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Organ and tissue transplantation has always been a difficult endeavor, not least because the supply of organs and tissues for transplantation is so short.  One new way of potentially solving this problem draws upon not just biology and medicine, but desktop manufacturing and printing technologies.

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Desktop Manufacturing
What is desktop manufacturing?  It's essentially the construction of 3D objects by printing them.  Traditionally, 3D objects are created by molding of a metal or plastic, or machining a metal or plastic form until the desired shape is achieved.  In desktop manufacturing, however, a computer-controlled printer literally prints a 3D object, typically from a flowable plastic.  A good introduction to desktop manufacturing can be seen in this New York Times video:

Desktop manufacturing is, in part, an outgrowth of printing technology, including inkjet printing technology, in which an ink is sprayed by a printhead on a flat surface (for example, paper).  Inkjet printing is typically used by less-expensive printers.  The droplets of ink sprayed by an inkjet printer are typically quite small; at 300 dots per inch (dpi), each ink droplet is approximately 84 micrometers in diameter.

But wait - who says we need to print only ink? Desktop manufacturing showed us we can "print" plastics--or for that matter, any sufficiently flowable material.

And aren't cells much smaller than 84 micrometers?  Yes!  Typically, they are about 10-30 micrometers in diameter.

So can we print cells?  Yes we can!

Bioprinting
Bioprinting is simply the depositing of cells, usually in some sort of protective matrix, on a surface so as to build a three-dimensional structure that is biologically relevant.  One example of bioprinting is shown in the diagram below:

bioprinting02

In this diagram, cells, or balls of cells, are deposited by a printer onto a flat substrate (in gray), as shown in panel 1.  Once a ring of cells is deposited, another layer of substrate is laid down on top of the first ring, and more cells are printed.  This process is repeated until, as in panel 3, a structure (a tube) is completed.  The structure is then cultured for a time, during which the cells, or balls of cells, fuse and stick together to form a discrete, unitary structure that can be, for example, transplanted into a recipient.  During this last step, the substrate, no longer necessary, is degraded.

Who were the bioprinting pioneers?  Enter Gabor Forgacs of the University of Missouri, and Anthony Atala of Wake Forest University, two of the pioneers of organ bioprinting.  Two videos, one about Dr. Forgacs' work, and the next about Dr. Atala's, explain the process in more detail:

One of the realizations that Dr. Forgacs brought to bioprinting, and a principle that makes the technology work, is that cells taken from the body tend to self-assemble into biologically-relevant--and useful--patterns.  That is, if one just prints cells close to each other, they tend to form structures in a bioprinting context as they do in the body.

Sounds pretty amazing! And pretty cutting-edge, meaning good ideas are a bit ahead of practice.  So what are some real-world applications of the bioprinting technology?  Anthony Atala's group at Wake Forest University is working on skin bioprinting in conjunction with the military to treat, for example, burn wounds:

So what about more complex organs?  Can they be built by bioprinting, too?  Well, one of the more complex organs in terms of cellular structure is the kidney; it is also one of the more easily damaged organs, and the most needed for transplantations.  As such, it is the "holy grail" of bioprinting.

The heart of the kidney is the interaction between blood supply and ureter in the lobule:

glomerulus

Note that blood, which enters the lobule from the left in this diagram, enters the glomerulus first, at which point urine is extracted and passes to the Bowman's capsule.  The urine then passed down the ureter through the Loop of Henle, past more blood vessels that act to recapture excess water from the urine.  Urine then passes through the collecting duct on its way to the bladder.

The challenge, then, is to take the idea of building the simple tube, as shown in the diagram above, and extrapolate that into printing cells that will replicate not just the complex web of blood vessels in the glomerulus and Loop of Henle, but the Bowman's capsule and ureters, as well.  Efforts are currently underway at Dr. Forgacs' and Atala's labs, and in other labs, to accomplish the bioprinting of an organ as complex as the kidney.

What is fascinating is that bioprinting technology involved depends upon literally centuries of biological knowledge, including that provided by:
- Marcello Malphigi, who, in the 1600s, discovered the kidney structure known as the glomerulus (the first structure in the kidney that, with the Bowman's capsule, filters blood);
- Sir William Bowman, who in 1841, discovered the Bowman's capsule, which surrounds the glomerulus;
- Clifford Grobstein, who parsed out the interaction between mesenchymal and epithelial cells that form the developing kidney;
- Gustav Born, who in the 1800s discovered that cell masses from different parts of amphibian embryos merged when placed in contact with each other (the basis of bioprinting);
- H. V. Wilson, who discovered that sponge cells, fuse when placed into contact with each other, a discovery that led to the understanding of cell attachment molecules (critical for bioprinting);
- August Krogh, who won a Nobel Prize in medicine in 1920 for his discovery that capillaries (the smallest blood vessels) open up or constrict according to the demands of the tissues they serve;
- Judah Folkman, who, since the 1970s, worked to explain how vasculature, including development of capillaries, affected tumor growth (observations that apply to how transplanted organs or tissues will fare in a recipient);
- Alexis Carrel, who won the Nobel Prize in medicine in 1912 for accomplishing the first organ transplant between species;
- Johannes Holtfreter, who discovered that the different disaggregated cells of amphibian embryos re-aggregated in a predictable, organized way;
- Malcolm Steinberg, who developed the theory of differential cell adhesion, which explained why cells re-agregated in predictable ways;
- Joseph Murray, who received the Nobel Prize in medicine in 1990 for his successful transplant in 1954 of a kidney between identical twins, and his other kidney transplantation studies;
- Robert Langer, who discovered that cells could be combined with artificial matrices to produce artificial tissues; and
- Lauri Saxen, who wrote the definitive treatise on kidney development.

To say nothing about the advances in printer technology over the last thirty years!

Even in the most arcane and cutting-edge of modern technologies, we stand on the shoulders of giants, and lesser giants, that preceded us.

So, in a decade or two, if you get something as biologically simple as a burn, or as complex as a malfunctioning kidney, you may end up visiting what looks like a high-tech manufacturing facility in which skin, a part of a kidney, or some other tissue or organ will be printed to order for you.  Stay tuned.

Extended (Optional)

Originally posted to The Orchid on Thu Sep 29, 2011 at 10:28 PM PDT.

Also republished by SciTech and Community Spotlight.

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