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Transplantable bioengineered forelimb


  1. Transplantable bioengineered forelimb developed in an ...
  2. 3 days ago - In their report, the researchers describe using an experimental approach previously used to build bioartificial organs to engineer rat forelimbs ...
  3. Scientists Make Progress in Tailor-Made Organs - NYTimes ...
  4. Sep 15, 2012 - Implanting such a “bioartificial” organ would be a first-of-its-kind ... Now, however, researchers like Dr. Macchiarini are building organs with a ...


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Transplantable bioengineered forelimb developed in an animal model

June 2, 2015
Massachusetts General Hospital
A team of investigators has made the first steps towards development of bioartificial replacement limbs suitable for transplantation. In their report, the researchers describe using an experimental approach previously used to build bioartificial organs to engineer rat forelimbs with functioning vascular and muscle tissue.

A suspension of muscle progenitor cells is injected into the cell-free matrix of a decellularized rat limb, which provides shape and structure onto which regenerated tissue can grow.
Credit: Bernhard Jank, M.D., Ott Laboratory, Massachusetts General Hospital Center for Regenerative Medicine
A team of Massachusetts General Hospital (MGH) investigators has made the first steps towards development of bioartificial replacement limbs suitable for transplantation. In their report, which has been published online in the journal Biomaterials, the researchers describe using an experimental approach previously used to build bioartificial organs to engineer rat forelimbs with functioning vascular and muscle tissue. They also provided evidence that the same approach could be applied to the limbs of primates.
"The composite nature of our limbs makes building a functional biological replacement particularly challenging," explains Harald Ott, MD, of the MGH Department of Surgery and the Center for Regenerative Medicine, senior author of the paper. "Limbs contain muscles, bone, cartilage, blood vessels, tendons, ligaments and nerves -- each of which has to be rebuilt and requires a specific supporting structure called the matrix. We have shown that we can maintain the matrix of all of these tissues in their natural relationships to each other, that we can culture the entire construct over prolonged periods of time, and that we can repopulate the vascular system and musculature."
The authors note that more than 1.5 million individuals in the U.S. have lost a limb, and although prosthetic technology has greatly advanced, the devices still have many limitations in terms of both function and appearance. Over the past two decades a number of patients have received donor hand transplants, and while such procedures can significantly improve quality of life, they also expose recipients to the risks of life-long immunosuppressive therapy. While the progenitor cells needed to regenerate all of the tissues that make up a limb could be provided by the potential recipient, what has been missing is the matrix or scaffold on which cells could grow into the appropriate tissues.
The current study uses technology Ott discovered as a research fellow at the University of Minnesota, in which living cells are stripped from a donor organ with a detergent solution and the remaining matrix is then repopulated with progenitor cells appropriate to the specific organ. His team and others at MGH and elsewhere have used this decellularization technique to regenerate kidneys, livers, hearts and lungs from animal models, but this is the first reported use to engineer the more complex tissues of a bioartificial limb.
The same decellularization process used in the whole-organ studies -- perfusing a detergent solution through the vascular system -- was used to strip all cellular materials from forelimbs removed from deceased rats in a way that preserved the primary vasculature and nerve matrix. After thorough removal of cellular debris -- a process that took a week -- what remained was the cell-free matrix that provides structure to all of a limb's composite tissues. At the same time, populations of muscle and vascular cells were being grown in culture.
The research team then cultured the forelimb matrix in a bioreactor, within which vascular cells were injected into the limb's main artery to regenerate veins and arteries. Muscle progenitors were injected directly into the matrix sheaths that define the position of each muscle. After five days in culture, electrical stimulation was applied to the potential limb graft to further promote muscle formation, and after two weeks, the grafts were removed from the bioreactor. Analysis of the bioartificial limbs confirmed the presence of vascular cells along blood vessel walls and muscle cells aligned into appropriate fibers throughout the muscle matrix.
Functional testing of the isolated limbs showed that electrical stimulation of muscle fibers caused them to contract with a strength 80 percent of what would be seen in newborn animals. The vascular systems of bioengineered forelimbs transplanted into recipient animals quickly filled with blood which continued to circulate, and electrical stimulation of muscles within transplanted grafts flexed the wrists and digital joints of the animals' paws. The research team also successfully decellularized baboon forearms to confirm the feasibility of using this approach on the scale that would be required for human patients.
Ott notes that, while regrowing nerves within a limb graft and reintegrating them into a recipient's nervous system is one of the next challenges that needs to be faced, the experience of patients who have received hand transplants is promising. "In clinical limb transplantation, nerves do grow back into the graft, enabling both motion and sensation, and we have learned that this process is largely guided by the nerve matrix within the graft. We hope in future work to show that the same will apply to bioartificial grafts. Additional next steps will be replicating our success in muscle regeneration with human cells and expanding that to other tissue types, such as bone, cartilage and connective tissue."

Story Source:
The above story is based on materials provided by Massachusetts General Hospital. Note: Materials may be edited for content and length.

Journal Reference:
  1. Bernhard J. Jank, Linjie Xiong, Philipp T. Moser, Jacques P. Guyette, Xi Ren, Curtis L. Cetrulo, David A. Leonard, Leopoldo Fernandez, Shawn P. Fagan, Harald C. Ott. Engineered composite tissue as a bioartificial limb graft. Biomaterials, 2015; 61: 246 DOI: 10.1016/j.biomaterials.2015.04.051

Cite This Page:
Massachusetts General Hospital. "Transplantable bioengineered forelimb developed in an animal model." ScienceDaily. ScienceDaily, 2 June 2015. .

Bioprinter can print 3D samples of human tissue
Treating severe burns typically involves grafting a healthy patch of skin taken from elsewhere on the body. But large burns present a problem. That has researchers at Wake Forest experimenting with a treatment method that involves applying a small number of healthy skin cells onto the injury and letting them grow organically over the wound. 3-D-bioprinted skin potentially could be produced faster, provided Organovo can successfully replicate the cell structure of human epidermis.

L’Oreal already has a massive lab in Lyon, France, to produce its patented skin, called Episkin, from incubated skin cells donated by surgery patients. The cells grow in a collagen culture before being exposed to air and UV light to mimic the effects of aging. Organovo pioneered the process of bioprinting human tissues, most notably creating a 3-D-printed liver system. Both parties benefit from the partnership: L’Oreal gets Organovo’s speed and expertise, and Organovo gets funding and access to L’Oreal’s comprehensive knowledge of skin, acquired through many years and over $1 billion in research and development.

At the moment, L’Oreal uses its epidermis samples to predict as closely as possible how human skin will react to the ingredients in its products. If L’Oreal can more quickly iterate on the molecular composition of its skin samples, it can produce more accurate results, conceivably across different skin phenotypes. That means products like sunscreen and age-defying serums—which inevitably will yield varying results across varying skin types—can be tweaked for greater efficacy.

L’Oreal also has a history of selling Episkin to other cosmetic and pharmacology companies. The company won’t disclose the going rate, but in 2011 toldBloomberg it sold half-centimeter-wide samples for €55 each (about $78 each at the time). That said, Guive Balooch, who runs L’Oreal’s in-house tech incubator, says the bioprinting will be done primarily for research purposes.

Organovo's Novogen MMX Bioprinter can print 3D samples of human tissue.
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Balooch approached Organovo after seeing its human liver model. While the two companies still need to settle on an exact plan for the skin samples, the bioprinting process for epidermis will be roughly similar to that of the liver. It happens in three steps, says Michael Renard, a VP at Organovo. Once scientists have collected the human cells from the various companies that harvest and sell them, they use a proprietary in-house technology to turn the cells into a “bio-ink” that feeds into the bioprinters. The actual manufacturing isn’t all that different from what you might see with a standard 3D printer.

“In concept, it’s the same idea of programming the 3-D printer to print architecture on an X-Y-Z axis,” he says, referring to the CAD designs that typically inform 3-D printers. “We just happened to use living human cells. There’s delicacy involved.” During the last step, the structure of cells is nourished (Renard won’t say how) and kept in a temperature-controlled environment so they can fuse into a cohesive mass of tissue.

There are still a bevy of unknowns, such as when Organovo will start production and just how much faster it will be compared to L’Oreal’s current derma-farming methods. Still, Renard says Organovo produces at  “a commercial scale,” so it stands to reason the same will go for skin. That’s a vague start, but these things—you know, the rapid manufacturing of human flesh—don’t happen overnight.