Now that they had their box, the Cytori team faced one more hurdle: finding suitable subjects. "There aren't good animal models for breast reconstruction after cancer," Hedrick says. "That's why we went to humans so soon."
They found their humans in Japan, where the company had connections to surgeons through their business partners.
As a top-up from Wired Magazine, a 27 minute audio interview was published by a Wired editor and the author of the article Sharon Begley. Actually the audio is quite nice and worth a listen- so you find it here-
But Japan made sense for another reason: There, the disfigurement of a mastectomy or lumpectomy is tantamount to social banishment. Much of a traditional woman's social life centers on public baths, and those whose breast cancer has left them deformed seldom go. When Keizo Sugimachi, a surgeon and president of Kyushu Central Hospital in Fukuoka, learned what Cytori was developing, he launched an investigator-initiated (.as opposed to Cytori-sponsored) trial, dubbed Restore 1.
Over the course of six months in 2006, he treated 20 women who'd had a partial mastectomy two to five years before. It was also the first clinical use of Cytori's Celution System. Hedrick assisted on nearly all of the procedures and helped orchestrate how each would progress. They developed it all on the fly, using a lot of guesswork. How much fat do you extract? How many cells do you add back into the mix? How do you combine the liposuctioned fat with enzymes and growth factors and the other magic potions (all trade secrets) in the Celution machine? Do you overtreat, giving a woman more cell-enhanced tissue than you think is needed in case some of it doesn't take? Where do you make the incision in the breast to inject the cells? How do you deal with scarring from the radiation most mastectomy patients get after surgery?
"I think we just guessed right," Hedrick says. "We solved a lot of the problems in the first operation. If it didn't work, it was because we put too much in, or didn't treat the scar, or didn't prepare the tissue bed right."
They got better with each case, improving the protocol as they went. In December 2007, Sugimachi told the San Antonio Breast Cancer Symposium that all 20 of the women in Restore I tolerated the procedure just fine, none had an immune response, and 79 percent were satisfied with the outcome. There was no significant loss of breast size between one month and the final assessment 12 months later.
That was a crucial barometer, given what happens when plastic surgeons inject fat alone, which was a popular cosmetic-surgery technique in the 1980s and 1990s: The injected fat tended to vanish into the surrounding tissue several weeks later like butter into the crannies of a hot English muffin. (Women who opted for this method were encouraged to think of breast enhancement like a dye job once the effect fades, go back for another session.) But Cytori's adipose stem cells stuck around.
This is because Cytori's cells are not becoming breast tissue, as you might assume if you heard that someone was using stem cells for boob jobs. You don't sprinkle the cells in petri dishes and come back in a few weeks to find a crop of breasts. Instead, the fat cells in the Celution mixture provide the volume, filling the divot in the lumpectomy, the missing quadrant in the quadran lectomy, or the empty skin pouch in the mastectomy.
Think of them as the big dumb grunts of the battalion. The regenerative cells in the mixture encourage the growth of a blood supply. They're the clever engineers who provide the supply lines that the fat cell grunts need to survive. And that combination is what promises to distinguish the breasts built with—and now let's switch to the more accurate term—adipose regenerative ceils from those built with fat injections alone. "If you give the tissue blood, it will survive and not be reabsorbed," Leuven University's Vranckx says. Sensation is about as good as before since the relevant nerves are in the skin and muscle (and, with luinpectomies, the nipple remains intact).
It's the cells' ability to induce the formation of blood vessels, however, that also makes them attractive as therapy for ischemic heart disease.
Although some researchers have claimed that adipose regenerative cells can differentiate into epithelial cells, which can form capillaries and other blood vessels, the evidence is pointing to something more modest but no less useful: The cells churn out proteins, among them vascular endothelial growth factor, that induce surrounding cells to form blood vessels. As a result, cells that had been starved for blood and therefore oxygen are suddenly awash in both.
If the science part of this was figuring out how to process the fat in the box, the art comes in doing the injections. You don't take a big syringe full of the stuff from the Celution machine and cram it into the breast as if you were filling a cannoli. You meticulously inject hundreds of tiny dollops, like a patissier making little rosettes with a piping tube on a fancy cake. To accomplish that, Cytori created the Cell-brush. It has a blunt tip to make tiny cuts that break the scar tissue, transforming it into a biological mesh. As the Cellbrush is moved, the surgeon turns a wheel, which releases the tissue half a cc at a time. "You do that hundreds of times and you create a lattice with stem cells," Hedrick says. Adds Calhoun, "It's really as close to sculpture as anything done in plastic surgery today." The injection area is not painful afterward, while the liposuction site is only slightly sore. Patients go home that same day.
A clinical trial in Europe in 2008 and 2009, called Restore 2, used the next generation of the Celution machines, also with tantalizing results. It studied women who'd had a partial mastectomy, including Irene MacKenzie, 51, who works for the national health service in Scotland. She was diagnosed with breast cancer six years ago, and after a partial mastectomy was told by her surgeons that reconstruction wasn't necessary, let alone possible.
MacKenzie had heard about a surgeon, Eva Weiler-Mithoff of the Glasgow Royal Infirmary, who might be able to help. MacKenxie sought her out and in the spring of 2008, Weiler-Mithoff called and told her about the Restore 2 trial, for which she was a lead investigator. MacKenzie signed on. She liked the results but in January 2009 returned to Weiler-Mithoff for another go.
"She told me maybe we should have put more cells in. so I went back," says MacKenzie, who now pronounces herself delighted with her new breast. In December 2009, Weiler-Mithoff told the San Antonio Breast Cancer Symposium that the procedure improved breast deformity in most of the 31 patients who were assessed, with the new breasts holding up for the six to 12 months that the women had been followed. How the new breast felt and moved on the chest wall kept improving. "One of the most striking aspects of the trial was how happy the patients were" with their new breast, says Weiler-Mithoff, who compares the injections to putting in "little pearl strings of fat." The women, she says, "felt whole again." MacKenzie's need for a touch-up, however, shows that not everyone gets the desired results the first time. In fact, all but one of Vranrkx's post-mastectomy patients needed at least two procedures.
The Celbrush, after all, is the instrument of an artist. "So far, we've been able to repair defects that we couldn't before," Vranckx says. "But it can take eight hours to do two breasts—eight hours bringing one droplet after another to the breast, it's sculpting, and not everyone can be a sculptor."
Restore 1 showed that Cytori's cells could rebuild breasts lost to cancer. The next logical step was trying it out for breast augmentation. Perhaps not surprisingly, once again this happened in Japan. The country has a strong and entrenched cultural prejudice against putting anything foreign into anyone´s body; organ transplants were slow to be adapted in Japan and still remain rare.But if that ick factor is the immovable object than the Western-inspired desire for bigger breasts is the irresistible force.6
In late 2007 cosmetic surgeon Tatsuro Kamakura of Cosmetic Surgery Seishin in Japan began a study of the Celution System for breast augmentation. Eventually enrolling 20 women. In 2008 he told the Congress of the Japan Aesthetic Surgery that the first three patients kept their new volume and that the tissue remained soft and natural. He had injected an average of 160 cc stem -cell loaded fat droplets, boosting breast circumference by an average of 4 centimeters (1.6 cup sizes).
In commercial use a new breast could run about $2.000 to $2.800, depending on physician charges. Its probably a 1$ billion market Calhoun says."You can buy an appliance with a 30 to 40 percentunpleasant rate or you can use your own cells. Which would you choose?" But the possibilities aren't boundless, "its not a.substitute for implants for women who want to look, uhm, unnaturally large," Hedrick says. "You can't take a flat chested woman and make her look like a dancer at a strip club. We're not targeting that market. If they don't care about looking natural, let them do silicone. The goal of this is a natural, soft-tissue feeling. Plus, there is a whole new market of women who would love another 100 to 200 cc, but would never have an implant. I think that's bigger than the current breast implant market"- a sea of women who wouldn't consider a silicone implant but who would be intrigued by the opportunity to have their breasts pumped with cells from their own bodies while reducing the fat in their hips and abdomen to boot.
Typically, experimental medical treatments go through years of testing in animals before they reach people, but as women in Japan were being treated with Cytori's cells, the company was still conducting studies on animals to assess the safety of the procedure.
As recently as 2007, Cytori's principal scientist, John Fraser, was performing key experiments on mice. The problem is that the reason adipose regenerative cells work inducing the formation of blood vessels -is also the reason they might be dangerous, especially to cancer survivors. Such angiogenesis, after all, is what allows metastatic tumors to thrive. But Fraser's experiment showed that in mice the adipose regenerative cells did not trigger the formation of breast tumors, promote their growth or cause them to metastasize to the lungs. The human t rials have not followed the women very long, so it is still! possible that a dangorous side effect like cancer, much worse than needing a touch up, as Irene MacKenzie did, will emerge. "People do challenge me: 'VVhy are we moving so fast?'" Fraser says, standing in a corridor adorned with posters of scientific results he and his colleagues have presented at conferences. Hedrick jumps in: "It's because we think Iike doctors taking care of patients. We have a lot of doctors working here. When we felt there was clear sailing, we hit the gas pedal. Where we felt there were obstacles, we slowed down." Adds Fraser. "We're not cowboys." They might find themselves in an industry shoot-out, however, as the allure of adipose derived 7stemcells has drawn other companies to the field.
The most flamboyant is AdiStem based in Hong Kong. Its process, like Cytori's, begins with liposuction. The fat is mixed with enzymes and centrifuged, then the precipitated cells are centrifuged again. That, however, is where the similarity ends. AdiStem next mixes its cells with plasma and exposes them to laser light, the company claims, to photoactivate stem cell functionality. C.F.O Vasilis Paspaliaris says the resulting cells can then potentially be used to treat autism, idiopathic pulmonary fibrosis, osteoarthritis of the knee and hip, type 2 diabetes, acne scarring, and hair loss, as well as in post lumpectomy cosmetic reconstruction.
Although Paspaliaris says all the results seem promising, he believes "the most convincing" are those for the face. Some Los Angeles cosmetic surgeons are already using the AdiStem process with face lifts. These claims have raised eyebrows. II hasn't helped that AdiStem posts videos of its autism "treatments 'on YouTube or that there are no peer-reviewed scientific papers on the use of photoactivation to increase stem cell functionality.
AdiStem "is one of many small opportunists who are jumping on the adipose-derived stem cell band wagon,"Calhoun says. "At the right time, we will protect our markets and enforce our patents, but at present it seems to be a potential waste of capital, resources, and energy."
Cvtori'.s bigger concern is that although these companies may pose no competitive thread, they are a PR disaster waiting to happen. Although regulators in Europe and Japan were satisfied with the animal and human studies Cytori submitted for approval of the Celution machine, the US Food and Drug Administration has yet to weigh in. Vranckx., who met with FDA officials, says that despite Fraser´s mouse experiments, the agency is worried about injecting blood vessel promoting cells into patients, who have had breast cancer. But although Cytori cannt market its Celution Sytem without FDA approval, doctors can purchase it,.just as they can prescribe a drug approved for one use for a completely unrelated purpose, but cannt advertise it for that use. In fact. the FDA tlakes the position that as long as cells are removed and returned to the same person in one procedure, a physician does not need approval to do it. Still, without F'DA approval Cytori can't promote its device; without promotion its unlikely to be widely adopted.
Cytori is currently in discussions with the FDA for permission to conduct a clinical trial of its device. If the trial is a success in particular, if there are no adverse effects from the cell injections the next step would be to seek FDA approval for the entire process or conduct a second trial. Although a lot could still go wrong surprises in clinical trials have killed many an experimental drug and device - Calhoun hopes positive results will launch his billion-dollar vision of regenerative medicine.
There is one other key feature that the next generation Celution machine shares with a photocopier, as Calhoun demonstrates. Just as the latter has a touch.screen control panel that displays options (paper size, number of copies, magnification), so does the Celution, only here, the options are organs.
See? There's a picture of a breast, a heart, a disc in the back,"he says. "You push that and the machine loads different software, which adds the right drugs, reagents, or other biochemicals to the liposuctioned fat cells. He envisions an iPhone like business model, with individual doctors doing apps to repair different organs with the perfect slurry of adipose regenerative cells. If it works, the breasts on his laptop will have plenty of company.