Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Foundations of gastrointestinal-based drug delivery and future developments

Nature Reviews Gastroenterology & Hepatology volume 19, pages 219–238 (2022)Cite this article

Subjects

Abstract

Gastrointestinal-based drug delivery is considered the preferred mode of drug administration owing to its convenience for patients, which improves adherence. However, unique characteristics of the gastrointestinal tract (such as the digestive environment and constraints on transport across the gastrointestinal mucosa) limit the absorption of drugs. As a result, many medications, in particular biologics, still exist only or predominantly in injectable form. In this Review, we examine the fundamentals of gastrointestinal drug delivery to inform clinicians and pharmaceutical scientists. We discuss general principles, including the challenges that need to be overcome for successful drug formulation, and describe the unique features to consider for each gastrointestinal compartment when designing drug formulations for topical and systemic applications. We then discuss emerging technologies that seek to address remaining obstacles to successful gastrointestinal-based drug delivery.

Key points

  • Unique characteristics of the gastrointestinal tract must be taken into account when designing drugs for oral or rectal administration.

  • Physical boundary conditions include swallowing constraints, lumen size, drug residence and transit times, mucin and epithelial turnover, and wall thickness of the gastrointestinal tract.

  • Differences in boundary conditions between anatomical compartments, as well as variation in absorptive area, pH, cells and transporters, permeability, and bacterial population, are both a challenge and an opportunity for targeted drug delivery.

  • Strategies to enable gastrointestinal delivery of biologics include non-physical technologies that stabilize the drug and/or enhance absorption, and physical technologies that use a device for mucosal penetration.

  • Strategies to achieve ultra-long (>24 h) systemic drug delivery include gastrointestinal resident systems and implants.

  • Additional emerging technologies in gastrointestinal drug delivery include high-throughput systems for drug development, electronics and closed-loop systems, novel triggers, microorganism-based and cell-based therapeutics, and new technologies to maximize the endoscope.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: General boundary conditions for engineering gastrointestinal drug delivery systems.
Fig. 2: Emerging technologies for gastrointestinal delivery of biologics.
Fig. 3: Emerging technologies for ultra-long drug delivery via gastrointestinal residency.
Fig. 4: Other emerging technologies.

Similar content being viewed by others

References

  1. Homayun, B., Lin, X. & Choi, H. J. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics 11, 129 (2019).

    CAS  PubMed Central  Google Scholar 

  2. Xu, Y., Shrestha, N., Preat, V. & Beloqui, A. Overcoming the intestinal barrier: a look into targeting approaches for improved oral drug delivery systems. J. Control. Rel. 322, 486–508 (2020).

    CAS  Google Scholar 

  3. Kaur, G., Arora, M. & Ravi Kumar, M. N. V. Oral drug delivery technologies-a decade of developments. J. Pharmacol. Exp. Ther. 370, 529–543 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Sabaté, E. Adherence to long-term therapies: evidence for action (World Health Organization, 2003).

  6. Traverso, G. & Langer, R. Special delivery for the gut. Nature 519, S19 (2015).

    CAS  PubMed  Google Scholar 

  7. Altreuter, D. H. et al. Changing the pill: developments toward the promise of an ultra-long-acting gastroretentive dosage form. Expert. Opin. Drug Deliv. 15, 1189–1198 (2018).

    PubMed  PubMed Central  Google Scholar 

  8. Vertzoni, M. et al. Impact of regional differences along the gastrointestinal tract of healthy adults on oral drug absorption: an UNGAP review. Eur. J. Pharm. Sci. 134, 153–175 (2019).

    CAS  PubMed  Google Scholar 

  9. Coffey, J. W., Gaiha, G. D. & Traverso, G. Oral biologic delivery: advances towards oral subunit, DNA and mRNA vaccines and the potential for mass vaccination during pandemics. Annu. Rev. Pharmacol. Toxicol. 61, 517–540 (2021).

    CAS  PubMed  Google Scholar 

  10. Irvine, D. J., Swartz, M. A. & Szeto, G. L. Engineering synthetic vaccines using cues from natural immunity. Nat. Mater. 12, 978–990 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Maccaferri, S. et al. Rifaximin modulates the colonic microbiota of patients with Crohn’s disease: an in vitro approach using a continuous culture colonic model system. J. Antimicrob. Chemother. 65, 2556–2565 (2010).

    CAS  PubMed  Google Scholar 

  12. US Food and Drug Administration. size, shape, and other physical attributes of generic tablets and capsules: guidance for industry (FDA, 2013).

  13. Steiger, C. et al. Ingestible electronics for diagnostics and therapy. Nat. Rev. Mater. 4, 83–98 (2018).

    Google Scholar 

  14. Hughes, T. A. T. & Wiles, C. M. Clinical measurement of swallowing in health and in neurogenic dysphagia. Q. J. Med. 89, 109–116 (1996).

    CAS  Google Scholar 

  15. Al-Sham Private University. Pharmaceutics II. Suppositories. Al-Sham Private University http://www.aspu.edu.sy/laravel-filemanager/files/18/13-14-%20Suppositories.pdf (2020).

  16. Caffarel-Salvador, E., Abramson, A., Langer, R. & Traverso, G. Oral delivery of biologics using drug-device combinations. Curr. Opin. Pharmacol. 36, 8–13 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. ASGE Standards of Practice Committee et al.Management of ingested foreign bodies and food impactions. Gastrointest. Endosc. 73, 1085–1091 (2011).

    Google Scholar 

  18. Uyemura, M. C. Foreign body ingestion in children. Am. Fam. Physician 72, 287–291 (2005).

    PubMed  Google Scholar 

  19. Kramer, R. E. et al. Management of ingested foreign bodies in children: a clinical report of the NASPGHAN Endoscopy Committee. J. Pediatr. Gastroenterol. Nutr. 60, 562–574 (2015).

    PubMed  Google Scholar 

  20. Bellinger, A. M. et al. Oral, ultra-long-lasting drug delivery: application toward malaria elimination goals. Sci. Transl. Med. 8, 365ra157 (2016).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  22. Medtronic. Pillcam SB 3 System. Medtronic https://www.medtronic.com/covidien/en-us/products/capsule-endoscopy/pillcam-sb-3-system.html#pillcam-sb-3-capsule (2020).

  23. 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  PubMed  Google Scholar 

  24. Worsoe, J. et al. Gastric transit and small intestinal transit time and motility assessed by a magnet tracking system. BMC Gastroenterol. 11, 145 (2011).

    PubMed  Google Scholar 

  25. Maurer, A. H. Gastrointestinal motility, part 2: small-bowel and colon transit. J. Nucl. Med. 56, 1395–1400 (2015).

    CAS  PubMed  Google Scholar 

  26. Maurer, A. H. Gastrointestinal motility, part 1: esophageal transit and gastric emptying. J. Nucl. Med. 56, 1229–1238 (2015).

    CAS  PubMed  Google Scholar 

  27. Pinto, J. F. Site-specific drug delivery systems within the gastro-intestinal tract: from the mouth to the colon. Int. J. Pharm. 395, 44–52 (2010).

    CAS  PubMed  Google Scholar 

  28. Hampson, F. C. et al. Alginate rafts and their characterisation. Int. J. Pharm. 294, 137–147 (2005).

    CAS  PubMed  Google Scholar 

  29. Tate, C. M. & Geliebter, A. Intragastric balloon treatment for obesity: review of recent studies. Adv. Ther. 34, 1859–1875 (2017).

    PubMed  Google Scholar 

  30. Fallon, S. C., Slater, B. J., Larimer, E. L., Brandt, M. L. & Lopez, M. E. The surgical management of Rapunzel syndrome: a case series and literature review. J. Pediatr. Surg. 48, 830–834 (2013).

    PubMed  Google Scholar 

  31. Konuma, H. et al. Endoscopic retrieval of a gastric trichobezoar. World J. Gastrointest. Endosc. 3, 20–22 (2011).

    PubMed  PubMed Central  Google Scholar 

  32. Levy, R. M. & Komanduri, S. Trichobezoar. N. Engl. J. Med. 357, e23 (2007).

    PubMed  Google Scholar 

  33. Gunther, C., Neumann, H., Neurath, M. F. & Becker, C. Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. Gut 62, 1062–1071 (2013).

    PubMed  Google Scholar 

  34. Schoellhammer, C. M., Langer, R. & Traverso, G. Of microneedles and ultrasound: physical modes of gastrointestinal macromolecule delivery. Tissue Barriers 4, e1150235 (2016).

    PubMed  PubMed Central  Google Scholar 

  35. Traverso, G. et al. Microneedles for drug delivery via the gastrointestinal tract. J. Pharm. Sci. 104, 362–367 (2015).

    CAS  PubMed  Google Scholar 

  36. Xia, F., Mao, J., Ding, J. & Yang, H. Observation of normal appearance and wall thickness of esophagus on CT images. Eur. J. Radiol. 72, 406–411 (2009).

    PubMed  Google Scholar 

  37. Reker, D. et al. “Inactive” ingredients in oral medications. Sci. Transl. Med. 11, eaau6753 (2019).

    PubMed  PubMed Central  Google Scholar 

  38. Allen, L. V. Jr Dosage form design and development. Clin. Ther. 30, 2102–2111 (2008).

    PubMed  Google Scholar 

  39. Shah, B., Tex, N. L. & Gibson, J. L. in The 21st Century Pharmacy Technician Ch. 4 (ed. Shoup, K.) 80–112 (Jones & Bartlett Learning, 2013).

  40. Ahadian, S. et al. Micro and nanoscale technologies in oral drug delivery. Adv. Drug Deliv. Rev. 157, 37–62 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. von Erlach, T. et al. Robotically handled whole-tissue culture system for the screening of oral drug formulations. Nat. Biomed. Eng. 4, 544–559 (2020).

    Google Scholar 

  42. Edington, C. D. et al. Interconnected microphysiological systems for quantitative biology and pharmacology studies. Sci. Rep. 8, 4530 (2018).

    PubMed  PubMed Central  Google Scholar 

  43. Hatton, G. B., Yadav, V., Basit, A. W. & Merchant, H. A. Animal farm: considerations in animal gastrointestinal physiology and relevance to drug delivery in humans. J. Pharm. Sci. 104, 2747–2776 (2015).

    CAS  PubMed  Google Scholar 

  44. Hossain, M., Abramowitz, W., Watrous, B. J., Szpunar, G. J. & Ayres, J. W. Gastrintestinal transit of nondisintegrating, nonerodible oral dosage forms in pigs. Pharm. Res 7, 1163–1166 (1990).

    CAS  PubMed  Google Scholar 

  45. Aoyagi, N. et al. Gastric emptying of tablets and granules in humans, dogs, pigs, and stomach-emptying-controlled rabits. J. Pharm. Sci. 81, 1170–1174 (1992).

    CAS  PubMed  Google Scholar 

  46. Kararli, T. T. Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm. Drug Dispos. 16, 351–380 (1995).

    CAS  PubMed  Google Scholar 

  47. Padmanabhan, P., Grosse, J., Asad, A. B., Radda, G. K. & Golay, X. Gastrointestinal transit measurements in mice with 99mTc-DTPA-labeled activated charcoal using NanoSPECT-CT. EJNMMI Res. 3, 60 (2013).

    PubMed  PubMed Central  Google Scholar 

  48. Swindle, M. M. & Smith, A. C. Swine in the Laboratory: Surgery, Anesthesia, Imaging, and Experimental Techniques 3rd edn (CRC Press, 2015).

  49. International Transporter Consortium. et al. Membrane transporters in drug development. Nat. Rev. Drug Discov. 9, 215–236 (2010).

    Google Scholar 

  50. Martinez, M. et al. Applying the biopharmaceutics classification system to veterinary pharmaceutical products. Part II. Physiological considerations. Adv. Drug Deliv. Rev. 54, 825–850 (2002).

    CAS  PubMed  Google Scholar 

  51. Casteel, S. W., Brown, L. D., Lattimer, J. & Dunsmore, M. Fasting and feeding effects on gastric emptying time in juvenile Swine. Contemp. Top. Lab. Anim. Sci. 37, 106–108 (1998).

    PubMed  Google Scholar 

  52. Stamatopoulos, K., O’Farrell, C., Simmons, M. & Batchelor, H. In vivo models to evaluate ingestible devices: present status and current trends. Adv. Drug Deliv. Rev. 177, 113915 (2021).

    CAS  PubMed  Google Scholar 

  53. Huelke, D. F., Nusholtz, G. S. & Kaiker, P. S. Use of quadruped models in thoraco-abdominal biomechanics research. J. Biomech. 19, 969–977 (1986).

    CAS  PubMed  Google Scholar 

  54. Dellon, E. S. et al. Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis. Gastroenterology 143, 321–324.e1 (2012).

    CAS  PubMed  Google Scholar 

  55. Dellon, E. S. et al. Efficacy of budesonide vs fluticasone for initial treatment of eosinophilic esophagitis in a randomized controlled trial. Gastroenterology 157, 65–73.e5 (2019).

    CAS  PubMed  Google Scholar 

  56. Hirano, I. et al. Budesonide oral suspension improves outcomes in patients with eosinophilic esophagitis: results from a phase 3 trial. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2021.04.022 (2021).

    Article  PubMed  Google Scholar 

  57. Takeda. First-ever U.S. pivotal phase 3 clinical study in eosinophilic esophagitis (EoE) completes: Takeda’s investigational therapy meets co-primary & key secondary efficacy endpoints. Takeda https://www.takeda.com/en-us/newsroom/news-releases/2019/first-ever-u.s.-pivotal-phase-3-clinical-study-in-eosinophilic-esophagitis-eoe-completes/#_edn11 (2019).

  58. Siersema, P. D. How to approach a patient with refractory or recurrent benign esophageal stricture. Gastroenterology 156, 7–10 (2019).

    PubMed  Google Scholar 

  59. Wu, H., Minamide, T. & Yano, T. Role of photodynamic therapy in the treatment of esophageal cancer. Dig. Endosc. 31, 508–516 (2019).

    PubMed  Google Scholar 

  60. Zhang, Y. et al. The effect of paclitaxel-eluting covered metal stents versus covered metal stents in a rabbit esophageal squamous carcinoma model. PLoS ONE 12, e0173262 (2017).

    PubMed  PubMed Central  Google Scholar 

  61. Van Den Abeele, J., Rubbens, J., Brouwers, J. & Augustijns, P. The dynamic gastric environment and its impact on drug and formulation behaviour. Eur. J. Pharm. Sci. 96, 207–231 (2017).

    Google Scholar 

  62. Liu, X. et al. Ingestible hydrogel device. Nat. Commun. 10, 493 (2019).

    PubMed  PubMed Central  Google Scholar 

  63. Verma, M. et al. A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment. Sci. Transl. Med. 11, eaau6267 (2019).

    PubMed  PubMed Central  Google Scholar 

  64. Twarog, C. et al. Intestinal permeation enhancers for oral delivery of macromolecules: a comparison between salcaprozate sodium (SNAC) and sodium caprate (C10). Pharmaceutics 11, 78 (2019).

    CAS  PubMed Central  Google Scholar 

  65. Buckley, S. T. et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci. Transl. Med. 10, eaar7047 (2018).

    PubMed  Google Scholar 

  66. Vita, R., Saraceno, G., Trimarchi, F. & Benvenga, S. Switching levothyroxine from the tablet to the oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-pump inhibitors. J. Clin. Endocrinol. Metab. 99, 4481–4486 (2014).

    CAS  PubMed  Google Scholar 

  67. Shah, V. P. & Amidon, G. L. G. L. Amidon, H. Lennernas, V.P. Shah, and J.R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability, Pharm Res 12, 413–420, 1995 — backstory of BCS. AAPS J. 16, 894–898 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Savjani, K. T., Gajjar, A. K. & Savjani, J. K. Drug solubility: importance and enhancement techniques. ISRN Pharm. 2012, 195727 (2012).

    PubMed  PubMed Central  Google Scholar 

  69. Maher, S., Mrsny, R. J. & Brayden, D. J. Intestinal permeation enhancers for oral peptide delivery. Adv. Drug Deliv. Rev. 106, 277–319 (2016).

    CAS  PubMed  Google Scholar 

  70. Malhaire, H., Gimel, J. C., Roger, E., Benoit, J. P. & Lagarce, F. How to design the surface of peptide-loaded nanoparticles for efficient oral bioavailability? Adv. Drug Deliv. Rev. 106, 320–336 (2016).

    CAS  PubMed  Google Scholar 

  71. Sanchez-Navarro, M., Garcia, J., Giralt, E. & Teixido, M. Using peptides to increase transport across the intestinal barrier. Adv. Drug Deliv. Rev. 106, 355–366 (2016).

    CAS  PubMed  Google Scholar 

  72. Nigam, S. K. What do drug transporters really do? Nat. Rev. Drug Discov. 14, 29–44 (2015).

    CAS  PubMed  Google Scholar 

  73. Shahdadi Sardo, H. et al. A review on 5-aminosalicylic acid colon-targeted oral drug delivery systems. Int. J. Pharm. 558, 367–379 (2019).

    CAS  PubMed  Google Scholar 

  74. Cohen, R. D., Lichtenstein, G. R., Safdi, A. V. & Sandborn, W.J. 5-ASA treatment for ulcerative colitis: what’s on the horizon? 4 (11 Suppl. 24), 5–14 (2008).

  75. Ye, B. & van Langenberg, D. R. Mesalazine preparations for the treatment of ulcerative colitis: are all created equal? World J. Gastrointest. Pharmacol. Ther. 6, 137–144 (2015).

    PubMed  PubMed Central  Google Scholar 

  76. Hanauer, S. B. & Stromberg, U. Oral pentasa in the treatment of active Crohn’s disease: a meta-analysis of double-blind, placebo-controlled trials. Clin. Gastroenterol. Hepatol. 2, 379–388 (2004).

    CAS  PubMed  Google Scholar 

  77. Gupta, V. et al. Delivery of exenatide and insulin using mucoadhesive intestinal devices. Ann. Biomed. Eng. 44, 1993–2007 (2016).

    PubMed  Google Scholar 

  78. Banerjee, A., Lee, J. & Mitragotri, S. Intestinal mucoadhesive devices for oral delivery of insulin. Bioeng. Transl. Med. 1, 338–346 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Banerjee, A. & Mitragotri, S. Intestinal patch systems for oral drug delivery. Curr. Opin. Pharmacol. 36, 58–65 (2017).

    CAS  PubMed  Google Scholar 

  80. Shen, Z. & Mitragotri, S. Intestinal patches for oral drug delivery. Pharm. Res. 19, 391–395 (2002).

    CAS  PubMed  Google Scholar 

  81. Toorisaka, E. et al. Intestinal patches with an immobilized solid-in-oil formulation for oral protein delivery. Acta Biomater. 8, 653–658 (2012).

    CAS  PubMed  Google Scholar 

  82. Li, J. et al. Gastrointestinal synthetic epithelial linings. Sci. Transl. Med. 12, eabc0441 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Lee, S. H. et al. Strategic approaches for colon targeted drug delivery: an overview of recent advancements. Pharmaceutics 12, 68 (2020).

    CAS  PubMed Central  Google Scholar 

  84. Takaya, T. et al. Importance of dissolution process on systemic availability of drugs delivered by colon delivery system. J. Control. Rel. 50, 111–122 (1998).

    CAS  Google Scholar 

  85. Philip, A. K. & Philip, B. Colon targeted drug delivery systems: a review on primary and novel approaches. Oman Med. J. 25, 79–87 (2010).

    PubMed  PubMed Central  Google Scholar 

  86. Sousa, T. et al. The gastrointestinal microbiota as a site for the biotransformation of drugs. Int. J. Pharm. 363, 1–25 (2008).

    CAS  PubMed  Google Scholar 

  87. Purohit, T. J., Hanning, S. M. & Wu, Z. Advances in rectal drug delivery systems. Pharm. Dev. Technol. 23, 942–952 (2018).

    CAS  PubMed  Google Scholar 

  88. Sutherland, L. & Macdonald, J. K. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst. Rev. 2, CD000543 (2006).

    Google Scholar 

  89. Svartz, N. Salazyopyrin, a new sulfanilamide preparation: A. Therapeutic results in rheumatic polyarthritis. B. Therapeutic results in ulcerative colitis. C. Toxic manifestations in treatment with sulfanilamide preparation. Acta Med. Scand. 110, 557–590 (1942).

    Google Scholar 

  90. Evonik. Oncare Web Portal. Evonik https://healthcare.evonik.com/en/oncare (2021).

  91. Kane, S. V. Systematic review: adherence issues in the treatment of ulcerative colitis. Aliment. Pharmacol. Ther. 23, 577–585 (2006).

    CAS  PubMed  Google Scholar 

  92. Testa, A., Castiglione, F., Nardone, O. M. & Colombo, G. L. Adherence in ulcerative colitis: an overview. Patient Prefer. Adherence 11, 297–303 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. Bezzio, C. et al. The problem of adherence to therapy in ulcerative colitis and the potential utility of multi-matrix system (MMX) technology. Expert. Rev. Gastroenterol. Hepatol. 11, 33–41 (2017).

    CAS  PubMed  Google Scholar 

  94. Center for Drug Evaluation and Reseearch. Application Number: 22-301 Administrative and Correspondence Documents (CDER, 2008).

  95. Miehlke, S. et al. Oral budesonide in gastrointestinal and liver disease: a practical guide for the clinician. J. Gastroenterol. Hepatol. 33, 1574–1581 (2018).

    Google Scholar 

  96. Dellon, E. S. et al. Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with Eosinophilic esophagitis. Gastroenterology 152, 776–786.e5 (2017).

    CAS  PubMed  Google Scholar 

  97. Oliva, S. et al. A new formulation of oral viscous budesonide in treating paediatric eosinophilic oesophagitis: a pilot study. J. Pediatr. Gastroenterol. Nutr. 64, 218–224 (2017).

    CAS  PubMed  Google Scholar 

  98. Nicholls, A. et al. Bioavailability profile of Uceris MMX extended-release tablets compared with Entocort EC capsules in healthy volunteers. J. Int. Med. Res. 41, 386–394 (2013).

    CAS  PubMed  Google Scholar 

  99. Brayden, D. J., Hill, T. A., Fairlie, D. P., Maher, S. & Mrsny, R. J. Systemic delivery of peptides by the oral route: formulation and medicinal chemistry approaches. Adv. Drug Deliv. Rev. 157, 2–36 (2020).

    CAS  PubMed  Google Scholar 

  100. Duran-Lobato, M., Niu, Z. & Alonso, M. J. Oral delivery of biologics for precision medicine. Adv. Mater. 32, e1901935 (2020).

    PubMed  Google Scholar 

  101. Aguirre, T. A. et al. Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials. Adv. Drug Deliv. Rev. 106, 223–241 (2016).

    CAS  PubMed  Google Scholar 

  102. Lamson, N. G., Berger, A., Fein, K. C. & Whitehead, K. A. Anionic nanoparticles enable the oral delivery of proteins by enhancing intestinal permeability. Nat. Biomed. Eng. 4, 84–96 (2020).

    CAS  PubMed  Google Scholar 

  103. Brayden, D. J. & Alonso, M. J. Oral delivery of peptides: opportunities and issues for translation. Adv. Drug Deliv. Rev. 106, 193–195 (2016).

    CAS  PubMed  Google Scholar 

  104. Heinis, C., Rutherford, T., Freund, S. & Winter, G. Phage-encoded combinatorial chemical libraries based on bicyclic peptides. Nat. Chem. Biol. 5, 502–507 (2009).

    CAS  PubMed  Google Scholar 

  105. Kong, X. D. et al. De novo development of proteolytically resistant therapeutic peptides for oral administration. Nat. Biomed. Eng. 4, 560–571 (2020).

    CAS  PubMed  Google Scholar 

  106. Busby, R. W. et al. Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur. J. Pharmacol. 649, 328–335 (2010).

    CAS  PubMed  Google Scholar 

  107. Knudsen, L. B. & Lau, J. The discovery and development of liraglutide and semaglutide. Front. Endocrinol. 10, 155 (2019).

    Google Scholar 

  108. Pridgen, E. M., Alexis, F. & Farokhzad, O. C. Polymeric nanoparticle technologies for oral drug delivery. Clin. Gastroenterol. Hepatol. 12, 1605–1610 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Farokhzad, O. C. & Langer, R. Impact of nanotechnology on drug delivery. ACS Nano 3, 16–20 (2009).

    CAS  PubMed  Google Scholar 

  110. Zhang, S., Langer, R. & Traverso, G. Nanoparticulate drug delivery systems targeting inflammation for treatment of inflammatory bowel disease. Nano Today 16, 82–96 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Niu, Z. et al. PEG-PGA enveloped octaarginine-peptide nanocomplexes: an oral peptide delivery strategy. J. Control. Rel. 276, 125–139 (2018).

    CAS  Google Scholar 

  112. Fox, C. B. et al. Fabrication of sealed nanostraw microdevices for oral drug delivery. ACS Nano 10, 5873–5881 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Anselmo, A. C. & Mitragotri, S. An overview of clinical and commercial impact of drug delivery systems. J. Control. Rel. 190, 15–28 (2014).

    CAS  Google Scholar 

  114. Mathiowitz, E. et al. Biologically erodable microspheres as potential oral drug delivery systems. Nature 386, 410–414 (1997).

    CAS  PubMed  Google Scholar 

  115. Wong, C. Y., Al-Salami, H. & Dass, C. R. Microparticles, microcapsules and microspheres: a review of recent developments and prospects for oral delivery of insulin. Int. J. Pharm. 537, 223–244 (2018).

    CAS  PubMed  Google Scholar 

  116. Trevaskis, N. L., Kaminskas, L. M. & Porter, C. J. From sewer to saviour–targeting the lymphatic system to promote drug exposure and activity. Nat. Rev. Drug Discov. 14, 781–803 (2015).

    CAS  PubMed  Google Scholar 

  117. Whitehead, K., Shen, Z. & Mitragotri, S. Oral delivery of macromolecules using intestinal patches: applications for insulin delivery. J. Control. Rel. 98, 37–45 (2004).

    CAS  Google Scholar 

  118. Fox, C. B. et al. Micro/nanofabricated platforms for oral drug delivery. J. Control. Rel. 219, 431–444 (2015).

    CAS  Google Scholar 

  119. Garcia-Castillo, M. D. et al. Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids. eLife 7, e34469 (2018).

    PubMed  PubMed Central  Google Scholar 

  120. Hu, Z. et al. Molecular targeting of FATP4 transporter for oral delivery of therapeutic peptide. Sci. Adv. 6, eaba0145 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Banerjee, A. et al. Ionic liquids for oral insulin delivery. Proc. Natl Acad. Sci. USA 115, 7296–7301 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Agatemor, C., Ibsen, K. N., Tanner, E. E. L. & Mitragotri, S. Ionic liquids for addressing unmet needs in healthcare. Bioeng. Transl. Med. 3, 7–25 (2018).

    PubMed  PubMed Central  Google Scholar 

  123. Pridgen, E. M. et al. Transepithelial transport of Fc-targeted nanoparticles by the neonatal Fc receptor for oral delivery. Sci. Transl. Med. 5, 213ra167 (2013).

    PubMed  PubMed Central  Google Scholar 

  124. Taverner, A. et al. Enhanced paracellular transport of insulin can be achieved via transient induction of myosin light chain phosphorylation. J. Control. Rel. 210, 189–197 (2015).

    CAS  Google Scholar 

  125. US Food and Drug Administration. FDA approves first oral GLP-1 treatment for type 2 diabetes (FDA, 2019).

  126. Biermasz, N. R. New medical therapies on the horizon: oral octreotide. Pituitary 20, 149–153 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Melmed, S. et al. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial. J. Clin. Endocrinol. Metab. 100, 1699–1708 (2015).

    CAS  PubMed  Google Scholar 

  128. Jørgensen, J. R. et al. Design of a self-unfolding delivery concept for oral administration of macromolecules. J. Control. Release 329, 948–954 (2021).

    PubMed  Google Scholar 

  129. Abramson, A., Halperin, F., Kim, J. & Traverso, G. Quantifying the value of orally delivered biologic therapies: a cost-effectiveness analysis of oral semaglutide. J. Pharm. Sci. 108, 3138–3145 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Abramson, A. et al. An ingestible self-orienting system for oral delivery of macromolecules. Science 363, 611–615 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Abramson, A. et al. A luminal unfolding microneedle injector for oral delivery of macromolecules. Nat. Med. 25, 1512–1518 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  133. Hashim, M. et al. Jejunal wall delivery of insulin via an ingestible capsule in anesthetized swine–a pharmacokinetic and pharmacodynamic study. Pharmacol. Res. Perspect. 7, e00522 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  137. Banerjee, A., Chen, R., Arafin, S. & Mitragotri, S. Intestinal iontophoresis from mucoadhesive patches: a strategy for oral delivery. J. Control. Rel. 297, 71–78 (2019).

    CAS  Google Scholar 

  138. Babaee, S. et al. Temperature-responsive biometamaterials for gastrointestinal applications. Sci. Transl. Med. 11, eaau8581 (2019).

    PubMed  PubMed Central  Google Scholar 

  139. Dhalla, A. K. et al. A robotic pill for oral delivery of biotherapeutics: safety, tolerability, and performance in healthy subjects. Drug Deliv. Transl. Res. https://doi.org/10.1007/s13346-021-00938-1 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Mitragotri, S., Blankschtein, D. & Langer, R. Ultrasound-mediated transdermal protein delivery. Science 269, 850–853 (1995).

    CAS  PubMed  Google Scholar 

  141. Rodriguez-Devora, J. I. et al. Physically facilitating drug-delivery systems. Ther. Deliv. 3, 125–139 (2012).

    CAS  PubMed  Google Scholar 

  142. Brown, M. T. & Bussell, J. K. Medication adherence: WHO cares? Mayo Clin. Proc. 86, 304–314 (2011).

    PubMed  PubMed Central  Google Scholar 

  143. Chen, C., Han, C. H., Sweeney, M. & Cowles, V. E. Pharmacokinetics, efficacy, and tolerability of a once-daily gastroretentive dosage form of gabapentin for the treatment of postherpetic neuralgia. J. Pharm. Sci. 102, 1155–1164 (2013).

    CAS  PubMed  Google Scholar 

  144. Assertio. Marketed products (Assertio, 2021).

  145. Navon, N. The accordion pill: unique oral delivery to enhance pharmacokinetics and therapeutic benefit of challenging drugs. Ther. Deliv. 10, 433–442 (2019).

    CAS  PubMed  Google Scholar 

  146. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01277107 (2014).

  147. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02605434 (2019).

  148. Ghosh, A. et al. Gastrointestinal-resident, shape-changing microdevices extend drug release in vivo. Sci. Adv. 6, eabb4133 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Kirtane, A. R. et al. A once-a-month oral contraceptive. Sci. Transl. Med. 11, eaay2602 (2019).

    PubMed  Google Scholar 

  150. Kirtane, A. R. et al. Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy. Nat. Commun. 9, 2 (2018).

    PubMed  PubMed Central  Google Scholar 

  151. Scranton, R. E., Avery, W., Kruger, C., Bellinger, A. & Silverman, B. Ultra long-acting oral therapies for Alzheimer’s: proof of principle [abstract]. Alzheimers Dement. 16 (S9), e043034 (2020).

    Google Scholar 

  152. Verma, M. et al. Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine. Proc. Natl Acad. Sci. USA 117, 11987–11994 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Morissette, S. L. et al. High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv. Drug Deliv. Rev. 56, 275–300 (2004).

    CAS  PubMed  Google Scholar 

  154. Shamay, Y. et al. Quantitative self-assembly prediction yields targeted nanomedicines. Nat. Mater. 17, 361–368 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Trapecar, M. et al. Gut-liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids. Cell Syst. 10, 223–239.e9 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Herland, A. et al. Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. Nat. Biomed. Eng. 4, 421–436 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Adler, S. N. & Metzger, Y. C. PillCam COLON capsule endoscopy: recent advances and new insights. Ther. Adv. Gastroenterol. 4, 265–268 (2011).

    Google Scholar 

  158. US Food and Drug Administration. PillCam® COLON 2 capsule endoscopy system. FDA https://www.accessdata.fda.gov/cdrh_docs/pdf12/K123666.pdf (2020).

  159. Kuo, B. et al. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment. Pharmacol. Ther. 27, 186–196 (2008).

    CAS  PubMed  Google Scholar 

  160. Berean, K. J. et al. The safety and sensitivity of a telemetric capsule to monitor gastrointestinal hydrogen production in vivo in healthy subjects: a pilot trial comparison to concurrent breath analysis. Aliment. Pharmacol. Ther. 48, 646–654 (2018).

    CAS  PubMed  Google Scholar 

  161. Brodwin, E. A Silicon Valley company just launched ‘smart’ cancer pills that track you with tiny sensors stamped into your medications. INDSIDER https://www.businessinsider.com/digital-smart-pill-drug-sensor-company-expands-cancer-proteus-2019-1 (2019).

  162. 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).

    PubMed  PubMed Central  Google Scholar 

  163. Abramson, A. et al. Ingestible transiently anchoring electronics for microstimulation and conductive signaling. Sci. Adv. 6, eaaz0127 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Ramadi, K. B., Srinivasan, S. S. & Traverso, G. Electroceuticals in the gastrointestinal tract. Trends Pharmacol. Sci. 41, 960–976 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Zhang, S. et al. An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease. Sci. Transl. Med. 7, 300ra128 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Coughlan, D. C., Quilty, F. P. & Corrigan, O. I. Effect of drug physicochemical properties on swelling/deswelling kinetics and pulsatile drug release from thermoresponsive poly(N-isopropylacrylamide) hydrogels. J. Control. Rel. 98, 97–114 (2004).

    CAS  Google Scholar 

  169. Yoshida, R. et al. Positive thermosensitive pulsatile drug release using negative thermosensitive hydrogels. J. Control. Rel. 32, 97–102 (1994).

    CAS  Google Scholar 

  170. Davoodi, P. et al. Drug delivery systems for programmed and on-demand release. Adv. Drug Deliv. Rev. 132, 104–138 (2018).

    CAS  PubMed  Google Scholar 

  171. Jiang, J., Tong, X., Morris, D. & Zhao, Y. Toward photocontrolled release using light-dissociable block copolymer micelles. Macromolecules 39, 4633–4640 (2006).

    CAS  Google Scholar 

  172. Sun, T., Dasgupta, A., Zhao, Z., Nurunnabi, M. & Mitragotri, S. Physical triggering strategies for drug delivery. Adv. Drug Deliv. Rev. 158, 36–62 (2020).

    CAS  PubMed  Google Scholar 

  173. Low, L. M., Seetharaman, S., He, K. Q. & Madou, M. J. Microactuators toward microvalves for responsive controlled drug delivery. Sens. Actuators B Chem. 67, 149–160 (2000).

    CAS  Google Scholar 

  174. Che Rose, L. et al. A SPION-eicosane protective coating for water soluble capsules: evidence for on-demand drug release triggered by magnetic hyperthermia. Sci. Rep. 6, 20271 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Jimenez, M., Langer, R. & Traverso, G. Microbial therapeutics: new opportunities for drug delivery. J. Exp. Med. 216, 1005–1009 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Charbonneau, M. R., Isabella, V. M., Li, N. & Kurtz, C. B. Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nat. Commun. 11, 1738 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Isabella, V. M. et al. Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nat. Biotechnol. 36, 857–864 (2018).

    CAS  PubMed  Google Scholar 

  178. Hwang, L. et al. RNAi-mediated beta-catenin knockdown in the gastrointestinal mucosa (GI) of patients with familial adenomatous polyposis (FAP): results of START-FAP trial [abstract]. J. Clin. Oncol. 35 (Suppl. 15), e15065 (2017).

    Google Scholar 

  179. Evelo. Our Platform. Evelo https://evelobio.com/science/ (2020).

  180. Foligne, B. et al. Prevention and treatment of colitis with Lactococcus lactis secreting the immunomodulatory Yersinia LcrV protein. Gastroenterology 133, 862–874 (2007).

    CAS  PubMed  Google Scholar 

  181. Limaye, S. A. et al. Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy. Cancer 119, 4268–4276 (2013).

    CAS  PubMed  Google Scholar 

  182. Steidler, L. et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289, 1352–1355 (2000).

    CAS  PubMed  Google Scholar 

  183. Vandenbroucke, K. et al. Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice. Gastroenterology 127, 502–513 (2004).

    CAS  PubMed  Google Scholar 

  184. Praveschotinunt, P. et al. Engineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut. Nat. Commun. 10, 5580 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Cao, Z., Wang, X., Pang, Y., Cheng, S. & Liu, J. Biointerfacial self-assembly generates lipid membrane coated bacteria for enhanced oral delivery and treatment. Nat. Commun. 10, 5783 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Cao, Z., Cheng, S., Wang, X., Pang, Y. & Liu, J. Camouflaging bacteria by wrapping with cell membranes. Nat. Commun. 10, 3452 (2019).

    PubMed  PubMed Central  Google Scholar 

  187. Shepherd, E. S., DeLoache, W. C., Pruss, K. M., Whitaker, W. R. & Sonnenburg, J. L. An exclusive metabolic niche enables strain engraftment in the gut microbiota. Nature 557, 434–438 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Thanuja, M. Y., Anupama, C. & Ranganath, S. H. Bioengineered cellular and cell membrane-derived vehicles for actively targeted drug delivery: so near and yet so far. Adv. Drug Deliv. Rev. 132, 57–80 (2018).

    CAS  Google Scholar 

  189. Wu, H. H., Zhou, Y., Tabata, Y. & Gao, J. Q. Mesenchymal stem cell-based drug delivery strategy: from cells to biomimetic. J. Control. Rel. 294, 102–113 (2019).

    CAS  Google Scholar 

  190. Galipeau, J. & Sensebe, L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22, 824–833 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Moussa, L. et al. A biomaterial-assisted mesenchymal stromal cell therapy alleviates colonic radiation-induced damage. Biomaterials 115, 40–52 (2017).

    CAS  PubMed  Google Scholar 

  192. Echeverri, G. J. et al. Endoscopic gastric submucosal transplantation of islets (ENDO-STI): technique and initial results in diabetic pigs. Am. J. Transpl. 9, 2485–2496 (2009).

    CAS  Google Scholar 

  193. Pang, Y. et al. Endoscopically injectable shear-thinning hydrogels facilitating polyp removal. Adv. Sci. 6, 1901041 (2019).

    CAS  Google Scholar 

  194. Kusano, T. et al. Evaluation of 0.6% sodium alginate as a submucosal injection material in endoscopic submucosal dissection for early gastric cancer. Dig. Endosc. 26, 638–645 (2014).

    PubMed  Google Scholar 

  195. ASGE Technology Committee et al.Enteroscopy. Gastrointest. Endosc. 82, 975–990 (2015).

    Google Scholar 

  196. Clarke, L. L. A guide to Ussing chamber studies of mouse intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1151–G1166 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Westerhout, J., Wortelboer, H. & Verhoeckx, K. in The Impact of Food Bioactives on Health: In Vitro and Ex Vivo Models (eds Verhoeckx, K. et al.) 263–273 (Springer, 2015).

  198. Salamanca, C. H., Barrera-Ocampo, A., Lasso, J. C., Camacho, N. & Yarce, C. J. Franz diffusion cell approach for pre-formulation characterisation of ketoprofen semi-solid dosage forms. Pharmaceutics 10, 148 (2018).

    CAS  PubMed Central  Google Scholar 

  199. Ng, S. F., Rouse, J. J., Sanderson, F. D., Meidan, V. & Eccleston, G. M. Validation of a static Franz diffusion cell system for in vitro permeation studies. AAPS PharmSciTech. 11, 1432–1441 (2010).

    PubMed  PubMed Central  Google Scholar 

  200. Franz, T. J. Percutaneous absorption on the relevance of in vitro data. J. Invest. Dermatol. 64, 190–195 (1975).

    CAS  PubMed  Google Scholar 

  201. Zachos, N. C. et al. Human enteroids/colonoids and intestinal organoids functionally recapitulate normal intestinal physiology and pathophysiology. J. Biol. Chem. 291, 3759–3766 (2016).

    CAS  PubMed  Google Scholar 

  202. Yoo, J. H. & Donowitz, M. Intestinal enteroids/organoids: a novel platform for drug discovery in inflammatory bowel diseases. World J. Gastroenterol. 25, 4125–4147 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Foulke-Abel, J. et al. Human enteroids as an ex-vivo model of host-pathogen interactions in the gastrointestinal tract. Exp. Biol. Med. 239, 1124–1134 (2014).

    Google Scholar 

  204. Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011).

    CAS  PubMed  Google Scholar 

  205. Sato, T. & Clevers, H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194 (2013).

    CAS  PubMed  Google Scholar 

  206. Jalili-Firoozinezhad, S. et al. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Nat. Biomed. Eng. 3, 520–531 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Novak, R. et al. Robotic fluidic coupling and interrogation of multiple vascularized organ chips. Nat. Biomed. Eng. 4, 407–420 (2020).

    PubMed  PubMed Central  Google Scholar 

  208. Sontheimer-Phelps, A. et al. Human colon-on-a-chip enables continuous in vitro analysis of colon mucus layer accumulation and physiology. Cell Mol. Gastroenterol. Hepatol. 9, 507–526 (2020).

    PubMed  Google Scholar 

  209. Kamm, R. D. et al. Perspective: the promise of multi-cellular engineered living systems. APL Bioeng. 2, 040901 (2018).

    PubMed  PubMed Central  Google Scholar 

  210. Esch, E. W., Bahinski, A. & Huh, D. Organs-on-chips at the frontiers of drug discovery. Nat. Rev. Drug Discov. 14, 248–260 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Kasendra, M. et al. Development of a primary human small intestine-on-a-chip using biopsy-derived organoids. Sci. Rep. 8, 2871 (2018).

    PubMed  PubMed Central  Google Scholar 

  212. Ripken, D. & Hendriks, H. F. J. in The Impact of Food Bioactives on Health: In Vitro and Ex Vivo Models (eds Verhoeckx, K. et al.) 255–262 (Springer, 2015).

  213. Lukovac, S. & Roeselers, G. in The Impact of Food Bioactives on Health: In Vitro and Ex Vivo Models (eds Verhoeckx, K. et al.) 245–253 (Springer, 2015).

  214. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    CAS  PubMed  Google Scholar 

  215. Koo, B. K. et al. Controlled gene expression in primary Lgr5 organoid cultures. Nat. Methods 9, 81–83 (2011).

    PubMed  Google Scholar 

  216. Roeselers, G., Ponomarenko, M., Lukovac, S. & Wortelboer, H. M. Ex vivo systems to study host-microbiota interactions in the gastrointestinal tract. Best. Pract. Res. Clin. Gastroenterol. 27, 101–113 (2013).

    CAS  PubMed  Google Scholar 

  217. Sato, T. & Clevers, H. Primary mouse small intestinal epithelial cell cultures. Methods Mol. Biol. 945, 319–328 (2013).

    PubMed  Google Scholar 

  218. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    CAS  PubMed  Google Scholar 

  219. Watson, C. L. et al. An in vivo model of human small intestine using pluripotent stem cells. Nat. Med. 20, 1310–1314 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Lukovac, S. et al. Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids. mBio 5, 01438-14 (2014).

    Google Scholar 

  221. Altay, G. et al. Self-organized intestinal epithelial monolayers in crypt and villus-like domains show effective barrier function. Sci. Rep. 9, 10140 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Ashammakhi, N. et al. Gut-on-a-chip: current progress and future opportunities. Biomaterials 255, 120196 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Bhatia, S. N. & Ingber, D. E. Microfluidic organs-on-chips. Nat. Biotechnol. 32, 760–772 (2014).

    CAS  PubMed  Google Scholar 

  224. Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Ingber, D. E. Reverse engineering human pathophysiology with organs-on-chips. Cell 164, 1105–1109 (2016).

    CAS  PubMed  Google Scholar 

  226. Kim, H. J., Li, H., Collins, J. J. & Ingber, D. E. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc. Natl Acad. Sci. USA 113, E7–E15 (2016).

    CAS  PubMed  Google Scholar 

  227. Choe, A., Ha, S. K., Choi, I., Choi, N. & Sung, J. H. Microfluidic gut-liver chip for reproducing the first pass metabolism. Biomed. Microdevices 19, 4 (2017).

    PubMed  Google Scholar 

  228. Maschmeyer, I. et al. Chip-based human liver-intestine and liver-skin co-cultures–a first step toward systemic repeated dose substance testing in vitro. Eur. J. Pharm. Biopharm. 95, 77–87 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Maschmeyer, I. et al. A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab Chip 15, 2688–2699 (2015).

    CAS  PubMed  Google Scholar 

  230. Materne, E. M. et al. The multi-organ chip–a microfluidic platform for long-term multi-tissue coculture. J. Vis. Exp. https://doi.org/10.3791/52526 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  231. Sandimmune (cyclosporine) package insert (Novartis Pharmaceuticals Corporation, 2006).

  232. Neoral (cyclosporine) package insert (Novartis, 2009).

  233. DDAVP (desmopressin) package insert (Ferring Pharmaceuticals, 2020).

  234. Linzess (linaclotide) package insert (Allergan Pharmaceuticals, 2017).

  235. Trulance (plecanatide) package insert (Synergy, 2016).

  236. Rybelsus (semaglutide) package insert (Novo Nordisk, 2019).

  237. Mycapssa (octreotide) package insert (Chiasma, 2020).

  238. Vivlodex (meloxicam) package insert (Iroko Pharmaceuticals, 2015).

  239. 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 

  240. Abilify (aripiprazole) package insert (Otsuka Pharmaceuticals, 2021).

  241. Asacol (mesalamine) package insert (Allergan, 2020).

  242. Salazopyrin (sulfasalazine) package insert (Pharmacia & Upjohn Company, 2009).

  243. Pentasa (mesalamine) package insert (Takeda, 2004).

  244. Nylund, K., Hausken, T., Odegaard, S., Eide, G. E. & Gilja, O. H. Gastrointestinal wall thickness measured with transabdominal ultrasonography and its relationship to demographic factors in healthy subjects. Ultraschall Med. 33, E225–E232 (2012).

    CAS  PubMed  Google Scholar 

  245. Mohammed, M. A., Syeda, J. T. M., Wasan, K. M. & Wasan, E. K. An overview of chitosan nanoparticles and its application in non-parenteral drug delivery. Pharmaceutics 9, 53 (2017).

    PubMed Central  Google Scholar 

  246. Kurtz, C. B. et al. An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans. Sci. Transl. Med. 11, eaau7975 (2019).

    CAS  PubMed  Google Scholar 

  247. Conley, R., Gupta, S. K. & Sathyan, G. Clinical spectrum of the osmotic-controlled release oral delivery system (OROS), an advanced oral delivery form. Curr. Med. Res. Opin. 22, 1879–1892 (2006).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank R. Langer, A. Kirtane and M. Gala for their helpful review and discussion of the manuscript. This work was funded in part by the National Institutes of Health (Grant no. EB-000244), Helmsley Trust and Novo Nordisk. J.N.C. was supported in part by the National Institutes of Health (Grant no. 5T32DK007191-45) and the Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School. G.T. was supported in part by the Karl van Tassel (1925) Career Development Professorship and the Department of Mechanical Engineering, Massachusetts Institute of Technology, and the Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jacqueline N. Chu

  2. Massachusetts Institute of Technology, Cambridge, MA, USA

    Jacqueline N. Chu & Giovanni Traverso

  3. Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Giovanni Traverso

Authors
  1. Jacqueline N. Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giovanni Traverso
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.N.C. and G.T. wrote, edited and reviewed the article.

Corresponding author

Correspondence to Giovanni Traverso.

Ethics declarations

Competing interests

J.N.C. is a co-inventor on a provisional patent application describing gastric-resident systems for extended drug release and intra-gastric sensing and was a consultant for Synlogic Therapeutics. G.T. is a co-inventor on multiple patents and provisional patent applications describing ingestible systems and devices that support the development of drug delivery systems for small and macromolecule therapeutics. G.T. has a financial interest and/or receives consulting fees from: Suono Bio, Celero Systems, Vivtex, Lyndra, Inc., Bilayer Therapeutics and Novo Nordisk. These companies are developing a set of distinct approaches to gastrointestinal drug delivery. Complete details of all relationships for profit and not for profit for G.T. can be found on Dropbox (https://www.dropbox.com/sh/szi7vnr4a2ajb56/AABs5N5i0q9AfT1IqIJAE-T5a?dl=0).

Additional information

Peer review information

Nature Reviews Gastroenterology and Hepatology thanks S. Sinha, who co-reviewed with J. Gubatan; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chu, J.N., Traverso, G. Foundations of gastrointestinal-based drug delivery and future developments. Nat Rev Gastroenterol Hepatol 19, 219–238 (2022). https://doi.org/10.1038/s41575-021-00539-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-021-00539-w

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing