THE FUTURE OF HEALTH: IS THE KEY TO OUR FUTURE THE EVOLUTION OF ARTIFICIAL ORGANS?

Paul Fagette, PhD

Historian in Residence, Dept. of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL

Historian, Biomedical Engineering Society

PART 1: Artificial Organs 1942-2009 - Historic Background and Achievements

PART 3: Regenerative Medicine - Growing the Cure

PART 2: Current Global Health - Chronic Disease in the Ascendency

PART 4: The Role of Artificial Organs in this Changing World

OUTLINE

PART 1: Artificial Organs: 1942-2009 - Historic Background and Achievements

• World War II was truly a turning point in the political history of the planet and in medical science.

• In the pre-war period, considerable effort by many countries resulted in a better understanding of human physiology and pathology.

• Generally, the main focus of medicine was infectious disease research and clinical treatment. For example, approximately half of all US physicians between 1900 and 1950 trained as pathologists.

• In the post-World War II era, the United States and its allies emerged victorious with a modern industrial infrastructure and a strong faith in technology.

• As new vaccines increasingly subdued infectious disease, a new dynamic was introduced into medicine: artificial organs.

• Focused largely in North America and Western Europe, technological devices were created to supplement and supplant physiological function.

• Artificial organs increased in importance as the availability of transplantation organs leveled out quickly.

• Dialysis devices evolved between 1942 and 1955. Willem Kolff and others.

• Heart Lung By-Pass Machine – 1954 - John Gibbon, C. Walton Lillehei and Richard DeWall, and Clarence Dennis.

• Mechanical Heart Valves – 1955 on.

• Artificial Pacemaker – 1950s on – Earl Bakken and others.

• Bioprosthetic Heart Valves – 1970s on.

• Ventricular Assist Devices – 1960 on – Michael DeBakey and others.

Timeline

• In the last 25 years, technological achievements have occurred in pulmonary assist devices, infusion pumps, cochlear implants, and more recently epi- and sub-retinal implants.

• Bioartificial assistance based on hollow fiber technology for liver and pancreatic failures have emerged on a limited scale.

• Rotary blood pumps dating from the 1970s have emerged as a major assist device in the last decade.

• Importantly, it must be noted that surgical expertise has progressed in a parallel manner.

• Two areas of artificial organs typify the technological achievements: cardiovascular assist devices and kidney dialysis devices for both acute and chronic disorders.

• Note: artificial organs have been developed within a strong academic, industrial, and governmental setting.

One historic pictorial example: dialysis technology

• The last photo is reflective of the inherent nature of artificial organs relative to the necessary infrastructure support.

• This Fresenius Hemodialysis unit is in use around the globe but requires a constant water supply, a stable electrical network, a qualified technician, etc.

• These devices also have a heparin pump requiring proper adjustment and administration.

• A device such as this is not easily integrated into an area without electricity, potable water, and the like.

Artificial organs were developed in countries with:

• Strong medical infrastructures capable of the necessary surgical delivery, post-operative care, and clinical care, and pharmaceutical support.

• Larger national communication/transportation systems, sufficient economic base to support medical infrastructure for delivery, application, and research, all of which infer a reasonable degree of political stability

PART 2: Current Global Health - Chronic Disease in the Ascendency

• In 2005, the World Health Organization identified a changing disease pattern.

• Chronic diseases are now the major health challenges and a stumbling block to economic growth in developing countries.

• In particular, heart disease and diabetes mellitus both require long-term support and, according to the WHO report, are not restricted to older segments of the population.

• The greatest impact is on working-age males and females who compromise the primary workforce. Women in child-bearing years are also affected.

• WHO estimates that non-communicable disorders will result in ¾ of all mortalities by 2030. Cancer, cardiovascular disease, and traffic accidents will account for about 56% of all deaths by that decade.

• It should also be noted that the medical world will continue to challenged by older infectious disorders such as malaria and emergent ones like HIV and Ebola.

• In a positive vein, HIV/Aids estimates have been revised downward and there are positive signs for controlling malaria. Importantly, these diseases can also affect heart and renal systems.

• In developed countries significant progress has been made in treatment for cardiovascular disease by a combination of behavioral and drug therapy. Education and treatment for smoking also plays a prominent role.

• In a seminal article, Greenberg et al carefully chronicled the advent of ischemic heart disease and stroke as the leading causes of death world-wide. Death from communicable, maternal, pre-natal, and nutritional disorders is predicted to fall significantly over the next 30 years.

• In contrast, heart disease and stroke will remain at the top followed by pulmonary disease and lung cancer. In developing countries, the loss of family unit income is the fastest route to poverty.

Greenberg H et al. Global Health Assistance for Chronic Illness: A Look at the Practical. Progress in Cardiovascular Diseases, 2008, 51, 1:89-96

• The World Health Organization has made intervention and prevention a major goal. But this policy is dependent to a large degree on the extant medical infrastructure in a targeted country. Not taking these steps to insure the health of one’s population can have devastating results in the long run.

• In the older disease paradigm, infectious disease would take its greatest toll in the young and the old; those in between would simply survive or die.

• The ascendancy of chronic disease creates another economic setting. These diseases usually don’t kill immediately but are long-lived and progressively debilitating incurring considerable expense and draining the most dynamic component from a population.

World Health Statistics 2008, WHO

World Health Statistics 2008, WHO

• Cancer is among the leading causes of mortality globally. Again, early detection, e.g., mammogram, plays a significant role in prevention and control.

• Meningococcal meningitis appears in Africa in waves, 1996-07 and 2006-07. Control can be effected with timely medical oversight and subsequent vaccination.

• WHO categorizes the “tobacco epidemic” as the most preventable cause of cancer mortality. Tobacco kills between a third and a half of users and profoundly affects other disorders.

ANALOGOUS EXAMPLES

Meningococcal meningitis belt, World Health Statistics 2008, WHO

World Health Statistics 2008, WHO

World Health Statistics 2008, WHO

WHAT DOES IT ALL MEAN?

The emergence on a global scale of chronic cardiovascular disease, diabetes, and accompanying disorders that affect the former two create a favorable environment for artificial organs in the 21st century. However, there is another approach slowly ramping up and will play a major role in medicine.

PART 3: Regenerative Medicine - Growing the Cure

Success has been achieved in recent years in regenerative medicine, comprised of tissue engineering, growth factor research, and stem cell application. Cellular biologists, endocrinologists, cell and tissue engineers, materials scientists and engineers, physicians and surgeons, and more contribute to this relatively new and complex field. General approaches are:

• Culture replacement tissues, including bone and vessels, ex vivo, and then transplant the tissue back into the patient host. In the future, repair organs in vivo.

• Culture specific cellular groups, e.g., neuronal, and infuse them into damaged tissue sectors.

• Culture and grow tissue/organ parts from stem cells, either embryonic or partially differentiated.

• The field had high expectations early on but progress was slow. The major efforts and achievements were in tissue engineers developing bioreactors along with the identification of necessary growth factors.

Shastri VP. Future of Regenerative Medicine: Challenges and Hurdles. Artificial Organs, 30, 10:828-834

Success has been achieved in growing skin, intestinal tissues, and some urinary tissues. Continued success will be dependent upon research in:

• Underlying biologic processes

• Appropriate technologies to replicate processes

• Enhanced R & D into stem cells at all levels of development

• Biomaterials and subsequent biocompatibility issues

• Inflammatory and immunological reactions, and importantly, blood and coagulation issues

Regenerative medicine, an almost evolutionary step, holds great promise in clinical treatment. But artificial organs will continue to play a role but increasingly at a nano scale.

Artificial organs are marvelous technological innovations but are hindered by at least 2 important issues.

• The first is their cost which limits their accessibility to patients.

• The second is related to blood reaction. Patients usually require constant anti-coagulation treatment which again determines candidates for such devices. The one exception is bioprosthetic heart valves but the immune system eventually compromises them.

However, again, for both of these treatment approaches to be applied to a wider audience, a minimal level of medical infrastructure must be in place. If this requirement is necessary for artificial organs, then regenerative medicine also requires significant support. The biological culturing of cells, both ex and in vivo, and cellular development are perhaps even more challenging without a proper developmental setting.

Regenerative medicine began with growing tissues in bioreactors and will continue to do so. But its future lies in the ability to utilize the power of the body itself and grow replacement tissues and organs.

PART 4: The Role of Artificial Organs in this Changing World

• In the next several decades, education, re-education, and prevention will play a prominent role in medical planning especially for WHO.

• This is an economically viable approach given that many areas of the developing world have political instability and/or lack an adequate medical infrastructure.

• Preventing chronic heart disorders and diabetes are infinitely less expensive than treatment; and WHO has a record of success in this approach.

• Preventative medical policies include a significant and integral drug treatment component. A global drug industry has provided a wide range of pharmaceutical options for cardiovascular disorders.

• Exactly how these drugs will be distributed at a reasonable cost and in what manner, e.g., either through local government agencies or philanthropic organizations is a lingering issue.

• Professional medical societies, e.g., the International Society of Nephrology, will continue to be involved in the identification of easily determined markers for disorder, exchange of information, training of physicians and staff, and input to national and global medical policies.

• Chronic disease will unfortunately require more than prevention and drugs. Intervention will occur at multiple levels and artificial organs and regenerative medicine techniques can play a role.

• The difficulty for each area lie in the implementation and follow-up. The devil is always in the details.

MAIN ISSUES SURROUNDING EXTENSION OF ARTIFICIAL ORGANS AND USE OF

REGENERATIVE MEDICINE

1. Ethical considerations about limitations of applications and violating religious and spiritual beliefs.

• A continuing challenge in the last century and now is how countries can deal with inequalities in access to education, employment, services, health services, etc., both within their borders and between countries. Nationally, a range of political policies have been implemented around the world. Globally, philanthropic efforts, national aid policies, and WHO provide part of the answer.

• While the larger inequities lay outside the realm of this discussion, It has been suggested that a degree of justice can be met with the sharing of expertise and resources so there is the opportunity for change.

• The mechanical focus of artificial organs and the ability of regenerative medicine to work within an individual might alleviate cultural or religious beliefs. In some cases, xenografts might work in place of organ donation.

HM Sass. Ethics of Allocation of Highly Advanced Medical Technologies. Artificial Organs, 1998, 22, 3:263-268

• Shared resources, barring any social or religious stigma, are dependent on the target countries to develop institutions to continue the implementation. How will this occur?

• The United Nations and WHO develop medical and economic policy. And the developed countries meet regularly in the G7 and G20 summits on economic policy. When will there be a parallel summit on health policy from the developed nations?

2. Both mechanical devices and cultured cellular approaches are at present inherently expensive and long-lived in research and development. Industry expects a reasonable return on its investment. How will this issue be resolved with developing economies?

• Cardiovascular and other device production has achieved a high degree of proficiency. Continual production efficiency will improve and prices will drop.

• Drug companies have successfully built facilities in developing regions; can this occur with devices?

• Cultured cellular and organ components are complex resulting in expensive production techniques. This industry is in its infancy and the costs are high in the near future. Considerable industrial production improvement will have to occur for this area to be available on a wider scale. Hence, industrial engineers and others will play a prominent role.

3. Both areas require an adequate medical infrastructure for implementation and long-term follow-up. One does not implant a device and send the patient out into a remote region alone. Monitoring, drug regimen, and oversight are a part of the treatment.

• In a decentralized economic structure, how does one create or foster the development of a medical service infrastructure?

• Adequate transportation and communication systems must be in place. For example, Rwanda, with the densest population in Africa, has invested in both systems in recent years laying the basis for future development.

• Building a hospital in a national center is a first step. A cohesive clinical outreach system is also required.

• The design and implementation of such systems should be a component of aid and lending programs.

• An investment in a healthy population pays off in a stronger production and market economy.

4. Transplantation medical specialists require extensive training in appropriate medical facilities. The same is true for specialists who culture replacement cells. Where will they come from? Right now many travel from abroad or medical centers such as Cairo into the needy areas. How and when will they be trained in homeland institutions?

• I have differentiated a medical training facility from the larger medical infrastructure. It includes a hospital but also requires a significant investment beyond the hospital in order to train medical scientists.

• Many of the national training hospitals are only able to conduct limited clinical research. Their physicians are over-whelmed with clinical duties and there are limited research facilities.

• The professional societies are able to sponsor some physicians to travel and join in research.

• A stronger viable research link between developing and developed countries would engender a stronger medical information link.

• The construction of new medical training facilities with research capability would enable many countries to train physicians and surgeons and deliver new technologies and treatments.

5. Will continued efforts to control infectious disease have an effect on chronic disorders?

• Absolutely. HIV and malaria have serious consequences on end stage renal failure. Better control and treatment will have a positive downstream effect.

• Malarias affect about 400 million people globally, mostly in Africa.

• Two major renal syndromes can result: Chronic malarial nephropathy (CMN) and acute malarial nephropathy (AMN).

• CMN usually affects children 4-8 years old and proceeds to chronic and progressive renal failure even after the infection is cured.

• AMN accounts for acute renal failure between 1 to about 5% of native patients and 25-30% of non-Africans. The mortality can be from 15 to 45%.

RS Barsoum. Malarial Acute Renal Failure. Journal of the American Society of Nephrology, 2000:2147-2154.

• HIV is estimated to decline from #6 to #10 in leading causes of death by 2030. Still, its debilitating effects will result in long-term and expensive treatment.

• For example, HIV-related renal diseases stand as the 3rd leading cause of end stage renal disease among African-Americans.

• In addition to the other drug and related treatments for HIV, patients will need to undergo dialysis.

6. What technologies from artificial organs and regenerative medicine will have an impact in the future? What will it take for them to be integrated into the global medical community?

• Kidney dialysis or hemodialysis is the most ubiquitous treatment using a artificial organ on the planet. It is effective in treatment for acute syndromes which are short-lived.

• Acute treatment can be delivered in a mobile manner and under extreme conditions, e.g., generators.

• Dialysis for chronic sufferers presents different dilemmas. Currently, Patients have to be treated on a long-term basis for life at least 3 times a week.

• Stable electrical and potable water systems are needed.

• The future holds some hope. Continued research into nanotechnology for membranes, monitoring, feedback, and miniaturization is moving toward wearable and implantable devices. With cellular components, these devices can perform detoxification and some synthetic function allowing more freedom.

• Stem cell techniques hold hope to repair a dysfunctional kidney. In situ repair avoids immunological concerns and uses the body itself as the bioreactor. New nephrons could be grown in vitro and then transplanted.

• Such treatment requires a central laboratory facility and necessary surgical staff.

• Ventricular assist devices are moving towards smaller implanted devices but are currently temporary until transplantation.

• Anti-coagulation regimen is an integral component requiring monitoring and oversight.

• Patients also have to wear energy sources (battery packs).

• These devices are very expensive, ~$50,000.

• Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure trials have shown that long term application of devices is viable.

• Issues of size, energy, flow characteristics, and costs have to be overcome.

• Cardiac tissue engineering has the promise of a surgical repair using host tissue. Damaged valves, vessels, and tissue, contractile included, can be replaced surgically.

• Significant advancement in this area is occurring and would be available globally as long as there was a central laboratory facility and trained surgical staff.

• Diabetes presents different difficulties relative to cardiac and renal systems. This insidious disease works it damage over a lifetime. Insulin injections or pumps effectively delay the debilitating effects.

• Pancreas transplants are limited and risky.

• Cadaveric beta cell transplantation allows the patient to be insulin free but not of the disease.

• Encapsulated porcine beta cells are available on a larger scale and work in the same fashion.

• Effective prevention programs are an important step.

• Regenerative medicine or possibly gene therapy hold the best promise.

• The potential for widely available artificial lungs, bioartificial livers and kidneys is uncertain. These devices are used for short-term application until transplantation.

• The potential of regenerative medicine may allow for future wider application.

• In summary, continue in-depth research into regenerative medicine and refinement of artificial organs that runs parallel to fostering sufficient medical infrastructures globally.

• Mahalo ā nui to the American Association for the Advancement of Science for this opportunity and to my colleagues here today.