Artificial organs look likely to
play an increasingly important role in transplantation.
Fully Functioning Artificial Human Heart Muscle Developed
The final key that brought this discovery together was rocking the samples to bathe and splash them, improving nutrient delivery. [Duke University]
Duke University researchers say they have created an artificial human
heart muscle large enough to patch over damage seen in patients who have
suffered a heart attack. The advance takes a major step toward the end
goal of repairing dead heart muscle in human patients, the team adds.
The study (“Cardiopatch Platform Enables Maturation and Scale-Up of Human Pluripotent Stem Cell-Derived Engineered Heart Tissues”) appears online in Nature Communications.
“Despite increased use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for drug development and disease modeling studies, methods to generate large, functional heart tissues for human therapy are lacking. Here we present a “Cardiopatch” platform for 3D culture and maturation of hiPSC-CMs that after 5 weeks of differentiation show robust electromechanical coupling, consistent H-zones, I-bands, and evidence for T-tubules and M-bands. Cardiopatch maturation markers and functional output increase during culture, approaching values of adult myocardium,” write the investigators.
“Cardiopatches can be scaled up to clinically relevant dimensions, while preserving spatially uniform properties with high conduction velocities and contractile stresses. Within window chambers in nude mice, cardiopatches undergo vascularization by host vessels and continue to fire Ca2+ transients. When implanted onto rat hearts, cardiopatches robustly engraft, maintain pre-implantation electrical function, and do not increase the incidence of arrhythmias. These studies provide enabling technology for future use of hiPSC-CM tissues in human heart repair.”
“Despite increased use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for drug development and disease modeling studies, methods to generate large, functional heart tissues for human therapy are lacking. Here we present a “Cardiopatch” platform for 3D culture and maturation of hiPSC-CMs that after 5 weeks of differentiation show robust electromechanical coupling, consistent H-zones, I-bands, and evidence for T-tubules and M-bands. Cardiopatch maturation markers and functional output increase during culture, approaching values of adult myocardium,” write the investigators.
“Cardiopatches can be scaled up to clinically relevant dimensions, while preserving spatially uniform properties with high conduction velocities and contractile stresses. Within window chambers in nude mice, cardiopatches undergo vascularization by host vessels and continue to fire Ca2+ transients. When implanted onto rat hearts, cardiopatches robustly engraft, maintain pre-implantation electrical function, and do not increase the incidence of arrhythmias. These studies provide enabling technology for future use of hiPSC-CM tissues in human heart repair.”
Duke engineers have engineered a heart patch large enough to cover most
damage caused by heart attacks. These videos show the patch contracting
on its own, a 3D visualization the patch's cells, and the rocking bath
that proved critical to the heart patch's record-breaking size. [Nenad
Bursac/Duke University]
"Right now, virtually all existing therapies are aimed at reducing the
symptoms from the damage that's already been done to the heart, but no
approaches have been able to replace the muscle that's lost, because
once it's dead, it does not grow back on its own," said Ilya Shadrin, a
biomedical engineering doctoral student at Duke University and first
author on the study. "This is a way that we could replace lost muscle
with tissue made outside the body."
Unlike some human organs, the heart cannot regenerate itself after a heart attack. The dead muscle is often replaced by scar tissue that can no longer transmit electrical signals or contract, both of which are necessary for smooth and forceful heartbeats.
New therapies, such as the one being developed by Shadrin and his advisor Nenad Bursac, Ph.D., professor of biomedical engineering at Duke, are needed to prevent heart failure and its lethal complications.
Current clinical trials are testing injection of stem cells derived from bone marrow, blood, or the heart itself directly into the affected site in an attempt to replenish some of the damaged muscle. While there do seem to be some positive effects from these treatments, their mechanisms are not fully understood. Fewer than 1% of the injected cells survive and remain in the heart, and even fewer become cardiac muscle cells.
Heart patches, on the other hand, could conceivably be implanted over the dead muscle and remain active for a long time, providing more strength for contractions and a smooth path for the heart's electrical signals to travel through, notes Shadrin. These patches also secrete enzymes and growth factors that could help recovery of damaged tissue that hasn't yet died.
For this approach to work, however, a heart patch must be large enough to cover the affected tissue. It must also be just as strong and electrically active as the native heart tissue, or else the discrepancy could cause deadly arrhythmias.
This is the first human heart patch to meet both criteria, says Dr. Bursac. "Creating individual cardiac muscle cells is pretty commonplace, but people have been focused on growing miniature tissues for drug development," he explains. "Scaling it up to this size is something that has never been done and it required a lot of engineering ingenuity."
The cells for the heart patch are grown from human pluripotent stem cells. Dr. Bursac and Shadrin have successfully made patches using many different lines of human stem cells, including those derived from embryos and those artificially forced, or "induced," into their pluripotent state.
Various types of heart cells can be grown from these stem cells: cardiomyocytes, fibroblasts, and endothelial and smooth muscle cells. The researchers place these cells at specific ratios into a jelly-like substance where they self-organize and grow into functioning tissue.
"It turns out that rocking the samples to bathe and splash them to improve nutrient delivery is extremely important," said Shadrin. "We obtained three to five times better results with the rocking cultures compared to our static samples."
The results improved on the researchers' previous patches, which were 1 cm2 and 4 cm2. They successfully scaled up to 16 cm2 and five to eight cells thick. Tests show that the heart muscle in the patch is fully functional, with electrical, mechanical, and structural properties that resemble those of a normal, healthy adult heart.
"This is extremely difficult to do, as the larger the tissue that is grown, the harder it is to maintain the same properties throughout it," said Dr. Bursac. "Equally challenging has been making the tissues mature to adult strength on a fast timescale of five weeks while achieving properties that typically take years of normal human development."
Dr. Bursac and Shadrin have already shown that these cardiac patches survive, become vascularized, and maintain their function when implanted onto mouse and rat hearts. For a heart patch to ever actually replace the work of dead cardiac muscle in human patients, however, it would need to be much thicker than the tissue grown in this study. And for patches to be grown that thick, they need to be vascularized so that cells on the interior can receive enough oxygen and nutrients. Even then, researchers would have to figure out how to fully integrate the heart patch with the existing muscle.
"Full integration like that is really important, not just to improve the heart's mechanical pumping, but to ensure the smooth spread of electrical waves and minimize the risk of arrhythmias," said Shadrin.
"We are actively working on that, as are others, but for now, we are thrilled to have the 'size matters' part figured out," added Bursac.
Unlike some human organs, the heart cannot regenerate itself after a heart attack. The dead muscle is often replaced by scar tissue that can no longer transmit electrical signals or contract, both of which are necessary for smooth and forceful heartbeats.
New therapies, such as the one being developed by Shadrin and his advisor Nenad Bursac, Ph.D., professor of biomedical engineering at Duke, are needed to prevent heart failure and its lethal complications.
Current clinical trials are testing injection of stem cells derived from bone marrow, blood, or the heart itself directly into the affected site in an attempt to replenish some of the damaged muscle. While there do seem to be some positive effects from these treatments, their mechanisms are not fully understood. Fewer than 1% of the injected cells survive and remain in the heart, and even fewer become cardiac muscle cells.
Heart patches, on the other hand, could conceivably be implanted over the dead muscle and remain active for a long time, providing more strength for contractions and a smooth path for the heart's electrical signals to travel through, notes Shadrin. These patches also secrete enzymes and growth factors that could help recovery of damaged tissue that hasn't yet died.
For this approach to work, however, a heart patch must be large enough to cover the affected tissue. It must also be just as strong and electrically active as the native heart tissue, or else the discrepancy could cause deadly arrhythmias.
This is the first human heart patch to meet both criteria, says Dr. Bursac. "Creating individual cardiac muscle cells is pretty commonplace, but people have been focused on growing miniature tissues for drug development," he explains. "Scaling it up to this size is something that has never been done and it required a lot of engineering ingenuity."
The cells for the heart patch are grown from human pluripotent stem cells. Dr. Bursac and Shadrin have successfully made patches using many different lines of human stem cells, including those derived from embryos and those artificially forced, or "induced," into their pluripotent state.
Various types of heart cells can be grown from these stem cells: cardiomyocytes, fibroblasts, and endothelial and smooth muscle cells. The researchers place these cells at specific ratios into a jelly-like substance where they self-organize and grow into functioning tissue.
"It turns out that rocking the samples to bathe and splash them to improve nutrient delivery is extremely important," said Shadrin. "We obtained three to five times better results with the rocking cultures compared to our static samples."
The results improved on the researchers' previous patches, which were 1 cm2 and 4 cm2. They successfully scaled up to 16 cm2 and five to eight cells thick. Tests show that the heart muscle in the patch is fully functional, with electrical, mechanical, and structural properties that resemble those of a normal, healthy adult heart.
"This is extremely difficult to do, as the larger the tissue that is grown, the harder it is to maintain the same properties throughout it," said Dr. Bursac. "Equally challenging has been making the tissues mature to adult strength on a fast timescale of five weeks while achieving properties that typically take years of normal human development."
Dr. Bursac and Shadrin have already shown that these cardiac patches survive, become vascularized, and maintain their function when implanted onto mouse and rat hearts. For a heart patch to ever actually replace the work of dead cardiac muscle in human patients, however, it would need to be much thicker than the tissue grown in this study. And for patches to be grown that thick, they need to be vascularized so that cells on the interior can receive enough oxygen and nutrients. Even then, researchers would have to figure out how to fully integrate the heart patch with the existing muscle.
"Full integration like that is really important, not just to improve the heart's mechanical pumping, but to ensure the smooth spread of electrical waves and minimize the risk of arrhythmias," said Shadrin.
"We are actively working on that, as are others, but for now, we are thrilled to have the 'size matters' part figured out," added Bursac.
South African surgeon Christiaan Barnard
announced that he had successfully performed the first human-to-human
heart transplant in the early hours of December 3, 1967.
The pioneering operation, compared to the first Moon landing in its significance for humankind, was performed at Groote Schuur Hospital in Cape Town and saw Barnard take the heart of 25-year-old Denise Darvall, who was left brain-dead after being hit by a car, and transplant it to 53-year-old Louis Washkansky.
Fifty years on, how has medicine evolved and what is the future of this life-saving procedure?
These figures reflect "the tip of the iceberg," according to the European Commission and "reflect an impressive reality even if they cover data from various transplant systems with different national policies and as well as evolving dynamics".
The management of waiting lists is a national competence in the EU, as is whether member states wish to adopt an "opt-in" consent process (where citizens choose to go on a donor list) or an "opt-out" system (organ donation is the default option at the time of death).
In the UK for example, where there is currently an opt-in process, the waiting list for heart transplants has nearly trebled in ten years, according to charity the British Heart Foundation.
The risk of rejection is still present, but Magdi Yacoub, professor of heart surgery at Imperial College London, believes advances in preventing rejection are on the horizon.
Bezuidenhout believes co-operation and input are required from governments, NGOs, academia, business, policymakers and healthcare workers themselves to provide cardiovascular care in areas that need it.
"It’s not acceptable that in the US you have one cardiac centre for every 120 000 people, while in Mozambique two cardiac centres service 27 million people and are situated two kilometres apart," added Heather Coombes, CEO of University of Cape Town start-up company Strait Access Technologies.
Now retired from John Radcliffe Hospital in Oxford, Westaby developed artificial heart pumps for almost a decade and believes that, when combined with stem-cell injections to regenerate diseased heart muscle, this method could provide a new alternative to transplants with fewer risks.
The double procedure has already been used on a terminally-ill, 52-year-old man in northern Greece who is alive six years on.
“Heart transplants are terrific but a mechanical heart pump along with stem cells is the way forward and I’m confident that within a few years we will see more people being fitted with these pumps than those having transplants,” said Westaby.
On the other hand, some of his peers disagree, arguing that "biology is best".
"Entirely mechanical hearts will never be a replacement (for human ones),” said Magdi Yacoub.
He did, however, acknowledge the limitations of human-to-human transplants: "The challenges include scarcity of donor organs, inefficiency and complications of currently available immune-suppressing drugs, resulting in complications such as infection, risk of cancer and chronic renal failure. The good news is none of these challenges is insuperable."
Transplantation to treat organ failure has
progressed significantly over recent decades. While early surgeries had
very poor survival times, with patients often extending their lives by
only a few days or weeks, medical advances since the 1960s mean that
organ transplantation has become a viable way of treating patients with
organ failure.
Where are we now?
As at the end of September 2016, 6,599 patient were on the NHS organ transplant waiting list. For those lucky enough to receive an organ, the survival times are the highest they have ever been. For operations taking place between 2008 and 2010, the five-year survival rates were 90% for kidney, 71% for heart and 82% for liver transplants – much higher than the figures 15 years earlier, at 69%, 63% and 64% respectively.
However, the existence of a waiting list is a worry for many patients with end-stage organ failure. In 2015, 479 patients died while waiting for a transplant. Why does this waiting list exist?
Put simply, the waiting list exists because the demand for organs outstrips the supply. The demand for organs follows organ failure brought about by disease, genetic disorders, lifestyle habits, accidents and senescence (the ageing process that leads to deterioration of organs). The physical supply could come from human donors, xenotransplantation (using tissue from animals) or artificial organs. The national stance on organ donation consent also affects the supply, as could the overall NHS budget in the UK.
Which organs are in demand?
The vast majority of patients on UK waiting lists require kidney transplants, with fewer people requiring liver, lung and heart transplants.
Disease and lifestyle habits are the underlying cause of this demand. For example, patients could require a kidney transplant as a result of diabetes, an infection or prolonged high blood pressure leading to kidney failure. Alcohol misuse could lead to the need for a liver transplant, and damage caused by smoking or cystic fibrosis would mean someone requires replacement lungs.
The demand for organs is likely to rise in the future. While the demand for organs as a result of accidents (for example, from poisoning or physical trauma) is low, ageing of the population is likely to increase the demand.
Furthermore, even with lower rates of smoking, urban air pollution and migration to cities are a concern as they increase rates of chronic obstructive pulmonary disease.
Obesity trends are also likely to lead to future rises in demand for organs, in particular for kidneys and hearts.
A closer look at organ supply
Around 4,600 organ transplants were carried out from April 2015 to March 2016 in the UK, arising from around 2,400 human donors (one donor can save up to eight lives). The majority of these organs – 77% – came from deceased donors, with the remainder, in particular liver and kidney transplants, coming from living donors.
Human donors
The key challenge lies in matching organs to patients, by tissue, blood type and other medical criteria, to decrease the chance of organ rejection. The patient’s immune system is suppressed to reduce the risk of organ rejection. However, a weakened immune system increases the risk of viral and bacterial infection, so a careful balance is required in terms of immunosuppressant medication.
Xenotransplantation
Transplanting heart valves from pigs is a common procedure. Here, the pig cells are chemically stripped before human cells grow around them after they are implanted.
However, there are known issues with transplanting whole organs, namely the rejection of animal tissue, potential infection from animal viruses and whether they could function in a human body.
Recent advances in gene editing technology have renewed the interest in xenotransplantation; for example, there have been initial attempts to grow human organs in animals such as pigs.
Artificial organs
The artificial organ market is expected to grow by 9.1% compound per annum from 2017 to 2022 from $26.8bn (£20.3bn) in 2016 to $45.2bn (£34.2bn) by 2022, according to a study by Zion Market Research. Given they would mean a lower risk of organ rejection and that organs could be mass produced to meet demand, it is a very promising industry that could address the shortage of organs.
Artificial hearts in the US are currently used as a stopgap before patients receive a biological organ; patients are provided with a fully functioning artificial heart. One patient was supported for nearly four years with an artificial heart before receiving a successful human heart transplant.
Human trials of artificial kidneys to tackle end-stage renal disease are about to begin. Another promising area of experimental research is 3D bioprinting technology, which could be used to create replica organs for transplant into humans.
Considerations for the insurance industry
Major organ transplant (MOT) is a listed condition under a typical critical illness (CI) product. In 2014, the Association of British Insurers amended the MOT definition in its Statement of Best Practice to include the qualification ‘from another person’.
In the short term – say, over the next five years – we anticipate a limited impact on the CI product. An insured life requiring an organ transplant would be placed on the waiting list. This in itself would be a trigger the CI claim under the existing definition. Thus, it does not matter whether the transplanted organ comes from a human donor, an animal or an artificial source or, indeed, if the operation happens at all.
The key benefits of artificial organs are that they open up the possibility of mass production and patients are less likely to experience organ rejection. Depending on technological progress and capacity in the NHS, transplant waiting lists could significantly be reduced or even disappear.
Without the waiting list, it will start to matter much more whether a policyholder receives an organ from a human donor or an artificial source. There may be a period of uncertainty here, where the industry questions whether artificial organ transplants warrant a partial or full sum assured payment. However, with much lower rejection risks, the conclusion may be that artificial transplants are not as life threatening as human donor transplants.
Another potential grey area for a valid payment is if the transplanted organ was a bio-artificial organ or if it were grown in a laboratory using human cells. Would payment still be declined because the organ did not originate from a human donor?
If we assume that we use only artificial organs for transplants, the current CI definition would lead us to having zero incidence rates, assuming we stick firmly to this definition. Realistically, even with zero incidence rates for a typical CI product, the overall price would reduce by only about 1% (assuming the demand for organs remain fairly stable), since the magnitude of these rates is small compared to heart attack, stroke and cancer.
In the long term – 25 years or more – we could eventually get to a stage where complex organ transplant procedures became routine with little risk of organ rejection. Furthermore, transplants could be carried out while patients are still relatively healthy.
The potential for moral hazard risk is something to consider in the future; people may have less of an incentive to look after their health if they are ‘protected’ from the consequences of organ failure.
Using artificial organs could reduce the incidence rates of CI conditions; for example, a person diagnosed with a localised cancer where the severity is not high enough for a claim payment could have the affected organ replaced, thus avoiding a future claim payment. Similarly, those at risk of heart attacks as a result of problems with the organ itself could get an artificial heart. This argument still holds if xenotransplantation becomes the solution for the organ shortage, although whether its disadvantages could be overcome remains to be seen.
Term and longevity products
For term products, carrying out an artificial organ transplant means that we have effectively delayed the death of a policyholder from organ failure. The SynCardia artificial heart transplant patient who survived for nearly four years before a human heart transplant is a good example of this.
However, the extent of such improvements on mortality would be small as they would be restricted to the minority of policyholders who required an organ transplant in the first place.
In the longer term, we may start to see further improvements in mortality rates; people with organ failure from cardiovascular diseases or cancer could get their organs replaced and deaths delayed. Therefore, the overall cost for term assurance could decrease. The opposite is true for annuities, with mortality improvements leading to higher costs as people delay their death from organ failure. The overall impact will depend on the speed at which the technology is incorporated into mainstream medicine; there is often a high degree of uncertainty in projecting medical advances.
Conclusion
While recent advances in organ transplant technology have led to improved survival times, the current reliance on human donors restricts the overall supply and means there is a waiting list. Artificial organs could be a way to eliminate the waiting list in the future.
The use of artificial organs is unlikely to affect CI products in the short term and give a very small improvement in mortality trends. In the long run, artificial organ transplants could become a cost-effective way of treating multiple diseases; someone with cardiovascular disease or localised cancer could have the affected organ replaced, potentially reducing the effects of heart attack and cancers on CI business. The impact on term assurance policies could be significant; if we can delay the deaths of several lives by 5-10 years, we could see a wave of mortality improvements.
Validating and quantifying these scenarios would require a lot of assumptions about the future and could take considerable time. You would have to look at other medical advances and their respective costs – for example, immunotherapy could be more cost effective at treating or preventing diseases than organ transplant. However, on the demand side, you could argue that the need for artificial organs is as high as ever, considering the rising obesity levels and the ageing population.
The pioneering operation, compared to the first Moon landing in its significance for humankind, was performed at Groote Schuur Hospital in Cape Town and saw Barnard take the heart of 25-year-old Denise Darvall, who was left brain-dead after being hit by a car, and transplant it to 53-year-old Louis Washkansky.
Fifty years on, how has medicine evolved and what is the future of this life-saving procedure?
Donor lists remain long
A total of over 63,000 patients were on organs' waiting lists on 31 December 2013 in the European Union, 3,450 of which were waiting for a new heart.These figures reflect "the tip of the iceberg," according to the European Commission and "reflect an impressive reality even if they cover data from various transplant systems with different national policies and as well as evolving dynamics".
The management of waiting lists is a national competence in the EU, as is whether member states wish to adopt an "opt-in" consent process (where citizens choose to go on a donor list) or an "opt-out" system (organ donation is the default option at the time of death).
In the UK for example, where there is currently an opt-in process, the waiting list for heart transplants has nearly trebled in ten years, according to charity the British Heart Foundation.
Rejection of transplants
In the 60s, Washkansky was given strong anti-rejection drugs to suppress his immune system and keep his body from rejecting the heart. He lived for 18 days with a functioning heart until he died of pneumonia.Since then, anti-rejection drugs have been developed making transplantation more viable.The risk of rejection is still present, but Magdi Yacoub, professor of heart surgery at Imperial College London, believes advances in preventing rejection are on the horizon.
Access to the procedure still limited in much of the world
At a conference in tribute to the first heart transplant, Professor Bezuidenhout from the University of Cape Town’s cardiovascular research unit said there needed to be solutions for the millions of people who are not benefiting from cardiac surgery due to access and financial issues.Bezuidenhout believes co-operation and input are required from governments, NGOs, academia, business, policymakers and healthcare workers themselves to provide cardiovascular care in areas that need it.
"It’s not acceptable that in the US you have one cardiac centre for every 120 000 people, while in Mozambique two cardiac centres service 27 million people and are situated two kilometres apart," added Heather Coombes, CEO of University of Cape Town start-up company Strait Access Technologies.
Transplants: soon a thing of the past?
With the above issues still proving major challenges to medical staff 50 years on, some experts, such as internationally renowned heart surgeon Professor Stephen Westaby, believe human-to-human heart transplants may become "almost irrelevant".Now retired from John Radcliffe Hospital in Oxford, Westaby developed artificial heart pumps for almost a decade and believes that, when combined with stem-cell injections to regenerate diseased heart muscle, this method could provide a new alternative to transplants with fewer risks.
The double procedure has already been used on a terminally-ill, 52-year-old man in northern Greece who is alive six years on.
“Heart transplants are terrific but a mechanical heart pump along with stem cells is the way forward and I’m confident that within a few years we will see more people being fitted with these pumps than those having transplants,” said Westaby.
On the other hand, some of his peers disagree, arguing that "biology is best".
"Entirely mechanical hearts will never be a replacement (for human ones),” said Magdi Yacoub.
He did, however, acknowledge the limitations of human-to-human transplants: "The challenges include scarcity of donor organs, inefficiency and complications of currently available immune-suppressing drugs, resulting in complications such as infection, risk of cancer and chronic renal failure. The good news is none of these challenges is insuperable."
Implantable Artificial Kidney Moves Closer to Reality
Scientists
are developing an artificial kidney that can replicate the work of the
real organs and potentially eliminate the need for dialysis.
12345
Researchers
at the University of California, San Francisco (UCSF), are developing
an implantable artificial kidney that can closely replicate the
functions of real kidneys.
If they are successful, the scientists’ work could help eliminate the need for dialysis.
Kidney transplants for patients with end-stage renal disease (ESRD) have a high rate of success.
About 93 percent of transplanted kidneys are still working after a year and 83 percent are functioning after three years.
But while more than 25,000 kidneys are transplanted each year, as of early 2016, more than 100,000 people were on the transplant waiting list in the United States.
Patients commonly wait five to 10 years for a suitable organ to become available.
Average life expectancy for dialysis patients is five to 10 years, although some have lived for decades.
However,
dialysis — which filters out some (but not all) toxins from the
bloodstream that would normally be eliminated by the kidneys — must be
performed on a daily basis if done at home via peritoneal dialysis.
It requires three visits to a clinic weekly if performed via hemodialysis.
“The implantable bioartificial kidney is an alternative to dialysis and other externally wearable devices that would tether patients or limit their mobility,” Shuvo Roy, a professor in the UCSF Department of Bioengineering and Therapeutic Sciences and co-inventor of the device, told Healthline. “A live kidney transplant from a matching donor is still considered one of the best treatment options for ESRD, but unfortunately, there is shortage of organ donors that prevents transplants from being available to the vast majority of ESRD patients. Unlike transplants, our device will not require that patients be on immunosuppressive drugs to prevent rejection.”
Human trials of the device are about to begin.
Roy
said the bioartificial kidney could eventually be used by the vast
majority of the people now on dialysis and the kidney transplant list.
“This is a long-term solution, and any case where a kidney transplant is needed, our device will be a viable option,” said Roy.
Powered by the body’s own blood pressure, the device does not require the external tubes or tethers associated with wearable artificial kidneys, such as that invented by Victor Gura of Cedars-Sinai Medical Center in Los Angeles. That device was tested on seven dialysis patients at the University of Washington Medical Center in Seattle in 2015.
The two-part implanted artificial kidney incorporates recent developments in silicon nanotechnology, which makes it possible to mass-produce reliable, robust, and compact filtering membranes.
The technology also has novel molecular coatings that protect the silicon membranes and make them blood-compatible.
“A hemofilter module processes incoming blood to create a watery ultrafiltrate that contains dissolved toxins as well as sugars and salts,” explained Roy. “Second, a bioreactor of kidney cells processes the ultrafiltrate and sends the sugars and salts back into the blood. In the process, water is also reabsorbed back into the body, concentrating the ultrafiltrate into ‘urine,’ which will be directed to the bladder for excretion.”
Patients with the implant may still be required to take hormonal supplements, however, as they currently do on dialysis, said Roy.
Development of alternatives to current treatments for kidney disease is “very important, since the outcomes of premature mortality and poor quality of life are common for the dialysis population, particularly for in-center hemodialysis,” Dr. Joseph Vassalotti, chief medical officer for the National Kidney Foundation, told Healthline.
Initial clinical trials on the individual modules are expected to begin early next year.
Testing of a working prototype of the bioartificial kidney is slated for 2020.
“The long-term challenges center around keeping the device operating trouble-free after implantation beyond a few months,” said Roy. “Some problems won’t become clear until we do clinical trials.”
In addition to $6 million in government grants, the Kidney Project has received substantial donations from individuals in furtherance of its work to create an implantable artificial kidney.
“Their support is a testament to the acute need for a revolution in ESRD treatment, and the donations we have received are invaluable in allowing our research to progress,” said Roy.
In the future, scientists may be able to grow artificial kidneys.
In 2013, researchers, led by Melissa Little of the University of Queensland's Institute for Molecular Bioscience, were able to grow a primitive kidney from human stem cells.
In 2016, researchers from the Salk Institute in California reported that they were able to grow nephron progenitor cells, which can differentiate into kidney tissue, in the lab.
Such research continues, but the ability to grow replacement organs remains a more distant dream than an implantable artificial kidney.
If they are successful, the scientists’ work could help eliminate the need for dialysis.
Kidney transplants for patients with end-stage renal disease (ESRD) have a high rate of success.
“The implantable bioartificial kidney is an alternative to dialysis and other externally wearable devices that would tether patients or limit their mobility,” Shuvo Roy, a professor in the UCSF Department of Bioengineering and Therapeutic Sciences and co-inventor of the device, told Healthline. “A live kidney transplant from a matching donor is still considered one of the best treatment options for ESRD, but unfortunately, there is shortage of organ donors that prevents transplants from being available to the vast majority of ESRD patients. Unlike transplants, our device will not require that patients be on immunosuppressive drugs to prevent rejection.”
Human trials of the device are about to begin.
“This is a long-term solution, and any case where a kidney transplant is needed, our device will be a viable option,” said Roy.
How the device works
Roy leads The Kidney Project, a national research initiative centered on development and testing of a surgically implanted, freestanding bioartificial kidney that performs "the vast majority of the filtration, balancing, and other biological functions of the natural kidney.”Powered by the body’s own blood pressure, the device does not require the external tubes or tethers associated with wearable artificial kidneys, such as that invented by Victor Gura of Cedars-Sinai Medical Center in Los Angeles. That device was tested on seven dialysis patients at the University of Washington Medical Center in Seattle in 2015.
The two-part implanted artificial kidney incorporates recent developments in silicon nanotechnology, which makes it possible to mass-produce reliable, robust, and compact filtering membranes.
The technology also has novel molecular coatings that protect the silicon membranes and make them blood-compatible.
“A hemofilter module processes incoming blood to create a watery ultrafiltrate that contains dissolved toxins as well as sugars and salts,” explained Roy. “Second, a bioreactor of kidney cells processes the ultrafiltrate and sends the sugars and salts back into the blood. In the process, water is also reabsorbed back into the body, concentrating the ultrafiltrate into ‘urine,’ which will be directed to the bladder for excretion.”
Patients with the implant may still be required to take hormonal supplements, however, as they currently do on dialysis, said Roy.
Development of alternatives to current treatments for kidney disease is “very important, since the outcomes of premature mortality and poor quality of life are common for the dialysis population, particularly for in-center hemodialysis,” Dr. Joseph Vassalotti, chief medical officer for the National Kidney Foundation, told Healthline.
The steps ahead
The Kidney Project is raising money to complete preclinical studies of the device modules and to build full-scale prototypes for the first round of human studies.Initial clinical trials on the individual modules are expected to begin early next year.
Testing of a working prototype of the bioartificial kidney is slated for 2020.
“The long-term challenges center around keeping the device operating trouble-free after implantation beyond a few months,” said Roy. “Some problems won’t become clear until we do clinical trials.”
In addition to $6 million in government grants, the Kidney Project has received substantial donations from individuals in furtherance of its work to create an implantable artificial kidney.
“Their support is a testament to the acute need for a revolution in ESRD treatment, and the donations we have received are invaluable in allowing our research to progress,” said Roy.
In the future, scientists may be able to grow artificial kidneys.
In 2013, researchers, led by Melissa Little of the University of Queensland's Institute for Molecular Bioscience, were able to grow a primitive kidney from human stem cells.
In 2016, researchers from the Salk Institute in California reported that they were able to grow nephron progenitor cells, which can differentiate into kidney tissue, in the lab.
Such research continues, but the ability to grow replacement organs remains a more distant dream than an implantable artificial kidney.
Where are we now?
As at the end of September 2016, 6,599 patient were on the NHS organ transplant waiting list. For those lucky enough to receive an organ, the survival times are the highest they have ever been. For operations taking place between 2008 and 2010, the five-year survival rates were 90% for kidney, 71% for heart and 82% for liver transplants – much higher than the figures 15 years earlier, at 69%, 63% and 64% respectively.
However, the existence of a waiting list is a worry for many patients with end-stage organ failure. In 2015, 479 patients died while waiting for a transplant. Why does this waiting list exist?
Put simply, the waiting list exists because the demand for organs outstrips the supply. The demand for organs follows organ failure brought about by disease, genetic disorders, lifestyle habits, accidents and senescence (the ageing process that leads to deterioration of organs). The physical supply could come from human donors, xenotransplantation (using tissue from animals) or artificial organs. The national stance on organ donation consent also affects the supply, as could the overall NHS budget in the UK.
Which organs are in demand?
The vast majority of patients on UK waiting lists require kidney transplants, with fewer people requiring liver, lung and heart transplants.
Disease and lifestyle habits are the underlying cause of this demand. For example, patients could require a kidney transplant as a result of diabetes, an infection or prolonged high blood pressure leading to kidney failure. Alcohol misuse could lead to the need for a liver transplant, and damage caused by smoking or cystic fibrosis would mean someone requires replacement lungs.
The demand for organs is likely to rise in the future. While the demand for organs as a result of accidents (for example, from poisoning or physical trauma) is low, ageing of the population is likely to increase the demand.
Furthermore, even with lower rates of smoking, urban air pollution and migration to cities are a concern as they increase rates of chronic obstructive pulmonary disease.
Obesity trends are also likely to lead to future rises in demand for organs, in particular for kidneys and hearts.
A closer look at organ supply
Around 4,600 organ transplants were carried out from April 2015 to March 2016 in the UK, arising from around 2,400 human donors (one donor can save up to eight lives). The majority of these organs – 77% – came from deceased donors, with the remainder, in particular liver and kidney transplants, coming from living donors.
Human donors
The key challenge lies in matching organs to patients, by tissue, blood type and other medical criteria, to decrease the chance of organ rejection. The patient’s immune system is suppressed to reduce the risk of organ rejection. However, a weakened immune system increases the risk of viral and bacterial infection, so a careful balance is required in terms of immunosuppressant medication.
Xenotransplantation
Transplanting heart valves from pigs is a common procedure. Here, the pig cells are chemically stripped before human cells grow around them after they are implanted.
However, there are known issues with transplanting whole organs, namely the rejection of animal tissue, potential infection from animal viruses and whether they could function in a human body.
Recent advances in gene editing technology have renewed the interest in xenotransplantation; for example, there have been initial attempts to grow human organs in animals such as pigs.
Artificial organs
The artificial organ market is expected to grow by 9.1% compound per annum from 2017 to 2022 from $26.8bn (£20.3bn) in 2016 to $45.2bn (£34.2bn) by 2022, according to a study by Zion Market Research. Given they would mean a lower risk of organ rejection and that organs could be mass produced to meet demand, it is a very promising industry that could address the shortage of organs.
Artificial hearts in the US are currently used as a stopgap before patients receive a biological organ; patients are provided with a fully functioning artificial heart. One patient was supported for nearly four years with an artificial heart before receiving a successful human heart transplant.
Human trials of artificial kidneys to tackle end-stage renal disease are about to begin. Another promising area of experimental research is 3D bioprinting technology, which could be used to create replica organs for transplant into humans.
Considerations for the insurance industry
Major organ transplant (MOT) is a listed condition under a typical critical illness (CI) product. In 2014, the Association of British Insurers amended the MOT definition in its Statement of Best Practice to include the qualification ‘from another person’.
In the short term – say, over the next five years – we anticipate a limited impact on the CI product. An insured life requiring an organ transplant would be placed on the waiting list. This in itself would be a trigger the CI claim under the existing definition. Thus, it does not matter whether the transplanted organ comes from a human donor, an animal or an artificial source or, indeed, if the operation happens at all.
As
transplant technology develops, artificial organs are likely, in my
view, to play an increasingly important role. The time frame for this
will depend on the organ; artificial hearts are already being
transplanted and artificial kidney developments are looking promising.
Being able to provide artificial versions of these two organs alone
could reduce the current waiting list by more than 80%.
The key benefits of artificial organs are that they open up the possibility of mass production and patients are less likely to experience organ rejection. Depending on technological progress and capacity in the NHS, transplant waiting lists could significantly be reduced or even disappear.
Without the waiting list, it will start to matter much more whether a policyholder receives an organ from a human donor or an artificial source. There may be a period of uncertainty here, where the industry questions whether artificial organ transplants warrant a partial or full sum assured payment. However, with much lower rejection risks, the conclusion may be that artificial transplants are not as life threatening as human donor transplants.
Another potential grey area for a valid payment is if the transplanted organ was a bio-artificial organ or if it were grown in a laboratory using human cells. Would payment still be declined because the organ did not originate from a human donor?
If we assume that we use only artificial organs for transplants, the current CI definition would lead us to having zero incidence rates, assuming we stick firmly to this definition. Realistically, even with zero incidence rates for a typical CI product, the overall price would reduce by only about 1% (assuming the demand for organs remain fairly stable), since the magnitude of these rates is small compared to heart attack, stroke and cancer.
In the long term – 25 years or more – we could eventually get to a stage where complex organ transplant procedures became routine with little risk of organ rejection. Furthermore, transplants could be carried out while patients are still relatively healthy.
The potential for moral hazard risk is something to consider in the future; people may have less of an incentive to look after their health if they are ‘protected’ from the consequences of organ failure.
Using artificial organs could reduce the incidence rates of CI conditions; for example, a person diagnosed with a localised cancer where the severity is not high enough for a claim payment could have the affected organ replaced, thus avoiding a future claim payment. Similarly, those at risk of heart attacks as a result of problems with the organ itself could get an artificial heart. This argument still holds if xenotransplantation becomes the solution for the organ shortage, although whether its disadvantages could be overcome remains to be seen.
Term and longevity products
For term products, carrying out an artificial organ transplant means that we have effectively delayed the death of a policyholder from organ failure. The SynCardia artificial heart transplant patient who survived for nearly four years before a human heart transplant is a good example of this.
However, the extent of such improvements on mortality would be small as they would be restricted to the minority of policyholders who required an organ transplant in the first place.
In the longer term, we may start to see further improvements in mortality rates; people with organ failure from cardiovascular diseases or cancer could get their organs replaced and deaths delayed. Therefore, the overall cost for term assurance could decrease. The opposite is true for annuities, with mortality improvements leading to higher costs as people delay their death from organ failure. The overall impact will depend on the speed at which the technology is incorporated into mainstream medicine; there is often a high degree of uncertainty in projecting medical advances.
Conclusion
While recent advances in organ transplant technology have led to improved survival times, the current reliance on human donors restricts the overall supply and means there is a waiting list. Artificial organs could be a way to eliminate the waiting list in the future.
The use of artificial organs is unlikely to affect CI products in the short term and give a very small improvement in mortality trends. In the long run, artificial organ transplants could become a cost-effective way of treating multiple diseases; someone with cardiovascular disease or localised cancer could have the affected organ replaced, potentially reducing the effects of heart attack and cancers on CI business. The impact on term assurance policies could be significant; if we can delay the deaths of several lives by 5-10 years, we could see a wave of mortality improvements.
Validating and quantifying these scenarios would require a lot of assumptions about the future and could take considerable time. You would have to look at other medical advances and their respective costs – for example, immunotherapy could be more cost effective at treating or preventing diseases than organ transplant. However, on the demand side, you could argue that the need for artificial organs is as high as ever, considering the rising obesity levels and the ageing population.
