Primum non Nocere. First, do no Harm. It is a guiding principle in medicine, although in the world of skin care and topical aesthetic medicine, we seem to have been lulled into a sense of complacency at times. It is rare to see complications of topically applied solutions, and when we do they are usually non-fatal and self-limiting. Which is due to the fact that the skin itself is well designed as a protective barrier. Most of what we slather on never gets past the top few layers of cells,, which is why so many technologies have been invented to try and overcome that amazing ability to reject foreign substances. But skin is, in fact, vulnerable when we ignore certain basic physiologic imperatives. Even intact skin can be an entry portal to a few molecules of a substance applied to it.
What happens next? A chemical applied to skin may be ignored, or perceived as benign or even “friend, not foe”. Alternatively, a substance may be identified as a dangerous foreign invader, resulting in an emergency response system designed to fend off potential damage. This is how our skin protects us against harmful agents of all sorts, be they chemical or biological. The warning signals are transmitted by communicating molecules (cytokines) in a mechanism called paracrine (cell-to-cell) and autocrine (amplified within cells) signaling. These signals cause cells of the immune system to be mobilized to the site of penetration, setting up an inflammatory reaction whose purpose is to wall off or destroy the invader, thereby restoring the skin’s integrity whenever it is breached.
Nearly anything that the body does not recognize as its own (e.g. things that are not “physiologic” to humans – chemicals that humans don’t themselves make) or as a friendly is subject to being identified as an enemy alien when applied to skin.
Different parts of the immune system get involved depending on the nature of the invader. Biologic pathogens get special attention. Toxins are obvious – these are substances most people will react to. Like poison ivy. Then there are things that some people respond to because they are “allergic” to them. That is partly based on genetics, but other factors play a role. Pollens of various sorts are an example. Some people are allergic when they breathe these in, causing hay fever and other respiratory problems. Foods can also cause allergies. Allergic reactions to chemicals in foods and in the air can be fatal. Skin also can be a portal to such dramatic emergency responses. A very dramatic example involving skin is bee venom allergy. All it takes in a single small prick into the superficial dermis of susceptible (allergic) individuals, depositing a tiny amount of a toxic chemical, for this to trigger a potentially deadly systemic (total body) reaction called anaphylaxis.
The most common form of allergy testing in a physician’s office is called prick or puncture testing. A diluted drop of a test substance is placed on the skin and then that skin pricked with a very small needle. The tested area of the skin is observed for about 15 minutes to see if a reaction develops. The “wheal”—a raised, red, itchy bump and surrounding “flare”—indicates the presence of the allergy antibody when the person is exposed to specific allergens. The larger the wheal and flare, the greater the sensitivity.
Although skin testing may seem simple, it must be carried out by trained practitioners with an understanding of the variables and risks of the testing procedure. Often multiple substances are tested simultaneously on a patient’s back or arm.
Microneedling mimics the allergist’s “skin test”
This classical paradigm for skin testing is mimicked when microneedling is performed in the presence of a substance applied to skin before, during, or soon after needling. Both cosmetic or medical needling accomplish this. The applied substance will gain access to areas beyond the skin’s natural protective surface. After needling, the protective barrier is no longer intact, and the skin is vulnerable to whatever it comes into contact with for several hours until the microneedling channels have formed effective “plugs” (early phase of the healing cascade) to restore skin barrier defenses.
Acute and chronic inflammation
We have been describing sudden onset or “acute” types of reactions involving the immune system and skin’s defensive mechanisms. But not all inflammatory events are immediate – some are slower in onset and present in more occult or insidious manner. We might term that a “subacute” response, distinguishable by the types of immune cells involved, and their behavior. A granuloma is one type of subacute immune inflammatory response that tends to develop over weeks or even months, gradually becoming apparent as a focal or localized lesion. These are discussed in more detail below.
Perhaps the most common skin reaction to irritants is one best described as chronic and insidious. We sometimes call this “subclinical” inflammation, as it may not cause surface signs of redness and swelling. But, below the surface, inflammation is taking its toll on matrix proteins and structural cells of the dermis. It is what we call “skinflamm’aging”, as it resembles skin changes associated with aging itself. Indeed, it is accelerating that process (rather than slowing it down). Even trickier, there may be a temporary masking of the signs of aging on the surface (swelling from inflammation can distort skin and reduce the appearance of wrinkles).
Chronic forms of inflammation are less likely to be associated with a single or minimal exposure to an offending chemical (e.g. with microneedling) than with daily application of a toxin. But it is not uncommon to see people using the same cosmeceutical both during microneedling. In this case we might consider the microneedling exposure to be a “sensitizing” dose which sets the skin up for stronger immune responses to the same chemicals applied chronically.
Our close colleague and occasional BFT blogger, Dr. Lance Setterfield, M.D. (DrLance), spends the majority of his time traveling the globe giving master’s courses and seminars in techniques of microneedling. He has written the definitive book on the subject. Since the publication of the first edition of his book, there has been published a case series documenting the problem of granulomas developing after facial microneedling.
A granuloma is a type of inflammatory process where the immune system tries to wall off to substances that it perceives as foreign but is unable to eliminate. A granuloma can form in response to organic or inorganic material, microorganisms, chemicals, etc. Granulomas can be infectious or sterile. They can undergo necrosis. They can inflame and distort nearby tissues.
In addition to granulomas, needled skin can show a variety of other “pathologic” responses to foreign substances. Allergic responses, or hypersensitivity reactions, as we have described above, is one. Irritant contact dermatitis is another. These are generally more serious when substances are applied to recently needled rather than intact skin. The signs can be swelling, redness, pain, and even loss of function (e.g. speech and eating disturbances, visual distortions, breathing difficulties).
Such reactions can be difficult to detect at first, because a certain amount of hyperemia (redness) and swelling is common following medical needling. Microneedling by its very design causes a measured degree of damage resulting in inflammation. Indeed, it is the normal, physiologic response to that damage that brings with it the desired aesthetic result. Usually things calm down within hours or a few days, depending on the needling depth and other treatment parameters including skin characteristics of the patient. If they do not follow the expected course, something more insidious (and pathological) may be at work.
It goes without saying that all patients need to be fully informed of the potential complications before such procedures, and that they sign an informed consent. This protects both patient and clinician in the event of an adverse result.
Here we get to the crux of the matter. We have debated this extensively, and it has been the subject of considerable discussion amongst those who spend a good deal of time working with microneedling, and who have contributed to the evidence base.
DrLance likes to call these offending substances “troublemakers”. In the first edition of his book he has a whole section devoted to these. With his experience since that book was published, and as clinicians worldwide have shared their experiences, the paradigm has shifted somewhat. It seems that there are a lot of troublemakers, and it might be a much shorter list to identify those that are not than those that are, in practice or in theory.
A conservative approach to microneedling adjuncts would be to only apply substances which are:
- Physiologic to the human body (in other words, humans make those same molecules as part of their genetic machinery or metabolic processes, and
- Do not pose problems in theory or practice based on their nature, function, or origin, and
- Helpful in that they offer something good, not just absence of something bad
The first two safety concepts overlap, but not completely. Clearly, not everything that is physiologic is desirable, for other reasons, e.g. due to its origin or other factors. For instance, hyaluronic acid is physiologic (made by humans abundantly). High molecular weight HA is trophic to skin, but low molecular weight fragments can have the opposite effect. Thus, although HA is generally biochemically a good thing (hydration, pen glide, potential sealant) you want to be careful of its source or origin (some companies sell LMW or MMW HA which can be catabolic).
Dr. Setterfield’s recent example
The controversy that erupted on Dr. Setterfield’s blog provides an interesting example. One commenter kept touting the use of a cosmeceutical during needling that contains (amongst other things) the mucous of snails. This controversy persists, even after DrLance revealed his personal experience in observing a severe problem arising when a snail mucous product was used during microneedling.
What is this stuff anyway? Well, it seems that is in not just any mucous, but the defensive mucous produced when a snail is under threat (e.g. poke it with a stick). The abused snail in question goes by several names, as mollusk biologists cannot seem to agree on the proper taxonomy. Cryptomphalus asperses, Cornu aspersum, Cryptomphalus asperses, Helix aspersa all seem to refer to the same critter, a common garden snail.
Now, we at BFT wrote about snail snot and fairy dust some time ago as it proved to be the perfect tongue-in-cheek target for our discussions of the epistemology of skin care (theory of knowledge) which we find important because there are so many things we find worthy of ridicule, (as regular BFT readers know). Now, we have updated our research on the snail snot phenomenon, and will update you quite soon with Snail Snot II. It is actually an interesting story, complete with a genesis tale of “accidental discovery” (you know how we love those) in distant, non-English speaking lands (it is a national shame that the U.S. is so far behind in cosmeceutical biochemistry. Why is that??). A subplot is the drama of patents (follow the money), who makes & sells it (some real conundrums) and the latest research (interesting, maybe even surprising).
But we digress. Today we skip over all the potential benefits of snail snot and point out the glaringly obvious (you have already guessed it if you have read this far). This is a really bad idea as an adjunct to microneedling for reasons of safety (real and theoretical).
Xeno chemicals are high-likelihood troublemakers
We find it truly remarkable that well-meaning folks are poking your skin with needles after applying a mixture of xeno (foreign, animal, not human) proteins and other chemicals. This is not rocket science, folks. Look at the common allergens tested in a typical allergy test in the doctor’s office. Feathers. Cat dander. Sheep wool. All animal derived. This is an allergy test gone wild! A total face allergy test.
So, we looked up the research that would tell us what was in this concoction. Not surprisingly, extremely little is known. Snails don’t have their own NIH division to sponsor solid biochemistry research into mollusk slime.
This publication documented several functional assays, such as human fibroblast proliferation, to try to make the case that the cocktail of snail biochemicals acted as a growth factor for skin. And yes, behold, a very weak effect on human fibroblast survival and proliferation. What the researchers failed to mention is that you can add just about anything to a culture of fibroblasts and see the same thing. Proliferation in dermal fibroblasts is something of a stress response in itself. As I like to say, you can simply spit into your fibroblast culture and make them pump out more ECM materials. Of course, when you look at the cytokine content of human spit/snot, not to mention the defensins (host defense peptides) etc., you can see that it (just like gastric slime) has remarkable stress resisting or defensive properties itself.
Snail “growth factors”. Ahem.
Now, here’s the kicker. The authors of this work went on to postulate that snail snot contains a growth factor, and speculate that it is just like human bFGF (basic fibroblast growth factor). The problem is (as they state it) there is no assay for snail bFGF. If it even exists. I would point out a bigger problem: there is no evidence that snails make anything of the sort. The lower on the phylogenetic scale, the smaller the array of cytokines and growth factors, and they are highly species specific. We know a lot about the drosophila genome, and those guys (fruit flies) have a very limited repertoire. Even our not-so-distant mammalian cousins (e.g. mice) make different versions of growth factors, and these do not fit the human receptors for same. So, even if snails make a growth factor (let’s call it SGF) how does this growth message get transmitted to human fibroblasts without a SGF receptor? Or are they also speculating that humans have AGF receptors? By what logic do we validate that speculation?
This “growth factor” story is troublesome. The publication that makes this claim stretches credulity, is marred by internal inconsistencies, and just fails to impress as serious research. Because human cells have no receptors for snail GF’s that may or may not exist, there cannot be paracrine cell-to-cell communication of a trophic message between human keratinocytes as there is for human cytokines and GF’s. The paracrine (and autocrine amplification) of these chemicals is part of why they have a distinct advantage, and why human GF-based products can work even with minimal penetration or nanogram doses. This is the beauty of receptor biochemistry. The equally valid speculation that follows is that if there was an effect of some snail snot chemical in churning fibroblasts it might well be due to a stress response, not a coordinated physiologic response. After all, these is stressed snail snot, right? So a stress chemical (conserved from mollusks to humans) is a far more likely hypothesis than a conserved “growth factor”.
This is not mere species confusion, it is also market obfuscation. Trying to capitalize on real human biochemistry advances by using the same word (growth factor) when it contains nothing of the power or biochemical elegance conferred by the real thing. This reminds BFT of the whole plant stem cell farce. Plant stem cells have little in common biochemically with human stem cells. Using the stem cell phrase/meme association bastardizes the real science, and confuses people. Not nice. Not truthful.
Does it even do anything good?
Having dealt with the safety side of the picture, discussing what should not be applied to skin during microneedling, we are left with the equally germane notion, that being “does it help?”. Since microneedling has a known biochemical effect of it’s own, why bother to add anything to the picture? What sort of things might actually improve the dermal regenerative response to microneedling
Let us first dispense with mechanics. Microneedling with a pen is made easier if friction between the device and the skin is reduced. This is typically referred to as “glide”. There are a number of chemicals that could provide glide. The most commonly used is hyaluronate (HA). It is physiologic to humans, and has the advantage of also being ostensibly the most researched facial filler on the planet. Not to say that it has a perfect safety record (it doesn’t) but perfection is the enemy of good, and we are not aware of reports of microneedling related adverse reactions to HA alone. So, it is safe (as long as it is the high molecular weight version), and effective for glide, and barrier restoration (at least in theory).
Beyond mechanics, what about some positive effects form a biochemical approach? What would you want? Logic dictates we would want something that would amplify or compliment the known mechanism of action of the microneedling itself. Not something that would get in the way.
Microneedling microtrauma and healing
Microneedling induces minor, controlled damage to skin and sets in motion a predictable healing cascade. The well-characterized sequential phases of healing begins with hemostasis and ends with restoration though tissue regeneration. Given time, and with repetition, your body’s natural regenerative processes will fashion a final result that is aesthetically desirable. The extent of that change, however, is limited by variables such as an individuals age, health, skin type, and a host of other matters. Our regenerative capabilities, like so many others it seems, begin to decline from the moment we are conceived. The clock is constantly ticking.
True regenerative ability actually peaks at about 16 weeks gestation – fetuses have a remarkable ability to heal in a way that is without any fibrosis. Fibrosis, to oversimplify matters, is healing that is marred by scarring or poor quality cross linking of matrix proteins (collagen & elastin). By the time we are 50, we have lost about 95% of the regenerative capacity we had as fetuses. The older we get, the more prone we are to fibrotic healing. Hence, the signs of aging, skin and internal organs alike. This largely has to do with senescence and a loss of the type of stem cells associated with rescue and regeneration.
Now, before we go any further down this path, let us remind you that we (DrGeorge and DrJohn) are stem cell research docs. We are all about cytokines & growth factors (which are the key products of a certain class of human stem cells known to be at the very core of our human regenerative capacity). As such, we have our biases (and we remind you about them all the time), idiosyncrasies (science curmudgeons), and pet peeves. In fact, we just reminded you of one of our pet peeves (calling things from plants & snails growth factors so as to capitalize on human growth factor research without ever having done any). We will try to avoid talking about our own products, as this is a noncommercial science & beauty blog. But we readily acknowledge that our opinions are influenced by our own work. There you have it, our usual disclaimer.
OK, so how would one go about improving on microneedling (without bringing in “troublemakers”, as DrLance likes to call them)? I suppose you could invent a pharmaceutical substance that replicates or accelerates what microneedling does. Or, you can take a page from nature, examine precisely what microneedling does, how it does it, and fill in the gaps. Here is one gap: older people (like me) don’t mount the same cytokine & growth factor response as young people do. The older I get, the worse I perform. The older I get, the more prone I am to healing by fibrosis. The older I get, the more prone I am to releasing inflammatory cytokines, which can flip the switch from anabolic (volume restoring) to catabolic (tissue dissolving) growth factor profiles. So, how about supplementing my microneedling induced GF&C profile with something to push it towards that youthful (even fetal) GF&C profile? That makes sense. Good physiology, logical, and with no troublemakers.
The further advantage of using human biochemicals (in fact they are “natural” in the purest sense of the word, my fellow humans) has to do with the issue mentioned above of penetration or absorption. Growth factors (including snail ones, if they actually have any) tend to be large molecules. Very little penetration. In wounds, chance of get eaten up quickly by proteases. Not so with human biochemicals. The message molecules attaches to a cell receptor, and that cell makes more of the same chemical, and excretes it between cells to signal the cells nearby (deeper) and so forth. A cascade, with built in amplification. Not so with pharmaceuticals unless designed to attach to the same receptors. In which case they are termed analogs to growth factors and cytokines. To which we say, “why bother”, when human specialized stem cells abundantly make the real thing and in just the right ratios, along with a bunch of other relevant factors). And if we don’t want to use the ones they make, we can make our own by employing recombinant technologies informed by stem cell bioinformatics. Truly “bioequivalent”, in fact, bio-identical molecules.
Growth factors in isolation
Mind you, to be fair, growth factors applied willy nilly, without giving thought to the bigger picture, can transform them into troublemakers. Single growth factors (we have written here extensively about EGF applied alone) can distort the process of tissue regeneration. Nature doesn’t apply single growth factors to a problem. They come in complex arrays (cocktails) perfectly balanced for coordinated regeneration.
This post is way over word budget. Lets open this to comments & questions.