When cosmetic surgeon Allan Wu first heard the woman's complaint, he wondered if she was imagining things or making it up. A resident of Los Angeles in her late sixties, she explained that she could not open her right eye without considerable pain and that every time she forced it open, she heard a strange click—a sharp sound, like a tiny castanet snapping shut. After examining her in person at The Morrow Institute in Rancho Mirage, Calif., Wu could see that something was wrong: Her eyelid drooped stubbornly, and the area around her eye was somewhat swollen. Six and a half hours of surgery later, he and his colleagues had dug out small chunks of bone from the woman's eyelid and tissue surrounding her eye, which was scratched but largely intact. The clicks she heard were the bone fragments grinding against one another.



About three months earlier the woman had opted for a relatively new kind of cosmetic procedure at a different clinic in Beverly Hills—a face-lift that made use of her own adult stem cells. First, cosmetic surgeons had removed some the woman's abdominal fat with liposuction and isolated the adult stem cells within—a family of cells that can make many copies of themselves in an immature state and can develop into several different kinds of mature tissue. In this case the doctors extracted mesenchymal stem cells—which can turn into bone, cartilage or fat, among other tissues—and injected those cells back into her face, especially around her eyes. The procedure cost her more than $20,000, Wu recollects. Such face-lifts supposedly rejuvenate the skin because stem cells turn into brand-new tissue and release chemicals that help heal aging cells and stimulate nearby cells to proliferate.



During the face-lift her clinicians had also injected some dermal filler, which plastic surgeons have safely used for more than 20 years to reduce the appearance of wrinkles. The principal component of such fillers is calcium hydroxylapatite, a mineral with which cell biologists encourage mesenchymal stem cells to turn into bone—a fact that escaped the woman's clinicians. Wu thinks this unanticipated interaction explains her predicament. He successfully removed the pieces of bone from her eyelid in 2009 and says she is doing well today, but some living stem cells may linger in her face. These cells could turn into bone or other out-of-place tissues once again.



Dozens, perhaps hundreds, of clinics across the country offer a variety of similar, untested stem cell treatments for both cosmetic and medical purposes. Costing between $3,000 and $30,000, the treatments promise to alleviate everything from wrinkles to joint pain to autism. The U.S. Food and Drug Administration (FDA) has not approved any of these treatments and, with a limited budget, is struggling to keep track of all the unapproved therapies on the market. At the same time, pills, oils, creams and moisturizers that allegedly contain the right combination of ingredients to mobilize the body's resident stem cells, or contain chemicals extracted from the stem cells in plants and animals, are popping up in pharmacies and online. There's Stem Cell 100, for example, MEGA STEM and Apple Stem Cell Cloud Cream. Few of these cosmetics have been properly tested in published experiments, yet the companies that manufacture them say they may heal damaged organs, slow or reverse natural aging, restore youthful energy and revitalize the skin. Whether such cosmetics may also produce unintended and potentially harmful effects remains largely unexamined. The increasing number of untested and unauthorized stem cell treatments threaten both people who buy them and researchers hoping to conduct clinical trials for promising stem cell medicine.



When is a skin cream a drug?

So far, the FDA has only approved one stem cell treatment: a transplant of bone marrow stem cells for people with the blood cancer leukemia. Among the increasing number of unapproved stem cell treatments, some clearly violate the FDA's regulations whereas others may technically be legal without its approval. In July 2012, for example, the U.S. District Court upheld an injunction brought by the FDA against Colorado-based Regenerative Sciences to regulate just one of the company's several stem cell treatments for various joint injuries as an "unapproved biological drug product." The decision hinged on what constitutes "minimal manipulation" of cells in the lab before they are injected into patients. In the treatment that the FDA won the right to regulate, stem cells are grown and modified in the lab for several weeks before they are returned to patients; in Regenerative Sciences's other treatments, patients' stem cells are extracted and injected within a day or two. Regenerative Sciences now offers the legally problematic treatment at a Cayman Island facility.



Many stem cell cosmetics reside in a legal gray area. Unlike drugs and "biologics" made from living cells and tissues, cosmetics do not require premarket approval from the FDA. But stem cell cosmetics often satisfy the FDA's definitions for both cosmetics and drugs. In September 2012 the FDA posted a letter on its Web site warning Lancôme, a division of L'Oréal, that the way it describes its Genifique skin care products qualify the creams and serums as unapproved drugs: they are supposed to "boost the activity of genes," for example, and "improve the condition of stem cells." Other times the difference between needing or not needing FDA approval comes down to linguistic nuance—the difference between claiming that a product does something or appears to do something.



Personal Cell Sciences, in Eatontown, N.J., sells some of the more sophisticated stem cell–based cosmetics: an eye cream, moisturizer and serum infused with chemicals derived from a consumer's own stem cells. According to its website and marketing materials, these products help "make skin more supple and radiant," "reduce the appearance of fine lines and wrinkles around the eyes and lips," "improve cellular renewal" and "stimulate cell turnover for renewed texture and tone." In exchange for $3,000, Personal Cell Sciences will arrange for a participating physician to vacuum about 60 cubic centimeters (one quarter cup) of a customer's fat from beneath his or her skin and ship it on ice to American CryoStem Corp. in Red Bank, N.J., where laboratory technicians isolate and grow the customer's mesenchymal stem cells to around 30 million strong. Half these cells are frozen for storage; from the other half, technicians harvest hundreds of different kinds of exuded growth factors and cytokines—molecules that help heal damaged cells and encourage cells to divide, among other functions. These molecules are mixed with many other ingredients—including green tea extract, caffeine and vitamins—to create the company's various "U Autologous" skin care products, which are then sold back to the consumer for between $400 and $800. When the customer wants a refill, technicians thaw some of the frozen cells, collect more cytokines and produce new bottles of cream.



In an unpublished safety trial sponsored by Personal Cell Sciences, Frederic Stern of the Stern Center for Aesthetic Surgery in Bellevue, Wash., and his colleagues monitored 19 patients for eight weeks as they used the U Autologous products on the left sides of their faces. A computer program meant to objectively analyze photos of the volunteers' faces measured an average of 25.6 percent reduction in the volume of wrinkles on the treated side of the face. Analysis of tissue biopsies revealed increased levels of the protein elastin, which helps keep skin taut, and no signs of unusual or cancerous cell growth.



Only skin deep?

Supposedly, the primary active ingredients in the U Autologous skin care products are the hundreds of different kinds of cytokines they contain. Cytokines are a large and diverse family of proteins that cells release to communicate with and influence one another. Cytokines can stimulate cell division or halt it; they can suppress the immune system or provoke it; they can also change a cell's shape, modulate its metabolism and force it to migrate from one location to another like a cowboy corralling cattle. Researchers have only named and characterized some of the many cytokines that stem cells secrete. Some of these molecules certainly help repair damaged cells and promote cell survival. Others seem to be involved in the development of tumors. In fact, some recent evidence suggests that the cytokines released by mesenchymal stem cells can trigger tumors by accelerating the growth of dormant cancer cells. Personal Cell Sciences does not pick and choose among the cytokines exuded by its customers' stem cells—instead, it dumps them all into its skin care products.



Based on the available evidence so far, topical creams containing cytokines from stem cells pose far less risk of cancer than living stem cells injected beneath the skin. But scientists do not yet know enough about stem cell cytokines to reliably predict everything they will do when rubbed into the skin; they could interact with healthy skin cells in a completely unexpected way, just as the unintended interplay between calcium hydroxylapatite and stem cells produced bones in the Los Angeles woman's eye. Stern acknowledges that unusual tissue growth is a concern for any treatment based on stem cells and the chemicals they release. "Down the line, we want to continue watching that," he says. Unlike many other clinics, he and his colleagues have been keeping tabs on their patients through regular follow-ups. John Arnone, CEO of American CryoStem and founder of Personal Cell Sciences, says the fact that U Autologous skin care products contain such a diversity of cytokines does not bother him: "I've seen worse things out there. I've been putting this formulation for almost a year on myself prior to the study. I'm the best guinea pig here."



Beyond the considerable risks to consumers, unapproved stem cell treatments also threaten the progress of basic research and clinical trials needed to establish safe stem cell therapies for serious illnesses. By harvesting stem cells, subsequently nourishing them in the lab and transplanting them back inside the human body, scientists hope to improve treatment for a variety of medical conditions, including heart failure, neurodegenerative disorders like Parkinson's, and spinal cord injuries—essentially any condition in which the body needs new cells and tissues. Researchers are investigating many stem cell therapies in ongoing, carefully controlled clinical trials. Some of the principal questions entail which of the many kinds of stem cells to use; how to safely deliver stem cells to patients without stimulating tumors or the growth of unwanted tissues; and how to prevent the immune system from attacking stem cells provided by a donor. Securing funding for such research becomes all the more difficult if shortcuts taken by private clinics and cosmetic manufacturers—and the subsequent botched procedures and unanticipated consequences—imprint a stigma on stem cells.



"Many of us are super excited about stem cells, but at same time we have to be really careful," says Paul Knoepfler, a cell biologist at the University of California, Davis, who regularly blogs about the regulation of stem cell treatments. "These aren't your typical drugs. You can stop taking a pill and the chemicals go away. But if you get stem cells, most likely you will have some of those cells or their effects for the rest of your life. And we simply don't know everything they are going to do."