The overall goal of this multidisciplinary research project, supported by the National Science Foundation - Frontiers of Integrative Biological

Research program, is to further advance our understanding of self-assembly during the organization of cells and tissues into functional organ modules. The two developmental processes, with common and distinct features to be investigated in detail in the project: fusion of cardiac cushions during the formation of cardiac chambers (left) and the appearance of limb buds the precursors of the limbs (right). (The images refer to chicken embryos.)

The strategy of our multidisciplinary approach for addressing this fundamental biological problem of tremendous complexity is based on the recognition that although morphogenetic processes are under strict genetic control, genes do not create shapes and forms: physical mechanisms and processes do. Our efforts to reveal the principles of cellular organization will focus on two specific, apparently similar developmental phenomena: the formation of cardiac cushions and limb buds. The major biophysical framework within which these processes will be studied is tissue liquidity, the in vitro- and in vivo-demonstrated concept according to which embryonic tissues mimic the behavior of liquids. The molecular basis of this behavior will be investigated through genetic manipulations, and the interplay between biomolecular and biophysical determinants will be explored by the combination of experimental and modeling techniques. The knowledge gained from these studies will serve as biological validation for new methods for building three-dimensional living structures of specific geometries. The proposed research will thus have both basic and applied science components. The former will be based on key scientific concepts underlying early development, cellextracellular matrix (ECM) interactions, epithelialmesenchymal transformation and physical mechanisms of morphogenesis. The latter will rely on the technology of bioprinting, specifically, our custom-built bioprinters operating with "bioink" particles composed of spheroidal cell aggregates and "biopaper" made of biocompatible ECM-containing hydrogels.

Schematics of building a tubular organ module by bioprinting. The blue sheets represent the biopaper or scaffold gel. The gel and the histotypical spherical bioink particles are deposited/printed layer-by-layer. The outlined program will be carried out by the integration of developmental, cell and molecular biology with the physical and engineering sciences, modeling with experiments, and research with education. In the course of this project we anticipate that we will discover new principles of multicellular selforganization (morphogenesis, organogenesis), which in turn will enable us to develop functional biological structures for basic science purposes (e.g., in vitro studies of mechanisms of development and tumor formation), and applications such as targeted drug testing and delivery, and organ (module) replacement. Due to its strongly cross-disciplinary character, our research program will provide excellent training grounds for students who will be facing challenges awaiting educators and scientists in the life sciences entering the 21st century workplace. Our educational activity will be centered on five major components: curriculum development, student research programs, student/educator forums, special summer programs and outreach. What if the tens of thousands of people waiting for organ transplants in the United States didn't have to wait? What if burn victims could replace their scars with skin that was indistinguishable from their own? What if an amputee could replace an entire limb with one that felt, looked and behaved exactly as the original? In what could be the first step toward human immortality, scientists say they've found a way to do all of these things and more with the use of a technology found in many American homes: an ink-jet printer. Researchers around the world say that by using the technology, they can actually "print" living human tissue and one day will be able to print entire organs. "The promise of tissue engineering and the promise of 'organ printing' is very clear: We want to print living, three-dimensional human organs," Dr. Vladimir Mironov said. "That's our goal, and that's our mission." What's in a Name? Though the field is young, it already has a multitude of names.

"Some people call this 'bio-printing.' Some people call this 'organ printing.' Some people call this 'computer-aided tissue engineering.' Some people call this 'bio-manufacturing,'" said Mironov, associate professor at the Medical University of South Carolina and one of the leading researchers in the field. "It looks like every new guy who joins into this field tries to introduce a new term." The commonly used term is "organ printing" and is simple in concept, but incredibly complex and challenging in its execution. "What we do is we modify -- it's a regular ink-jet printer -- but we do not use the paper-feed mechanism, so basically we just have a cartridge moving back and forth and where the paper goes we put a petri dish," explained Thomas Boland, an associate professor at Clemson University. Boland says that there is some liquid in the dish and that in place of ink cartridges are cartridges filled with cells and a "crosslinker." The crosslinker is a chemical that causes the liquid in the petri dish to gel, giving the printer a soft but solid Jell-O-like surface to print the cells on. The process can be repeated over and over, adding liquid, gelling it, printing more cells, and building layer upon layer, creating three dimensions. Limitations and Obstacles Right now, scientists are limited to a maximum of about 2 inches of thickness. Crossing that threshold presents one of the technique's first big hurdles. "When you print something very thick, the cells on the inside will die -- there's no nutrients getting in there -- so we need to print channels there and hope that they become blood vessels," Boland said. In any given human organ, there are blood vessels feeding the organ to keep it alive and working properly. Without the blood vessels, the organ will die and that's the problem facing researchers in building an organ for use in a human: How do you get the printed organ to grow and maintain blood vessels? Although there are a few competing schools of thought on this, like most things in science, work, ingenuity, and maybe a little money are what researchers say will put printed organs in live humans.

"In the future -- maybe 50 years from now -- we will be able to make very complex organs and bones, and very complex tissues," he said. And when they can, they won't have to worry about rejection because the replacement part will be catered to the individual receiving it. ABSTRACT

Tissue engineering technology promises to solve the organ transplantation crisis. However, assembly of vascularized 3D soft organs remains a big challenge. Organ printing, which we define as computer-aided, jet-based 3D tissue-engineering of living human organs, offers a possible solution. Organ printing involves three sequential steps: pre-processing or development of "blueprints" for organs; processing or actual organ printing; and postprocessing or organ conditioning and accelerated organ maturation. A cell printer that can print gels, single cells and cell aggregates has been developed. Layer-by-layer sequentially placed and solidified thin layers of a thermo-reversible gel could serve as "printing paper". Combination of an engineering approach with the developmental biology concept of embryonic tissue fluidity enables the creation of a new rapid prototyping 3D organ printing technology, which will dramatically accelerate and optimize tissue and organ assembly.

Printing Organs in Inkjet Printer Can Save Two Lives a Minute Anthony Atala's state-of-the-art lab grows human organs -- muscles, blood vessels, bladders, and more. In this video, he shows footage of his bio-engineers working with advanced technology, including a machine that "prints" human tissue.

Dr. Mercola's Comments:

Dr. Aubrey de Grey, one of the leading anti aging biologists, has long stated that he believes the way we will extend our lifespan beyond 120 years old is to replace the parts that wear out.

That is one of the reasons why I find this line of research so appealing because it seems to be a real world implementation of Dr. de Grey's strategy. Of course, this technology can also be used for organ replacement not due to aging. As of February 10, 2010, there were over 105,600 people waiting for an organ donation in the United States. However, from January to November 2009, just over 26,000 organ transplants took place. The number of people in need of organ transplants is simply rising faster than the number of available donors, and as a result 19 people die every day due to this shortage. So it would be nothing short of miraculous if we could one day replace virtually every organ or tissue in patients' bodies with young pristine organs as they age or become diseases or injured. Recently, steps toward achieving this goal have advanced greatly, including the amazing work being conducted at Dr. Anthony Atala's Wake Forest Institute for Regenerative Medicine.

Lab-Grown Organs and Tissues are Here

Currently, Dr. Atala and his colleagues are working on developing organs and tissues for virtually every part of the human body. They were the first to create human bladders in the lab, and successfully implant them in patients. They are also in the process of engineering a human ear and developing technology to print skin directly on burns using an ordinary inkjet printer! The Institute has also identified a new type of non-controversial stem cells that come from amniotic fluid and placenta. Adult stem cells (as opposed to embryonic stem cells, which are at the heart of the stem cell controversy) are a truly exciting part of the future of medicine, especially anti-aging medicine. As you age, your stem cells diminish in quality and quantity, so just when you require strong stem cells the most, you're becoming deficient. Hence your organs and tissues eventually wear out and need to be restored or replaced. What makes stem cells so special is their potential to develop into many different cell types. When a stem cell divides, it either becomes another type of cell, such as a muscle cell or brain cell, or it remains a stem cell. Further, these cells act as an internal repair system in many types of tissues, dividing a seemingly infinite number of times to replenish other cells.

The new type of stem cells identified by Wake Forest scientists can be used to form blood vessel, bone, liver, muscle and other types of tissues, and they say a bank of 100,000 specimens could potentially provide 99 percent of the U.S. population with a genetic match for transplantation. Not only are these stem cells easily obtainable, but they can be grown in large quantities because they typically double every 36 hours.

Regenerative Medicine at its Finest

Currently researchers at the Institute are also working to grow more than 22 different types of organs and tissues in the lab and are developing cell therapies for diseases such as diabetes and muscular dystrophy. Your body already has an amazing ability to regenerate, such as healing a skin wound or broken bone. It's also true for organs, such as your liver. Right now, scientists can implant special smart biomaterials to form a matrix to help your body's tissues rebuild themselves, but it only works for small areas, typically 1 centimeter or less. These new advances will make it possible to not only replace entire organs, but also to repair much larger areas. Already, one man was able to regenerate a lost fingertipusing a special powder substance called extracellular matrix -- a mix of protein and connective tissue surgeons use to repair tendons. It signals your body to start the process of tissue regrowth, and in just four weeks his fingertip grew back completely. Scientists are also using patients' own cells to grow organs in the lab, as there's little risk of rejection when using your own adult stem cells. This means you're less likely to need dangerous immunosuppressive drugs that are common with some treatments. When I served as the kidney transplant coordinator for the University of Illinois prior to starting medical school in 1978, it was clear that the ability to produce organs -- and not have to put people on waiting lists -- would be an amazing accomplishment of modern medicine. It seems we are now closer to this goal than ever before.