INNOVATION ARTICLES THE IDEA SUBMISSION PORTAL FROM MEDTRONIC


Dr Nathan Welham

Voice restoration

Dr Nathan Welham

Marie Gethins
May 2016

Physician and poet Oliver Wendell Holmes once said, “Speak clearly, if you speak at all; carve every word before you let it fall.” Sadly, for patients with damaged vocal folds their ability to communicate is severely restricted with limited treatment options available. This may change in the future with researchers successfully growing bioengineered replacement vocal tissue, helping people regain their voices and ability to effectively communicate.

By forcing air over vocal folds, that reside in the larynx, humans create speech. These vocal folds generate sound waves through vibration several hundred times per second. A soprano signing at a high pitch may be a thousand time per second. Therefore, the tissue must be quite pliable in order to create the variety of sounds speech entails, but also tough enough to deal with impact stretches and strains. Scarring, due to surgery or disease, can stiffen the area, causing significant problems in communication. There are more than 157,000 new cases of laryngeal cancer annually worldwide, with almost 40,000 in Europe alone. In ability to communicate can affect income, job satisfaction, social interaction and induce stress and depression.

Recently a cross-functional team successfully recreated vocal fold tissue. Researcher Dr Nathan Welham from the University of Wisconsin School of Medicine and Public Health explained initially the team sought to find a benchmark, “The thinking behind this project was that if we use the tissues from people we can recreate a tissue that has a good function and may be in doing so we will learn enough about the target phenotype.”

Using cells from four human donors and one cadaver, the cells were grown in the lab and then transferred to a collagen scaffold. Two weeks later, the team ran a variety of tests and were surprised that the bioengineered tissue vibrated and sounded similar to natural tissue. A flexible lower layer had formed with an upper covering of epithelial cells. Many of the same proteins also were found, and a protective membrane was forming that in natural tissue provides a barrier against irritants and pathogens. Welham said, “It actually felt like real tissue.”


THE RESULTS WERE REALLY EXQUISITE, MUCH BETTER THAN WE THOUGHT


Next the researchers tested the bioengineered tissue's ability to transmit sound by transplanting the tissue onto canine cadaver larynges. Results were again very promising with high-speed imaging showing that the created material vibrated in a similar way to natural vocal folds. “The results were really exquisite, much better than we thought,” Welham said. Then the team tested the tissue in living mice that have been engineered to have human immune systems. To test for Host versus graft disease, at 21-days post graft, one group had autologous human lymphocytes introduced, another autogenic human lymphocytes, which set-up the adaptive immune system in the mouse. Another graft group did not have human lymphocytes introduced, the challenge coming from the mouse's innate immune system. “Also, to our surprise, they were well tolerated, he said.

One question remaining is that bioengineered vocal fold tissue has a much less complex fibre structure than natural adult tissue, which develops through speech from birth until past puberty. Welham explained, “Ideally we think that they would develop, but the reason that we think that human vocal fold has the structure it has in adults and changes the way it does throughout puberty is related in some part due to hormonal factors but mostly due to this mechanical environment that it is in. What's encouraging is that the kind of testing that we did showed a pretty good voice function regardless of the structure being somewhat immature. I think there's potential there.”

Although it is early days in the research, Welham predicts that scalability will not be an issue with likely more than 170 bioengineered vocal fold sets of various sizes being created from the five human sets. He said, “If patients are screened appropriately we can bank and expand the cells. The thing that works in our favour is that unlike [the usual] one-to-one donor situation, we are not transplanting vocal folds, we are harvesting the cells and then expanding them significantly. It just requires the right set-up and making the larynx part of the organ donation picture.”

On possible indications, Welham agrees that cancer, particularly where larger tumours have affected the vocal folds or the patient has suffered radiation damage is a large area. He also said that patients with human papilloma virus in the larynx and has ravaged the tissue could be candidates because it is difficult to eradicate. Patients with this problem may have 40 to 60 surgeries which result in a lot of scar tissue. However, as the therapy is not restoring nerve function, nerve tissue damage is not an indication.

Next steps for the team are additional pre-clinical trials for long term safety, as well as practical considerations in transitioning this therapy in screening, banking, and manufacturing.

Dr Welham stressed that this exciting innovation could not come about without the merging of several disciplines. “Many research projects that capture the headlines in medical journals do involve an amazing mismatch of people and expertise - a perfect storm of talent. It must involve a combination of different disciplines, not working in isolation. Having the right partners in order to piece the thing together and understand it is important. A big team really makes a big difference.”


References

1Interview with Professor Nathan Welham

2Laryngeal (larynx) cancer incidence statistics (2014), Available here: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/laryngeal-cancer/incidence#heading-Four

3Bioengineered vocal fold mucosa for voice restoration (2015), Available here: http://stm.sciencemag.org/content/7/314/314ra187

4Bioengineering the Vocal Fold: A Review of Mesenchymal Stem Cell Applications (2011), Available here: http://cdn.intechopen.com/pdfs/15692.pdf

5Functional vocal cord tissue grown in lab (2015), Available here: https://www.sciencedaily.com/releases/2015/11/151118180459.htm

6Scientists grow working vocal cord tissue in the lab (2015), Available her: http://www.sciencemag.org/news/2015/11/scientists-grow-working-vocal-cord-tissue-lab