A team of scientists at Massachusetts General Hospital in Boston have taken the first steps toward developing “bioartificial” replacement limbs that are suitable for human transplantation, according to a new report published in the journal Biomaterials.
The development could have life-changing implications for the more than 1.5 million Americans who have lost a limb. While prosthetic limb technology has greatly advanced in recent years, the devices still have many limitations in both function and appearance.
Human hand transplantation has been performed numerous times over the past 20 years, with great potential to improve patients’ quality of life. However, this procedure comes attached with lifelong risks from immunosuppressive therapy.
This problem could be solved by using the patient’s own progenitor cells to regenerate the tissue for a new limb — rather than rely on a donor — but an appropriate matrix or scaffold has yet to be devised on which scientists would be able to grow the new tissue.
“The composite nature of our limbs makes building a functional biological replacement particularly challenging,” said senior investigator Dr. Harald Ott, of the Massachusetts General Hospital Department of Surgery and the Center for Regenerative Medicine. He explains:
“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.”
In animal models, Dr. Ott and colleagues have previously been able to regenerate kidneys, livers, hearts and lungs, using a detergent solution to strip living cells from the donor organ, which is then repopulated with appropriate progenitor cells. However, this latest study represents the first use of this technique to regenerate the more complex tissues of a bioartificial limb.
Using the limb of a deceased rat, the researchers applied the detergent solution to strip away the cellular materials from the limbs while still preserving the vascular structure and nerve matrix, a process that took about a week. This remaining material provided a structure for all of the composite tissues required by the limb.
The team then injected cells cultured for the muscles and vascular system, and, after five days, used electrical stimulation to promote muscle formation. When tested, the regenerated muscle tissue had the strength of 80 percent of what would be seen in newborn animals.
In the final step, the scientists transplanted the workable limb with new tissue onto a live recipient rat. Once the forelimb was transplanted, blood quickly began to circulate in the new limb, and when the muscles within the graft were stimulated electrically, the wrists and digital joints of the rats’ paws flexed appropriately.
The researchers will have to see if they can reintegrate transplanted limbs into a recipient’s nervous system, but studies have shown that in patients with transplanted limbs, nerves do grow back into the graft to allow for both motion and sensation. “We hope in future work to show that the same will apply to bioartificial grafts,” said Dr. Ott.
The team has already successfully repeated the decellularization process on baboon forearms, demonstrating the feasibility of using the technique on a scale similar to human patients. Next, they will attempt muscle regeneration using human cells, before expanding the process to human bone, cartilage and connective tissue.