Good afternoon. Thank you for asking me to speak today. My name is JF and I’m a MRC-Sparks CRTF at the UCL ICH. I’m an ENT registrar and interested in conditions that affect the throat in particular the voice-box or larynx. We doing some exciting work at UCL that I’d like to share with you today including the use of regenerative medicine techniques to create new voice-boxes from scratch to help children that are born with devastating conditions that affect their airways and cause problems with breathing and swallowing and also adults that have equally devastating conditions including conditions such as cancer.

As surgeons there are several options available to us for laryngeal replacement. 1st is use of the patient’s own tissues, so called autologous transplantation but this is associated with poor functional outcomes and problems from the donor sites. The 2nd option i.e. the use of plastic materials to create a voice-box has been tried and is pretty unsuccessful and leads to unsatisfactory outcomes for patients. The 3rd option is essentially conventional organ transplantation in an analagous way to kidney or liver transplantation but as we’ve heard about today is associated with shortages in donor organs and requires lifelong immunosuppressive medication to prevent rejection with their associated risks / side-effects and toxicity. The 4th area is a new, exciting area where we are aiming to create new tissues and organs from scratch using a combination of scaffolds and stem cells that I’ll be discussing later.

There have only been 2 successful cases of laryngeal allotransplantation performed Worldwide in the U.S, the last one being last year in collaboration between us and Univ California Davis. The main reason for the low number of patients is several fold – there are issues around the ethics, namely shortages in organ donors and requirement to be on lifelong immunosuppressive medications for what, after all, is a QOL procedure. With kidneys, livers, hearts etc the decision is easy as they are often life and death decisions. Patients here on the other hand are in effect, exchanging an improved QOL for the need to be on lifelong immunosuppressive medications with their associated risks of infections and cancers which are not easy decisions and the indications for such procedures is not clear and which patients will make best candidates. In addition, we have to make sure the nerves re-wire in the correct fashion to enable the transplanted voice-box to function correctly once it is transplanted. Also there are careful cost-benefit analyses required especially in today’s NHS.

A working group has recently been set up at the RCS Eng to examine the case for laryngeal Tx in the UK. The committee was made up of leading UK surgeons in the field and they concluded that laryngeal Tx should be allowed to proceed in the UK. They felt the expected improvement in QOL was enough / sufficient to justify the procedure and outweighed the potential for risks in the right patient.

Old one taken out, plumbing of new vessels and nerves, windpipe and top, thyroid, parathyroids.

Perfect candidate for 2nd World’s laryngeal Tx as totally scarred up larynx and she was already on lifelong immunosuppressive therapy for a previous kidney/pancreas Tx.

These are her vocal cords 10 weeks following surgery and the operation was hailed as a major success and she has a remarkably good voice and good swallowing function. The vocal cords don’t separate completely and therefore she still has a breathing tube in her neck to help her to breathe but it is hoped that in time this will be removed.

This is Brenda Jensen at the press conference in Jan 2011. She said…and she is really pleased with the outcome of the surgery.

As I mentioned the vocal cords don’t separate as much as we would like them too and at UCL we are working at ways to enable the nerves and muscle of the larynx to grow more efficiently into the larynx which in turn will also help us in solving similar problems such as for the food-pipe / swallowing disorders. Several options are available to us including the use of other neighbouring nerves to assist in vocal cord movement, use of nerve growth factors …next slide… and there is a group in the USA using pacemakers within the larynx to electrically stimulate the laryngeal muscles to assist contraction of the muscles…

and there is a group in the USA using pacemakers within the larynx to electrically stimulate the muscles of the voice-box to assist in their contraction…

As I eluded to earlier regenerative medicine is an exciting area and something that we are actively involved with here at UCL. This allows us the opportunity to create new tissues and organs from scratch in the laboratory using a combination of stem cells seeded on to scaffold backbones; so-called off-the-shelf products. This has clear advantages of overcoming shortages in organ donors and because these organs are not rejected by the immune system, in the same way as conventional organs, they prevent the need/requirement for lifelong immunosuppresive medications. This is Tony Atala who is director of WFIRM which is also leading the way in regenerative medicine or engineering new organs in the laboratory. He’s a urologist so he is interested in replacing the bladders of patients and they have lots of success in replacing the bladders of children born with conditions that result in bladder defects.

Chris Mason is head of the UCL centre for Stem cells and Regenerative medicine and he has defined regen. Med as …

This is a tissue-engineered larynx that we have been working on in the laboratory in large animal models in collaboration between the Ear Institute, UCL ICH and the NPIMR and we hope to translate this to humans in the forthcoming years…

At the ICH and NPIMR we have been working on engineering intestine in the laboratory to help children that born with and adults that lose their intestine as a result of disease, so called short bowel syndrome which leads to the lack of absorption of nutrients and death. We have had success in small animals and it is hoped to apply this to humans in forthcoming years. From studying these organs, namely the larynx and intestine we hope to be able to apply the same technology to other patients including children born without diaphragms and children and adults that have problems with their food-pipes.

I would like to finish with a quote by Christopher Reeve who helped to set-up and fund the California Institute for Regen Med, another World leading centre in Regen Med. He died shortly before the project was fully up and running but he said before this… We’re probably at the “improbable” stage at this moment in time but we hope to be able to translate our laboratory successes to humans in the next few years taking us to the “inevitable” phase of our journey.

Laryngeal replacement : chasing the dream Jonathan Fishman BM BCh (Oxon), MA (Cantab), MRCS, DOHNS MRC-Sparks Clinical Research Fellow UCL INSTITUTE OF CHILD HEALTH 'Bringing the regenerative medicine, stem cell and tissue engineering community together'

How to replace a larynx/organ Autologous tissues Prosthetic materials Allografting Regenerative medicine replacement versus regeneration

Issues with laryngeal transplantation Ethical framework Indications Nerve supply Immunosuppression Cost-benefit

The committee’s view is that some patients may reasonably and autonomously decide that, in the context of their values and in spite of the statistical uncertainties, the potential benefits of LT outweigh the risks and burdens. In light of the potential medical benefits and the proportionate risks, the procedure is not contrary to clinical integrity. The committee concluded that it would be unacceptably paternalistic to assert that restoration of voice, improved deglutition and cosmesis, and the ability to laugh, cry, cough and kiss, were not sufficiently important to a patient’s overall well-being to justify a major surgical intervention and continued immunosuppression. Although some members of the committee observed that they would probably not choose LT for themselves, all agreed that it would be reasonable for some individuals with a different constellation and weighting of values to opt for LT and that, for these individuals, the procedure could constitute a net benefit. The committee concluded that it would be unacceptably paternalistic to assert that restoration of voice, improved deglutition and cosmesis, and the ability to laugh, cry, cough and kiss, were not sufficiently important

Transplantation

Brenda Longstanding diabetes, renal failure Kidney/ pancreas transplant 2006 Lifelong immunosuppression

10 week laryngoscopy

“I don’t know what the future may bring, but it sure will be better than what we’ve left behind” Brenda Jensen, January 20th, 2011

Means of reanimating the larynx Selective reinnervation Neurotrophins Electrical stimulation

Laryngeal Pacing

Regenerative Medicine Cells Stem cells Gene therapy Biomaterials Nanotechnology “The use of cells and tissues to restore or replace function” Mason, 2009

So many of our dreams at first seem impossible, then they seem improbable, and then, when we summon the will, they soon become inevitable. Christopher Reeve In the final days of his life, Reeve urged California voters to vote yes on Proposition 71,[78] which would establish the California Institute for Regenerative Medicine, and allot $3 billion of state funds to stem cell research.[79]Proposition 71 was approved less than one month after Reeve's death.