Medical Device Daily National Editor

It's fairly easy to grow cells. But you can't just put them together in the lab, Lego-like. Thus far, only nature has been able to manipulate cells into tissues, tissues into organs, in any sort of uniform and sustainable way.

The main barrier for doing this artificially? The inability to create vascular support for artificial tissues and organs to feed and grow them with the necessary blood and other nutrients.

Now, a group of researchers at Brown University (Providence, Rhode Island) believe they have created a foundation for solving this problem, via the"self-assembly' of tissues in three dimensions, growing 3-D"micro-tissues" designed in patterns that suggest methods for vascular support.

These 3-D tissues offer an important advance for the field of tissue engineering, according to Jeffrey Morgan, PhD, a professor of medical science and engineering in Brown's bioengineering department.

Additionally, he said that these tissues may provide an alternative for the use of animals in some types of research.

The inability to build artificial tissues with the necessary vascular support is"a major problem for the field of tissue engineering," Morgan told Medical Device Daily.

"What we've shown, what were trying to address, is building structures that have an open lumen of controllable size."

These lumen spaces have been created in various shapes and geometries, indicating an ability to mimic natural tissues and the vasculature for providing blood flow and essential nutrients for growth.

Importantly, the new work accomplished this, based on earlier work by Morgan and a team of his students, the development of a specialized Petri dish that enabled the formation of tissues in 3-D (that innovation described in the September 2007 issue of Tissue Engineering).

The"3-D" Petri dish is made of agarose, a complex carbohydrate derived from seaweed with the consistency of Jell-O.

The key feature of this device is that cells do not adhere to the agarose material. Unable to adhere to the dish, the cells aggregate to one another in an activity Morgan describes as"self-assembly."

"In the typical Petri dish," Morgan told MDD,"the cells attach to plastic, spread around, move around and proliferate," the resultant cell cultures existing essentially in just two dimensions.

"We wanted a technology that would create 3-D structures. Cells in 3-D are more like the native tissues and organs that they come from," he said.

"In the agarose-based Petri dish, cells may attempt to stick to the dish," he said,"but they can't [so they] stick to each other," creating thicker pattern tissues.

"Because [the cells] are alive, they fuse with one another and that fusion creates a tissue with open spaces. We knew that cells will self-assemble, given the right environment, and we wanted to harness that power, design a device where we could control that process.

"The next step," he said,"is to figure out how to get those lined with endothelial cells."

Morgan's innovative Petri dishes are made into different"molds," he said, making it possible to assemble the micro-tissues into various geometric shapes.

"One of the powers of our technology is that we use rapid prototyping to create these molds, and computer-aided design to create any design that we want and mold that into the agarose."

The micro-tissues were grown in one of the 3-D Petri dishes, harvested, and then added to the more complex 3-D molds, shaped either like a honeycomb, with holes, or a donut with a hole in the middle. Skin cells fused with liver cells in the more complex molds to form even larger microstructures.

The researchers said they found that the molds helped control the shape of the final micro-tissue. They also found that they could control the rate of fusion of the cells by aging them for a longer or shorter time before they were harvested.

Morgan said the research builds a path to"tissue models that more closely mimic natural tissue already inside the body in terms of function and architecture. This shows we can control the size, shape and position of cells within these 3-D structures."

The work is just one phase of what Morgan described as"the tack" in his lab:"to understand the rules of self-assembly. How do living cells assemble these structures, the cellular processes that control this self-assembly, what controls position of cells within a larger macro tissue?"

As basic research, Morgan acknowledged that the study doesn't lead in a straight line to clinical use, but he said it could provide important pathways to tissue engineers focused on creating products for patient use.

"We're really approaching the fundamental rules of this cell aggregation process," he said."It's relevant to many different tissues and organs, to understand as building materials and how we can harness that."

He added:"This is relevant to virtually any tissue. We think this is one step toward using building blocks to build complex-shaped tissues that might one day be transplanted."

One product that he said would be potentially useful for lab work would be the creation of tissues types substituting for testing ordinarily done with animals.

Funding for the study was provided by the National Science Foundation (Arlington, Virginia) and the International Foundation for Ethical Research (Chicago), the mission of the latter group to reduce the use of animals in research.

The research is described in the March 1 issue of Biotechnology and Bioengineering and posted on the journal's web site.