BWH Clinical & Research News

What’s New in Research: May 2016

Connecting Organs-On-Chips Through Free-Form Blood Vessels

A new form of vascular module for integrating organ-on-chips

A new in vitro microphysiology system called multi-organ-on-chips can now be used to study the effects of drugs and disease by imitating human organ function. Ideally, these miniature organs, or organoids, could be integrated to study inter-organoid interactions through a simulated blood vessel network. However, conventional blood vessel-on-a-chip models are bulky and inert connecting tubes generate too much waste volume relative to the small size of individual organoids.

Ali Khademhosseini, PhD, and his team from the BWH Biomaterials Innovation Research Center, addressed these issues by developing a new form of vascular module based on polydimethylsiloxane (PDMS) hollow tubes, which emulate properties of human blood vessels. The researchers’ two new templating strategies and biofunctionalization techniques are reported in Lab on a Chip.

These templating strategies yield flexible tubes with adjustable diameters and wall thicknesses that can more accurately simulate the different dimensions of arteries, veins and capillaries. PDMS is biocompatible and gas-permeable, making it a suitable material for culturing mammalian cells. The surface alone is not biologically functional though, so Khademhosseini and his team also introduced mimetic vascular functions by coating the tubes’ interiors with endothelial cells.

 “The PDMS vascular tubes can integrate multiple organs-on-chip devices and may enable new mechanistic insights into organ-specific diseases and effects of exposures to biological and chemical insults,” said the authors.

Paper Cited: Zhang, W., et al (2016). Elastomeric free-form blood vessels for interconnecting organs on chip systems. Lab on a Chip DOI: 10.1039/C6LC00001K

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Dual-sided Pill Slowly Releases Drug in the Gut

A collaborative research team from BWH and the Massachusetts Institute of Technology has designed a slow-release pill that safely attaches to the lining of the gastrointestinal (GI) tract. Named after Janus, the double faced Roman god, the pill has two sides with unique properties: its mucoadhesive side allows it to attach to the mucus layer of the GI tract and its omniphobic side resists the movement of fluids in the tract. This increased resistance allows the pill to stay in the tract and release treatment for a longer time, which could reduce the necessary dosing frequency for many drugs. Giovanni Traverso, MB, BChir, PhD, and his team’s results are published in Advanced Healthcare Materials.

Mucoadhesives are useful for orally-delivered medicines as they extend the time spent in the GI tract and steady the rate of drug release. However, these benefits are limited by the turbulent movement of food and fluids in the GI tract. The addition of an omniphobic side – one with repellant qualities – effectively addresses this problem. This Janus device is relatively inexpensive, simple and quick to replicate, making it especially useful for scale-up and industrial applications.

“Since the pill stays in the GI tract longer, this Janus device has significant potential to reduce the frequency of drug administration and therefore promote medication compliance,” Traverso said. “This Janus prototype opens up a broad spectrum of emerging applications.”

Paper Cited: Lee, Y.-A. L., Zhang, S., Lin, J., Langer, R. and Traverso, G. (2016), A Janus Mucoadhesive and Omniphobic Device for Gastrointestinal Retention. Advanced Healthcare Materials. doi: 10.1002/adhm.201501036

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Cellular Trojan Horse Yields Potential Cancer Treatment

Confocal microscopy image of stem cells loaded with drug containing polymeric microparticles. Image courtesy of JMK and OL, Brigham and Women’s Hospital.

A collaborative BWH and Johns Hopkins University (JHU) co-led team has found proof-of-concept evidence for a potential cancer treatment that leverages microparticles and mesenchymal stem cells. The researchers devised an approach to stably internalize chemotherapy loaded microparticles into cells. With the help of a powerful prodrug – developed by collaborators at JHU – that is specifically activated by prostate cells, the researchers effectively targeted and killed prostate cancer tumor cells in proof of concept experiments. The researchers’ results were recently published in Biomaterials.

“In cancer therapeutics, one of the great challenges is finding how to specifically deliver high doses of chemotherapeutics to a tumor, but minimize the systemic toxicity,” said Jeffrey Karp, PhD, the BWH senior author.

Prostate cancer affects over 2.5 million Americans, but there is an unmet need for targeted treatment with minimal systemic toxicity, especially for metastatic disease. Prostate cancer tumors are characterized by a mixed cell population, which makes targeting the different kinds of cells with one treatment very difficult.

“Mesenchymal stem cells represent a potential vehicle that can be engineered to seek out tumors,” said Oren Levy, PhD, co-lead author. “Loading those cells with a potent chemotherapeutic drug is a promising cell-based Trojan horse approach to deliver drugs to sites of cancer.”

This cell-based drug delivery platform, supported in part by the Prostate Cancer Foundation and Movember Foundation, successfully kills tumor cells via a strong “bystander effect.”

“The prodrug only becomes toxic in the presence of the tumor microenvironment, which adds another layer of specificity to this targeted delivery system,” said John Isaacs, PhD, the JHU senior author.

In the future, researchers hope to harness this versatile particle-in-a-cell platform technology for use with different drugs to target an array of diseases, including cancer and neurodegenerative diseases.

 Paper Cited: Levy, O., Brennen, N. et al (2016). A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer. Biomaterials, DOI: 10.1016/j.biomaterials.2016.03.023

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Racial Disparities Mitigated for Universally Insured Military Patients

Racial disparities within the U.S. health system are estimated to account for more than 83,000 deaths and an average of more than $57 billion in excess healthcare expenditures per year. To mitigate disparities, clinicians must first understand the role that external factors (like insurance) play. A recent longitudinal analysis published in the Journal of Trauma and Acute Care Surgery is the first of its kind to find that racial disparities do not exist among a population of universally insured Emergency General Surgery (EGS) patients within the military insurance healthcare system.

The study was a collaborative effort between the Center for Surgery and Public Health (CSPH) at BWH and the Uniformed Services University for Health Sciences (USUHS). Researchers analyzed five years (2006-2010) of TRICARE data, which provides insurance to active, reserve and retired members of the US Armed Services and dependents. EGS conditions (including a wide spectrum of procedures from appendectomy to colectomy) were primarily chosen because their emergent nature is thought to lessen subjective external factors.

Researchers looked at mortality, major morbidity, and readmission rates for 101,011 EGS patients representing four racial groups (White, Black, Asian, or Other), a population which is broadly representative of the insured American public. They found no differences in mortality and readmission rates at 30, 90 or 180 days for patients across racial groups, and only minimal differences in major morbidity between black and white patients. These findings are a stark departure from the disparities which have been demonstrated among those in the general (civilian) population.

“The fact that racial disparities are not present among military members and their dependents is a testament to the equality that exists in the armed services,” said Adil Haider, MD, MPH, Kessler Director of CSPH (a joint initiative of BWH, Harvard Medical School and the Harvard T. H. Chan School of Public Health) and senior author of the study. “This mitigation of disparities provides an example for which we as a nation must strive.”

Paper cited: Zogg C.K. et. al. “Racial Disparities in Emergency General Surgery: Do Differences in Outcomes Persist Among Universally Insured Military Patients?” Journal of Trauma and Acute Care Surgery. DOI: 10.1097/TA.0000000000001004

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