Article | Published:

A pH-responsive supramolecular polymer gel as an enteric elastomer for use in gastric devices

Nature Materials volume 14, pages 10651071 (2015) | Download Citation

Abstract

Devices resident in the stomach—used for a variety of clinical applications including nutritional modulation for bariatrics, ingestible electronics for diagnosis and monitoring, and gastric-retentive dosage forms for prolonged drug delivery—typically incorporate elastic polymers to compress the devices during delivery through the oesophagus and other narrow orifices in the digestive system. However, in the event of accidental device fracture or migration, the non-degradable nature of these materials risks intestinal obstruction. Here, we show that an elastic, pH-responsive supramolecular gel remains stable and elastic in the acidic environment of the stomach but can be dissolved in the neutral-pH environment of the small and large intestines. In a large animal model, prototype devices with these materials as the key component demonstrated prolonged gastric retention and safe passage. These enteric elastomers should increase the safety profile for a wide range of gastric-retentive devices.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Endoluminal bariatric techniques. Gastrointest. Endosc. 76, 1–7 (2012).

  2. 2.

    et al. BioEnterics intragastric balloon: The Italian experience with 2,515 patients. Obes. Surg. 15, 1161–1164 (2005).

  3. 3.

    et al. Oligopeptide complex for targeted non-viral gene delivery to adipocytes. Nature Mater. 13, 1157–1164 (2014).

  4. 4.

    et al. Silk-based conformal, adhesive, edible food sensors. Adv. Mater. 24, 1067–1072 (2012).

  5. 5.

    , , , & Biologically derived melanin electrodes in aqueous sodium-ion energy storage devices. Proc. Natl Acad. Sci. USA 110, 20912–20917 (2013).

  6. 6.

    & The ingestible telemetric body core temperature sensor: A review of validity and exercise applications. Br. J. Sports. Med. 41, 126–133 (2007).

  7. 7.

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

  8. 8.

    Gastroretentive dosage forms. Crit. Rev. Ther. Drug 10, 143–195 (1993).

  9. 9.

    , & Gastric retentive drug-delivery systems. Crit. Rev. Ther. Drug 15, 243–284 (1998).

  10. 10.

    & Floating drug delivery systems: An approach to oral controlled drug delivery via gastric retention. J. Control Release 63, 235–259 (2000).

  11. 11.

    et al. Sustained gastrointestinal activity of dendronized polymer–enzyme conjugates. Nature Chem. 5, 582–589 (2013).

  12. 12.

    , , & Localization of magnetic pills. Proc. Natl Acad. Sci. USA 108, 2252–2257 (2011).

  13. 13.

    Measurement of the diameter of the pylorus in man: Part I. Experimental project for clinical application. Am. J. Surgery 124, 331–333 (1972).

  14. 14.

    , , & in Gastrointestinal Motility in Health and Disease (ed Duthie, H. L.) Ch. 38, 349–359 (Springer, 1978).

  15. 15.

    & Esophageal diameter and the treatment of achalasia. Digest Dis. Sci. 14, 611–618 (1969).

  16. 16.

    , & A new endoscopic elastic band ligating device. Gastrointest. Endosc. 32, 230–233 (1986).

  17. 17.

    Evidence-based review of the bioenterics intragastric balloon for weight loss. Obes. Surg. 18, 1611–1617 (2008).

  18. 18.

    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).

  19. 19.

    , , & Duodenal obstruction: A complication of percutaneous endoscopic gastrostomy tube migration. Am. J. Gastroenterol. 85, 1037–1038 (1990).

  20. 20.

    et al. Efficacy, tolerance and safety of new intragastric air-filled balloon (Heliosphere BAG) for obesity: The experience of 17 cases. Obes. Surg. 20, 1227–1230 (2010).

  21. 21.

    et al. Intragastric balloon for “non-morbid” obesity: A retrospective evaluation of tolerance and efficacy. Obes. Surg. 14, 539–544 (2004).

  22. 22.

    & Perspective: Special delivery for the gut. Nature 519, S19 (2015).

  23. 23.

    & Synthetic polymers as potential enteric and sustained-release coatings. J. Pharm. Sci. 51, 808 (1962).

  24. 24.

    , , , & Polymer blends for controlled release coatings. J. Control Release 125, 1–15 (2008).

  25. 25.

    , , & Stimuli-responsive supramolecular polymeric materials. Chem. Soc. Rev. 41, 6042–6065 (2012).

  26. 26.

    , & Using the dynamic bond to access macroscopically responsive structurally dynamic polymers. Nature Mater. 10, 14–27 (2011).

  27. 27.

    , , & Shape-memory effects in polymer networks containing reversibly associating side-groups. Adv. Mater. 19, 2851–2855 (2007).

  28. 28.

    et al. A multiresponsive, shape-persistent, and elastic supramolecular polymer network gel constructed by orthogonal self-assembly. Adv. Mater. 24, 362–369 (2012).

  29. 29.

    , & Controlled supramolecular assembly of micelle-like gold nanoparticles in PS-b-P2VP diblock copolymers via hydrogen bonding. J. Am. Chem. Soc. 133, 16986–16996 (2011).

  30. 30.

    , , & An electrically and mechanically self-healing composite with pressure- and flexion-sensitive properties for electronic skin applications. Nature Nanotech. 7, 825–832 (2012).

  31. 31.

    , , & Multiphase design of autonomic self-healing thermoplastic elastomers. Nature Chem. 4, 467–472 (2012).

  32. 32.

    & Saloplastics: Processing compact polyelectrolyte complexes. Adv. Mater. 27, 2420–2432 (2015).

  33. 33.

    , & Advanced functional polymers for medicine. Adv. Healthc. Mater. 3, 1939–1940 (2014).

  34. 34.

    et al. Emerging applications of stimuli-responsive polymer materials. Nature Mater. 9, 101–113 (2010).

  35. 35.

    , , & Floating drug delivery systems for prolonging gastric residence time: A review. Curr. Drug Deliv. 8, 494–510 (2011).

  36. 36.

    et al. Rapid self-healing hydrogels. Proc. Natl Acad. Sci. USA 109, 4383–4388 (2012).

  37. 37.

    & Structure and hydrogen bond dynamics of water–dimethyl sulfoxide mixtures by computer simulations. J. Chem. Phys. 98, 8160–8173 (1993).

  38. 38.

    & The return of a forgotten polymer–polycaprolactone in the 21st century. Prog. Polym. Sci. 35, 1217–1256 (2010).

  39. 39.

    & Macroscale delivery systems for molecular and cellular payloads. Nature Mater. 12, 1004–1017 (2013).

  40. 40.

    & The effect of tablet size on the gastric emptying of non-disintegrating tablets. Int. J. Pharm. 62, R9–R11 (1990).

  41. 41.

    et al. Controlled gastric emptying. 1. effects of physical properties on gastric residence times of nondisintegrating geometric shapes in beagle dogs. Pharm. Res. 5, 533–536 (1988).

  42. 42.

    & Factors influencing the gastric residence of dosage forms in dogs. J. Pharm. Sci. 98, 844–860 (2009).

  43. 43.

    , , , & Swine as models in biomedical research and toxicology testing. Vet. Pathol. 49, 344–356 (2012).

  44. 44.

    & Aqueous gel permeation chromatography: The effect of solvent ionic strength. J. Appl. Polym. Sci. 23, 419–427 (1979).

Download references

Acknowledgements

This work was funded in part by the Bill and Melinda Gates Foundation Grant OPP1096734 (to R.L.) and the NIH Grant EB000244 (to R.L.). The paper was partly sponsored by the Alexander von Humboldt Foundation under the auspices of the Max Planck Research Award to R.L. funded by the Federal Ministry of Education and Research. A.M.B. was supported in part by NIH T32 5T32HL007604-29. J.Z. was supported by the Laboratory Directed Research and Development program at Oak Ridge National Laboratory, which is sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy. Use of the Advanced Photon Source, an Office of Science User Facility operated for the US Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the US DOE under Contract No. DE-AC02-06CH11357. We would like to thank J. Haupt and M. Jamiel for expert veterinary support. We are indebted to L. Wood, P. Eckhoff, D. Hartman, S. Kern, S. Hershenson and B. Nikolic for fruitful discussions that stimulated the development of this material. The findings and conclusions reported in this paper are those of the authors and do not necessarily reflect positions or policies of the Bill and Melinda Gates Foundation.

Author information

Affiliations

  1. Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Shiyi Zhang
    • , Andrew M. Bellinger
    • , Dean L. Glettig
    • , Ross Barman
    • , Young-Ah Lucy Lee
    • , Cody Cleveland
    • , Veronica A. Montgomery
    • , Li Gu
    • , Robert Langer
    •  & Giovanni Traverso
  2. Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Andrew M. Bellinger
  3. Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA

    • Ross Barman
    •  & Giovanni Traverso
  4. Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA

    • Jiahua Zhu
  5. Department of Biomedical Engineering, Biomedical Device Laboratory, Texas A&M University, College Station, Texas 77843, USA

    • Landon D. Nash
    •  & Duncan J. Maitland
  6. Harvard–MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Robert Langer

Authors

  1. Search for Shiyi Zhang in:

  2. Search for Andrew M. Bellinger in:

  3. Search for Dean L. Glettig in:

  4. Search for Ross Barman in:

  5. Search for Young-Ah Lucy Lee in:

  6. Search for Jiahua Zhu in:

  7. Search for Cody Cleveland in:

  8. Search for Veronica A. Montgomery in:

  9. Search for Li Gu in:

  10. Search for Landon D. Nash in:

  11. Search for Duncan J. Maitland in:

  12. Search for Robert Langer in:

  13. Search for Giovanni Traverso in:

Contributions

S.Z., R.L. and G.T. designed the material and experiments. S.Z. prepared the material and the device. S.Z., A.M.B., D.L.G., R.B., Y.-A.L.L., J.Z., V.A.M., C.C., L.D.N., D.J.M., L.G. and G.T. characterized the material, analysed the data and wrote the paper. R.L. and G.T. supervised the research. All authors discussed the progress of research and reviewed the manuscript.

Competing interests

The authors declare Provisional US patent application No. 62/010,992 filed on 11 June 2014.

Corresponding authors

Correspondence to Robert Langer or Giovanni Traverso.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nmat4355

Further reading