Regenerative medicine

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A colony of human embryonic stem cells Humanstemcell.JPG
A colony of human embryonic stem cells

Regenerative medicine deals with the "process of replacing, engineering or regenerating human or animal cells, tissues or organs to restore or establish normal function". [1] This field holds the promise of engineering damaged tissues and organs by stimulating the body's own repair mechanisms to functionally heal previously irreparable tissues or organs. [2]

Contents

Regenerative medicine also includes the possibility of growing tissues and organs in the laboratory and implanting them when the body cannot heal itself. When the cell source for a regenerated organ is derived from the patient's own tissue or cells, [3] the challenge of organ transplant rejection via immunological mismatch is circumvented. [4] [5] [6] This approach could alleviate the problem of the shortage of organs available for donation.

Some of the biomedical approaches within the field of regenerative medicine may involve the use of stem cells. [7] Examples include the injection of stem cells or progenitor cells obtained through directed differentiation (cell therapies); the induction of regeneration by biologically active molecules administered alone or as a secretion by infused cells (immunomodulation therapy); and transplantation of in vitro grown organs and tissues (tissue engineering). [8] [9]

History

The ancient Greeks postulated whether parts of the body could be regenerated in the 700s BC. [10] Skin grafting, invented in the late 19th century, can be thought of as the earliest major attempt to recreate bodily tissue to restore structure and function. [11] Advances in transplanting body parts in the 20th century further pushed the theory that body parts could regenerate and grow new cells. These advances led to tissue engineering, and from this field, the study of regenerative medicine expanded and began to take hold. [10] This began with cellular therapy, which led to the stem cell research that is widely being conducted today. [12]

The first cell therapies were intended to slow the aging process. This began in the 1930s with Paul Niehans, a Swiss doctor who was known to have treated famous historical figures such as Pope Pius XII, Charlie Chaplin, and king Ibn Saud of Saudi Arabia. Niehans would inject cells of young animals (usually lambs or calves) into his patients in an attempt to rejuvenate them. [13] [14] In the year 1956, a more sophisticated process was created to treat leukemia by inserting bone marrow from a healthy person into a patient with leukemia. This process worked mostly due to both the donor and receiver in this case being identical twins. Nowadays, bone marrow can be taken from people who are similar enough to the patient who needs the cells to prevent rejection. [15]

The term "regenerative medicine" was first used in a 1992 article on hospital administration by Leland Kaiser. Kaiser's paper closes with a series of short paragraphs on future technologies that will impact hospitals. One paragraph had "Regenerative Medicine" as a bold print title and stated, "A new branch of medicine will develop that attempts to change the course of chronic disease and in many instances will regenerate tired and failing organ systems." [16] [17]

The term was brought into the popular culture in 1999 by William A. Haseltine when he coined the term during a conference on Lake Como, to describe interventions that restore to normal function that which is damaged by disease, injured by trauma, or worn by time. [18] Haseltine was briefed on the project to isolate human embryonic stem cells and embryonic germ cells at Geron Corporation in collaboration with researchers at the University of Wisconsin–Madison and Johns Hopkins School of Medicine. He recognized that these cells' unique ability to differentiate into all the cell types of the human body (pluripotency) had the potential to develop into a new kind of regenerative therapy. [19] [20] Explaining the new class of therapies that such cells could enable, he used the term "regenerative medicine" in the way that it is used today: "an approach to therapy that ... employs human genes, proteins and cells to re-grow, restore or provide mechanical replacements for tissues that have been injured by trauma, damaged by disease or worn by time" and "offers the prospect of curing diseases that cannot be treated effectively today, including those related to aging". [21] [22]

Later, Haseltine would go on to explain that regenerative medicine acknowledges the reality that most people, regardless of which illness they have or which treatment they require, simply want to be restored to normal health. Designed to be applied broadly, the original definition includes cell and stem cell therapies, gene therapy, tissue engineering, genomic medicine, personalized medicine, biomechanical prosthetics, recombinant proteins, and antibody treatments. It also includes more familiar chemical pharmacopeia—in short, any intervention that restores a person to normal health. In addition to functioning as shorthand for a wide range of technologies and treatments, the term “regenerative medicine” is also patient friendly. It solves the problem of confusing or intimidating language discourage to patients.

The term regenerative medicine is increasingly conflated with research on stem cell therapies. Some academic programs and departments retain the original broader definition while others use it to describe work on stem cell research. [23]

From 1995 to 1998 Michael D. West, PhD, organized and managed the research between Geron Corporation and its academic collaborators James Thomson at the University of Wisconsin–Madison and John Gearhart of Johns Hopkins University that led to the first isolation of human embryonic stem and human embryonic germ cells, respectively. [24]

In March 2000, Haseltine, Antony Atala, M.D., Michael D. West, Ph.D., and other leading researchers founded E-Biomed: The Journal of Regenerative Medicine. [25] The peer-reviewed journal facilitated discourse around regenerative medicine by publishing innovative research on stem cell therapies, gene therapies, tissue engineering, and biomechanical prosthetics. The Society for Regenerative Medicine, later renamed the Regenerative Medicine and Stem Cell Biology Society, served a similar purpose, creating a community of like-minded experts from around the world. [26]

In June 2008, at the Hospital Clínic de Barcelona, Professor Paolo Macchiarini and his team, of the University of Barcelona, performed the first tissue engineered trachea (wind pipe) transplantation. Adult stem cells were extracted from the patient's bone marrow, grown into a large population, and matured into cartilage cells, or chondrocytes, using an adaptive method originally devised for treating osteoarthritis. The team then seeded the newly grown chondrocytes, as well as epithelial cells, into a decellularised (free of donor cells) tracheal segment that was donated from a 51-year-old transplant donor who had died of cerebral hemorrhage. After four days of seeding, the graft was used to replace the patient's left main bronchus. After one month, a biopsy elicited local bleeding, indicating that the blood vessels had already grown back successfully. [27] [28]

In 2009, the SENS Foundation was launched, with its stated aim as "the application of regenerative medicine – defined to include the repair of living cells and extracellular material in situ – to the diseases and disabilities of ageing". [29] In 2012, Professor Paolo Macchiarini and his team improved upon the 2008 implant by transplanting a laboratory-made trachea seeded with the patient's own cells. [30]

On September 12, 2014, surgeons at the Institute of Biomedical Research and Innovation Hospital in Kobe, Japan, transplanted a 1.3 by 3.0 millimeter sheet of retinal pigment epithelium cells, which were differentiated from iPS cells through Directed differentiation, into an eye of an elderly woman, who suffers from age-related macular degeneration. [31]

In 2016, Paolo Macchiarini was fired from Karolinska University in Sweden due to falsified test results and lies. [32] The TV-show Experimenten aired on Swedish Television and detailed all the lies and falsified results. [33]

Research

Widespread interest and funding for research on regenerative medicine has prompted institutions in the United States and around the world to establish departments and research institutes that specialize in regenerative medicine including: The Department of Rehabilitation and Regenerative Medicine at Columbia University, the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, the Center for Regenerative and Nanomedicine at Northwestern University, the Wake Forest Institute for Regenerative Medicine, and the British Heart Foundation Centers of Regenerative Medicine at the University of Oxford. [34] [35] [36] [37] In China, institutes dedicated to regenerative medicine are run by the Chinese Academy of Sciences, Tsinghua University, and the Chinese University of Hong Kong, among others. [38] [39] [40]

In Dentistry

A diagram of a human tooth. Stem cells are located in the pulp in the center. Human tooth diagram-en.svg
A diagram of a human tooth. Stem cells are located in the pulp in the center.

Regenerative medicine has been studied by dentists to find ways that damaged teeth can be repaired and restored to obtain natural structure and function. [42] Dental tissues are often damaged due to tooth decay, and are often deemed to be irreplaceable except by synthetic or metal dental fillings or crowns, which requires further damage to be done to the teeth by drilling into them to prevent the loss of an entire tooth.

Researchers from King's College London have created a drug called Tideglusib that claims to have the ability to regrow dentin, the second layer of the tooth beneath the enamel which encases and protects the pulp (often referred to as the nerve). [43]

Animal studies conducted on mice in Japan in 2007 show great possibilities in regenerating an entire tooth. Some mice had a tooth extracted and the cells from bioengineered tooth germs were implanted into them and allowed to grow. The result were perfectly functioning and healthy teeth, complete with all three layers, as well as roots. These teeth also had the necessary ligaments to stay rooted in its socket and allow for natural shifting. They contrast with traditional dental implants, which are restricted to one spot as they are drilled into the jawbone. [44] [45]

A person's baby teeth are known to contain stem cells that can be used for regeneration of the dental pulp after a root canal treatment or injury. These cells can also be used to repair damage from periodontitis, an advanced form of gum disease that causes bone loss and severe gum recession. Research is still being done to see if these stem cells are viable enough to grow into completely new teeth. Some parents even opt to keep their children's baby teeth in special storage with the thought that, when older, the children could use the stem cells within them to treat a condition. [46] [47]

Extracellular matrix

Extracellular matrix materials are commercially available and are used in reconstructive surgery, treatment of chronic wounds, and some orthopedic surgeries; as of January 2017 clinical studies were under way to use them in heart surgery to try to repair damaged heart tissue. [48] [49]

Cord blood

Though uses of cord blood beyond blood and immunological disorders is speculative, some research has been done in other areas. [50] Any such potential beyond blood and immunological uses is limited by the fact that cord cells are hematopoietic stem cells (which can differentiate only into blood cells), and not pluripotent stem cells (such as embryonic stem cells, which can differentiate into any type of tissue). Cord blood has been studied as a treatment for diabetes. [51] However, apart from blood disorders, the use of cord blood for other diseases is not a routine clinical modality and remains a major challenge for the stem cell community. [50] [51]

Along with cord blood, Wharton's jelly and the cord lining have been explored as sources for mesenchymal stem cells (MSC), [52] and as of 2015 had been studied in vitro, in animal models, and in early stage clinical trials for cardiovascular diseases, [53] as well as neurological deficits, liver diseases, immune system diseases, diabetes, lung injury, kidney injury, and leukemia. [54]

See also

Related Research Articles

Stem cell Undifferentiated biological cells that can differentiate into specialized cells

In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell in a cell lineage. They are found in both embryonic and adult organisms, but they have slightly different properties in each. They are usually distinguished from progenitor cells, which cannot divide indefinitely, and precursor or blast cells, which are usually committed to differentiating into one cell type.

An artificial organ is a human made organ device or tissue that is implanted or integrated into a human — interfacing with living tissue — to replace a natural organ, to duplicate or augment a specific function or functions so the patient may return to a normal life as soon as possible. The replaced function does not have to be related to life support, but it often is. For example, replacement bones and joints, such as those found in hip replacements, could also be considered artificial organs.

Tissue engineering Biomedical engineering discipline

Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biological tissues. Tissue engineering often involves the use of cells placed on tissue scaffolds in the formation of new viable tissue for a medical purpose but is not limited to applications involving cells and tissue scaffolds. While it was once categorized as a sub-field of biomaterials, having grown in scope and importance it can be considered as a field in its own.

Hematopoietic stem cell transplantation Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous, allogeneic or syngeneic.

Graft-versus-host disease Medical condition

Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.

Embryonic stem cell Pluripotent stem cell of the inner cell mass of the blastocyst

Embryonic stem cells are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells. Isolating the embryoblast, or inner cell mass (ICM) results in destruction of the blastocyst, a process which raises ethical issues, including whether or not embryos at the pre-implantation stage have the same moral considerations as embryos in the post-implantation stage of development.

Cell therapy Therapy in which cellular material is injected into a patient

Cell therapy is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-cells capable of fighting cancer cells via cell-mediated immunity in the course of immunotherapy, or grafting stem cells to regenerate diseased tissues.

Cord blood is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells, which can be used to treat hematopoietic and genetic disorders such as cancer. There is growing interest from cell therapeutics companies in developing genetically modified allogenic natural killer cells from umbilical cord blood as an alternative to CAR T cell therapies for rare diseases.

Adult stem cell Multipotent stem cell in the adult body

Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile, adult animals, and humans, unlike embryonic stem cells.

Stem-cell line Culture of stem cells that can be propagated indefinitely

A stem cell line is a group of stem cells that is cultured in vitro and can be propagated indefinitely. Stem cell lines are derived from either animal or human tissues and come from one of three sources: embryonic stem cells, adult stem cells, or induced stem cells. They are commonly used in research and regenerative medicine.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition. As of 2016, the only established therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone-marrow transplantation, but the cells can also be derived from umbilical cord blood. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes and heart disease.

An amniotic epithelial cell is a form of stem cell extracted from the lining of the inner membrane of the placenta. Amniotic epithelial cells start to develop around 8 days post fertilization. These cells are known to have some of the same markers as embryonic stem cells, more specifically, Oct-4 and nanog. These transcription factors are the basis of the pluripotency of stem cells. Amniotic epithelial cells have the ability to develop into any of the three germ layers: endoderm, mesoderm, and ectoderm. They can develop into several organ tissues specific to these germ layers including heart, brain, and liver. The pluripotency of the human amniotic epithelial cells makes them useful in treating and fighting diseases and disorders of the nervous system as well as other tissues of the human body. Artificial heart valves and working tracheas, as well as muscle, fat, bone, heart, neural and liver cells have all been engineered using amniotic stem cells. Tissues obtained from amniotic cell lines show promise for patients suffering from congenital diseases or malformations of the heart, liver, lungs, kidneys, and cerebral tissue.

Nova Southeastern University College of Dental Medicine

The Nova Southeastern University College of Dental Medicine is the dental school of Nova Southeastern University. It is located in Fort Lauderdale, Florida, United States. When it opened in 1997, it was the first new dental school to open in the United States in 24 years. It is the largest dental school in Florida. The school is accredited by the American Dental Association.

Neural tissue engineering is a specific sub-field of tissue engineering. Neural tissue engineering is primarily a search for strategies to eliminate inflammation and fibrosis upon implantation of foreign substances. Often foreign substances in the form of grafts and scaffolds are implanted to promote nerve regeneration and to repair damage caused to nerves of both the central nervous system (CNS) and peripheral nervous system (PNS) by an injury.

Dental pulp stem cells (DPSCs) are stem cells present in the dental pulp, which is the soft living tissue within teeth. They are pluripotent, as they can form embryoid body-like structures (EBs) in vitro and teratoma-like structures that contained tissues derived from all three embryonic germ layers when injected in nude mice. DPSCs can differentiate in vitro into tissues that have similar characteristics to mesoderm, endoderm and ectoderm layers. DPSCs were found to be able to differentiate into adipocytes and neural-like cells. These cells can be obtained from postnatal teeth, wisdom teeth, and deciduous teeth, providing researchers with a non-invasive method of extracting stem cells. As a result, DPSCs have been thought of as an extremely promising source of cells used in endogenous tissue engineering.

Adult mesenchymal stem cells (MSCs) are being used by researchers in the fields of regenerative medicine and tissue engineering, to artificially reconstruct human tissue which has been previously damaged. Mesenchymal stem cells have the capacity to become any type of fully developed cell, which can contribute to replacing muscle tissues or internal organs. To help discover the therapeutic uses of these stem cells they are grown in laboratories or by using medication to stimulate new cell growth within the human body. In MSC therapy the cells are extracted from the adult patient’s bone marrow via a procedure called bone marrow aspiration. This usually involves inserting a needle into the back of the patients hip bone and removing the sample from there. These cells are then grown under controlled in vitro conditions in a lab, so that they can multiply and same time mature( also referred to as differentiated. This process may take two to three weeks. The kind of mature, fully differentiated cell phenotype and the number of those cells created though this can be influenced in three ways. Firstly by varying the initial seed density in the culture medium, secondly through changing the conditions of the medium during expansion, and lastly through the addition of additives such as proteins or growth hormones to the culture medium. They are then harvested and put back into the patient through local delivery or systemic infusion.

Regenerative endodontics

Regenerative endodontic procedures is defined as biologically based procedures designed to replace damaged structures such as dentin, root structures, and cells of the pulp-dentin complex. This new treatment modality aims to promote normal function of the pulp. It has become an alternative to heal apical periodontitis. Regenerative endodontics is the extension of root canal therapy. Conventional root canal therapy cleans and fills the pulp chamber with biologically inert material after destruction of the pulp due to dental caries, congenital deformity or trauma. Regenerative endodontics instead seeks to replace live tissue in the pulp chamber. The ultimate goal of regenerative endodontic procedures is to regenerate the tissues and the normal function of the dentin-pulp complex.

Regeneration in humans is the regrowth of lost tissues or organs in response to injury. This is in contrast to wound healing, or partial regeneration, which involves closing up the injury site with some gradation of scar tissue. Some tissues such as skin, the vas deferens, and large organs including the liver can regrow quite readily, while others have been thought to have little or no capacity for regeneration following an injury.

Spinal cord injury research seeks new ways to cure or treat spinal cord injury in order to lessen the debilitating effects of the injury in the short or long term. There is no cure for SCI, and current treatments are mostly focused on spinal cord injury rehabilitation and management of the secondary effects of the condition. Two major areas of research include neuroprotection, ways to prevent damage to cells caused by biological processes that take place in the body after the insult, and neuroregeneration, regrowing or replacing damaged neural circuits.

Shimon Slavin

Shimon Slavin, M.D., is an Israeli professor of medicine. Slavin pioneered the use of immunotherapy mediated by allogeneic donor lymphocytes and innovative methods for stem cell transplantation for the cure of hematological malignancies and solid tumors, and using hematopoietic stem cells for induction of transplantation tolerance to bone marrow and donor allografts.

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Further reading

Non-technical further reading

Technical further reading