Answer: Neuromodulators have been around since the late 70s/early 80s, and we've been using them cosmetically since the early 90s. In that time, we haven't seen any long-term complications.

To fully understand the long-term effects of injectable dermal fillers and neurotoxins, first we need to look at the pathophysiology of the aging face. We know now that the face does not age as one homogeneous object, but rather as a complex three-dimensional puzzle with multiple tissue layers. The craniofacial skeletal support is upholstered by a sandwich of fat, muscle, and fat. The layers include a superficial fat layer, the superficial musculoaponeurotic system, and then a deeper layer of fat―all wrapped in an outer layer of skin. While these layers change individually, changes in one layer greatly impact the way the adjacent tissue changes. What this indicates is that aging of the face is a very complex biologic process.

Frequently, prior to undergoing a cosmetic procedure, patients wonder if they’ll look worse when the effect of the filler or neuromodulator wears off. However, most patients will look even better after a year. For example, as we age the glabellar complex gets into a kind of a tug of war with the frontalis muscle, which is trying to pull the brows up and out. If we can put that glabellar complex in a time-out, then that muscle may atrophy to some degree. So even when the patient stops the neuromodulator, they’re not going to frown at rest to the degree that they did before.

Results of clinical studies have shown that if patients had a touch-up at six months, they could get almost 18 months out of a hyaluronic acid filler injection (Figure).^1,2 I think that replacing that volume or maybe slowing loss may be a part of that equation. We have some research in skin that demonstrates that as skin loses collagen, the fibroblasts (the cells in the skin that make collagen) begin to produce less collagen. And not only do they produce less collagen in an environment that has reduced collagen, they also make more collagenase.³ Therefore, replacing that volume may keep the skin from aging as quickly as it otherwise would.

Another important point to consider is that the earlier you intervene, the less time, effort and product will be required to address an area of concern. Essentially, it will take a lot less to help a 35-year-old than it will a 55-year-old. For example, a little neurotoxin in the glabella is going to make a 38-year-old woman (who comes in complaining that people think she looks tired or angry) look fantastic. But it may take more than that one intervention to refresh the look of a 50- or 60-year old patient. Again, the earlier that you start, the less costly and the easier it is to address aging.

For an optimal long-term effect, it’s essential to recognize the specific changes―loss of skin elasticity, loss of fat, loss of bony support―that are aging the face and to address the structures specifically. We have a number of impressive injectable products to do that. We can replace volume with volumizers that stimulate the body's own collagen like calcium hydroxylapatite and poly-L-lactic acid, and we can replace hyaluronic acid in the lower layers of the skin as it diminishes.

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Answer: Not only is the answer yes, but we'll get a better result if we do use a combination of agents. Again, we need to understand facial anatomy and the changes that occur to all the facial structures during aging. If we understand what's happening, and we can modulate different parts in that equation all at once, we'll get a better result.

First we need to consider the two layers in the skin: the epidermis and the dermis. The epidermis is the layer that protects us from sun and water loss. It does that by making wax and pigment that form a protective layer at the top of that epidermal layer, roughly analogous to bark on a tree. We want that outer layer to look very smooth, like green bark, rather than bumpy dry bark. As our skin ages, those layers of wax and pigment begin to separate, and the edges curl. This changes the way that the skin reflects light, making it look duller and dryer than younger skin. So keeping that outermost layer well hydrated helps make the skin look smoother and younger.

The lower layer of skin, the dermis, contains collagen. This is a structural protein that acts as scaffolding for the face. That scaffolding offers support to all of the structures that are in the dermis: hair follicles, oil glands, sweat glands, blood vessels, etc. Collagen, and all the structures that it supports, are floating in an ocean of hyaluronic acid. Hyaluronic acid looks very much like refrigerated gelatin until we're 30, and starts to resemble gelatin that's been left on the counter overnight as we advance past 30. The commercially available hyaluronic acid products today are stabilized, and derived from a non-animal source. We can inject these into the dermis to give a little bit of strength and integrity back to that lower layer of the skin. The collagen-stimulating agents, such as calcium hydroxylapatite and poly-L-lactic acid, actually stimulate the body to make more of its own collagen.

Underneath the skin you have both a superficial layer of fat and a deep layer of fat that the superficial musculoaponeurotic muscle runs through. We know now that that fat is highly compartmentalized, almost like a three-dimensional puzzle in which each compartment abuts each other and creates the unbroken, rolling topography of the face. As those fat pads begin to change in size, they separate from one another. Over time what used to look like one rolling plane now begins to separate out into hills and valleys. Where light used to be reflected uniformly, there are now flat areas and concavities that create shadows. As the muscle loses some of its support from that deep fat, and bones begin to remodel, the muscles seem to appear more visible. We can see that in the “11s” that form in the glabellar area. As the glabellar complex pulls in and down, there is less support underneath those muscles. At the same time the skin above the muscles is losing collagen and elasticity, and we begin to see those facial expression lines.

Finally, we know that bone remodels a great deal as we age. After about age 50 or at menopause, women lose approximately 30% of their bone mass. That underlying craniofacial support is like a table, and the overlying soft tissue envelope is the tablecloth. If we take a leaf or 2 out of the table, the tablecloth will sag to the floor. So do you hem the tablecloth or do you just put the leaf back in the table? Well it just depends on which is worse. If the patient has lost a great deal of underlying support, that's where we would want to start. We can place dermal fillers in a supraperiosteal location to duplicate the bone that used to be there. We can also place dermal fillers in the superficial or deep fat layer to replace what's been lost in specific fat compartments.

When we consider all that is contributing to aging the face, it’s clear that for many patients one agent will not necessarily do it all. We can knock out the muscles like the glabellal depressors with neuromodulators, and get a nice brow lift. But after a certain amount of time and volume loss, we can’t restore the anterior projection of the brow―one of the “curves of youth”―without restoring volume under the brow with hyaluronic acid fillers. Volume under the brows may also serve to lift the eyelids in a patient without significant dermatochalasis. So using dermal fillers and neurotoxins at the same time really is a symbiotic thing, where they augment the effect of the other.

There are many examples of this. “Crow’s feet” are one of the most common aging concerns. We can treat them with a neuromodulator, but over time the volume loss in the temple, bony orbit and under the brow in that area needs to be addressed too, or the neuromodulator alone will no longer work to the degree that it originally did. Additionally many patients think that all lines around the eyes can be eradicated with neuromodulators although we recognize that some of these lines are formed from the movement of the zygomaticus as we smile and cannot be treated in this way. “Marionette lines” may reflect the loss of soft tissue support, both superior and inferior to the modiolus muscle, as well as remodeling of the underlying craniofacial support. We can get a nice result by injecting product underneath that marionette in a fairly young person, but in an older patient with less bony and soft tissue support that same injection may just make the area look worse.

Using both fillers and neuromodulators can help address more of the multifactorial changes seen in facial aging and therefore result in more natural appearing corrections.

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Answer: In terms of emerging injectable products, we’re very lucky. We can look forward to both new products, as well as new delivery options. Several new hyaluronic acid products are now, or will soon be, commercially available. One product that will be available in the coming months is a soft “fine line” filler (Belotero, Merz) that can be used in a fashion similar to the older collagen products, and may have a niche around the lips and eyes. Another is a “beefier” product that offers significant and long lasting volume, and may be commercially available in the next 18-24 months (Voluma, Allergan). Both have been used in Europe for several years with excellent safety profiles.

There will soon be three commercially available neurotoxins (Botox/Allergan, Dysport/Medicis, Xeomin/Merz). They seem to have much in common, with only very slight differences in onset and duration of effect, but many studies looking at these issues can be found in the current literature.

There’s also excitement around a topical neurotoxin.⁴ This agent was effective and well tolerated in a phase 2 trial. This formulation may help avoid some of the complications associated with injections, such as bruising, pain, erythema, and infection. Pain is one of the top reasons cited by patients for holding back from treatment, so we’re looking forward to learning more about this agent.

In terms of new delivery systems, we're starting to do a lot of work with blunt-tip cannulas. Cannulas eliminate the risk of inadvertent vascular injection (which may lead to ischemia and necrosis), as well as greatly decrease the risk of bruising for the patient. I think that we'll see a lot more use of these cannulas for both of these reasons.

When facelifts and injectable agents are used well, no one can tell. But when they’re done poorly or agents are overused, we all recognize it. The more we understand about the pathophysiology of the aging face, the more we'll be able to achieve natural-looking results.

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