Regenerative Medicine: Are We There?

More than 84,000 people in the U.S. are waiting for organ transplants.¹ Is it possible that within the next couple of decades, transplant waiting lists could be eliminated? That’s the goal of the promising new field of regenerative medicine. Up until now, medicine has been all about replacements. If your kidney isn’t working, replace it with another one. But, with regenerative medicine, the cause is treated, and structure and function are restored to damaged tissues and organs using tissue from synthetic materials and patients’ own existing organs. While this new science is just on the cusp of changing the treatment landscape, organs are already being grown in the laboratory and implanted into patients today. Regenerative medicine is all about harnessing the power of the body to heal, dramatically improving medical care for millions and saving millions in medical costs.

Regenerative Medicine Defined

Regenerative medicine evolved from the field of tissue engineering, which is the “practice of combining scaffolds, cells and biologically active molecules into functional tissues.” Regenerative medicine includes tissue engineering but also incorporates research on self-healing, using the body’s own systems, sometimes with the help of foreign biological materials, to recreate cells and rebuild tissues and organs. Bot focus on cures instead of treatments for complex, often chronic, diseases.²

In 2006, the National Institutes of Health defined regenerative medicine as “the process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage or congenital defects.”³ The field encompasses three separate approaches to augment, repair, replace or regenerate organs and tissues: cell-based therapies, small molecules and biologics and synthetic and bio-based materials. With cell-based therapies, living cells replace damaged or diseased cells and/or tissue, stimulate healing and regeneration in diseased tissue, and deliver small molecule therapies to targeted areas. The use of chemicals and cellular components in small molecules and biologics induce dormant cells to regain regenerative properties. Synthetic and bio-based materials are implanted into the body for reconstructive purposes such as joint replacement, bone repair, artificial ligaments and tendons, dental implants, heart valves and wound repair. These materials work in partnership with native cells to support reconstruction and healing.⁴

A Growing Industry

In 2012, the Alliance for Regenerative Medicine (ARM), the national voice for regenerative medicine, estimated the industry to include more than 700 companies in the fields of biology, chemistry, engineering and physical sciences. Forty-three percent of these companies are developing regenerative medicines (cell- and tissue-based therapies: 65 percent; regenerative compounds and devices: 25 percent; biopharmaceuticals: 10 percent). Another 48 percent are developing tools and nontherapeutic products. And, 9 percent are companies providing services and manufacturing.

Also in 2012, there were approximately 300 cell- and tissue-based therapeutics commercially available or in clinical development around the world. Fifty-five of the available products are described and marketed as regenerative medicine products. Products commercially available are for musculoskeletal/orthopedic (38 percent), wound/noncardiac ischemic (26 percent), skin/soft tissue (15 percent), ocular (11 percent), cardiac (4 percent), oncology (3 percent) and diabetes (3 percent). And, all but one of the top-15 regenerative medicine products are for skin, wound, bone or cartilage repair, used to treat more than 500,000 patients through the end of 2011.

The United States boasts the greatest number of companies developing regenerative medicine products, as well as has the greatest number of those products in ongoing trials. The greatest number of products are in Phase II clinical trials (45 percent).  Those in late-stage trials (Phase II/II, III and pivotal) include musculoskeletal/orthopedic products (34 percent), oncology (27 percent), wound/noncardiac ischemic (15 percent), cardiac (15 percent), ocular (2 percent) and other (7 percent).⁴

The Role of Stem Cells

Stem cells — key components of regenerative medicine — are self-renewing primitive cells that are able to develop into functional, differentiated cells. In other words, they are able to branch out and change. The two broad categories of stem cells are adult stem cells and embryonic stem (ES) cells. Adult stem cells are referred to as “multipotent” (also known as mesenchymal) cells because they can develop into multiple, but not all, types of cells in the body. ES cells, which are derived from preimplantation embryos, are unique because they are “pluripotent,” meaning they can develop into all cells and tissues in the body, and they self-renew indefinitely in their undifferentiated state.⁵

Regenerative medicine researchers are studying both ES and adult stem cells. They are also looking at various types of progenitor cells, described as “oligopotent,” meaning they can differentiate to form one or more kinds of cells but cannot divide and reproduce indefinitely, which means they are more limited than stem cells. Also under study are bioengineered cells called “induced pluripotent” stem cells.⁶

The most common regenerative therapies using stem cells begin with a patient’s own cells. Once collected, these cells are grown in large quantities in the lab and injected back into the patient. A number of products developed with stem cells are currently on the market, including Provenge (Dendreon) for prostate cancer, Apligraf (Novartis) to treat diabetic foot ulcers, Carticel (Genzyme) to replace knee cartilage, Gintuit (Organogenesis) to promote healing after gum surgery and Fibrocell (Fibrocell Science) to replace fibroblasts. In addition, some of the most advanced clinical trials of products developed with stem cells involve treating congestive heart disease and regrowing muscles in soldiers who were wounded in explosions.⁷

In hopes of creating new therapies, scientists have been searching for ways to control how stem cells develop into other cell types. Recently, researchers at the National Institute of Biomedical Imaging and Bioengineering discovered that confining the growth of pluripotent cells in different types of defined spaces triggered very specific gene networks that determined the ultimate fate for the cells, which may help to harness stem cells for medical uses.²

From Skin to Organs

Since the first derivation of primary embryonic stem cells in 1995 and the first cloning of a mammal (Dolly the sheep) in 1996, this new field has achieved promising breakthroughs.

In 2007, the Armed Forces Institute of Regenerative Medicine (AFIRM) was created by the U.S. Army Medical Research and Materiel Command to lead the efforts to develop advanced regenerative medicine techniques for injured U.S. military personnel. Dr. Rocky Tuan, founding director of the Center for Military Medicine Research at the University of Pittsburgh and co-director at AFIRM, says the institution currently has more than 60 projects in its portfolio. One of these is skin regeneration, which includes treating burns and scars that are common among injured service personnel. Regenerative medicine does away with skin transplants and instead allows skin to grow back naturally using the patient’s own cells. With the “spray-on” skin, doctors harvest a small piece of skin (smaller than what is required for grafts) that is broken down using an enzyme solution and sprayed back onto the damaged skin. The product, ReCell (marketed by Avita Medical), is one of a limited number of regenerative procedures.8

Another project at AFIRM involves regenerating cartilage. Osteoarthritis, a degenerative joint condition often associated with older generations, is becoming prevalent among soldiers due to the physical demands of operational tours, including carrying heavy loads over long distances. Earlier this year, Dr. Tuan unveiled a procedure for 3D print cartilage grown from human stem cells. Creating the artificial cartilage requires stem cells, biological factors to make the cells grow into cartilage and a scaffold. The 3-D printing extrudes thin layers of stem cells in a solution that retains its shape (acting as a scaffold) and provides growth factors.8 The 3-D technology to grow cartilage was first developed by researchers at St. Vincent’s

Hospital Melbourne, part of the University of Wollongong-headquartered Australian Research Council Centre of Excellence for Electromaterials Science (ACES). Their product uses scaffolds fabricated on 3-D printing equipment to grow cartilage over a 28-day period from stem cells extracted from tissue under the knee cap.⁹ Prior to this, the only product on the market for cartilage damage was Carticel (Genzyme), the first and only cell therapy that uses the patient’s own cartilage cells, called chondrocytes, and implants them into the damaged area that then grows to form new cartilage.⁸

Regrowing muscle on patients with leg injuries is also part of AFIRM’s projects. Dr. Stephen Badylak, a regenerative medicine specialist at the University of Pittsburgh, is testing implants of “extracellular matrix” (connective tissue that holds cells together) to boost muscle mass. The material, supplied by ACell Inc., comes from pigs and is thought to release chemical signals that promote regrowth of healthy tissue instead of scar tissue. A study of the treatment is measuring changes in strength and muscle volume, and in early testing, patients have shown up to 10 percent to 20 percent improvement in strength of the muscle after treatment.¹⁰

Using scaffold seeded with a patient’s own cells is a growing area of research. Scientists at the McGowan Institute at the University of Pittsburgh Medical Center are working on a method to encourage the growth of healthy tissue instead of scar tissue to reconstruct the esophagus and trachea (part of the food tube). In early studies, a damaged section of the food tube was replaced with a specially formed scaffold constructed from a material already being used in humans, and within 90 days, the scaffold was replaced with functional tissue. They are also developing scaffolds made of U.S. Food and Drug Administration (FDA)-approved biodegradable polymers and protein beads to help the peripheral nervous system regrow. The scaffolds act as guides for axons, the long arms of nerve cells, to grow longer and in the right directions. In early studies, a nerve guide seeded with stem cells derived from fat restored some hind leg mobility in paralyzed rats.¹¹

Much more other research in regenerative medicine is ongoing. Scientists at the University of Pittsburgh and Rice University are working on growing bone to fix jawbone and other facial defects. Researchers at Massachusetts General and Rutgers University are trying to grow eyelid muscles.¹⁰ And, in August, FDA gave approval to Asterias Biotherapeutics Inc. to begin a clinical trial of its stem cell therapy in patients with spinal cord injury. The Phase I/IIa clinical trial is a follow-on to the California Institute for Regenerative Medicine-funded trial begun by Geron Corp. in 2010, which was halted. This new trial will involve doses of stem cells up to 10 times greater than the initial study in which follow-up studies of the five patients have shown no serious side effects, and in four of five patients, MRI scans have shown that the actual injury site had shrunk and that the cells may have had some positive effects in reducing the deterioration of spinal cord tissue.¹²

The first success of regenerative medicine of organs in humans occurred in 2006 when scientists at Wake Forest University successfully implanted bladders grown in a laboratory into patients with bladder disease. Last year, a bioengineered windpipe was implanted into a 2-year-old girl, the youngest person ever to receive a lab-grown organ and only the sixth operation of its kind in the U.S.⁸

Other artificial organs are also being studied. In 2011, researchers at Japan’s RIKEN Center derived a working pituitary gland from mouse stem cells. To grow a working pituitary gland, a hypothalamus is needed. To overcome this, the researchers created a 3-D cell culture and tried combinations of signaling factors until it worked. They then implanted the lab-grown glands into mice with pituitary defects, and the mice quickly showed restored levels of key pituitary hormones, and behavioral symptoms of pituitary problems disappeared.¹³

This year, British scientists at the University of Edinburgh became the first in the world to grow a fully functional organ — a thymus — from scratch by transplanting cells originally made in a cell. They converted connective tissue cells from a mouse embryo directly into a completely different cell strain by flipping a genetic switch in their DNA. The resulting thymic epithelial cells were mixed with other thymus cell types and transplanted into mice, where they spontaneously organized themselves and grew into a whole structured organ. According to Professor Clare Blackburn of the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh: “The ability to grow replacement organs from cells in the lab is one of the ‘holy grails’ in regenerative medicine. But the size and complexity of lab-grown organs has been limited. By directly reprogramming cells, we’ve managed to produce an artificial cell type that, when transplanted, can form a fully organized and functional organ.”¹⁴

Policy and Legislation

Over the years, FDA has offered courses in regenerative medicine, including a two-day interactive course in 2006 titled “FDA’s Regulation of Regeneration Medicine including Stem Cell Treatments, Tissue Engineering and Gene Therapies” and its Regenerative Medicine Program, a multi-center fellowship in regenerative medicine.^15,16

FDA is the key gatekeeper for the regulatory pathway for regenerative medicine products. It rates each product by deconstructing the key components of each to determine which ones are most important in providing benefit to the patient. For example, if the regenerative medicine product consists of living cells that are delivered to the patient, it would be regulated as a cellular therapy. If it consists of cells that are genetically modified outside of the body and given to the patient, it would be considered gene therapy. If it consists of cells that are combined with a natural synthetic biomaterial, it would be regulated as a biologic-device combination product.¹⁷

In 2010, the National Institutes of Health established the NIH Center for Regenerative Medicine (NIH CRM), which according to its website, is currently “at a transition point.” In May, it held a workshop with leaders in the field to help prioritize challenges to be addressed. The goal of NIH CRM is to work through hurdles to the development of induced pluripotent stem cell therapies.¹⁸

In March, ARM introduced the Regenerative Medicine Promotion Act of 2014 in the U.S. Senate. Major provisions of the bill include creation of a multi-agency Regenerative Medicine Coordinating Council within the Department of Health and Human Services, and calling for a detailed assessment of federal activities in regenerative medicine, as well as progress compared with national programs in other countries. The goal of the bill is to outline a coordinated effort to allow the U.S. to “advance toward innovative, life-saving therapies and create the regulatory infrastructure necessary to encourage private investment in promising regenerative medicine research,” said Morrie Ruffin, managing director of ARM. “Dovetailing with this bill, ARM has outlined a national strategy for regenerative medicine and is seeking rapid implementation of these programs,” said Michael Werner, executive director of ARM. “To date, ARM has worked with the White House, the U.S. Food and Drug Administration, National Institutes of Health, National Institute of Standards and Technology and members of Congress to further define and promote adoption of this proposed strategy.”¹⁹

The Future of Medicine

Regenerative therapies are now being hailed as the future of medicine. According to ARM, “the promise of regenerative medicine is that altering the course of disease will eliminate the need for daily therapies, reduce hospitalizations and avert expensive medical procedures, thus enabling patients to lead healthier and more productive lives.” Much has been accomplished in the last two decades, with significant growth in the number of companies focused on regenerative medicine and considerably more research being conducted than mentioned in this article. “Regenerative medicine is not just a future hope,” says ARM. “It’s a reality today.”⁴