Fat as a Regenerative Resource

Marco: Hi, Carlo.

Carlo: Hi, Marco.

Marco: Top-notch medicine. We come from the same school — the great Professor Donati.

Carlo: Exactly. I'm glad to hear it.

Marco: Carlo, let's talk about your studies on fat — a field that connects us and has brought us together quite a bit. What insight sparked your research?

Carlo: More than an insight, it was a passion I've always had for molecular biology, biology, and science in general. If you recall, those were the years when people were talking about fat stem cells, trying to isolate them from adipose tissue. On the surface it seemed like a smart idea — isolate the stem cells, concentrate them within the fat itself, and assume that would work better. But in reality it became clear — something I had also observed in burn patients, where the thinner the skin graft, the better it takes — that reducing the size of the fat particles to be transplanted could be more effective. At the time this was being attempted with increasingly thinner cannulas, which took forever to extract the tissue.

Marco: You're both a bit impatient as surgeons —

Carlo: Certainly — and innovative. I thought: if we harvest the fat with normal cannulas that preserve the tissue structure much better, and then reduce it to very small sizes while maintaining that structure, this should make the stem cells present in the vascular network of the adipose tissue work better. So the idea was this: find a way to break adipose tissue down into tiny pieces without destroying it, and see if that works better.

Marco: Why has adipose tissue turned out to be such a valuable regenerative resource? I ask on behalf of the people watching at home.

Carlo: Adipose tissue is extensively vascularized by microvessels — it has an enormous network of them. Lining these microvessels are cells called pericytes, the precursors of mesenchymal stem cells — the cells that repair tissue. As plastic surgeons, we also had the fortune that patients willingly underwent liposuction, so we had an abundance of tissue that seemed useless, destined for the bin, but which turns out to be extremely valuable.

Marco: So research on this fat, once it was discovered it was rich in stem cells —

Carlo: Right. Attempts were made to isolate the stem cells, but isolation wasn't really the right approach, because the cells lose information when separated from their context. The concept became: leave everything together, fracture the tissue into very small pieces, and if you manage not to destroy them — which is the hard part — they attach, they function for a very long time, and they're given the time to regenerate naturally. And it works.

Marco: To clarify for viewers at home, Carlo — it's important they understand that fat, so often disliked, is in fact enormously useful for the reasons you've described. Professor Tremolada speaks about the regenerative aspects, but we both know — and he is a leading expert on this — that fat also produces a volumizing effect in the areas where it's needed, and a pain-relieving effect, for example in irradiated and reconstructed breasts, with very significant potential.

Carlo: Yes, absolutely. Fat has frontiers that are still largely unexplored — but even those already mapped are impressive. The entire microvascular network, with these cells on top — and the adipocytes themselves, the fat cells, are known to produce substances, almost like a personalised pharmacy at our disposal.

Marco: Priceless.

Carlo: Priceless — and if you leave everything together rather than trying to separate components, as with the stromal vascular fraction or with isolated stem cells, the result is much better, because no information is lost.

Marco: Probably works even better because these are tiny pieces, easy to insert into joints or other areas.

Carlo: Exactly.

Marco: Let's get to the point, so we can clarify once and for all what the procedure is — especially in the joint — where the fat you describe is used.

Carlo: The idea didn't start with putting fat into joints — which fifteen years ago seemed like heresy. It started from the fact that in maxillofacial surgery, fat is often used as interposition in joints, including the temporomandibular joint. Given that fat is so rich in stem cells, and given the studies on isolated stem cells — which sometimes worked and sometimes didn't — I asked myself: why not simply inject the microfractured fat directly into the joint? Instead of taking a piece of isolated fat and performing an open procedure, do it with an injection.

Marco: From the outside — much less traumatic.

Carlo: Much less traumatic. These are very small pieces, and the joint is a difficult environment — tissue doesn't take root easily there. But we've demonstrated that microfractured fragments of around 300 microns — so small they can't even be extracted with the thinnest cannulas — take root perfectly in the synovium, the membrane that drives joint regeneration.

Marco: Which is enormously enhanced.

Carlo: Enormously enhanced. If we didn't have natural joint regeneration, we'd all be champions at twenty. It's a natural process — this simply facilitates and potentiates it.

Marco: Beyond creating, as I've always imagined, a powerful anti-inflammatory effect.

Carlo: And it's biphasic — if I may explain, because I'm obsessive about the molecular biology. These cells sitting on the vessels detach when you introduce the tissue as Lipogems®. As they detach, they recognise through their receptors what's happening, identify the molecular problem in the surrounding tissue, and begin releasing substances — anti-inflammatory and morphine-like compounds. That's the pain-relieving effect: Arnold's syndrome, reconstructed breasts, painful scars. They work remarkably well, as you know. The full effect comes in around six weeks, but they begin signalling immediately, communicating to the already-differentiated local stem cells what to do. It's an extraordinarily powerful message, and the key is precisely the microfracturing.

Marco: What can't be regenerated today?

Carlo: It seems nerve tissue can't yet be regenerated — though I'm convinced it will be.

Marco: I feel exactly the same way.

Carlo: We've had some encouraging experiences — parts of the face that weren't moving, eyebrows that wouldn't rise, that gradually began moving symmetrically with the opposite side following lipofilling injections. Peripheral nerves, and especially peripheral muscles that appear lost — even years later, where traditionally you can do almost nothing — a muscle pre-treated with Lipogems® or adipose tissue, in my view somewhat less potently, can recover functionality. For example, after a subsequent nerve graft, the recovery comes more easily.

Marco: I'd love to talk with you specifically about muscle — the big future is there. Colleagues who share our passion for biology are already fascinated by what a muscle can do, and how to enhance it through fat. But looking ten years ahead — what will remain of today's regenerative medicine? Where do you think we'll end up?

Carlo: Today's regenerative medicine is, in my view, still held back by regulatory issues. Our National Transplant Centre in Italy has overcome this — it recognises the procedure. I remember the early difficulties: at conferences, people came simply to question whether what I did was a lawful or unlawful transplant.

Marco: Just think of it.

Carlo: I used to say: it's a graft. I had used a skin graft; this time, a fat graft. The problem is the concept of homo-functionality — the idea, held in theory by the EMA, the European Medicines Agency, that you must transplant a tissue into the same tissue. My position is: this is a microvessel transplant. Microvessels are everywhere, so you can transplant them anywhere — you simply have to demonstrate safety. That's what the National Transplant Centre has accepted, and thanks to this, Italy is becoming one of the most advanced centres in the world.

Marco: Rules help research enormously — research shouldn't be completely unrestricted. We surgeons know that well. Carlo — for you, such an expert on fat regeneration: what's the question that regenerative surgery and medicine haven't yet asked themselves? Looking further ahead, what questions could we pose?

Carlo: In my view, regenerative medicine is fundamentally about supporting anything that amplifies the body's own regenerative capacity. We could go further by using regenerative medicine systems to treat pathologies. I'm conducting research along these lines — and I've founded another company in Lausanne, Exogems, focused on exosomes. These are likely two directions we'll pursue in the future. Through the vesicles released by adipose tissue, we'll probably open the door to allogeneic therapies — meaning you can take fat from one person and give it to another. The second exceptional development — two publications are already out on this — is that adipose tissue, and particularly microfractured tissue, because of its favourable pharmacokinetics, is an extraordinary drug delivery system. With Professor Broggi at Besta, we're doing very interesting work to see whether microfractured tissue, combined with paclitaxel — a powerful anticancer agent with significant side effects — might be used in certain applications.

Marco: This research is truly promising for the future, Carlo. You've been enormously helpful in giving our viewers a glimpse into the future of medicine. Thank you.

Carlo: Thank you for having me.