Skip to main content

Thank you for visiting 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.

Perspective: Special delivery for the gut

Wanted: biomaterials for a risky journey. Giovanni Traverso and Robert Langer explain the gastrointestinal frontier.

“Drugs don't work if people don't take them.” That succinct analysis by former US surgeon general C. Everett Koop points the way towards the huge contribution that biomaterials technology can make to health care.

in developed nations, adherence to long-term therapies is only 50%.

Giovanni Traverso

The failure of patients to follow instructions for taking medication is a major barrier to effective clinical care. In developed nations, adherence to long-term therapies is only 50%, and it is much lower in developing countries and in people who take multiple drugs with complex dose regimens1. Medication non-adherence is estimated to cost more than US$100 billion in avoidable hospitalizations every year in the United States. Technologies that would enable extended drug release — lasting for up to several months — through the gastrointestinal (GI) tract could therefore radically improve delivery of medical therapies. This may be especially useful for patients in areas afflicted by war, regions with poor access to health care, patients suffering from psychiatric illness or dementia, and paediatric populations.

Robert Langer Credit: Bachrach

There is good reason to suppose that the gut could host long-acting medication — known as depot formulations — for weeks or even months without significant adverse effects. We know this, for example, from observation of patients with bezoars — indigestible masses trapped in the GI tract that typically pose no problem until they grow quite large2. Patients also are generally able to tolerate intra-gastric balloons for several months3 in their quest to lose weight.

Potential challenges

But translating this possibility into a reality poses a big challenge. To begin with, the gut's typical healthy transit time (from mouth to anus) is about 30 hours. This transit would have to be extended significantly for a drug to achieve weekly or monthly dosing. Furthermore, the GI environment has tremendous variability: pH in different sections ranges from 1 (extremely acidic) to 7 (neutral). Natural variability in the timing and content of meals results in frequent changes in lipid abundance. Then there are the high bacterial loads, 100% humidity, 37 °C temperature and a huge variety of proteases, lipases and other enzymes that work against biomaterial integrity and long-term drug stability. Thus it is imperative to prolong this transit time, which in turn requires developing materials that can withstand extreme conditions while delivering the drug continuously and without compromising safety.

There are two basic engineering approaches to extend transit time. One is to slow a drug's passage through the GI system by using devices that increase friction with the gut's mucosal walls4. The other is to prolong retention by loading drugs into devices that are larger than the points in the gut that limit passage of materials beyond a certain size: the pyloric sphincter at the exit of the stomach and the anus5. Also crucial to the successful development of such technologies are ways to ensure that drugs survive the harsh GI environment.

Significant efforts have been made using a range of materials, including bioadhesives4 and swellable polymers6. But so far, systems are able to provide extended release times only on the order of hours. It will take a multidisciplinary effort to realize systems that can be safely retained in the GI tract for weeks or months, that deliver drugs continuously and with predictable kinetics during that time.

One big issue is safety. Any drug-delivery system that is intended to work in the gastric environment requires mechanisms that enable it to be automatically disassembled in the event of accidental passage through the pylorus, or if the drug being delivered causes an adverse reaction. Such designs require expertise in physiology, polymer chemistry, chemical engineering and mechanical engineering — plus the ability to design a system for testing in a large animal model.

Prolonged release

The clinical applications could be vast. Non-adherence is of particular concern in the treatment of infectious diseases, where it can increase spread of infectious agents as well as rates of multi-drug resistance7. Other potential applications include extended-release GI systems for antibodies, DNA and RNA, now available only by injection. Similar technologies could also enable long-term delivery of chemicals that stimulate or inhibit growth of specific bacterial species in the GI tract; such agents are likely to be of significant interest as we learn more about the role of the microbiome in human disease.

We challenge the drug-delivery and medical-device community to unify their efforts in engineering and biomaterials to develop extended drug-release systems that can be orally delivered, as a novel approach to the prevalent and costly problem of medication non-adherence. To achieve this goal, safe, extended GI retention of delivery systems will have to be demonstrated in large animal models to maximize the chances for success in the translation to humans. Extended-release systems that retain their properties in the GI environment and pass without obstruction once they have released their therapeutic payload could revolutionize current clinical-care models and maximize effective treatment for a wide range of diseases in a variety of clinical settings.


  1. Sabaté, E. (ed.) Adherence to long-term therapies: evidence for action. (WHO, 2003).

    Google Scholar 

  2. Fallon, S. C., Slater, B. J., Larimer, E. L., Brandt, M. L. & Lopez, M. E. J. Pediatr. Surg. 48, 830–834 (2013).

    Article  Google Scholar 

  3. Kethu, S. R. et al. Gastrointest. Endosc. 76, 1–7 (2012).

    Article  Google Scholar 

  4. Lam, P. L. & Gambari, R. J. Control Release 178, 25–45 (2014).

    CAS  Article  Google Scholar 

  5. Cargill, R. et al. Pharm. Res. 5, 533–536 (1988).

    CAS  Article  Google Scholar 

  6. Gordi, T., Hou, E., Kasichayanula, S. & Berner, B. Clin. Ther. 30, 909–916 (2008).

    CAS  Article  Google Scholar 

  7. Ereqat, S., Spigelman, M., Bar-Gal, G. K., Ramlawi, A. & Abdeen, Z. Lancet Infect. Dis. 11, 662 (2011).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Giovanni Traverso or Robert Langer.

Related links

Related links

Related links in Nature Research

Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies

A holistic approach to targeting disease with polymeric nanoparticles

Macroscale delivery systems for molecular and cellular payloads

Stimuli-responsive nanocarriers for drug delivery

Managing diabetes with nanomedicine: challenges and opportunities

Related external links

Keeping Score on How You Take Your Medicine (New York Times, 2011).

'Nonadherence': A bitter pill for drug trials (Science, 2014).

Beyond Belief — How People Feel about Taking Medications for Heart Disease (New England Journal of Medicine, 2015).

Advanced progress of microencapsulation technologies: In vivo and in vitro models for studying oral and transdermal drug deliveries (Journal of Controlled Release, 2014).

Adherence to long-term therapies: evidence for action (WHO, 2003).

Medication Adherence Resource Center.

Adherence to medication (New England Journal of Medicine, 2005).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI:

Further reading


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