Regenerative Medicine

Regenerative medicine in the early 2000s was a new interdisciplinary branch of medicine that drew on fields as different as engineering, biology, physics, and chemistry in order to repair or replace damaged tissues and organs. The term regenerative comes from a Latin word that means “to reproduce” or “to regrow.”

What Is Regenerative Medicine?

Regenerative medicine is a field of medicine that began around 1985 with research into tissue engineering—the development in vitro * of tissues or even entire body organs from living cells and various materials to support the growing cells. Some doctors and researchers continued to use “regenerative medicine” as a synonym for tissue engineering.

Regenerative medicine began to be identified more with stem cell * * questions.

These questions were raised again when a sheep named Dolly was successfully cloned in Scotland in 1996. Cloning * refers to a process in which multiple cells are obtained from a single cell and contain the same genetic material. Dolly was the first large mammal to be successfully cloned from an adult stem cell. After this initial success, some scientists proposed the experimental cloning of human embryos.

What Are the Major Types of Regenerative Medicine?

Although the general public usually thinks of regenerative medicine in terms of stem cell research, there are at least four different fields within regenerative medicine.

Medical devices and artificial organs

An important branch of regenerative medicine involves work on medical devices. The Food and Drug Administration (FDA) defines a medical device as any product used in health care that does not involve chemical activity or use by the body's metabolism * . The FDA's definition of medical devices includes test kits for the diagnosis of disease as well as such items as medical lasers, contact lenses, surgical sutures, and heart pacemakers.

Medical devices being developed by researchers in regenerative medicine include artificial organs or parts of organs that can be used to support a failing heart or liver until a transplant organ can be found. One such device in use is a ventricular assist device, or VAD. A VAD is a batterypowered pump that can be implanted in one or both of the lower ventricles (chambers) of the patient's heart to support its function until a suitable replacement heart is obtained. Another medical device being studied by researchers at the Mayo Clinic as an alternative to liver transplantation is the Spheroid Reservoir Bioartificial Liver, which can support healing and regeneration of the injured liver, and improve outcomes and reduce mortality rates for patients with acute liver failure without requiring a transplant.

One type of engineered tissue that was developed in the 1980s as a treatment for burn victims was classified by the FDA as a medical device because it involves the use of material from nonhuman cells. This laboratory-made tissue is based on extracellular matrix (eks-truh-SELL-you-lar MAY-tricks), or ECM, derived from pig bladders or intestines. ECM is the part of the living tissue in all animals that lies outside the cell walls and gives support to the cells. It consists of complex carbohydrates * and proteins. The ECM in human as well as animal tissues is essential for growth and wound healing. ECM derived from pigs serves two important purposes in the treatment of human injuries. First, it prevents the body's immune system * from reacting to the injury by forming scar tissue. Second, it speeds up the process of tissue repair by the body's own cells. ECM is used to treat various injuries from torn ligaments and tendons to second-degree burns, chronic pressure ulcers, and diabetic skin ulcers.

Tissue engineering

Tissue engineering, which was the first type of regenerative medicine to attract attention, remains an important field. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) conducted research in tissue engineering to treat such disorders and diseases as broken bones, damaged spinal discs, and injuries involving the growth plates (areas of cartilage at the end of the long bones in children where growth of the bone occurs until the child reaches adult height).

Tissue engineering makes use of cells extracted from living tissue and seeded into artificial structures known as scaffolds. The scaffolds may be composed of either natural or artificial materials. Most scaffolds are designed to break down in or be absorbed by the body as the new tissue is formed—much like absorbable surgical sutures—although some are intended for permanent placement.

The cells that are to be seeded or implanted in the scaffold may be derived from the body of the person who is to receive the engineered tissue, from another human, or from a different animal species. Cells that are taken from the patient who will receive the new tissue are called autologous (aw-TAW-low-gus) cells. Those that are taken from another human are known as allogenic (all-oh-JEN-ik) cells, and those taken from animals are called xenogenic (zehn-oh-JEN-ik) cells.

The cells are extracted from their source by a series of steps. For a liquid tissue such as blood, the cells can be removed by processing in a centrifuge. A centrifuge is a machine that whirls a liquid at a high rate of speed inside a cylinder. The heavier cells or particles move away from the center and can be separated from the lighter particles. The cells in a solid tissue, such as skin or muscle, are removed in two steps. The tissue is first minced into very fine pieces and then placed in an enzyme * solution to remove the extracellular matrix. The tissue cells that remain are then separated from the enzyme liquid in a centrifuge.

After the cells have been extracted, they are implanted in a scaffold that has been formed into the shape of the tissue to be replaced. The most successful engineered tissues were those that had been developed to replace cartilage, skin, or blood vessels. About 22 different types of human cells are being grown in the laboratory, including cells from muscle tissue; lung, liver, and heart tissue; nerve tissue; and eye tissue. One research project involved engineering cells capable of secreting insulin, the hormone required to prevent or treat diabetes. The most notable breakthrough as of that year was in growing a complete human organ through tissue engineering. It took place in 2004, when doctors at Children's Hospital in Boston transplanted urinary bladders grown in the laboratory into children and adolescents with bladders damaged by birth defects. The cells used to construct the new bladders were derived from the patients’ own tissues. In 2008, a team of doctors in Spain created a new airway from cells taken from the patient and grown on airway tissue taken from a donor. Five years later this laboratory-engineered airway was functioning normally.




Doctors harvest donor bone marrow, which will be used for the treatment of severe aplastic anemia and some types of leukemia. Bone marrow is also a source of stem cells used in regenerative medicine.





Doctors harvest donor bone marrow, which will be used for the treatment of severe aplastic anemia and some types of leukemia. Bone marrow is also a source of stem cells used in regenerative medicine.
Cell-based therapies

Cell-based therapies, also known as cellular therapy, are the area of regenerative medicine that is the most controversial. Cellular therapy makes use of stem cells, which are unspecialized cells that have the potential to form a wide range of specialized cells. The process in which stem cells give rise to more specialized cells is called differentiation * . The two basic types of stem cells in humans are embryonic stem cells and adult stem cells. Embryonic stem cells divide and multiply to eventually form all the specialized tissues in the human embryo * . Adult stem cells function as a repair system for the body, forming new specialized cells in various tissues when needed, and replacing worn-out cells in the skin, blood, and digestive system.

All stem cells have two basic properties. The first is self-renewal, which means that stem cells can go through many cycles of cell division and remain unspecialized. The second characteristic is potency, defined as the ability to form specialized cells of different types. There are three types of potency in stem cells. Some stem cells are totipotent, which means that they can form all the different cell types needed for human development and eventually give rise to a complete living organism. Totipotent stem cells are found only in the fertilized human egg and the first few cell divisions after fertilization (the first four to five days after fertilization). Pluripotent stem cells can form most but not all types of cells in the body. They are descended from totipotent stem cells and can be found in children and adults. Multipotent stem cells can form different types of specialized cells, but only within a closely related family of cells. Blood-forming stem cells are an example of multipotent stem cells. Most adult stem cells are multipotent.

Because adult stem cells are pluripotent, they will differentiate into many different types of cells that may or may not be useful in the person who receives them. Embryonic stem cells will produce a type of tumor if injected directly into another organism. There is the possibility of transplant rejection when embryonic stem cells are used. Experimentation with human embryonic stem cells is controversial because these stem cells are derived from early embryos, a practice which some people view as the destruction of a potential human being.

The use of adult stem cells in developing new treatments for various diseases is less controversial because these cells do not require the destruction of an embryo. In addition, adult stem cells can sometimes be taken from the body of the patient who will receive treatment, which eliminates the risk of transplant rejection. Most adult stem cells are multipotent and are derived from specific tissues; a few are pluripotent and are found mostly in bone marrow and the blood from a newborn's umbilical cord * . Cord blood can be harvested shortly after a baby's birth and stored in a public (cost-free) or private (for-profit) blood bank.

THE CONTRIBUTIONS OF RITA LEVI-MONTALCINI

The developmental biologist Rita Levi-Montalcini (1909–2012) was born in Turin, Italy, in 1909 and graduated from the medical school there in 1936. She went to work with her professor, Giuseppe Levi, but her career was cut short by a decree from Italian dictator Benito Mussolini and subsequent laws barring non-Aryan Italians from working in universities or practicing medicine. Not one to be deterred, she continued her research from a laboratory she set up in her bedroom.

In 1946, Levi-Montalcini went to work at Washington University in St. Louis, Missouri, where she stayed for 30 years. During that time, she discovered the nerve growth factor, which was the first growthregulating signal substance to be discovered. That discovery helped increase the understanding of degenerative diseases and opened the way to stem cell and regenerative medicine. In 1986, Levi-Montalcini and her collaborator Stanley Cohen received the Nobel Prize in Physiology or Medicine for their discoveries of nerve growth factor (NGF) and epidermal growth factor (EGF).

Some therapies based on the use of adult stem cells, such as bone marrow transplants for leukemia * * , multiple sclerosis * , hearing loss, and type 1 diabetes.

Stem cell research is conducted by using cells from a stem cell line, which is a family of dividing cells created from a single stem cell. The cells can be maintained in vitro for long periods in a laboratory. Embryonic stem cells are detached as single cells from the mass of cells at the center of the embryo and placed on a low laboratory container known as a Petri dish. The stem cell is provided with nutrients and growth factors—proteins that stimulate cell growth—that enable it to continue to divide without differentiating into specialized cells. Stem cells are cultured * in a high-humidity environment in an incubator at body temperature (about 98° F or 36° C).

Clinical translation

Clinical translation, or translational medicine, is the process of moving research in regenerative medicine into clinical trials using human volunteers. It emerged as a way to speed up moving discoveries in the laboratory into actual practical applications. In the past, doctors involved in research worked in different settings (usually universities or government institutes) from those who worked on turning basic scientific discoveries into useful new drugs or medical devices. Translational medicine aims to provide benefits to society as quickly as possible by linking basic discoveries to clinical investigation, and then translating the results of clinical trials into changes in actual medical or surgical practice.

What Are the Issues Involved in Regenerative Medicine?

Political and social issues

Regenerative medicine sparked a number of heated debates in the area of public policy as well as medicine and religion, most of which focused on embryonic stem cell research. Major issues surrounding stem cell research include questions as to whether limiting stem cell research is heartless and anti-scientific. Celebrities such as Christopher Reeve (paralyzed in an accident) and Michael J. Fox (diagnosed with Parkinson's disease * ) have tried to convince the public that embryonic stem cells hold the promise of cures for all kinds of diseases within the near future. Newspaper editorials have used such words as “medical miracles” and even “magic” to describe the potential of embryonic stem cell research.

In November 2007 the debate over embryonic stem cells was changed by the announcement that teams of scientists in Japan and the United States had developed a technique for producing induced pluripotent stem cells, or iPSCs. Induced pluripotent stem cells are essentially adult stem cells from human skin that have been “reprogrammed” by gene therapy viruses that contain four reprogramming factors. The skin cells are transformed over a two-week period into pluripotent stem cells that have the same properties as human embryonic stem cells. A major advantage of iPSCs is that no embryo is formed and no embryo is destroyed to create them.

The following political and social questions are related to regenerative medicine:

SCIENTIFIC FRAUD: HWANG WOO-SUK

A major case of scientific fraud in South Korea cast a shadow on embryonic stem cell research around the world in 2004 and 2005. Hwang Woo-Suk (1953–), a veterinarian who became involved in biotechnology, claimed to have created a stem cell line from a cloned human embryo and to have generated 11 stem cell lines specific to individual patients from cloned human embryos. Hwang had become a respected leader in the field of animal cloning in 1999, when he claimed to have successfully cloned a dairy cow. If his cloning of a human embryo had been true, it would have made cloning a possible approach to developing routine treatments for human diseases.

By the fall of 2005, some of Hwang's colleagues began to ask questions about his research, and by December 2005, investigators showed beyond doubt that his cloned stem cell lines were fakes. Hwang was also investigated for misusing government funding for his own purposes and for forcing some of his younger female colleagues to donate their eggs for his research. Moreover, the discovery of his fraud was a political as well as scientific embarrassment because Hwang had made international headlines by publicly criticizing President George W. Bush's policy on embryonic stem cell research in May 2005. The Hwang episode demonstrates that the large sums of money and political influence attached to scientific research in the early 21st century could cause some people to mislead the public about the current state of regenerative medicine or even to commit outright fraud.

Medical and scientific issues

Some scientific issues in regenerative medicine have been discussed, such as the development of induced pluripotent stem cells and newer advances in tissue engineering. A number of scientific problems remain:

As of 2016, stem cells were being used for life-saving treatments for patients with leukemia, lymphoma, other blood disorders, and some solid tumors. Stem cell technology has been used for more than 20 years in bone marrow transplants, in which the patient's bone marrow stem cells are replaced with those from a healthy, matching donor. If the transplant is successful, the stem cells will migrate into the patient's bone marrow and begin producing new, healthy leukocytes (white blood cells) to replace the abnormal cells.

Adult stem cells are being harvested from the bloodstream to produce peripheral blood stem cells (PBSCs). While most blood stem cells reside in the bone marrow, a small number are present in the bloodstream. PBSCs can be obtained directly from blood, making them easier to collect than bone marrow stem cells. The problem is that PBSCs are limited, so collecting enough to perform a transplant can be challenging.

The stem-cell-rich blood found in the umbilical cord has proven useful in treating the same types of health problems as those treated using bone marrow stem cells and PBSCs.

A good deal of basic research in cell biology remains to be done to expand the use of stem cells to control or cure diseases.

Religious issues

Many people who object to the destruction of embryos do not have any ethical objections to the use of adult stem cells or the development of iPSCs for regenerative medicine. Another possibility that is more acceptable on religious grounds is the use of cells obtained from the fluid in the amniotic sac * . In January 2007, researchers at Wake Forest University discovered a new type of stem cell in amniotic fluid. These cells could be removed from the fluid without causing the death of an embryo.

People concerned with the religious ramifications of stem cell research note that respect for human life implies the equality of all human life. Many are concerned that accepting the destruction of human embryos for scientific research in the hopes of lowering healthcare costs will lead by degrees to the acceptability of such “cost-saving” measures as the euthanasia of people with terminal illnesses.

Another concern of this same group of people is based on history: the dark side of medical experimentation on humans in the 20th century. The Tuskegee experiments on African American men with untreated syphilis (1932–1972); the infamous experiments by German doctors in Nazi concentration camps in the 1940s; and the Japanese experiments conducted on prisoners of war in the 1930s and 1940s all show that human beings in positions of power can act without any concern for moral standards. It is not surprising that healthcare authorities in many developed countries set up regulatory frameworks for research in regenerative medicine in the hope of preventing future abuses of this type.

What Are the Possibilities of Regenerative Medicine?

The Department of Health and Human Services published a report in 2005 titled 2020: A New Vision: A Future for Regenerative Medicine. Much of the report is taken up with discussion of such political concerns as FDA oversight of products and devices used in regenerative medicine; coordination of research among the dozen federal agencies currently involved in regenerative medicine; and cooperation among universities, private industry, and the government. The report outlines some goals for regenerative medicine in the United States by 2020:

Stem Cell Research and Teeth

A team of researchers are studying the role of stem cells in repairing or replacing teeth. These researchers looked at the process of tooth growth in laboratory rats and surmised that the stem cells in the rodents are never permitted to become dormant. In humans, dental stem cells of the molars (the large flat teeth at the back of the mouth) stop developing after crown (the part of the tooth covered by enamel) formation. The researchers want to use the knowledge of rodent dentition to learn how to reactivate human dental stem cells and regrow part of the molar roots.

* diseases as heart disease and diabetes rather than periodic treatments. Much of the current high cost of health care in the United States involves managing these diseases and treating their complications.
  • Speeding up laboratory development of whole organs for transplant as well as the creation of “patches” of engineered tissue to solve the growing gap between the need for organ transplants and the number of donated organs available.
  • Investigating treatments that might prevent tissue and organ damage before it starts.
  • See also Aging • Cancer: Overview • Leukemia • Lymphoma • Wounds

    Resources

    Books and Articles

    Atala, Anthony, et al., editors. Principles of Regenerative Medicine. 2nd ed. Waltham, MA: Academic Press, 2010.

    Devolder, Katrien. The Ethics of Embryonic Stem Cell Research. London: Oxford University Press, 2015.

    Knoepfler, Paul. Stem Cells: An Insider's Guide. Singapore: World Scientific Publishing Company, 2013.

    Krimsky, Sheldon. Stem Cell Dialogues: A Philosophical and Scientific Inquiry into Medical Frontiers. New York: Columbia University Press, 2015.

    Stoltz, Jean François, et al. “Stem Cells and Regenerative Medicine: Myth or Reality of the 21st Century.” Stem Cells International, May 2015. http://www.hindawi.com/journals/sci/2015/734731/ (accessed March 12, 2016).

    Websites

    International Society for Stem Cell Research. “Learn about Stem Cell Treatments.” http://www.isscr.org/visitor-types/public/aboutstemcell-treatments (accessed March 12, 2016).

    National Institute of Biomedical Imaging and Bioengineering. “Tissue Engineering and Regenerative Medicine.” National Institutes of Health. http://www.nibib.nih.gov/science-education/science-topics/tissueengineering-and-regenerative-medicine (accessed March 12, 2016).

    National Institutes of Health. “Stem Cell Information.” (accessed March 12, 2016).

    Organizations

    California Institute for Regenerative Medicine. 210 King St., San Francisco, CA 94107. Telephone: 415-396-9100. Website: https://www.cirm.ca.gov (accessed March 12, 2016).

    Institute for Stem Cell Biology and Regenerative Medicine. Stanford School of Medicine, 265 Campus Dr., 3rd Floor, Stanford, CA 94305. Telephone: 650-736-8325. Website: http://stemcell.stanford.edu (accessed March 13, 2016).

    McGowan Institute for Regenerative Medicine. 450 Technology Dr., Suite 300, Pittsburgh, PA 15219. Telephone: 412-624-5500. Website: http://www.mirm.pitt.edu (accessed March 13, 2016).

    National Institutes of Health. 9000 Rockville Pk., Bethesda, MD 20892. Toll-free: 800-411-1222. Website: http://www.nih.gov (accessed March 13, 2016).

    U.S. Food and Drug Administration. 10903 New Hampshire Ave., Silver Spring, MD 20993. Toll-free: 888-463-6332. Website: http://www.fda.gov (accessed March 13, 2016).

    Wake Forest Institute for Regenerative Medicine. Medical Center Blvd., Winston-Salem, NC 27157. Telephone: 336-716-2011. Website: http://www.wakehealth.edu/WFIRM (accessed March 13, 2016).

    * in vitro means in the laboratory or other artificial environment rather than in the living body.

    * stem cell is an unspecialized cell that gives rise to differentiated cells.

    * ethical means having to do with questions of what is right and wrong, or with moral values.

    * cloning (KLOH-ning) is a process in which a group of cells or even an entire organism is grown from a single stem cell and is genetically identical to it.

    * metabolism (meh-TAB-o-liz-um) is the process in the body that converts foods into the energy necessary for body functions.

    * carbohydrates are the nutrients in food that help provide energy to the body.

    * immune system (im-YOON SIStem) is the system of the body composed of specialized cells and the substances they produce that help protect the body against disease-causing germs.

    * enzyme (EN-zime) is a protein that helps speed up a chemical reaction in cells or organisms.

    * differentiation (DIF-feh-rent-seeAY-shun) is the process in which embryonic or adult stem cells give rise to more specialized cells.

    * embryo (EM-bree-o), in humans, is the developing organism from the end of the second week after fertilization to the end of the eighth week.

    * umbilical (um-BIH-lih-kul) cord is the flexible cord that connects a baby to the placenta, the organ that unites the unborn child to the mother's uterus, the organ in which the baby develops.

    * leukemia (loo-KEE-me-uh) is a form of cancer characterized by the body's uncontrolled production of abnormal white blood cells.

    * lupus (LOO-pus) is a chronic, or long-lasting, disease that causes inflammation of connective tissue, the material that holds together the various structures of the body.

    * multiple sclerosis (skluh-ROsis), or MS, is an inflammatory disease of the nervous system that disrupts communication between the brain and other parts of the body. MS can result in paralysis, loss of vision, and other symptoms.

    * cultured (KUL-churd) when referring to cells means growing the cells under carefully controlled conditions, in most cases outside their natural environment.

    * Parkinson's disease is a disorder of the nervous system that causes shaking, rigid muscles, slow movements, and poor balance.

    * amniotic sac (AM-nee-AH-tik SAK) is the sac formed by the amnion, the thin but tough membrane that lines the outside of the embryo in the uterus and is filled with fluid to cushion and protect the embryo as it grows.

    * chronic (KRAH-nik) means lasting a long time or recurring frequently.

    Disclaimer:   This information is not a tool for self-diagnosis or a substitute for professional care.

    (MLA 8th Edition)