Medical Device Daily Washington Editor

Stem cells are back in the news with the announcement yesterday that a team at the Massachusetts General Hospital Cardiovascular Research Center (MGHCRC; Boston) has isolated an embryonic stem cell that is the progenitor of three vital cell types in the heart, namely cardiac muscles, smooth muscles and endothelial cells. However, according to the lead researcher, device makers need not fear. These advances will not march into the thorax unaided, but will need devices for delivery and facilitation regardless of the ‘gee-whiz’ factor behind stem cell therapy.

Kenneth Chien, MD, director of the MGHCRC, said that the discovery of these embryonic stems cells in mice is “really the beginning of a different direction in cardiovascular therapy.” He described the breakthrough as providing medical science with “a renewable resource” because these stem cells can be cloned in the lab.

Needless to say, hurdles remain. Chien said that the so-called master cardiac stem cell is “extremely rare” and has, as yet, to demonstrate in vivo capability. The next phase of the research will be to expand and differentiate the pool of these cells and see how they behave in application.

Chien also cautioned against hope-inflating hype by pointing out that while “human cells respond similarly” to those of mice, the idea that the human version will prove out the same way remains to be tested. However, the team at MGHCRC is pursuing this aggressively.

As controversial as embryonic stem cells are, the inevitable next question is whether these master cells or any others are found in adult hearts. The odds of this are “extremely low,” Chien said.

“There are a small numbers of islet-positive cells in the adult heart,” he noted, and while another research group is looking into this, Chien did not see its prospects as robust. “My own thinking is that in the end, embryonic cells will be the preferred route” because they are substantially easier to work with. “It’s just a matter of time before we can differentiate these cells” into something with therapeutic value, he said.

The route of administration and the precise mechanism of effect are not cast in stone. Chien said that while a section of heart muscle could be grown in a dish or that stem cells could be injected into a sick heart, a matrix of cells could also be applied to the external surfaces of heart tissue to obtain a therapeutic effect. “These stem cells can secrete (various) factors without having to become cardiovascular cells,” he said, adding that “one of the interesting directions to take is to see whether this will be of value in preventing thrombosis.” Chien characterized the use of endothelial cells in combination with devices as “a very intriguing area.”

Despite all the promising implications, the notion of growing an entire heart in vitro is not on the horizon due to the numerous inputs needed to get stem cells to form the desired tissue type. “Maybe components, but not the entire heart” could be regenerated this way.

“I don’t think the problem of regenerative medicine will be answered by stem cells alone,” Chien remarked. The task of creating wholly new organs outside the body is outside the realm of plausibility at present, and further advances will inevitably call on innovation from device makers.

“Devices and stem cells are two tectonic plates that have come together,” Chien observed. “I think the two areas need each other” to bring modern technology from the lab to the patient.

Anticarcinogenic to piggyback on nanomatter

Society might not be ready for nanomatter, but nanomatter and the scientists who are working with it are getting ready to have a big impact on medicine. An article appearing in the Nov. 15 edition of Clinical Cancer Research details the work of a multidisciplinary team of 15 researchers at the University of Michigan Health System (UMHS; Ann Arbor) in their efforts to deliver a photo-reactive agent to take the bite out of brain tumors. According to one of the researchers, this approach could serve as a vehicle for a wide range of cancer detection and treatment modes in the years to come.

The team of researchers sought to attack cancer in a manner that would cut down on systemic exposure in connection with the use of a photo-reactive agent, Photofrin, made by Axcan (Mont-Saint-Hilaire, Quebec). Photofrin (porfimer sodium) takes the increasingly popular route to tumor shrinkage, that of inflicting damage to tumor vasculature. In this case, the drug substance does its work only when exposed to low-intensity laser light.

Axcan nailed down an FDA approval for Photofrin in 2003 for treatment of pre-cancerous dysplasia in Barrett’s esophagous, a condition in which the lining of the lower third of the esophagous reacts to esophageal reflux by morphing into tissue normally found in the small intestine. The problem with this adaptation is that if any cells in the affected tissue sustain sufficient genetic damage, they could proliferate into an esophageal adenocarcinoma, which is occasionally fatal.

The team at UMHS had been working on this concept for a year or two when they noticed a paper on a binding protein known as F3 that appeared three years ago in the Journal of Cell Biology. The article prompted the researchers to investigate whether this protein might be coupled with Photofrin to attack brain tumors. F3 binds to endothelial cells in blood vessels, but also to a receptor called nucleolin, which is commonly found on the surface of a cancer cell known as MDA 435. As chance would have it, researchers have identified this cell on the surfaces of some breast cancer tumors as well several brain tumors.

The primary motive for using nanomaterial to deliver Photofrin to these MDA 435 cells was to insulate health tissue from the effects of the Photofrin, which makes the patient’s entire body extraordinarily sensitive to sunlight when injected systemically. Brian Ross, PhD, the co-director of the Center for Molecular Imaging at UMHS, told Medical Device Daily that the nanoparticle they used is made from polyacrylamide, “prepared using a microemulsion chemical approach so that the drug can be encapsulated.”

“We think that the concept could work for most tumor types because this receptor is over-expressed in tumor vasculature in general,” Ross said. Scientists have not yet deduced why so many tumors express nucleolin on their surfaces, but he said that the question is under investigation.

Once the nanoparticles have parked on the tumor cells, a physician activates the laser wand to trigger the Photofrin. Thankfully, the drug requires only a small dose of laser energy to do its work, allowing physicians to employ a wand that is “a fiber optic cable half a millimeter in diameter in diameter,” Ross said. The opening in the skull necessary to get such an item inside is a millimeter or less in diameter, making this a procedure that ranks fairly low on the invasiveness scale.

The UMHS team has not investigated how effective this approach might be for deep brain tumors, such as astrocytomas that attach to the brain stem, but Ross did not rule out such applications.

“The fact that it’s a multifunctional mode allows a diverse set of opportunities to be explored, including early detection and diagnosis,” Ross noted, and he found “the concept of using it as a diagnostic tool intriguing.” This approach could make use of photon and positron emissions that are already in use with SPECT and PET scanners.

As for the payload for this kind of “nano” delivery vehicle, Ross opined that “[t]he sky is the limit.” Now it’s just a question of how long it will take to bring such advances into the clinical setting.