Ingestible electronics for diagnostics and therapy

Abstract

The gastrointestinal (GI) tract offers the opportunity to detect physiological and pathophysiological signals from the human body. Ingestible electronics can gain close proximity to major organs through the GI tract and therefore can serve as clinical tools for diagnostics and therapy. In this Review, we summarize the physiological and anatomical characteristics of the GI tract, which present both challenges and opportunities for the development of ingestible devices. We describe recent breakthroughs in materials science, electrical engineering and data science that have permitted the exploration of technologies for sensing and therapy via the GI tract. Novel sensing opportunities include electrochemical, electromagnetic, optical and acoustic protocols, which have the capacity to sense luminal or extra-luminal analytes in the GI tract. We review therapeutic interventions, such as anatomical targeting for drug delivery, delivery of macromolecules and electrical signals. Finally, we investigate major challenges associated with ingestible electronics, including safety, communication, powering, steering and tissue interactions. Ingestible electronics are an exciting area of scientific innovation and they may pave the way for a new era in medicine, enabling patients to receive remote, electronically assisted health care.

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Fig. 1
Fig. 2: Gastrointestinal anatomy, physiology and pathophysiology.
Fig. 3: Clinically applied ingestible electronics.
Fig. 4: Technologies for ingestible electronics.
Fig. 5: Material design for ingestible electronics.
Fig. 6: Communication concepts for ingestible electronics.
Fig. 7: Major challenges for ingestible electronics.

References

  1. 1.

    Jacobson, B. & Mackay, R. S. A. pH-endoradiosonde. Lancet 272, 1224 (1957).

    CAS  Google Scholar 

  2. 2.

    Mackay, R. S. & Jacobson, B. Endoradiosonde. Nature 179, 1239–1240 (1957).

    CAS  Google Scholar 

  3. 3.

    Vonardenne, M. & Sprung, H. B. Über Versuche mit einem verschluckbaren Intestinalsender. Naturwissenschaften 45, 154–155 (1958).

    Google Scholar 

  4. 4.

    Farrar, J. T., Zworykin, V. K. & Baum, J. Pressure-sensitive telemetering capsule for study of gastrointestinal motility. Science 126, 975–976 (1957).

    CAS  Google Scholar 

  5. 5.

    Lesho, J. C. & Hogrefe, A. F. Ingestible size continuously transmitting temperature monitoring pill. US Patent 07236885 (1988).

  6. 6.

    Sparling, P. B., Snow, T. K. & Millard-Stafford, M. L. Monitoring core temperature during exercise: ingestible sensor versus rectal thermistor. Aviat. Space Environ. Med. 64, 760–763 (1993).

    CAS  Google Scholar 

  7. 7.

    O’Brien, C., Hoyt, R. W., Buller, M. J., Castellani, J. W. & Young, A. J. Telemetry pill measurement of core temperature in humans during active heating and cooling. Med. Sci. Sports Exerc. 30, 468–472 (1998).

    Google Scholar 

  8. 8.

    Iddan, G., Meron, G., Glukhovsky, A. & Swain, P. Wireless capsule endoscopy. Nature 405, 417 (2000).

    CAS  Google Scholar 

  9. 9.

    Swain, P. Wireless capsule endoscopy. Gut 52, iv48–iv50 (2003).

    Google Scholar 

  10. 10.

    Xin, L., Liao, Z., Jiang, Y. P. & Li, Z. S. Indications, detectability, positive findings, total enteroscopy, and complications of diagnostic double-balloon endoscopy: a systematic review of data over the first decade of use. Gastrointest. Endosc. 74, 563–570 (2011).

    Google Scholar 

  11. 11.

    Committee, A. T. et al. Wireless capsule endoscopy. Gastrointest. Endosc. 78, 805–815 (2013).

    Google Scholar 

  12. 12.

    Bettinger, C. J. Materials advances for next-generation ingestible electronic medical devices. Trends Biotechnol. 33, 575–585 (2015).

    CAS  Google Scholar 

  13. 13.

    Kim, Y. J., Wu, W., Chun, S. E., Whitacre, J. F. & Bettinger, C. J. Biologically derived melanin electrodes in aqueous sodium-ion energy storage devices. Proc. Natl Acad. Sci. USA 110, 20912–20917 (2013).

    CAS  Google Scholar 

  14. 14.

    Yin, L. et al. Materials, designs, and operational characteristics for fully biodegradable primary batteries. Adv. Mater. 26, 3879–3884 (2014).

    CAS  Google Scholar 

  15. 15.

    Hu, W., Lum, G. Z., Mastrangeli, M. & Sitti, M. Small-scale soft-bodied robot with multimodal locomotion. Nature 554, 81–85 (2018).

    CAS  Google Scholar 

  16. 16.

    Zhang, S. et al. A pH-responsive supramolecular polymer gel as an enteric elastomer for use in gastric devices. Nat. Mater. 14, 1065–1071 (2015).

    CAS  Google Scholar 

  17. 17.

    Zhu, C. X. et al. Stretchable temperature-sensing circuits with strain suppression based on carbon nanotube transistors. Nat. Electron. 1, 183–190 (2018).

    Google Scholar 

  18. 18.

    Lei, T. et al. Biocompatible and totally disintegrable semiconducting polymer for ultrathin and ultralightweight transient electronics. Proc. Natl Acad. Sci. USA 114, 5107–5112 (2017).

    CAS  Google Scholar 

  19. 19.

    Kang, S. K., Koo, J., Lee, Y. K. & Rogers, J. A. Advanced materials and devices for bioresorbable electronics. Acc. Chem. Res. 51, 988–998 (2018).

    CAS  Google Scholar 

  20. 20.

    Bonacchini, G. E. et al. Tattoo-paper transfer as a versatile platform for all-printed organic edible electronics. Adv. Mater. 30, e1706091 (2018).

    Google Scholar 

  21. 21.

    Pan, Y. H. Heading toward artificial intelligence 2.0. Engineering 2, 409–413 (2016).

    Google Scholar 

  22. 22.

    Traverso, G. et al. Physiologic status monitoring via the gastrointestinal tract. PLOS ONE 10, e0141666 (2015).

    CAS  Google Scholar 

  23. 23.

    Bettinger, C. J. Advances in materials and structures for ingestible electromechanical medical devices. Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.201806470 (2018).

    Article  Google Scholar 

  24. 24.

    Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    CAS  Google Scholar 

  25. 25.

    Rao, M. & Gershon, M. D. The bowel and beyond: the enteric nervous system in neurological disorders. Nat. Rev. Gastroenterol. Hepatol. 13, 517–528 (2016).

    CAS  Google Scholar 

  26. 26.

    Sender, R., Fuchs, S. & Milo, R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164, 337–340 (2016).

    CAS  Google Scholar 

  27. 27.

    Furness, J. B., Callaghan, B. P., Rivera, L. R. & Cho, H. J. The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv. Exp. Med. Biol. 817, 39–71 (2014).

    Google Scholar 

  28. 28.

    Berger, E. H. The distribution of parietal cells in the stomach: a histotopographic study. Am. J. Anat. 54, 87–114 (1934).

    Google Scholar 

  29. 29.

    Adams, D. H. Sleisenger and Fordtran’s gastrointestinal and liver disease. Gut 56, 1175–1175 (2007).

    Google Scholar 

  30. 30.

    Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).

    CAS  Google Scholar 

  31. 31.

    Waterman, M. & Gralnek, I. M. Capsule endoscopy of the esophagus. J. Clin. Gastroenterol. 43, 605–612 (2009).

    Google Scholar 

  32. 32.

    Blaser, M. J., Chyou, P. H. & Nomura, A. Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer, and duodenal ulcer risk. Cancer Res. 55, 562–565 (1995).

    CAS  Google Scholar 

  33. 33.

    Hunt, R. H. et al. The stomach in health and disease. Gut 64, 1650–1668 (2015).

    CAS  Google Scholar 

  34. 34.

    Fashner, J. & Gitu, A. C. Diagnosis and treatment of peptic ulcer disease and H. pylori infection. Am. Fam. Physician 91, 236–242 (2015).

    Google Scholar 

  35. 35.

    Camilleri, M. et al. Clinical guideline: management of gastroparesis. Am. J. Gastroenterol. 108, 18–37; quiz 38 (2013).

    CAS  Google Scholar 

  36. 36.

    Meyer, B., Beglinger, C., Neumayer, M. & Stalder, G. A. Physical characteristics of indigestible solids affect emptying from the fasting human stomach. Gut 30, 1526–1529 (1989).

    CAS  Google Scholar 

  37. 37.

    Nadeau, P. et al. Prolonged energy harvesting for ingestible devices. Nat. Biomed. Eng. 1, 0022 (2017).

    Google Scholar 

  38. 38.

    Gronborg, M. et al. Comprehensive proteomic analysis of human pancreatic juice. J. Proteome Res. 3, 1042–1055 (2004).

    CAS  Google Scholar 

  39. 39.

    Krause, W. J. Brunner’s glands: a structural, histochemical and pathological profile. Prog. Histochem. Cytochem. 35, 259–367 (2000).

    CAS  Google Scholar 

  40. 40.

    Graham, D. Y. et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann. Internal Med. 116, 705–708 (1992).

    CAS  Google Scholar 

  41. 41.

    Caspary, W. F. Physiology and pathophysiology of intestinal absorption. Am. J. Clin. Nutr. 55, 299S–308S (1992).

    CAS  Google Scholar 

  42. 42.

    Kaukinen, K., Maki, M., Partanen, J., Sievanen, H. & Collin, P. Celiac disease without villous atrophy: revision of criteria called for. Dig. Dis. Sci. 46, 879–887 (2001).

    CAS  Google Scholar 

  43. 43.

    Cornes, J. S. Number, size, and distribution of Peyer’s patches in the human small intestine. Part I: the development of Peyer’s patches. Gut 6, 225–229 (1965).

    CAS  Google Scholar 

  44. 44.

    Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    CAS  Google Scholar 

  45. 45.

    Maloy, K. J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).

    CAS  Google Scholar 

  46. 46.

    Heyman, M. B. Lactose intolerance in infants, children, and adolescents. Pediatrics 118, 1279–1286 (2006).

    Google Scholar 

  47. 47.

    Neurath, M. F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 14, 329–342 (2014).

    CAS  Google Scholar 

  48. 48.

    Doherty, T. J. Postoperative ileus: pathogenesis and treatment. Vet. Clin. North Am. Equine Pract. 25, 351–362 (2009).

    Google Scholar 

  49. 49.

    McAlindon, M. E., Ching, H. L., Yung, D., Sidhu, R. & Koulaouzidis, A. Capsule endoscopy of the small bowel. Ann. Transl Med. 4, 369 (2016).

    Google Scholar 

  50. 50.

    DeSesso, J. M. & Jacobson, C. F. Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats. Food Chem. Toxicol. 39, 209–228 (2001).

    CAS  Google Scholar 

  51. 51.

    Dinan, T. G. & Cryan, J. F. Brain–gut–microbiota axis — mood, metabolism and behaviour. Nat. Rev. Gastroenterol. Hepatol. 14, 69–70 (2017).

    CAS  Google Scholar 

  52. 52.

    Fung, T. C., Olson, C. A. & Hsiao, E. Y. Interactions between the microbiota, immune and nervous systems in health and disease. Nat. Neurosci. 20, 145–155 (2017).

    CAS  Google Scholar 

  53. 53.

    Jangi, S. et al. Alterations of the human gut microbiome in multiple sclerosis. Nat. Commun. 7, 12015 (2016).

    CAS  Google Scholar 

  54. 54.

    Keshavarzian, A. et al. Colonic bacterial composition in Parkinson’s disease. Mov. Disord. 30, 1351–1360 (2015).

    CAS  Google Scholar 

  55. 55.

    Ignacio, A., Morales, C. I., Camara, N. O. & Almeida, R. R. Innate sensing of the gut microbiota: modulation of inflammatory and autoimmune diseases. Front. Immunol. 7, 54 (2016).

    Google Scholar 

  56. 56.

    Spiljar, M., Merkler, D. & Trajkovski, M. The immune system bridges the gut microbiota with systemic energy homeostasis: focus on TLRs, mucosal barrier, and SCFAs. Front. Immunol. 8, 1353 (2017).

    Google Scholar 

  57. 57.

    Clemente, J. C., Manasson, J. & Scher, J. U. The role of the gut microbiome in systemic inflammatory disease. BMJ 360, j5145 (2018).

    Google Scholar 

  58. 58.

    Gimbert, C. & Lapointe, F. J. Self-tracking the microbiome: where do we go from here? Microbiome 3, 70 (2015).

    Google Scholar 

  59. 59.

    Pascal, V. et al. A microbial signature for Crohn’s disease. Gut 66, 813–822 (2017).

    CAS  Google Scholar 

  60. 60.

    Lehmann, F. S., Burri, E. & Beglinger, C. The role and utility of faecal markers in inflammatory bowel disease. Therap. Adv. Gastroenterol. 8, 23–36 (2015).

    Google Scholar 

  61. 61.

    Hara, A. K., Leighton, J. A., Sharma, V. K. & Fleischer, D. E. Small bowel: preliminary comparison of capsule endoscopy with barium study and CT. Radiology 230, 260–265 (2004).

    Google Scholar 

  62. 62.

    Apostolopoulos, P. et al. Evaluation of capsule endoscopy in active, mild-to-moderate, overt, obscure GI bleeding. Gastrointest. Endosc. 66, 1174–1181 (2007).

    Google Scholar 

  63. 63.

    Gerson, L. B. Use and misuse of small bowel video capsule endoscopy in clinical practice. Clin. Gastroenterol. Hepatol. 11, 1224–1231 (2013).

    Google Scholar 

  64. 64.

    Sung, J. J. et al. An updated Asia Pacific Consensus Recommendations on colorectal cancer screening. Gut 64, 121–132 (2015).

    CAS  Google Scholar 

  65. 65.

    Leddin, D. J. et al. Canadian Association of Gastroenterology position statement on screening individuals at average risk for developing colorectal cancer: 2010. Can. J. Gastroenterol. 24, 705–714 (2010).

    Google Scholar 

  66. 66.

    European Colorectal Cancer Screening Guidelines Working Group. European guidelines for quality assurance in colorectal cancer screening and diagnosis: overview and introduction to the full supplement publication. Endoscopy 45, 51–59 (2013).

    Google Scholar 

  67. 67.

    Goenka, M. K., Majumder, S. & Goenka, U. Capsule endoscopy: present status and future expectation. World J. Gastroenterol. 20, 10024–10037 (2014).

    Google Scholar 

  68. 68.

    Van de Bruaene, C., De Looze, D. & Hindryckx, P. Small bowel capsule endoscopy: where are we after almost 15 years of use? World J. Gastrointest. Endosc. 7, 13–36 (2015).

    Google Scholar 

  69. 69.

    Friedel, D., Modayil, R. & Stavropoulos, S. Colon capsule endoscopy: review and perspectives. Gastroenterol. Res. Pract. 2016, 9643162 (2016).

    Google Scholar 

  70. 70.

    Triester, S. L. et al. A meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with non-stricturing small bowel Crohn’s disease. Am. J. Gastroenterol. 101, 954–964 (2006).

    Google Scholar 

  71. 71.

    Jensen, M. D., Nathan, T., Rafaelsen, S. R. & Kjeldsen, J. Diagnostic accuracy of capsule endoscopy for small bowel Crohn’s disease is superior to that of MR enterography or CT enterography. Clin. Gastroenterol. Hepatol. 9, 124–129 (2011).

    Google Scholar 

  72. 72.

    Health Quality Ontario. Colon capsule endoscopy for the detection of colorectal polyps: an evidence-based analysis. Ont. Health Technol. Assess. Ser. 15, 1–39 (2015).

    Google Scholar 

  73. 73.

    Eliakim, R. et al. Prospective multicenter performance evaluation of the second-generation colon capsule compared with colonoscopy. Endoscopy 41, 1026–1031 (2009).

    CAS  Google Scholar 

  74. 74.

    Spada, C. et al. Second-generation colon capsule endoscopy compared with colonoscopy. Gastrointest. Endosc. 74, 581–589 (2011).

    Google Scholar 

  75. 75.

    Hagel, A. F. et al. Colon capsule endoscopy: detection of colonic polyps compared with conventional colonoscopy and visualization of extracolonic pathologies. Can. J. Gastroenterol. Hepatol. 28, 77–82 (2014).

    Google Scholar 

  76. 76.

    Saurin, J. C., Beneche, N., Chambon, C. & Pioche, M. Challenges and future of wireless capsule endoscopy. Clin. Endosc. 49, 26–29 (2016).

    Google Scholar 

  77. 77.

    Rondonotti, E. et al. Complications, limitations, and failures of capsule endoscopy: a review of 733 cases. Gastrointest. Endosc. 62, 712–716; quiz 752, 754 (2005).

    Google Scholar 

  78. 78.

    Kim, B., Lee, S., Park, J. H. & Park, J. O. Design and fabrication of a locomotive mechanism for capsule-type endoscopes using shape memory alloys (SMAs). IEEE ASME Trans. Mechatron. 10, 77–86 (2005).

    Google Scholar 

  79. 79.

    Wang, K., Yan, G., Ma, G. & Ye, D. An earthworm-like robotic endoscope system for human intestine: design, analysis, and experiment. Ann. Biomed. Eng. 37, 210–221 (2009).

    Google Scholar 

  80. 80.

    Quirini, M., Scapellato, S., Valdastri, P., Menciassi, A. & Dario, P. An approach to capsular endoscopy with active motion. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2007, 2827–2830 (2007).

    Google Scholar 

  81. 81.

    Glass, P., Cheung, E. & Sitti, M. A legged anchoring mechanism for capsule endoscopes using micropatterned adhesives. IEEE Trans. Biomed. Eng. 55, 2759–2767 (2008).

    Google Scholar 

  82. 82.

    Hafezi, H. et al. An ingestible sensor for measuring medication adherence. IEEE Trans. Biomed. Eng. 62, 99–109 (2015).

    Google Scholar 

  83. 83.

    Osterberg, L. & Blaschke, T. Adherence to medication. N. Engl. J. Med. 353, 487–497 (2005).

    CAS  Google Scholar 

  84. 84.

    Belknap, R. et al. Feasibility of an ingestible sensor-based system for monitoring adherence to tuberculosis therapy. PLOS ONE 8, e53373 (2013).

    CAS  Google Scholar 

  85. 85.

    Eisenberger, U. et al. Medication adherence assessment: high accuracy of the new Ingestible Sensor System in kidney transplants. Transplantation 96, 245–250 (2013).

    Google Scholar 

  86. 86.

    Frias, J. et al. Effectiveness of digital medicines to improve clinical outcomes in patients with uncontrolled hypertension and type 2 diabetes: prospective, open-label, cluster-randomized pilot clinical trial. J. Med. Internet Res. 19, e246 (2017).

    Google Scholar 

  87. 87.

    Camilleri, M. et al. Wireless pH-motility capsule for colonic transit: prospective comparison with radiopaque markers in chronic constipation. Neurogastroenterol. Motil. 22, 874–882 (2010).

    CAS  Google Scholar 

  88. 88.

    Hasler, W. L. The use of SmartPill for gastric monitoring. Expert Rev. Gastroenterol. Hepatol. 8, 587–600 (2014).

    CAS  Google Scholar 

  89. 89.

    Rao, S. S. et al. Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies. Neurogastroenterol. Motil. 23, 8–23 (2011).

    CAS  Google Scholar 

  90. 90.

    Niven, D. J. et al. Accuracy of peripheral thermometers for estimating temperature: a systematic review and meta-analysis. Ann. Internal Med. 163, 768–777 (2015).

    Google Scholar 

  91. 91.

    Kauer, W. K. H. et al. Composition and concentration of bile acid reflux into the esophagus of patients with gastroesophageal reflux disease. Surgery 122, 874–881 (1997).

    CAS  Google Scholar 

  92. 92.

    Finberg, L., Cheung, C. S. & Fleishman, E. The significance of the concentrations of electrolytes in stool water during infantile diarrhea. Am. J. Dis. Child 100, 809–813 (1960).

    CAS  Google Scholar 

  93. 93.

    Garner, C. E. et al. Volatile organic compounds from feces and their potential for diagnosis of gastrointestinal disease. FASEB J. 21, 1675–1688 (2007).

    CAS  Google Scholar 

  94. 94.

    Steiger, C., Luhmann, T. & Meinel, L. Oral drug delivery of therapeutic gases — carbon monoxide release for gastrointestinal diseases. J. Control. Release 189, 46–53 (2014).

    CAS  Google Scholar 

  95. 95.

    Kalantar-Zadeh, K. et al. A human pilot trial of ingestible electronic capsules capable of sensing different gases in the gut. Nat. Electron. 1, 79–87 (2018).

    Google Scholar 

  96. 96.

    Kam, S. Y. et al. Characterization of the human gastric fluid proteome reveals distinct pH-dependent protein profiles: implications for biomarker studies. J. Proteome Res. 10, 4535–4546 (2011).

    CAS  Google Scholar 

  97. 97.

    Turnbaugh, P. J. et al. The human microbiome project. Nature 449, 804–810 (2007).

    CAS  Google Scholar 

  98. 98.

    Inadomi, J. M. Screening for colorectal neoplasia. N. Engl. J. Med. 376, 149–156 (2017).

    Google Scholar 

  99. 99.

    Mimee, M. et al. An ingestible bacterial-electronic system to monitor gastrointestinal health. Science 360, 915–918 (2018).

    CAS  Google Scholar 

  100. 100.

    Duffy, M. J. et al. Use of faecal markers in screening for colorectal neoplasia: a European group on tumor markers position paper. Int. J. Cancer 128, 3–11 (2011).

    CAS  Google Scholar 

  101. 101.

    Gisbert, J. P. & McNicholl, A. G. Questions and answers on the role of faecal calprotectin as a biological marker in inflammatory bowel disease. Dig. Liver Dis. 41, 56–66 (2009).

    CAS  Google Scholar 

  102. 102.

    Mao, R. et al. Fecal calprotectin in predicting relapse of inflammatory bowel diseases: a meta-analysis of prospective studies. Inflamm. Bowel Dis. 18, 1894–1899 (2012).

    Google Scholar 

  103. 103.

    Costa, F. et al. Calprotectin is a stronger predictive marker of relapse in ulcerative colitis than in Crohn’s disease. Gut 54, 364–368 (2005).

    CAS  Google Scholar 

  104. 104.

    Garcia-Sanchez, V. et al. Does fecal calprotectin predict relapse in patients with Crohn’s disease and ulcerative colitis? J. Crohns Colitis 4, 144–152 (2010).

    Google Scholar 

  105. 105.

    Rizk, M., Belal, F., Ibrahim, F., Ahmed, S. & El-Enany, N. M. Voltammetric analysis of certain 4-quinolones in pharmaceuticals and biological fluids. J. Pharm. Biomed. Anal. 24, 211–218 (2000).

    CAS  Google Scholar 

  106. 106.

    Belal, F., Al-Malaq, H. A. & Al-Majed, A. A. Voltammetric determination of isoxsuprine and fenoterol in dosage forms and biological fluids through nitrosation. J. Pharm. Biomed. Analysis 23, 1005–1015 (2000).

    CAS  Google Scholar 

  107. 107.

    Mage, P. L. et al. Closed-loop control of circulating drug levels in live animals. Nat. Biomed. Eng. 1, 0070 (2017).

    Google Scholar 

  108. 108.

    Caffrey, C. M., Twomey, K. & Ogurtsov, V. I. Development of a wireless swallowable capsule with potentiostatic electrochemical sensor for gastrointestinal track investigation. Sens. Actuators B Chem. 218, 8–15 (2015).

    Google Scholar 

  109. 109.

    Rong, G., Corrie, S. R. & Clark, H. A. In vivo biosensing: progress and perspectives. ACS Sens. 2, 327–338 (2017).

    CAS  Google Scholar 

  110. 110.

    Arroyo-Curras, N. et al. Real-time measurement of small molecules directly in awake, ambulatory animals. Proc. Natl Acad. Sci. USA 114, 645–650 (2017).

    CAS  Google Scholar 

  111. 111.

    Campuzano, S., Yanez-Sedeno, P. & Pingarron, J. M. Electrochemical bioaffinity sensors for salivary biomarkers detection. Trends Analyt. Chem. 86, 14–24 (2017).

    CAS  Google Scholar 

  112. 112.

    Crespo, G. A. Recent advances in ion-selective membrane electrodes for in situ environmental water analysis. Electrochim. Acta 245, 1023–1034 (2017).

    CAS  Google Scholar 

  113. 113.

    Gao, W. et al. Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis. Nature 529, 509–514 (2016).

    CAS  Google Scholar 

  114. 114.

    Morris, D. et al. Bio-sensing textile based patch with integrated optical detection system for sweat monitoring. Sens. Actuators B Chem. 139, 231–236 (2009).

    CAS  Google Scholar 

  115. 115.

    Ou, J. Z. et al. Human intestinal gas measurement systems: in vitro fermentation and gas capsules. Trends Biotechnol. 33, 208–213 (2015).

    CAS  Google Scholar 

  116. 116.

    Kalantar-Zadeh, K. et al. Intestinal gas capsules: a proof-of-concept demonstration. Gastroenterology 150, 37–39 (2016).

    Google Scholar 

  117. 117.

    Ou, J. Z. et al. Potential of in vivo real-time gastric gas profiling: a pilot evaluation of heat-stress and modulating dietary cinnamon effect in an animal model. Sci. Rep. 6, 33387 (2016).

    CAS  Google Scholar 

  118. 118.

    Campbell, M. G. & Dinca, M. Metal-organic frameworks as active materials in electronic sensor devices. Sensors 17, 1108 (2017).

    Google Scholar 

  119. 119.

    Nakhleh, M. K. et al. Diagnosis and classification of 17 diseases from 1404 subjects via pattern analysis of exhaled molecules. ACS Nano 11, 112–125 (2017).

    CAS  Google Scholar 

  120. 120.

    Chan, D. K., Leggett, C. L. & Wang, K. K. Diagnosing gastrointestinal illnesses using fecal headspace volatile organic compounds. World J. Gastroenterol. 22, 1639–1649 (2016).

    CAS  Google Scholar 

  121. 121.

    Rockey, D. C., Koch, J., Cello, J. P., Sanders, L. L. & McQuaid, K. Relative frequency of upper gastrointestinal and colonic lesions in patients with positive fecal occult-blood tests. N. Engl. J. Med. 339, 153–159 (1998).

    CAS  Google Scholar 

  122. 122.

    Young, G. P. Screening for colorectal cancer: alternative faecal occult blood tests. Eur. J. Gastroenterol. Hepatol. 10, 205–212 (1998).

    CAS  Google Scholar 

  123. 123.

    Schostek, S. et al. Telemetric real-time sensor for the detection of acute upper gastrointestinal bleeding. Biosens. Bioelectron. 78, 524–529 (2016).

    CAS  Google Scholar 

  124. 124.

    Qiao, P., Liu, H., Yan, X., Jia, Z. & Pi, X. A. Smart capsule system for automated detection of intestinal bleeding using HSL color recognition. PLOS ONE 11, e0166488 (2016).

    Google Scholar 

  125. 125.

    Tokel, O., Inci, F. & Demirci, U. Advances in plasmonic technologies for point of care applications. Chem. Rev. 114, 5728–5752 (2014).

    CAS  Google Scholar 

  126. 126.

    Wijaya, E. et al. Surface plasmon resonance-based biosensors: from the development of different SPR structures to novel surface functionalization strategies. Curr. Opin. Solid State Mater. Sci. 15, 208–224 (2011).

    CAS  Google Scholar 

  127. 127.

    Masson, J. F. Surface plasmon resonance clinical biosensors for medical diagnostics. ACS Sens. 2, 16–30 (2017).

    CAS  Google Scholar 

  128. 128.

    Gluck, N. et al. A novel prepless X-ray imaging capsule for colon cancer screening. Gut 65, 371–373 (2016).

    CAS  Google Scholar 

  129. 129.

    Kimchy, Y. et al. Radiographic capsule-based system for non-cathartic colorectal cancer screening. Abdom. Radiol. 42, 1291–1297 (2017).

    Google Scholar 

  130. 130.

    Lifshitz, R. et al. in Proceedings of SPIE, Volume 10132 — Medical Imaging 2017: Physics of Medical Imaging (eds Flohr, T. G., Lo, J. Y. & Schmidt, T. G.) 101321O (SPIE, 2017).

  131. 131.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03356002 (2018).

  132. 132.

    Goetz, M., Malek, N. P. & Kiesslich, R. Microscopic imaging in endoscopy: endomicroscopy and endocytoscopy. Nat. Rev. Gastroenterol. Hepatol. 11, 11–18 (2014).

    Google Scholar 

  133. 133.

    East, J. E. & Rees, C. J. Making optical biopsy a clinical reality in colonoscopy. Lancet Gastroenterol. Hepatol. 3, 10–12 (2018).

    Google Scholar 

  134. 134.

    Kong, K., Kendall, C., Stone, N. & Notingher, I. Raman spectroscopy for medical diagnostics — from in-vitro biofluid assays to in-vivo cancer detection. Adv. Drug Deliv. Rev. 89, 121–134 (2015).

    CAS  Google Scholar 

  135. 135.

    Wang, K. K. et al. Use of probe-based confocal laser endomicroscopy (pCLE) in gastrointestinal applications. A consensus report based on clinical evidence. United European Gastroenterol. J. 3, 230–254 (2015).

    Google Scholar 

  136. 136.

    Rex, D. K. et al. The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest. Endosc. 73, 419–422 (2011).

    Google Scholar 

  137. 137.

    Kitabatake, S. et al. Confocal endomicroscopy for the diagnosis of gastric cancer in vivo. Endoscopy 38, 1110–1114 (2006).

    CAS  Google Scholar 

  138. 138.

    Shahid, M. W. et al. Diagnostic accuracy of probe-based confocal laser endomicroscopy and narrow band imaging for small colorectal polyps: a feasibility study. Am. J. Gastroenterol. 107, 231–239 (2012).

    Google Scholar 

  139. 139.

    Gaddam, S. et al. Novel probe-based confocal laser endomicroscopy criteria and interobserver agreement for the detection of dysplasia in Barrett’s esophagus. Am. J. Gastroenterol. 106, 1961–1969 (2011).

    Google Scholar 

  140. 140.

    Tabatabaei, N. et al. Clinical translation of tethered confocal microscopy capsule for unsedated diagnosis of eosinophilic esophagitis. Sci. Rep. 8, 2631 (2018).

    Google Scholar 

  141. 141.

    Huang, D. et al. Optical coherence tomography. Science 254, 1178–1181 (1991).

    CAS  Google Scholar 

  142. 142.

    Gora, M. J. et al. Tethered capsule endomicroscopy enables less invasive imaging of gastrointestinal tract microstructure. Nat. Med. 19, 238–240 (2013).

    CAS  Google Scholar 

  143. 143.

    Gora, M. J. et al. Tethered capsule endomicroscopy: from bench to bedside at a primary care practice. J. Biomed. Opt. 21, 104001 (2016).

    Google Scholar 

  144. 144.

    Tearney, G. J. et al. In vivo endoscopic optical biopsy with optical coherence tomography. Science 276, 2037–2039 (1997).

    CAS  Google Scholar 

  145. 145.

    Yun, S. H. et al. Comprehensive volumetric optical microscopy in vivo. Nat. Med. 12, 1429–1433 (2006).

    CAS  Google Scholar 

  146. 146.

    Odegaard, S., Nesje, L. B., Laerum, O. D. & Kimmey, M. B. High-frequency ultrasonographic imaging of the gastrointestinal wall. Expert Rev. Med. Devices 9, 263–273 (2012).

    CAS  Google Scholar 

  147. 147.

    Fatehullah, A. et al. Increased variability in ApcMin/+ intestinal tissue can be measured with microultrasound. Sci. Rep. 6, 29570 (2016).

    CAS  Google Scholar 

  148. 148.

    Stewart, F. et al. in 2015 IEEE International Ultrasonics Symposium (IUS 2015) 1032–1035 (IEEE, 2015).

  149. 149.

    Lay, H. S. et al. in 2016 IEEE International Ultrasonics Symposium (IUS 2016) 1254–1257 (IEEE, 2016).

  150. 150.

    Fujimoto, J. G., Pitris, C., Boppart, S. A. & Brezinski, M. E. Optical coherence tomography: an emerging technology for biomedical imaging and optical biopsy. Neoplasia 2, 9–25 (2000).

    CAS  Google Scholar 

  151. 151.

    Waldner, M. J. et al. Multispectral optoacoustic tomography in Crohn’s disease: noninvasive imaging of disease activity. Gastroenterology 151, 238–240 (2016).

    Google Scholar 

  152. 152.

    Knieling, F. et al. Multispectral optoacoustic tomography for assessment of Crohn’s disease activity. N. Engl. J. Med. 376, 1292–1294 (2017).

    Google Scholar 

  153. 153.

    Phan, T. D., Ismail, H., Heriot, A. G. & Ho, K. M. Improving perioperative outcomes: fluid optimization with the esophageal Doppler monitor, a metaanalysis and review. J. Am. Coll. Surg. 207, 935–941 (2008).

    Google Scholar 

  154. 154.

    Schoellhammer, C. M. & Traverso, G. Low-frequency ultrasound for drug delivery in the gastrointestinal tract. Expert Opin. Drug Delivery 13, 1045–1048 (2016).

    Google Scholar 

  155. 155.

    Gedawy, A., Martinez, J., Al-Salami, H. & Dass, C. R. Oral insulin delivery: existing barriers and current counter-strategies. J. Pharmacy Pharmacol. 70, 197–213 (2018).

    CAS  Google Scholar 

  156. 156.

    Duggirala, N. K., Perry, M. L., Almarsson, O. & Zaworotko, M. J. Pharmaceutical cocrystals: along the path to improved medicines. Chem. Commun. 52, 640–655 (2016).

    CAS  Google Scholar 

  157. 157.

    Schoellhammer, C. M. et al. Ultrasound-mediated gastrointestinal drug delivery. Sci. Transl Med. 7, 310ra168 (2015).

    Google Scholar 

  158. 158.

    Becker, D. et al. Novel orally swallowable IntelliCap(®) device to quantify regional drug absorption in human GI tract using diltiazem as model drug. AAPS PharmSciTech 15, 1490–1497 (2014).

    CAS  Google Scholar 

  159. 159.

    Soderlind, E. et al. Validation of the IntelliCap(R) system as a tool to evaluate extended release profiles in human GI tract using metoprolol as model drug. J. Control. Release 217, 300–307 (2015).

    Google Scholar 

  160. 160.

    Santini, J. T. et al. Microchip technology in drug delivery. Ann. Med. 32, 377–379 (2000).

    Google Scholar 

  161. 161.

    Wollborn, J. et al. Overcoming safety challenges in CO therapy — extracorporeal CO delivery under precise feedback control of systemic carboxyhemoglobin levels. J. Control. Release 279, 336–344 (2018).

    CAS  Google Scholar 

  162. 162.

    Kiourti, A., Psathas, K. A. & Nikita, K. S. Implantable and ingestible medical devices with wireless telemetry functionalities: a review of current status and challenges. Bioelectromagnetics 35, 1–15 (2014).

    Google Scholar 

  163. 163.

    Reardon, S. Electroceuticals spark interest. Nature 511, 18 (2014).

    CAS  Google Scholar 

  164. 164.

    Famm, K., Litt, B., Tracey, K. J., Boyden, E. S. & Slaoui, M. Drug discovery: a jump-start for electroceuticals. Nature 496, 159–161 (2013).

    CAS  Google Scholar 

  165. 165.

    van der Schaar, P. J. et al. A novel ingestible electronic drug delivery and monitoring device. Gastrointest. Endosc. 78, 520–528 (2013).

    Google Scholar 

  166. 166.

    Goffredo, R. et al. A swallowable smart pill for local drug delivery. J. Microelectromech. Syst. 25, 362–370 (2016).

    CAS  Google Scholar 

  167. 167.

    Yu, W., Rahimi, R., Ochoa, M., Pinal, R. & Ziaie, B. A. Smart capsule with GI-tract-location-specific payload release. IEEE Trans. Biomed. Eng. 62, 2289–2295 (2015).

    Google Scholar 

  168. 168.

    Goole, J. & Amighi, K. 3D printing in pharmaceutics: a new tool for designing customized drug delivery systems. Int. J. Pharmaceut. 499, 376–394 (2016).

    Google Scholar 

  169. 169.

    Singh, P. & Maibach, H. I. Iontophoresis in drug delivery: basic principles and applications. Crit. Rev. Ther. Drug Carrier Syst. 11, 161–213 (1994).

    CAS  Google Scholar 

  170. 170.

    Ita, K. Perspectives on transdermal electroporation. Pharmaceutics 8, 9 (2016).

    Google Scholar 

  171. 171.

    Aran, K. et al. An oral microjet vaccination system elicits antibody production in rabbits. Sci. Transl Med. 9, eaaf6413 (2017).

    Google Scholar 

  172. 172.

    Polat, B. E., Hart, D., Langer, R. & Blankschtein, D. Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. J. Control. Release 152, 330–348 (2011).

    CAS  Google Scholar 

  173. 173.

    Holland, C. K. & Apfel, R. E. Thresholds for transient cavitation produced by pulsed ultrasound in a controlled nuclei environment. J. Acoust. Soc. Am. 88, 2059–2069 (1990).

    CAS  Google Scholar 

  174. 174.

    Schoellhammer, C. M. et al. Defining optimal permeant characteristics for ultrasound-mediated gastrointestinal delivery. J. Control. Release 268, 113–119 (2017).

    CAS  Google Scholar 

  175. 175.

    Schoellhammer, C. M. et al. Ultrasound-mediated delivery of RNA to colonic mucosa of live mice. Gastroenterology 152, 1151–1160 (2017).

    CAS  Google Scholar 

  176. 176.

    Cummins, G. et al. Sonopill: a platform for gastrointestinal disease diagnosis and therapeutics. Presented at the 6th Joint Workshop on New Technologies for Computer/Robot Assisted Surgery (CRAS) in Pisa, Italy (2016).

  177. 177.

    Cox, B. F. et al. Ultrasound capsule endoscopy: sounding out the future. Ann. Transl Med. 5, 201 (2017).

    Google Scholar 

  178. 178.

    Li, F. et al. Retention of the capsule endoscope: \a single-center experience of 1000 capsule endoscopy procedures. Gastrointest. Endosc. 68, 174–180 (2008).

    Google Scholar 

  179. 179.

    Cheifetz, A. S. et al. The risk of retention of the capsule endoscope in patients with known or suspected Crohn’s disease. Am. J. Gastroenterol. 101, 2218–2222 (2006).

    Google Scholar 

  180. 180.

    Xin, L., Liao, Z., Du, Y. Q., Jiang, Y. P. & Li, Z. S. Retained capsule endoscopy causing intestinal obstruction — endoscopic retrieval by retrograde single-balloon enteroscopy. J. Interv Gastroenterol. 2, 15–18 (2012).

    Google Scholar 

  181. 181.

    Rogers, A. M., Kuperman, E., Puleo, F. J. & Shope, T. R. Intestinal obstruction by capsule endoscopy in a patient with radiation enteritis. JSLS 12, 85–87 (2008).

    Google Scholar 

  182. 182.

    Skovsen, A. P., Burcharth, J. & Burgdorf, S. K. Capsule endoscopy: a cause of late small bowel obstruction and perforation. Case Rep. Surg. 2013, 458108 (2013).

    Google Scholar 

  183. 183.

    Tashiro, Y. et al. Successful retrieval of a retained capsule endoscope with single incision laparoscopic surgery. Case Rep. Gastroenterol. 8, 206–210 (2014).

    Google Scholar 

  184. 184.

    Bass, D. M., Prevo, M. & Waxman, D. S. Gastrointestinal safety of an extended-release, nondeformable, oral dosage form (OROS®). Drug Saf. 25, 1021–1033 (2002).

    CAS  Google Scholar 

  185. 185.

    Li, N., Chen, Z., Ren, W., Li, F. & Cheng, H. M. Flexible graphene-based lithium ion batteries with ultrafast charge and discharge rates. Proc. Natl Acad. Sci. USA 109, 17360–17365 (2012).

    CAS  Google Scholar 

  186. 186.

    Nishide, H. & Oyaizu, K. Toward flexible batteries. Science 319, 737–738 (2008).

    CAS  Google Scholar 

  187. 187.

    Inui, T., Koga, H., Nogi, M., Komoda, N. & Suganuma, K. A miniaturized flexible antenna printed on a high dielectric constant nanopaper composite. Adv. Mater. 27, 1112–1116 (2015).

    CAS  Google Scholar 

  188. 188.

    Rai, T., Dantes, P., Bahreyni, B. & Kim, W. S. A. Stretchable RF antenna with silver nanowires. IEEE Electron Device Lett. 34, 544–546 (2013).

    CAS  Google Scholar 

  189. 189.

    Han, S. T. et al. An overview of the development of flexible sensors. Adv. Mater. 29, 1700375 (2017).

    Google Scholar 

  190. 190.

    Miyashita, S. et al. in 2016 IEEE International Conference on Robotics and Automation (ICRA 2016) 909–916 (IEEE, 2018).

  191. 191.

    du Plessis d’Argentre, A. et al. in 2018 IEEE International Conference on Robotics and Automation (ICRA 2018) 1511–1518 (IEEE, 2018).

  192. 192.

    Chyan, Y. et al. Laser-induced graphene by multiple lasing: toward electronics on cloth, paper, and food. ACS Nano 12, 2176–2183 (2018).

    CAS  Google Scholar 

  193. 193.

    Dagdeviren, C. et al. Flexible piezoelectric devices for gastrointestinal motility sensing. Nat. Biomed. Engineer. 1, 807–817 (2017).

    Google Scholar 

  194. 194.

    Keller, A., Stevens, L., Wallace, G. G. & Panhuis, M. I. H. 3D printed edible hydrogel electrodes. MRS Adv. 1, 527–532 (2016).

    CAS  Google Scholar 

  195. 195.

    Ghosh, U., Ning, S., Wang, Y. & Kong, Y. L. Addressing unmet clinical needs with 3D printing technologies. Adv. Healthc. Mater. 7, e1800417 (2018).

    Google Scholar 

  196. 196.

    Chirwa, L. C., Hammond, P. A., Roy, S. & Cumming, D. R. Electromagnetic radiation from ingested sources in the human intestine between 150 MHz and 1.2 GHz. IEEE Trans. Biomed. Eng. 50, 484–492 (2003).

    Google Scholar 

  197. 197.

    Chan, Y. M. H. M., Wu, K. L. & Wang, X. Experimental study of radiation efficiency from an ingested source inside a human body model. Conf. Proc. IEEE Eng. Med. Biol. Soc. 7, 7754–7757 (2005).

    Google Scholar 

  198. 198.

    Mackay, R. S. Radio telemetering from within the body: inside information is revealed by tiny transmitters that can be swallowed or implanted in man or animal. Science 134, 1196–1202 (1961).

    CAS  Google Scholar 

  199. 199.

    Hyoung, C. H. et al. Human body communication system and method. US Patent 12808178 (2008).

  200. 200.

    Chang, T. C., Wang, M. L., Charthad, J., Weber, M. J. & Arbabian, A. in 2017 IEEE International Solid-State Circuits Conference 460–461 (IEEE, 2017).

  201. 201.

    Nikolayev, D., Zhadobov, M., Sauleau, R. & Karban, P. in Advances in Body-Centric Wireless Communication: Applications and State-of-the-Art 143–186 (Institution of Engineering and Technology, 2016).

  202. 202.

    Xu, F. et al. Controllably degradable transient electronic antennas based on water-soluble PVA/TiO2 films. J. Mater. Sci. 53, 2638–2647 (2018).

    CAS  Google Scholar 

  203. 203.

    Barnett, B., Ofer, D., Sriramulu, S. & Stringfellow, R. in Batteries for Sustainability Ch. 9 (ed. Brodd, R. J.) 285–318 (Springer New York, 2013).

  204. 204.

    Ciuti, G., Menciassi, A. & Dario, P. Capsule endoscopy: from current achievements to open challenges. IEEE Rev. Biomed. Eng. 4, 59–72 (2011).

    Google Scholar 

  205. 205.

    Assat, G. & Tarascon, J. M. Fundamental understanding and practical challenges of anionic redox activity in Li-ion batteries. Nat. Energy 3, 373–386 (2018).

    CAS  Google Scholar 

  206. 206.

    Chan, C. K. et al. in Materials for Sustainable Energy 187–191 (World Scientific, 2010).

  207. 207.

    Braga, M. H. C. M. S., Murchison, A. J. & Goodenough, J. B. Nontraditional, safe, high voltage rechargeable cells of long cycle life. J. Am. Chem. Soc. 140, 6343–6352 (2018).

    CAS  Google Scholar 

  208. 208.

    Kato, Y. et al. High-power all-solid-state batteries using sulfide superionic conductors. Nat. Energy 1, 16030 (2016).

    CAS  Google Scholar 

  209. 209.

    Dong, K. et al. Microbial fuel cell as power supply for implantable medical devices: a novel configuration design for simulating colonic environment. Biosens. Bioelectron. 41, 916–919 (2013).

    CAS  Google Scholar 

  210. 210.

    Ramadass, Y. K. & Chandrakasan, A. P. in 2010 IEEE International Solid-State Circuits Conference (ISSCC 2010) 486–487 (IEEE, 2010).

  211. 211.

    Dagdeviren, C. et al. Conformal piezoelectric energy harvesting and storage from motions of the heart, lung, and diaphragm. Proc. Natl Acad. Sci. USA 111, 1927–1932 (2014).

    CAS  Google Scholar 

  212. 212.

    Farrar, J. T., Berkley, C. & Zworykin, V. K. Telemetering of intraenteric pressure in man by an externally energized wireless capsule. Science 131, 1814 (1960).

    CAS  Google Scholar 

  213. 213.

    Ben Amar, A., Kouki, A. B. & Cao, H. Power approaches for implantable medical devices. Sensors 15, 28889–28914 (2015).

    Google Scholar 

  214. 214.

    Lenaerts, B. & Puers, R. An inductive power link for a wireless endoscope. Biosens. Bioelectron. 22, 1390–1395 (2007).

    CAS  Google Scholar 

  215. 215.

    Poon, A. S. Y., O’Driscoll, S. & Meng, T. H. Optimal frequency for wireless power transmission into dispersive tissue. IEEE Trans. Antennas Propag. 58, 1739–1750 (2010).

    Google Scholar 

  216. 216.

    Ma, Y., Luo, Z., Steiger, C., Traverso, G. & Adib, F. in Proceedings of the 2018 Conference of the ACM Special Interest Group on Data Communication 417–431 (ACM, New York, NY, 2018).

  217. 217.

    Traverso, G., Kirtane, A. R., Schoellhammer, C. M. & Langer, R. Convergence for translation: drug-delivery research in multidisciplinary teams. Angew. Chem. Int. Ed. 57, 4156–4163 (2018).

    CAS  Google Scholar 

  218. 218.

    Kim, H. M. et al. Active locomotion of a paddling-based capsule endoscope in an in vitro and in vivo experiment (with videos). Gastrointest. Endosc. 72, 381–387 (2010).

    Google Scholar 

  219. 219.

    Mosse, C. A., Mills, T. N., Appleyard, M. N., Kadirkamanathan, S. S. & Swain, C. P. Electrical stimulation for propelling endoscopes. Gastrointest. Endosc. 54, 79–83 (2001).

    CAS  Google Scholar 

  220. 220.

    Woo, S. H., Kim, T. W., Mohy-Ud-Din, Z., Park, I. Y. & Cho, J. H. Small intestinal model for electrically propelled capsule endoscopy. Biomed. Eng. Online 10, 108 (2011).

    Google Scholar 

  221. 221.

    Singeap, A. M., Stanciu, C. & Trifan, A. Capsule endoscopy: the road ahead. World J. Gastroenterol. 22, 369–378 (2016).

    CAS  Google Scholar 

  222. 222.

    Carpi, F., Galbiati, S. & Carpi, A. Magnetic shells for gastrointestinal endoscopic capsules as a means to control their motion. Biomed. Pharmacother. 60, 370–374 (2006).

    CAS  Google Scholar 

  223. 223.

    Sendoh, M., Ishiyama, K. & Arai, K. I. Fabrication of magnetic actuator for use in a capsule endoscope. IEEE Trans. Magn. 39, 3232–3234 (2003).

    Google Scholar 

  224. 224.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03482661 (2018).

  225. 225.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03441945 (2018).

  226. 226.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02846155 (2016).

  227. 227.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02219529 (2015).

  228. 228.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01903629 (2015).

  229. 229.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03420729 (2018).

  230. 230.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02536144 (2018).

  231. 231.

    Keller, J. et al. Inspection of the human stomach using remote-controlled capsule endoscopy: a feasibility study in healthy volunteers (with videos). Gastrointest. Endosc. 73, 22–28 (2011).

    Google Scholar 

  232. 232.

    Rey, J. F. et al. Feasibility of stomach exploration with a guided capsule endoscope. Endoscopy 42, 541–545 (2010).

    CAS  Google Scholar 

  233. 233.

    Rey, J. F. et al. Blinded nonrandomized comparative study of gastric examination with a magnetically guided capsule endoscope and standard videoendoscope. Gastrointest. Endosc. 75, 373–381 (2012).

    Google Scholar 

  234. 234.

    Carpi, F., Galbiati, S. & Carpi, A. Controlled navigation of endoscopic capsules: concept and preliminary experimental investigations. IEEE Trans. Biomed. Eng. 54, 2028–2036 (2007).

    Google Scholar 

  235. 235.

    Carpi, F. & Pappone, C. Magnetic maneuvering of endoscopic capsules by means of a robotic navigation system. IEEE Trans. Biomed. Eng. 56, 1482–1490 (2009).

    Google Scholar 

  236. 236.

    Arezzo, A. et al. Experimental assessment of a novel robotically-driven endoscopic capsule compared to traditional colonoscopy. Dig. Liver Dis. 45, 657–662 (2013).

    Google Scholar 

  237. 237.

    Slawinski, P. R., Obstein, K. L. & Valdastri, P. Emerging issues and future developments in capsule endoscopy. Tech. Gastrointest. Endosc. 17, 40–46 (2015).

    Google Scholar 

  238. 238.

    Yan, X. H. et al. Multifunctional biohybrid magnetite microrobots for imaging-guided therapy. Sci. Robot. 2, eaaq1155 (2017).

    Google Scholar 

  239. 239.

    Sitti, M. Miniature soft robots — road to the clinic. Nat. Rev. Mater. 3, 74–75 (2018).

    Google Scholar 

  240. 240.

    Toennies, J. L., Tortora, G., Simi, M., Valdastri, P. & Webster, R. J. Swallowable medical devices for diagnosis and surgery: the state of the art. Proc. Inst. Mech. Eng. C 224, 1397–1414 (2010).

    Google Scholar 

  241. 241.

    Yim, S., Gultepe, E., Gracias, D. H. & Sitti, M. Biopsy using a magnetic capsule endoscope carrying, releasing, and retrieving untethered microgrippers. IEEE Trans. Biomed. Eng. 61, 513–521 (2014).

    Google Scholar 

  242. 242.

    Yim, S. & Sitti, M. Design and rolling locomotion of a magnetically actuated soft capsule endoscope. IEEE Trans. Robot. 28, 183–194 (2012).

    Google Scholar 

  243. 243.

    Kong, K., Yim, S., Choi, S. & Jeon, D. A. Robotic biopsy device for capsule endoscopy. J. Med. Devices 6, 031004 (2012).

    Google Scholar 

  244. 244.

    Simi, M., Gerboni, G., Menciassi, A. & Valdastri, P. Magnetic torsion spring mechanism for a wireless biopsy capsule. J. Med. Devices 7, 041009 (2013).

    Google Scholar 

  245. 245.

    Gorlewicz, J. L. et al. Wireless insufflation of the gastrointestinal tract. IEEE Trans. Biomed. Eng. 60, 1225–1233 (2013).

    Google Scholar 

  246. 246.

    Quaglia, C. et al. Wireless robotic capsule for releasing bioadhesive patches in the gastrointestinal tract. J. Med. Devices 8, 014503 (2013).

    Google Scholar 

  247. 247.

    Leung, B. H. K. et al. A therapeutic wireless capsule for treatment of gastrointestinal haemorrhage by balloon tamponade effect. IEEE Trans. Biomed. Eng. 64, 1106–1114 (2017).

    Google Scholar 

  248. 248.

    Woods, S. P. & Constandinou, T. G. Wireless capsule endoscope for targeted drug delivery: mechanics and design considerations. IEEE Trans. Biomed. Eng. 60, 945–953 (2013).

    Google Scholar 

  249. 249.

    Hassan, C., Zullo, A., Winn, S. & Morini, S. Cost-effectiveness of capsule endoscopy in screening for colorectal cancer. Endoscopy 40, 414–421 (2008).

    CAS  Google Scholar 

  250. 250.

    Gerson, L. & Lin, O. S. Cost-benefit analysis of capsule endoscopy compared with standard upper endoscopy for the detection of Barrett’s esophagus. Clin. Gastroenterol. Hepatol. 5, 319–325 (2007).

    Google Scholar 

  251. 251.

    Lu, Y. P. & Horsley, D. A. Modeling, fabrication, and characterization of piezoelectric micromachined ultrasonic transducer arrays based on cavity SOI wafers. J. Microelectromech. Syst. 24, 1142–1149 (2015).

    CAS  Google Scholar 

  252. 252.

    Sezen, A. S. et al. Passive wireless MEMS microphones for biomedical applications. J. Biomech. Eng. 127, 1030–1034 (2005).

    CAS  Google Scholar 

  253. 253.

    Arshak, K., Korostynska, O., Morris, D., Jafer, E. & Lyons, G. A review of low-power wireless sensor microsystems for biomedical capsule diagnosis. Microelectron. Int. 21, 8–19 (2004).

    Google Scholar 

  254. 254.

    Zhang, R. et al. Design and performance analysis of capacitive micromachined ultrasonic transducer (CMUT) array for underwater imaging. Microsys. Technol. 22, 2939–2947 (2016).

    Google Scholar 

  255. 255.

    Gaikwad, A. M., Chu, H. N., Qeraj, R., Zamarayeva, A. M. & Steingart, D. A. Reinforced electrode architecture for a flexible battery with paperlike characteristics. Energy Technol. 1, 177–185 (2013).

    CAS  Google Scholar 

  256. 256.

    Sun, J. Y. et al. Highly stretchable and tough hydrogels. Nature 489, 133–136 (2012).

    CAS  Google Scholar 

  257. 257.

    Kang, S. K. et al. Bioresorbable silicon electronic sensors for the brain. Nature 530, 71–76 (2016).

    CAS  Google Scholar 

  258. 258.

    Basar, M. R., Malek, F., Juni, K. M., Idris, M. S. & Saleh, M. I. M. Ingestible wireless capsule technology: a review of development and future indication. Int. J. Antennas Propag. 2012, 807165 (2012).

    Google Scholar 

  259. 259.

    Koziolek, M. et al. Investigation of pH and temperature profiles in the GI tract of fasted human subjects using the intellicap(®) system. J. Pharm. Sci. 104, 2855–2863 (2015).

    CAS  Google Scholar 

  260. 260.

    Sugrue, M. & Redfern, M. Computerized phonoenterography: the clinical investigation of a new system. J. Clin. Gastroenterol. 18, 139–144 (1994).

    CAS  Google Scholar 

  261. 261.

    Mannoor, M. S. et al. Graphene-based wireless bacteria detection on tooth enamel. Nat. Commun. 3, 763 (2012).

    Google Scholar 

  262. 262.

    Becker, C., Neurath, M. F. & Wirtz, S. The intestinal microbiota in inflammatory bowel disease. ILAR J. 56, 192–204 (2015).

    CAS  Google Scholar 

  263. 263.

    Seyedi, M., Ghuloom, G. & Cutler, A. F. Diagnosis of gastric H. pylori using a self-contained ingestible pH probe with radio transmitter. Gastroenterology 114, A282 (1998).

    Google Scholar 

  264. 264.

    Bins, M. et al. Prevalence of achlorhydria in a normal population and its relation to serum gastrin. Hepatogastroenterology 31, 41–43 (1984).

    CAS  Google Scholar 

  265. 265.

    Houpt, T. R. Gastric pressures in pigs during eating and drinking. Physiol. Behav. 56, 311–317 (1994).

    CAS  Google Scholar 

  266. 266.

    Reintam Blaser, A., Malbrain, M. & Regli, A. Abdominal pressure and gastrointestinal function: an inseparable couple? Anaesthesiol. Intensive Ther. 49, 146–158 (2017).

    Google Scholar 

  267. 267.

    Rao, S. S. et al. Investigation of colonic and whole-gut transit with wireless motility capsule and radiopaque markers in constipation. Clin. Gastroenterol. Hepatol. 7, 537–544 (2009).

    Google Scholar 

  268. 268.

    Vu, T., Lin, F., Alshurafa, N. & Xu, W. Y. Wearable food intake monitoring technologies: a comprehensive review. Computers 6, 4 (2017).

    Google Scholar 

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Acknowledgements

The authors thank H. Sun, currently a visiting student at the Massachusetts Institute of Technology (MIT), for help with the artwork. This work was funded in part by the Alexander von Humboldt Foundation (Feodor Lynen Fellowship to C.S.), the National Institutes of Health (grant no. EB-000244) and a Max Planck Research Award (to R.L., award letter dated 11 Feb 2008). G.T. was supported in part by the Division of Gastroenterology, Brigham and Women’s Hospital.

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C.S., A.A., P.N. and G.T. wrote the article. A.C. and R.L. edited and reviewed the article prior to submission. All authors contributed to the discussion.

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Correspondence to Giovanni Traverso.

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Competing interests

All authors are co-inventors on multiple patents or patent applications describing ingestible electronics and auxiliary systems. G.T. and R.L. have financial interest in Suono Bio, Celero Systems and Lyndra, Inc. These companies are developing a set of distinct approaches to drug delivery and, in some instances, incorporate electronics into their systems. P.N. is an employee of Analog Devices, Inc.

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Steiger, C., Abramson, A., Nadeau, P. et al. Ingestible electronics for diagnostics and therapy. Nat Rev Mater 4, 83–98 (2019). https://doi.org/10.1038/s41578-018-0070-3

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