Tag Archives: skin

Do You Have Bugs on Your Face – The Answer is Yes

I’ve had a couple of people ask me if there are really bugs on their faces. Apparently social media is abuzz with buggy skin. Here’s the scoop – The human skin has trillions of microorganisms on its surface, called the skin’s microbiome, and some components of the skin’s microbiota aren’t the typically talked about bacteria, viruses, and fungi. We are colonized by multicellular species including fungi, intestinal worms, and ectoparasites, such as lice, with nearly 2000 pathogen and parasite species characterized from human bodies Some are animals, micro-animals with enucleated cells, that inhabit and multiply within our skin’s pores. Demodex folliculorum and Demodex brevis are animals, called arachnids, present on facial skin. In one study,  “within our samples, 100% of people over 18 years of age appear to host at least one Demodex species, suggesting that Demodex mites may be universal associates of adult humans.” So, yes, you have bugs on your face.

D. folliculorum inhabit the area of the follicle above the sebaceous gland, where they appear to ingest cell contents. D. brevis, on the other hand, primarily inhabits the sebaceous glands associated with vellus hairs. For those of you who don’t like bugs, the good news is that typically these mites exist at densities of just one to a few mites per gland. Now the bad news for those of you who don’t like bugs: With approximately 5 million hair follicles spread across the body, you may have up to 5-10 million mites on your skin. One study used imaging techniques to characterize these mites. They found, the mite was measured to be 198 µm long and clearly showed 4 pairs of legs, a head and abdomen.” It’s a micro-animal as I mentioned. Some scientists have speculated that D. brevis may have colonized humans from wolves during their domestication.

They can be found in milia, but appear not to cause inflammation. However, abnormal proliferation of Demodex mites causes a skin disorder called demodicosis and has been linked to rosacea. Demodex mites can also cause local immunosuppression, allowing them to survive in human skin. Reduction of local immunity has been previously reported in patients who have been repeating facial application of topical steroids and other immunomodulators, resulting in an increased number of Demodex mites on their faces. Demodex mites also act as a carrier of the Bacillus oleronius bacterium that likely functions as a co-pathogen in the development of inflammatory process in rosacea by neutrophil induction and activation. Mites live for about 1-2 months on the skin. When they die, mites release chitinous exoskeletons and internal mite contents, including bacterial antigens that cause an increase in TLR-2 expression, triggering an inflammatory reaction and resulting in an immune response followed by neutrophil and macrophage activation.

To keep these mites at bay, don’t use products that suppress the skin’s immune system. You should cleanse your skin daily, using a gentle cleanser that doesn’t cause an immune reaction. NeoGenesis Cleanser is one that I formulated to be gentle on the skin, and meant to be used daily. If you need to remove makeup, use one that is gentle and doesn’t require scrubbing the skin. Scrubbing can irritate and strip away the outer layers of the stratum corneum. NeoGenesis Makeup Remover, called Erase the Day, is safe and gentle, and doesn’t require scrubbing. There are other gentle cleansers on the market, but carefully check their ingredients to make sure they don’t use irritating surfactants such as sodium lauryl sulfate (SLS). You can also use immune normalizing ingredients, such as the NeoGenesis S2RM technology. This technology was originally developed in my lab at UCSD to treat brain diseases. I did a podcast about this technology with the The Physiological Society, the oldest physiological society in the world. The technology I originally developed for the nervous system is now available in Neogenesis’ skin care products, Recovery, Skin Serum, Booster, and Eye Serum. Immunosuppressing ingredients include products that contain a significant amount of alcohol. For example, Martha Stewart uses a product on her face in which the 4th most concentrated ingredient is denatured alcohol. Not only is the alcohol bad for her skin, possibly suppressing immunity and disrupting the skin’s barrier function, but when alcohol is denatured, toxins are added to the alcohol. As I have written, be careful in choosing the products that you apply to your face, especially if they are a leave-on product that is used daily.

The Spread of Misinformation About Comedogenicity

Formulating a product with isopropyl myristate is non-comedogenic, especially as a wash-off product

The term comedogenicity refers to the potential of various chemicals to promote the abnormal keratinization (hyperkeratinization) and desquamation of follicular epithelium. These comedogenic chemicals lead to a partial (open comedone or blackhead) or complete obstruction of the pilosebaceous (closed comedone or whitehead) and accumulation of sebum. Basically the skin pores become blocked. FYI, The hair follicle, hair shaft, and sebaceous gland are known as the pilosebaceous unit. The comedogenicity of dermatological products was first demonstrated by Kligman AM and Mills OH in 1972 The comedogenicity of the ingredients, for example, apricot kernel seed oil, cocoa butter, corn oil, isopropyl myristate, mineral oil, acetylated lanolin, octyl palmitate, sunflower oil, sodium lauryl sulfate, tocopherol etc. has been described. However, how these data were acquired, and their meaning has been highly misconstrued by practitioners and lay people alike. The propagation of these misconceptions in the media, including social media, is ubiquitous.

To clarify, first, these results were conducted from testing of 100% concentration of the tested ingredients in animal models, namely on rabbit ears. However, the comedogenicity of ingredients should not be taken to be the same as finished products, given the mixtures of ingredients and application to human skin will alter the final comedogenicity of each product. 

I recently formulated a new product for the easy removal of makeup, without having to scrub the skin and without toxic, inflammatory ingredients. The product contains an ingredient called isopropyl myristate. Isopropyl Myristate has been given a ranking of “1” by the Environmental Work Group, their safest rating. It is a synthetic oil and is highly regarded as an emollient. I was asked after we introduced the product to the market if the Makeup Remover is comedogenic because of the inclusion of isopropyl myristate in the formula. Let’s look at this.

Neogenesis Makeup Remover is not comedogenic, and one of the ingredients it contains that has been mistakenly said to be comedogenic, Isopropyl Myristate, has been found by scientists in peer-reviewed publications to be non-comedogenic (Lee et al, 2015). Neogenesis Makeup Remover is a safe and effective makeup remover that features carefully chosen ingredients that are all ranked low in the Environmental Workgroup’s (EWG) analysis of an ingredient’s induction of, 1. Cancer, 2. Allergies & Immunotoxicity, and 3. Developmental and Reproductive Toxicity. The EWG’s analysis of Isopropyl Myristate gave it a “1,” the lowest ranking on a 10-point scale for causing all these 3 concerns and included no use restrictions.

NeoGenesis Makeup Remover is not comedogenic for two key reasons, 1. Isopropyl Myristate itself is non-comedogenic (Lee et al, 2015), and 2. Even if Isopropyl Myristate were comedogenic, the way NeoGenesis Makeup Remover is used as a product that is immediately washed-off, would not be comedogenic. As Dr. Zoe Draelos, M.D., a board-certified dermatologist has published in a peer-reviewed journal, “Finished products using comedogenic ingredients are not necessarily comedogenic” (Draelos and DiNardo, 2006). Whether an ingredient is comedogenic depends on many factors, including how the ingredient is used, such as is it left on the skin or washed-off, and the concentration of the ingredient, as well as what is the formulation in which the ingredient is used. In a formulation, some so-called comedogenic ingredients will be rendered non-comedogenic by other ingredients in the formula. Further, comedogenicity is a function of many factors not considered in these studies, including the phosphoprotein content of the lipid droplets in one’s skin and the other ingredients in the formula that may have anti-comedogenic potential.

How was the misinformation about Isopropyl Myristate started and why has it been propagated in the media and social media?  To understand the flaws in the comedogenic scale we need to know how these tests are performed. In 1972, Kligman and Mills developed a rabbit ear model for testing how skin pores can be clogged by ingredients. They would put the ingredient to be tested into the canals of rabbit ears for two weeks. Then they would sacrifice the animals, and measure whether the pores were clogged under a microscope. “Half of 25 facial cosmetic creams were found to be mildly comedogenic when tested in rabbits’ external ear canals” (Kligman and Mills, 1972). This is how the hoopla of comedogenicity started. Ten years later, Mills and Kligman (1982) developed a human model using “young adult, black men who have large follicles,” where the substances were applied under occlusion for one month to the upper part of the backs. Yes, you read it right, the substances were applied for one month using an occlusive dressing. Occlusion can cause many untoward effects including enhanced product absorption and penetration, therefore leading to a higher probability of comedone formation. And then, a “fast-setting cyanoacrylate glue to remove the follicular” was used to remove the follicles from the victim’s back. I say victim, because cyanoacrylates can cause contact dermatitis, i.e. irritation (Bitterman and Sandhu, 2017), and then the procedure involves ripping this set-glue off the backs of the volunteers. Irritation of the skin can change follicle architecture and lead to misleading false-positives. In using this flawed methodology, Mills and Kligman (1982) wrote that, “The rabbit model is more sensitive than the human.” I’ll finish the sentence for them, “The rabbit model is more sensitive than the human [model].” And a poor human model it is.

My take home from these studies is that I will not place Isopropyl Myristate on the ear canal of my pet rabbit for 24 hours straight, every day of the week, for one month because I don’t want my rabbit to have mildly clogged pores in his ears. I will, however, recommend using Neogenesis Makeup Remover to friends and loved ones that is quickly applied to the areas of the skin were makeup needs to be removed, and then using a gentle cleanser, such as NeoGenesis Cleanser, to wash away the Makeup Remover from the skin. As the American academy of Dermatology recommends, “Remove your makeup, including eye makeup, before going to bed. Use an oil-free makeup remover. After removing your makeup, wash your face with a gentle cleanser. Avoid scrubbing your face, even when removing makeup.” Your pores will thank you for having gently unclogged them of that makeup you applied in the morning.

References

Bitterman A, Sandhu K. Allergic contact dermatitis to 2-octyl cyanoacrylate after surgical repair: Humidity as a potential factor. JAAD Case Rep. 2017 Sep 23;3(6):480-481.

Draelos ZD and DiNardi JC (2006) A re-evaluation of the comedogenicity concept. JAAD, 54, ISSUE 3, P507-512.

Kligman AM, Mills OH. “Acne Cosmetica”. Arch Dermatol. 1972;106(6):843–850. doi:10.1001/archderm.1972.01620150029011

Lee E. et al (2015) Isopropyl Myristate and Cocoa Butter are not Appropriate Positive Controls for Comedogenicity Assay in Asian Subjects. J Cosmo Trichol 2015, 2:1.

Mills OH Jr, Kligman AM. A human model for assessing comedogenic substances. Arch Dermatol. 1982 Nov;118(11):903-5. PMID: 7138047.

Sorg O, Nocera T, Fontao F, Castex-Rizzi N, Garidou L, Lauze C, Le Digabel J, Josse G, Saurat JH. Lipid Droplet Proteins in Acne Skin: A Sound Target for the Maintenance of Low Comedogenic Sebum and Acne-Prone Skin Health. JID Innov. 2021 Sep 17;1(4):100057. 

Prebiotics, Probiotics, and Postbiotics as Part of the NeoGenesis Core Technologies

NeoGenesis is known for its core stem cell released molecules (S2RM) technology. Another core technology, the use of prebiotics, probiotics, and postbiotics is also key to the efficacy of Neogenesis products. These technologies are part of our therapeutic approach, using system therapeutics for physiological renormalization.

I coined the term “postbiotic” a few years ago in a peer-reviewed PubMed listed paper that details how important prebiotics, probiotics, and postbiotics are for human health. As a term that I recently coined, and that has rapidly gained wide popularity, I’d like to emphasize the definition of postbiotic. A postbiotic is a molecule that has been produced by a microorganism that provides benefit to the host, i.e. the person to which the molecule has been applied. Postbiotics can be naturally occurring, such as the butyrate that bacteria on our skin are producing. Butyrate is a short chain fatty acid that quells inflammation in the immune system of the skin. Butyrate can also be produced by bacteria in a laboratory, collected and added to a topical product, and then applied to the skin. This too is a postbiotic. We can describe the first instance, where bacteria on the skin are naturally producing butyrate as an endogenous postbiotic, and the second instance, where bacteria produce butyrate in the lab and then it is applied to the skin, as an exogenous postbiotic. Either way, butyrate on the skin is a postbiotic and providing benefits to the skin.

At Neogenesis, we use a form of butyrate in several of our products, including our probiotic product, MB-1. Yes, MB-1 actually has live bacteria and does not use antimicrobial preservatives that would kill the probiotic. So the MB-1 product has both postbiotics and probiotics. In an upcoming post I’ll tell you about another probiotic product that Neogenesis will be launching specially designed for atopic, inflammatory skin conditions. We also use butyrate in our Eye Serum, Booster, and our Barrier Renewal Cream. It’s a great postbiotic, and dermatologist researchers in Germany have found it to be particularly beneficial for modulating the immune system in atopic and inflammatory skin conditions.

Now for prebiotics. Hyaluronic acid (HA) is a prebiotic, and has been found to upregulate those short chain fatty acids, such as butyrate in the aforementioned paragraph. In this case, bacteria that are part of the body are fermenting HA and producing butyrate, a postbiotic. Hence, in this case HA is a prebiotic because bacteria on our skin are using it to produce butyrate, a beneficial molecules.

Now, for the kicker. HA can also be an exogenous postbiotic. That is, HA can be produced in the laboratory by bacteria, and then collected, packaged into a product, and applied to the skin. That’s a postbiotic, albeit an exogenous postbiotic because it wasn’t produced by bacteria on our skin. So in this case, HA is an exogenous postbiotic, having been produced by bacteria in the lab, but acts as a prebiotic because it is feeding bacteria on our skin that produce a postbiotic. Normally, HA is not a postbiotic in the skin. Rather, normally, HA is produced by our own cells in the skin. Fibroblasts in our skin normally produce the HA. I’ll have more about the microbiota of the skin in future posts, where we’ll learn about the skin’s microbiota in educating the immune system and in helping to maintain the acid mantle and barrier function.

Why I Don’t Recommend Ablative or Wounding Procedures of the Skin

Scientists appreciate that one of the most dangerous things a cell can do is to divide. That’s what happens following an ablative or wounding procedure to the skin.

I’ve previously published papers in peer-reviewed, PubMed listed journals explaining how wounds, including micro-wounding such as that caused by microneedling procedures, induces an inflammatory response in both the innate and adpative immune systems of the skin. Such wounding is especially problematic when performed repeatedly and when bone marrow mesenchymal stem cell cytokines are applied to the wound. Even with a properly performed procedure, without infection, sterile inflammation results. And as repeated wounding procedures result in chronic inflammation, oncogenic potential is increased. Cancer has been described as wounds that do not heal.

But wounding is more than inflammation. To close the wound and remodel the damaged tissue, many cells proliferate. That means they may grow in size, and importantly, replicate themselves. So when you have an ablative or wounding procedure performed on the skin, proliferation of cells will result. This happens following acid peels, laser treatments, microneedling and other procedures that wound the skin.

So what’s wrong with proliferation of cells? Let me give you a hint. Carcinomas arise from epithelial tissue and account for as many as 90 percent of all human cancers. Why so many cancer in epithelial tissue? Because epithelial cells, including some of the cells in the skin, have high rates of proliferation. When cells proliferate, replicating themselves, they must make a whole new set of DNA. During the replication of DNA, many errors are made. Mutations result. To maintain the normal processes of the genome throughout cell function and division, we have evolved a complex network of machinery known as the DNA damage response (DDR). At least 605 proteins organized in a hierarchy of 109 assemblies is involved in maintaining our DNA. It’s complicated and doesn’t work perfectly. According to the National Cancer Institute, “Each time a cell divides, it must first duplicate its genetic material in a process called DNA replication. Because defects in this process can cause mutations that eventually lead[s] to cancer.” One problem is that DNA replication errors, especially those occurring at regions that are hard to replicate, called fragile sites, can cause breaks in the DNA strands. This can increase the probability of cancer, primarily by making it more likely that fragments of chromosomes rearrange themselves, activating genetic regions in the DNA that lead to uncontrollable cell division. The more you wound the skin, the higher the probability of inducing such mutations and breaks in the DNA strands, and the higher the probability of cancer induction. The other cancer causing factor in wounds is that the cellular matrix and microenvironment in the skin are disrupted, and this has a profound influence on increasing the chances of cancer. This was taught to me many years ago by one of our professors, Dr. Mina Bissell, Ph.D., in the Dept of Molecular and Cell Biology at Berkeley.

So wounding in the skin, especially when repetitive, such has been promulgated by non-dermatologist physicians, such as John Sanderson, who lost his license to practice medicine because of incompetence, and Lance Setterfield in their blogs and books, who call for repetitive microneedling procedures for skin care, simply don’t know what they’re doing. Thanks to my pushback, of late, Mr. Setterfield (he has an undergraduate bachelor’s degree in medicine) has toned down his call for repetitive microneedling. I hope he stops promoting dangerous bone marrow mesenchymal stem cell cytokines too. I’ve published a number of papers on the problems associated with the use of these cells, even under the most stringent conditions where the cells are used for transplantation at hospitals for blood diseases.

Other physicians, such as Mitchel Schwartz have now joined in to the microneedling craze for the sake of money, and are selling automated microneedle stamping machines to whomever wants one. Schwartz claims his device doesn’t create damage or inflammation because the needles don’t roll over the skin at an obtuse angle, but are stamped, perpendicularly, into the skin. Utter BS. His device is electronically stamping thousands of wounds into the face, and generating an immune reaction in the epidermis and dermis, leading to inflammation in the skin and inflammation throughout the body. Schwartz is even selling these devices to estheticians in California where the state’s laws forbid such procedures to be performed by estheticians. Damn the laws and damn the inflammation and cancer, there’s money to be made by selling microneedling to everyone. And some physicians love their side hustles.

Conditioned Media and Exosomes: Stem Cell Released Molecules Journey From Topical Application to the Dermis

Recent studies have found that the conditioned media from skin-derived adipose mesenchymal stem cells (CM-ADMC) penetrate intact human skin and induce wound healing when topically applied. Exosomes are one mechanism by which the molecules penetrate the skin. Likewise, in animal models, CM-ADMC reduces inflammation and promotes wound healing when topically applied to intact skin.

I’ve developed products from the molecules that stem cells release (Maguire, 2013) that can be topically applied to have effects in the epidermis and dermis. This penetration of the molecules means that even the stratum corneum and the tight junctions in the epidermis are not barriers to the stem cell released molecules (SRM). We have much evidence for how these topically applied molecules penetrate and act throughout the skin’s layers to provide many benefits.

In the 1990s when I was a professor at the University of California, San Diego we were using a type of stem-cell genetically modified in order to have a living cell constituently secrete Nerve Growth Factor (NGF) into degenerating neural tissue to rescue the neurons and other cells from dying. In the process of studying the genetically modified cells, we discovered that the control stem cells that were not genetically modified to secrete NGF were working as well or better than the genetically modified fibroblast.  I realized that normal stem cells were releasing numerous molecules to repair and prevent neural degeneration, and that was an epiphanic moment for me – that we could use stem cells as cellular factories to produce these beneficial molecules. And this meant that if you use the stem cells to produce the molecules in the laboratory, you wouldn’t have to inject or otherwise administer stem cells themselves to the tissue. Rather you could culture and stimulate the stem cells in the laboratory to optimize the output of the molecules that the stem cells release for maximum therapeutic benefit. Many studies in the ensuing years have provided evidence that it is the release of molecules from stem cells that provide most of the stem cell’s therapeutic benefit.  Using the molecules themselves without the cells as a therapeutic is much easier and more straightforward, and more efficacious than injecting or administering stem cells to the patient where we don’t know the number of stem cells accruing in the injured area and where we don’t know if the stem cells are working correctly. That is, one doesn’t know if the cells are making and releasing the molecules into the injured area. Whereas, using the molecules means that you apply a defined, optimal dose of molecules directly to the injured tissue. Importantly, the molecules released from the stem cells, and not molecules artificially extracted from the stem cells, are critical for two key reasons. First, the molecules need to be fully formed for them to work properly, and it is the released molecules, not extracted molecules, that are fully formed. Not waiting for the molecules to be released means that extracted molecules may not have fully formed and may be misfolded, causing them to be ineffective and potentially dangerous. Second, the released molecules are packed into exosomes that are natural protection and penetration devices for the released molecules. Extracted molecules are not packaged into the exosomes.

Back in the 1990s and into the early 2000s stem cell therapeutics was mainly focused on embryonic stem cells. Embryonic stem cells were all the rage because those cells could fully differentiate, that is turn into or transform themselves into almost any cell type in the body. The idea was to use embryonic stem cells to make new tissues. The thought of using adult stem cells was carried forth by only a few of us during that time, and funding was tight for anything other than embryonic stem cells. The adult stem cells could not turn into any tissue in the body and had limited potential to differentiate into other cell types – and this was an anathema to academia as well as the investment community. Adult stem cells are tissue specific and have restricted lineage fates. Instead of developing an organism, as embryonic stem cells do, adult stem cells have partially matured (differentiated) into a phenotype that is used by a particular tissue to maintain and heal itself. The adult stem cells found in our tissues have evolved to maintain and heal our tissues, doing so mainly through the release of molecules (Maguire, 2013). At the time, when I proposed not only using adult stem cells as a therapeutic but also using just the molecules released from adult stem cells, there was little interest and sometimes downright bashing of my proposal. Despite zeitgeist focusing on embryonic stem cells, in the 1990s we began to use the stem cell released technology for repairing brain tissue (Maguire et al, 2019). Because we had been using genetically modified adult stem cells derived from the skin to begin our studies of repairing the brain, we realized that using these adult stem cells from skin might be used to heal the skin. This would yield proof of concept safety and efficacy studies that were less expensive and more quickly accomplished than having to deliver the molecules into the brain and measure the results in an organ that is much less accessible than the skin. This is how I began studying skin. The more I looked at the skin, the more fascinated I became, especially given we began to see very encouraging results using the molecules to heal wounds. With a beautiful, layered structure, constant turnover of stem cells, such as the keratinocytes, and powerful innate and adaptive immune systems, studying the skin became a labor of love. When we were injecting these molecules into the brain, it was easy to understand how they penetrated through the tissue. But when we began working on the skin, and the molecules were not only working in wounded skin with a degraded barrier, but were also working on intact skin with a normal barrier – we were surprised. I was taught, and indeed I taught my students that these large proteins we were working with would not penetrate skin barriers.

But the molecules were penetrating intact skin. We saw it, and so did others (Kim et al, 2017). Within 3 hours following application to the skin, the exosomes are penetrating the epidermis, at 18 hours they are deep in the epidermis, and within 3 days they have begun to increase the production of collagen and elastin in the dermis. How are they penetrating the skin? The simple answer is exosomes, a liposome-like structure. But the exosomes are more complicated than liposomes and have some extra features that seem to enable them to better penetrate tissue than a liposome. While having a more flexible structure than a liposome, allowing them to squeeze through closely packed structures, the exosome also has proteases and glycosidases contained on its surface (either attached or as transmembrane proteins), as well as on its inside (Sanderson et al, 2019). Those proteases and glycosidases are known to break down barriers, including tight junctions (Lin et al, 2020) and matrix molecules that would otherwise prevent the exosome’s penetration through that part of the tissue. So as the naturally flexible exosome is squeezing through structures in the skin, the proteases and glycosidases are temporarily breaking punctate structures that prevent their penetration. We now understand that cells in the skin use exosomes to send their signals to other cells (Cicero et al, 2015; Nasiri et al, 2020), including to directly modify immune cells (Zhou et al, 2020), and that these stem cell derived exosomes can be safely used for skin therapy (Maguire and Friedman, 2020). Work continues to further develop these technologies – stay tuned.

References

Kim YJ, Yoo SM, Park HH, Lim HJ, Kim YL, Lee S, Seo KW, Kang KS. Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulates rejuvenation of human skin. Biochem Biophys Res Commun. 2017 Nov 18;493(2):1102-1108.

Lin Y et al (2020) Exosomes derived from HeLa cells break down vascular integrity by triggering endoplasmic reticulum stress in endothelial cells, Journal of Extracellular Vesicles, 9:1.

Cicero, A., Delevoye, C., Gilles-Marsens, F. et al. (2015) Exosomes released by keratinocytes modulate melanocyte pigmentation. Nat Commun 6, 7506.

Maguire G. Stem cell therapy without the cells. Commun Integr Biol. 2013 Nov 1;6(6):e26631. doi: 10.4161/cib.26631. 

Maguire G, Friedman P. (2020) The safety of a therapeutic product composed of a combination of stem cell released molecules from adipose mesenchymal stem cells and fibroblasts. Future Sci OA. 6(7):FSO592.

Nasiri, G., Azarpira, N., Alizadeh, A. et al. (2020) Shedding light on the role of keratinocyte-derived extracellular vesicles on skin-homing cells. Stem Cell Res Ther 11, 421..

Sanderson RD, Bandari SK, Vlodavsky I. Proteases and glycosidases on the surface of exosomes: Newly discovered mechanisms for extracellular remodeling. Matrix Biol. 2019 Jan;75-76:160-169.

Zhou X et al (2020) Exosome-Mediated Crosstalk between Keratinocytes and Macrophages in Cutaneous Wound Healing. ACS Nano: 14, 10, 12732–12748