Subscribe to Clinical Compass™ Volume 6, Issue 7 - April 5, 2011

Regenerative Medicine: A "Glimpse Into the Future" of Clinical Care

by Sandra Haas Binford, MAEd

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The National Institutes of Health define regenerative medicine (tissue engineering) as "a rapidly growing, multidisciplinary field involving the life, physical, and engineering sciences that seeks to develop functional cell, tissue, and organ substitutes to repair, replace, or enhance biological function that has been lost due to congenital abnormalities, injury, disease, or aging."(1)

Regenerative medicine (RM) is considered the "next evolution of medical treatments" by the U.S. Department of Health and Human Services report 2020: A New Vision – A Future for Regenerative Medicine.(2) Its distinguishing characteristic of having the potential to cure disease means that this new field of science could revolutionize health care.(3,4) If there is one area in which cutting-edge science is being translated to clinical medicine,(5) it is here.

RM research is moving forward at breakneck pace around the world. On March 22, 2011, I had the opportunity to attend a lecture on regenerative medicine by George W. Weightman, MD, Major General (Ret.) in the United States Army, as well as Professor, Associate Director, and Chief Operating Officer of the Wake Forest University Institute for Regenerative Medicine (WFIRM) in Winston-Salem, North Carolina. At Wake Forest University alone, there are 70 ongoing projects, of which 24 have translational potential and 7 are hoped to be ready for clinical trial in the next 18 – 36 months (as of March 2011). These 7 projects include unique supporting technologies, which are innovations specifically developed for RM that have also found novel, clinical applications: rapid pathogen-detection products, bioreactor and bioprinter technologies, skin-stretching techniques, and oxygen-enhanced healing. Further, skin and cartilage substitutes are available, and laboratory-grown bladders, tracheas, blood vessels, and other tissues have been implanted in patients, Dr. Weightman stated. When such advances at one institute are considered with others taking place worldwide, the future clinical value of RM research is obvious.

Dr. Weightman offers us a "glimpse into the future," predicting that within the next 10 to 30 years, regenerative medicine will increasingly influence clinical medicine. While the purpose of this article is not to single out certain achievements, a few will be selected to demonstrate the clinical applications of RM science.

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Brief Techniques in Tissue Engineering

A brief explanation of tissue-engineering technique is necessary before exploring new frontiers in clinical applications of both RM products and the supporting technologies they require. Cellular biology and other basic science principles discovered in pursuit of tissue engineering often directly contribute to novel clinical applications of RM that are not typically considered to be within the realm of "regenerative medicine," as they lack a physical product. But the source of most of the excitement in RM is in the biologically viable products that promise new structure, function, and healthy cells in so many human medical conditions.

The Dream: An Alternative Cell Source
Many tissues may be grown from mature, differentiated, somatic cells. However, because of their unique nature and the fact that they do not respond well to growth factors, tissues for the heart, nerves, liver, and pancreas must be grown from stem cells.(6)

Here are some facts and clinically relevant features of 5 kinds of stem cells(7):

  • Embryonic stem cells are cultured from the blastocyst stage of embryonic development, during early gestation. At approximately five days' gestation, blastomeres (cells of the blastocyst) begin to differentiate into an outer layer of cells that will become part of the placenta, separating from the inner cell mass (ICM). The ICM cells are pluripotent, so have the potential to differentiate to any somatic cell type; but after embryo implantation in the uterus, most ICM cells differentiate. Yet if the ICM is removed and cultured under appropriate conditions, the pluripotent cells indefinitely proliferate and replicate.(8) Tumorigenicity is considered characteristic of embryonic stem cells.(9)
    • Clinical note: Beyond the ethical dilemma posed by their use, an important clinical and scientific concern is their exponential growth into tumors.(9)
  • Somatic ("adult") stem cells are relatively rare, undifferentiated cells found in many organs and differentiated tissues. They have a limited capacity for both self-renewal (in the laboratory) and differentiation,(9) present from before birth to advanced age. Fat cells and bone marrow are among the best sources of adult stem cells.(10,11)
    • Clinical note: According to Dr. Weightman, adult stem cells from bone marrow are able to reproduce only 8 – 10 times, but never grow tumors. The clinical significance of this is that 8-fold replication may be sufficient to produce clinically valuable tissue for many patients.
  • Umbilical cord blood stem cells are hematopoietic cells collected from the umbilical cord; they can produce all types of blood cells.
    • Clinical note: Cord blood is readily obtained at time of birth. It is used in patients who have undergone chemotherapy to destroy their bone marrow.(9)
  • Amnion-derived stem cells constitute a newly identified biological system in exhibiting three dimensions and three germ layers of in vivo development.(12) They may represent a stage between embryonic and "adult" stem cells, having markers consistent with both cell types. (13,14)
    • Clinical note: These cells have some characteristics of pluripotency, such as versatility, but do not form tumors when implanted in animals,(15) a possible advantage over embryonic stem cells in their potential for clinical use.
  • Using tissue-engineering technique via genetic manipulation, a differentiated somatic cell (e.g., from skin) can undergo a process of "reprogramming" and develop pluripotency like a stem cell. This form is known as an induced pluripotent stem cell (iPSC), which is also used to grow new tissue.(16) Both mouse and human iPSCs form tumors that contain cells from all three germ layers found in vertebrate animals.(9)
    • Clinical note: According to an NIH primer on stem cells, iPSCs are useful tools for drug development and modeling of diseases. They may be useful in transplantation medicine if tissue regeneration can use them as an autologous source, avoiding issues of histocompatibility.(9)
The most important take-away from this information, clinically and socially, is that somatic ("adult") undifferentiated stem cells and amnion-derived stem cells do not continue to grow tumors and are not socially controversial.

Cellular Seeding and Tissue Scaffolding
After a biopsy of source material, tissue engineering makes use of a tissue scaffold.(17) The expansion potential of tissue growth is dramatic. In 60 days, 1 cm2 (5 x 104 cells) can grow to 50 x 109 cells, enough to cover a football field, one cell deep. The medium, or broth, in which a regenerating tissue grows is important to its success, says Dr. Weightman. Growth factors, such as bone morphogenetic proteins, induce proliferation and differentiation into the kind of cells that are capable of responding to these factors.(17) Scaffolds are then seeded with the differentiated cells.

A tissue engineering scaffold is best created from a source that is compatible with the tissue to be engineered, allowing new cells the best opportunity to grow, assume the proper tissue shape, and establish intercellular connections. For example, acellular dermal matrix could be used to support new skin, while a piece of donor liver can be washed of all somatic cells if the goal is to regenerate a liver, Dr. Weightman explains. Using a tissue scaffold to support autologous cells eliminates the potential for tissue rejection in the recipient; both graft rejection and the immunosuppression needed to avoid it can reduce a patient's long-term health and quality of life.(2,18)

Supporting Technologies
In 2005, the top 4 needs and priorities of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) Tissue Engineering/Regenerative Medicine Meeting Summary hinted at the achievements and persistent efforts made since. Necessary developments were then and are now(19):
  • Enabling technologies for RM to move into 3-D regeneration; predictive modeling of tissue structure; microfabrication technologies; bioreactors to control the chemical and mechanical environment; tissue regeneration strategies that move beyond the limitations of current scaffolds to "instruct" cells to differentiate in a desired direction; and cross-cutting technologies for preservation needs.
  • Engineered, 3-D tissues as model systems for disease, as constructs for drug development, and as phantoms for imaging and drug delivery.
  • Effective scaffolds and novel strategies to promote and evaluate the supply of vessels and nerves to regenerated or engineered tissues.
    • Example: One technique uses encapsulated hydrogen peroxide; it can "fizz" and release oxygen to the new tissue for 1 – 2 weeks until the body supplies it, according to Dr. Weightman.
  • Engineering technologies for translational stem cell research, including bioreactors to rapidly expand stem cells; methods for controllable stem cell purification and separation; and control of induced cell differentiation in vivo such as by a device.

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Clinical Medicine Meets Regenerative Medicine

Clinical Advances Improve Quality of Life
The first report of an implanted, regenerated organ in a patient was in 2006, namely, a bladder grown from a healthy part of a bladder in a patient with spina bifida, where disease had left the original bladder scarred.(20) According to Dr. Weightman, a colleague of Anthony Atala, MD (lead author of the paper and the treating physician in that case), the organ has not failed in the 12 years from the surgical implantation of the new bladder until today. In the meantime, the patient has enjoyed improved quality of life, needing to catheterize 5 times per day instead of continuously. The 2006 report documents similar functional success in replacing dysfunctional bladders in 7 patients with spina bifida (mean follow-up, 46 months).(20)

In fact, a major advance in regenerative medicine was published just weeks ago in the March 7th issue of Lancet, reporting successful function of reconstructed, implanted urethras in humans.(21) This pilot study reconstructed urethras using autologous cells of 5 boys, who had a mean age of 11 at the time of implantation surgery. Although urethras can stricture after reconstruction—as can other long, tubular tissues—the implanted urethras were shown to remain functional in a clinical setting for up to 6 years (mean follow-up, 71 months). The study shows that "engineered urethras can be used in patients who need complex urethral reconstruction."(21)

How Does Regenerative Medicine Restore Function?
RM offers potential to treat diseases and conditions associated with both injury and aging. Cells cannot divide forever, and when they can no longer regenerate, a person becomes ill or aged through:

  • "Normal" cellular aging
  • Degenerative disease
  • Attack from within (e.g., cancer or autoimmune disease such as rheumatoid arthritis)
  • Environmental causes of aging
There are limits to what can be accomplished with currently available implant devices and other medicine. For example, artificial knees have a typical life expectancy of 15 years, yet no patient or surgeon would choose to replace a knee more than once. Joints or their components may someday be rejuvenated through RM.

The brain is like a muscle in that you must exercise it to avoid, or at least delay, age-related functional atrophy. The RM field is investigating Alzheimer's and Parkinson's diseases for treatment options. One research center for developing RM treatments for CNS-based illnesses and injuries is the Karolinska Institute in Stockholm, Sweden. The Institute has established two centers—one composed of thirteen research groups—that are actively investigating how RM could be useful in nervous system-related disorders, including Parkinson's disease and multiple sclerosis.

Overcoming Challenges, Achieving Clinical Successes
Advances in tissue engineering and regeneration do not need to reach the complexity of complete organs to be clinically meaningful. The increasing levels of difficulty in regenerating tissues and organs have defined and limited the clinical successes achieved so far:
  • Sheet of tissue (e.g., skin, bladder)
    • Bladder: A lining sheet of epithelial cell backed by smooth muscle cells built onto a matrix, formed into new bladders in human children with spina bifida.(20,22)
    • Skin: Pig skin has been "printed" with growing layers of cells between matrix through a supporting technology that utilizes inkjet printers for custom application of skin cells directly to a wound, according to Dr. Weightman.(23)
  • Tube of tissue (e.g., urethra)
    • Lengths of urethra succeeded after implantation in 5 boys.(21)
  • Solid tissue (e.g., liver)
    • Animal models of liver have successfully regenerated with vascularization in vitro.(24)
    • The first clinical studies on use of bone marrow stem cells revealed that functional hepatocytes in injured tissue (liver embolization) showed promising results. The same study reported generation of differentiated cardiac muscle cells and neurons from bone marrow stem cells.(25)
  • Organ (e.g., kidney)
    • Containing many tissues arranged in a complicated pattern, regeneration of a kidney could signal a possible solution to a major public health burden. In addition to medical costs of kidney disease, a critical shortage of organs for transplantation has left more than 60,000 people on the nationwide waiting list.(26)
    • Regeneration has succeeded in producing experimentally functional solid organ constructs, i.e., a miniature kidney that secretes urine when implanted in animals.(27)
  • Extremities (e.g., finger, ear)
    • Structures of muscle, tendon, and ligaments can be built,(28) an effort that would benefit injured military personnel.(29) In 2008, CBS News reported (with a companion interview) the story of a man's regrown fingertip, lost to accidental amputation. The man's brother, a researcher in regenerative medicine, sent him extracellular matrix made from pig bladders, a mix of protein and connective tissue.(30)
    • Replacement ears in laboratory.
Yet, even once a tissue or organ is made, two challenges remain, surmounting all others: For a new tissue or organ to work, it must have (1) blood and (2) nerves, i.e., the body must accept and supply the new tissue.

Military Applications for Treatment After Trauma
The Armed Forces Institute for Regenerative Medicine (AFIRM), an $85 million, federally funded project to apply the science of regenerative medicine to battlefield injuries, has formed 2 research consortiums under a U.S. Department of Defense grant. These are formed by (1) Wake Forest University in collaboration with the University of Pittsburgh and (2) Rutgers University in collaboration with the Cleveland Clinic. The U.S. Army focused on important clinical care needs for those injured in wartime, including(31):
  • Burns, which "consume a disproportionate amount of resources and require specialized care."(32) Patients with extensive burns must have skin immediately, but large grafts are difficult to secure and prone to subsequent contraction. While tissue expansion devices (implants) have historically offered skin expansion in plastic and reconstructive surgery, their use requires protracted expansion time, can be painful, has a high complication rate, and is not indicated within burned tissue.(33,34) Quickly creating new skin through RM, potentially even "bioprinting" it onto a wound,(23) could revolutionize skin replacement in burn patients.
  • Craniofacial injury, in which major complications are associated with both immediate and delayed definitive treatment; deployed surgeons must use clinical judgment to determine timing of repair.(35) Because these injuries cause a variety of deformities and disabilities in wounded soldiers, regenerative medicine offers an opportunity to restore form and function. Other research into wound healing is ongoing.
  • Compartment syndrome, a difficult-to-diagnose condition whose delayed or missed diagnosis can lead to permanent, devastating disability.(36,37) Regenerated, autologous materials to replace dead tissues could restore lost function after compartment syndrome.
  • Replacing a human ear or growing fingers and limbs in the lab, perhaps using "printed" tissue cells growing in a custom pattern or extracellular matrix, as described above. (23,30) These extremities can be lost or injured through battlefield trauma.
The Department of Defense press release announcing AFIRM explains a yet greater role: "In addition to developing clinical treatments, the AFIRM will serve as a training facility to develop experts in treating trauma with regenerative medicine and will serve as a resource to help the military develop tissues as needs are identified."(31)

Supporting technologies specifically developed to aid RM research—but that are not biologically viable RM products—offer clinical applications beyond RM. When the U.S. Army needed a faster method to diagnose an infected wound, it found a solution through reapplication of biotechnologies devised for RM acceleration of cellular growth, which proved faster than traditional culturing methods. According to Dr. Weightman, the benefit is the ability to treat specific infections with specific antibiotics sooner. In other words, an RM technology can be clinically useful in its own right, and belongs to the science of RM innovation, even if it is not an RM-derived tissue or organ for direct implantation.

Clinical Potential
The aging of America means that the number of people who could benefit from new organs, rejuvenated cells, and clinical technologies derived from RM is increasing rapidly (see also Table). Here is a small sample:
  • Functioning, engineered kidneys without rejection potential would save lives and billions of dollars. The End-Stage Renal Disease Program (Division of Kidney, Urologic, and Hematologic Diseases; National Institute of Diabetes and Digestive and Kidney Diseases) in 2007 showed $35.32 billion in public and private spending.(39)
  • The ability to replace dysfunctional beta cells of the pancreas could repair the ability to secrete insulin and cure type I diabetes.(40)
  • Cancer cells could be targeted with "killer" cells that would not harm healthy tissue as conventional cancer treatments do.
  • Stem cells used as agents and drug-delivery techniques using growth factors and genes could revolutionize therapeutic strategies of the future.(41,42)
Table. Estimated Number of Americans Who Could Benefit From Regenerative Medicine Therapies (U.S. National Academy of Sciences, 2002).(38)

Medical Condition

Number of Patients

Cardiovascular disease

58,000,000

Autoimmune diseases

30,000,000

Diabetes

16,000,000

Osteoporosis

10,000,000

Cancer

8,200,000

Alzheimer's disease

4,000,000

Parkinson's disease

1,500,000

Burns, severe

300,000

Spinal cord injuries

250,000

Birth defects

150,000
Source data: Committee on the Biological and Biomedical Applications of Stem Cell Research; Board on Life Sciences National Research Council; and Board on Neuroscience and Behavioral Health Institute of Medicine. Stem Cells and the Future of Regenerative Medicine. Washington, DC: National Academy Press; 2002.
Science may determine which growth factors, cytokines, and other proteins best stimulate the body to regrow tissues, so that doctors would not need invasive techniques to implant regenerative cells or tissues.

Rarely, research science can both offer an enormous potential benefit for human health and quality of life and be a fount of new basic research discovery. Stem cell biology succeeds in both, offering hope for curing diseases like diabetes, Parkinson's disease, neurological degeneration, and congenital heart disease.(17)

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The Social Interface of Regenerative Medicine

Ethical and Financial Concerns and Controversies
Like many health care innovations, the emergence of RM in clinical care will be controversial.(19) Controversy occurs partly because most of the new tissues and organs have not undergone clinical trials for widespread implantation and the cost of regenerative medicine is currently much higher than conventional procedures.(43) Which patients and illnesses should receive treatments derived from RM? And, most importantly, who decides?

Work toward development of the kidney, a complex organ of 30 tissues, suggests a future in which enormous per-patient costs of treatment by dialysis may be avoided. Considering the burden of approximately $1.25 million to keep a person alive for the typical 5 years on dialysis, regenerative medicine may offer savings. Dr. Weightman stated in his March 22 lecture, "Regenerative medicine is pretty inexpensive once we figure out how to do it. We need only an incubator."

There are financial incentives to pursue regenerative medicine. In March 2011, Dr. Atala testified before Congress, in a hearing of the U.S. House of Representatives Judiciary Subcommittee on the subject, "Regenerative Medicine: Strategic Innovation for Patient Health, Economic Benefit, and Job Creation," as follows(27):

In addition to the obvious benefits of reducing human suffering from disease, regenerative medicine has the potential to positively impact health care costs and workforce productivity and longevity. Early estimates project that regenerative medicine therapies will result in direct health care cost savings in the United States of $250 billion per year for the chronic diseases of renal failure, heart failure, stroke, diabetes, burn and spinal cord injuries.
However, Dr. Atala also specified that any clinical applications in regenerative medicine must be done carefully and deliberately: "The key is to go slow and have long-term follow-up. Keep patient safety first."(43) This indicates an ongoing concern: Olle Lindvall, MD, PhD, Professor and Chair of the Department of Clinical Neuroscience at Lund University, Sweden, stated in 2001, "Before applying a new therapy widely, it must show effectiveness in the reversal of actual symptoms and be successful in restoring normal function."(44)

Worldwide Potential in Regenerative Medicine
Worldwide interest and growing expertise are clear(45):
A groundbreaking international effort to support regenerative medicine technologies took place in the U.K. and U.S.A. on September 22, 2010. Regenerative medicine and stem cell therapy groups held simultaneous events to launch the first ever International Regenerative Medicine Legislative Day, in order to raise awareness among policymakers of the huge potential of these cutting-edge, revolutionizing technologies and highlight the need for appropriate laws and regulations to support research and product development. […] On the U.S. side, the Alliance for Regenerative Medicine (ARM) introduced landmark legislation to increase funding for regenerative medicine research, as well as create a regulatory environment that enables development and approval of safe and effective regenerative medicine products.
Currently, 12 – 15 major regenerative medicine centers are operating in the United States; other major centers are based in several European countries, Japan, China, and Australia. Much of the work done in regenerative medicine is highly collaborative among nations, but does require some protections of intellectual property in this hot, emerging field.

The United States government has organized the Multi-Agency Tissue Engineering Science (MATES) Interagency Working Group under the auspices of the Subcommittee on Biotechnology of the National Science and Technology Council. This working group forms the means by which federal agencies involved in regenerative medicine and tissue science and engineering coordinate their efforts. MATES contributes a fitting conclusion to this "glimpse into the future" of regenerative medicine and its effects on human health(46):
Tissue science and engineering is expected to contribute to revolutionary products for the full spectrum of biotechnology from the earliest diagnostic testing to the advanced stages of therapy. Thus, this field will be an integral part of the national debate on moving to a health care system that emphasizes prediction, personalization, and prevention, while continuing to improve treatments for end stage disease.

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Clinical Connections

  • In the next 10 to 30 years, simple tissues to complex organs that neither cause donor rejection nor grow tumors may be available for clinical use.
  • The "dream" of unlimited sources of donor organs and tissues may solve the undersupply of life-giving tissues for patients requiring transplants.
  • Rapid identification of infection has been developed for assessment of wartime injury and may become available in everyday clinical medicine.
  • Work toward development of the kidney, a complex organ of 30 tissues, suggests a future in which enormous per-patient costs of treatment by dialysis may be avoided.
  • Engineered tissues and organs offer improved quality of life for patients with discomfort or dysfunction.

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Trusted, Online Sites for Further Reading in RM

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Acknowledgements

The author gratefully acknowledges the contributions of George W. Weightman, MD, to this article.

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Post-Compass Questions™

Your responses to this issue's Compass Questions™ will be added to an ongoing needs assessment for educational programming in this important area. Responses to this issue's questions will be reported in an upcoming issue.

Question #1
NOW that you have read this article, how familiar you are with the CURRENT clinical and research status of the field of regenerative medicine?
Extremely familiar
Very familiar
Moderately familiar
Somewhat familiar
Not at all familiar

Question #2
NOW that you have read this article, rate how frequently you NOW PLAN to proactively seek out and review at least one trusted, online source of information on regenerative medicine.
Monthly
Quarterly
Semi-annually
Annually
Less than annually

Question #3
Which clinical advancement in regenerative medicine would help your patients most? Implantation, injection, or growth-promotion of tissues of the:
Nervous system (CNS and periphery, including skin)
Vascular system
Integumentary system
Gastrointestinal system
Genitourinary system
Musculoskeletal system
Endocrine system
Immune system
Respiratory system

Question #4
How interested are you in educational activities that explore advancements in regenerative medicine?
Extremely interested
Very interested
Moderately interested
Somewhat interested
Not at all interested


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References

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