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May 6, 2014

Organ-on-a-Chip Advance Goes to the Very Marrow

Organ-on-a-Chip Advance Goes to the Very Marrow

Microscopic view of engineered bone. The opening exposes the internal bony network, overlaid with colored images of blood cells and a supportive vascular network. [James Weaver, Harvard’s Wyss Institute]

  • Organs-on-chips are piling up faster than body parts in Dr. Frankenstein’s lab. Such chips, microfluidic devices that amount to compact, three-dimensional cell culture versions of real organs, already exist for skin, cartilage, bone, gut, artery, heart, and kidney. And that’s not all: scientists anticipate linking together collections of organ chips to create body chips. But such a microfluidic “creature” would require, at a minimum, an artificial circulatory system, which would in turn require a constant supply of fresh blood cells.

    That’s where the scheme may falter. Unless an in vitro model of hematopoiesis can be developed that is capable of showing all the cellular diversity and complex functions of living marrow, no scientist will ever exult, “It’s alive!” while standing over a newly animated system of organ chips.

    Current in vitro models of hematopoiesis fail to capture the complexities of bone marrow, which has an integral relationship with bone. Within bony nooks and crannies, bone marrow cells find varied hematopoietic niches, which accommodate cells that have very particular preferences. For example, some cells like warmer or cooler spots, and some prefer to sip or guzzle oxygen. What’s more, bone marrow cells communicate with each other by secreting and sensing a variety of biomolecules, which act locally to tell them whether to live, die, specialize, or multiply.

    Undeterred by these complexities, scientists at Harvard’s Wyss Institute for Biologically Inspired Engineering developed a bone marrow-on-a-chip that they say reproduces the structure, functions, and cellular makeup of bone marrow. These scientists described their work in the May 4 online issue of Nature Methods, in an article entitled “Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro.”

    In this article, the authors explain how they first engineered new bone in vivo, removed it whole, and perfused it with culture medium in a microfluidic device. The engineered bone marrow, wrote the authors, retained “hematopoietic stem and progenitor cells in normal in vivo-like proportions for at least one week in culture.”

    The novel part of the procedure was the engineering of new bone in vivo. Rather than try to reproduce a structure so complex as bone marrow by means of the usual techniques—collecting and nurturing cells in a simulated, chip-based environment—the Wyss Institute scientists enlisted the services of mice. “We figured, why not allow Mother Nature to help us build what she already knows how to build?” said Catherine S. Spina, an M.D.-Ph.D. candidate at Boston University, researcher at the Wyss Institute, and co-lead author of the paper.

    Wyss Institute scientists packed dried bone powder into an open, ring-shaped mold the size of a coin battery, and implanted the mold under the skin on the animal’s back. After eight weeks, they surgically removed the disk-shaped bone, which proved to have a honeycomb-like structure that looked identical to natural trabecular bone. The marrow, too, looked like the real thing—packed with blood cells, just like marrow from a living mouse. And when the researchers sorted the bone marrow cells by type and tallied their numbers, the mix of different types of blood and immune cells in the engineered bone marrow was identical to that in a mouse thighbone.

    To sustain the engineered bone marrow outside of a living animal, the researchers surgically removed the engineered bone from mice, then placed it in a microfluidic device that steadily supplied nutrients and removed waste to mimic the circulation the tissue would experience in the body.

    Bone marrow-on-a-chip, the researchers noted, have a range of exciting applications. The most immediate of these is a platform for drug testing. “This biomimetic microdevice offers a new approach for analysis of drug responses and toxicities in bone marrow as well as for study of hematopoiesis and hematologic diseases in vitro,” they wrote. Testing this notion themselves, the scientists demonstrated that engineered bone marrow “models organ-level marrow toxicity responses and protective effects of radiation countermeasure drugs, whereas conventional bone marrow culture methods do not.”

    In the future, the researchers could potentially grow human bone marrow in immune-deficient mice. “This could be developed into an easy-to-use screening-based system that’s personalized for individual patients,” said coauthor James Collins, Ph.D., a Core Faculty member at the Wyss Institute and the William F. Warren Distinguished Professor at Boston University, where he leads the Center of Synthetic Biology. The bone marrow-on-a-chip could also be used in the future to maintain a cancer patient’s own marrow temporarily while he or she underwent marrow-damaging treatments such as radiation therapy or high-dose chemotherapy.


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