 98007, USA.
Wen Tang
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Philip A. Welkhoff
Institute for Disease Modeling, 3150 139th Ave. SE, Bellevue, WA 98005, USA.
Ari Karchin
Global Good, Intellectual Ventures Laboratory, 14360 SE Eastgate Way, Bellevue, WA 98007, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Mingyuan Gao
Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Bei Yi Jie 2, Zhong Guan Cun, Beijing 100190, China.
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

Funding Information

Youth Innovation Promotion Association CAS: 2018042

Notes

*
These authors contributed equally to this work.
||
Corresponding author. Email: [email protected] (R.L.); [email protected] (A.J.)

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