Promising cell therapy applications pose more questions than answers

  • Orthopedics Today, November 2013

With few — but encouraging — human clinical studies, researchers remain cautiously optimistic about the use of cell therapy in orthopedics.

“I foresee a bright future for the use of cell therapy in orthopedic applications. We are paving the way to ultimately develop systems in which cells can be used to induce and or accelerate tissue healing,” the director of The New England Musculoskeletal Institute and Chairman of the Department of Orthopaedic Surgery at the University of Connecticut, Augustus D. Mazzocca, MS, MD, told Orthopedics Today.

According to Mazzocca and George F. Muschler, MD, to use the term “stem cells” to define the cells that may be used in therapy is incorrect. The cells used in most therapies will not have the capacity to “self renew” or perpetuate themselves indefinitely, which is the defining feature of a true stem cell, Muschler, of the Lerner Research Institute’s Department of Biomechanical Engineering and orthopedic surgeon at Cleveland Clinic in Ohio, noted.

“The biological term, ‘stem cell,’ has fallen into a state of gross misuse in much of the recent literature,” Muschler said. “Virtually all of the cell populations that we currently target or transplant with our therapies should be called progenitor cells, not stem cells. The term stem cell is sexy, but it is just not accurate.”

George F. Muschler, MD, noted that several terms have been used to define purified cell populations that have been culture expanded in the laboratory, and the potential uses of these cell populations are only beginning to be tested in clinical trials.

George F. Muschler, MD, noted that several
terms have been used to define purified cell
populations that have been culture expanded
in the laboratory, and the potential uses of
these cell populations are only beginning to be
tested in clinical trials.

Image: The Cleveland Clinic

A progenitor cell is defined as a cell that can proliferate and generate progeny that may be able to differentiate into the desired tissue. The class of progenitors most important to orthopedic surgeons are those that are already present in native tissues, the connective tissue progenitors or CTPs. A CTP has the potential to be activated and then proliferate to give rise to progeny that can differentiate into one or more connective tissues such as bone, cartilage, muscle, fat or blood, according to Muschler. Endothelial progenitors, that proliferate to regenerate vascular endothelium during revascularization, are another key progenitor cell population that contribute to all tissue regeneration, including connective tissues.

Tissue CTPs are a heterogeneous class of cells that are found in multiple locations in vivo, he noted. CTP populations often demonstrate different properties, depending on the tissue source or site from which they are harvested. These sites include marrow, periosetum, endosteum and cartilage. They also include vascular pericytes found in fat, muscle and other tissues.

In contrast to the heterogeneous mix of cells in native tissues, several terms have been used to define purified cell populations that have been culture expanded in a laboratory. Mesenchymal stem cells (MSCs) are defined as a cell population that has been expanded in culture under conditions that create a population of cells that homogeneously express a defined set of cell surface markers and have the capacity to differentiate in culture into several connective tissue phenotypes. Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are another classes of culture expanded cells, which have more extensive capacity for proliferation and differentiation, according to Muschler. The potential uses of culture expanded cell populations is only beginning to be tested in clinical trials, he noted.

FDA regulations

Current FDA regulation stemming from The United States of America v. Regenerative Sciences LLC, Christopher J. Centeno, MD, John R. Schultz, MD, and Michelle R. Cheever prevent the removal, manipulation expansion and reimplantation of human cells without an FDA-approved clinical trial, according to Lawrence V. Gulotta, MD, of Hospital for Special Surgery in New York City and C. Thomas Vangsness Jr., MD, of the University of Southern California in Los Angeles. The FDA pursued these rules as part of their charge to ensure the safety and efficacy of new medical products, according to Muschler.

“Testing in clinical trials is limited by the high cost of executing clinical trials. Development and testing of cell therapy products is also limited by the lack of clearly defined consensus around the standards and quantitative metrics that should be used to define the nature of cells being used, and the methods and standards that should be used to screen cells for biological hazards, such as infection or mutations. This creates great uncertainty regarding the regulatory pathway that will be required now and in the future. Development is also challenged by uncertainty regarding the environment around reimbursement for these new therapies,” Muschler told Orthopedics Today.

Lawrence V. Gulotta

Lawrence
V. Gulotta

Vangsness cited work by Paul Lu, PhD, and colleagues in which they discovered that neural stem cells allowed paralyzed rats to walk again. However, Vangsness noted that Neuralstem (Rockvalle, Md.), a company developing neural stem cell treatment, has yet to get FDA approval.

The high cost of conducting the clinical trials needed to prove the safety and efficacy of stem cell products has also deterred many companies from investing in these projects, according to Vangsness, who noted that some stem cell companies have gone out of business trying to get their products to market.

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