Tag Archives: Fibrosis

Regenerative Versus Reparative Healing of the Skin: Why You Don’t Need Inflammation to Heal Your Skin

Inflammation is for fighting pathogens, and it is destructive to the skin. Inflammation is not needed to regenerate the skin or induce collagen production, and actually slows and impedes the healing process. There is a potent and safe means to inhibit the inflammatory pathways and promote regenerative healing in the skin -S2RM Technology- stem cell released molecules from skin derived adipose mesenchymal stem cells and fibroblasts.

From: Liu et al 2017

I continuously hear that inflammation is needed to heal the skin and to produce collagen and rebuild the matrix. This is false, and I’ll tell you why, and tell you the differences in the two healing processes, i.e 1. non-inflammatory regenerative healing versus, 2. inflammatory reparative healing.

Once we’ve exited the sterile or nearly sterile womb, most postnatal wounds heal through reparative healing, which is a complex biological process involving cells, signaling molecules such as growth factors and other cytokines, and the extracellular matrix (ECM). Wound healing is simplified and described as occurring in four overlapping, highly coordinated stages: hemostasis, inflammatory, proliferation, and remodeling. In the womb, where there are no pathogens, inflammation is not needed to fight infection – there’s no pathogens present to infect the skin. In the fetus, the immune system in the skin is only beginning to develop and is not robust, and platelets that normally rush into wounded skin are not yet fully developed, and the blood cells are being produced in the liver and not in the bone marrow. Wound healing in the fetus is vastly different from that in the adult. Adipose mesenchymal stem cells (AMSCs) arise later in fetal development in order to control and resolve the newly formed inflammatory mechanisms in the skin that are important in the adult to fight infection using an inflammatory response.

Whether it is macrophages or T cells, including γδ T-cell subsets, or other immune cells, it is the AMSCs that serve to calm the early-onset inflammation by polarizing the immune cells from an inflammatory type to an anti-inflammatory, pro-regenerative type. This is in contrast to bone marrow mesenchymal stem cells (BMSCs), which are a major source of IL-7, thus producing inflammation, and playing a pathological role in the maintenance of inflammatory CD4 memory T-cells that are involved in autoimmunity and chronic inflammation. BMSCs and the molecules they release also have oncogenic potential, another reason why they are an inferior choice for therapeutic development.

Regenerative Non-Inflammatory Healing and Reparative-Inflammatory Healing

Fetal wounds heal in utero through regenerative healing; postnatal microenvironments with an attenuated inflammatory response, such as the oral mucosa, also heal with regenerative characteristics, including a reduced immune response and scarring. Regenerative healing occurs in a manner similar to the same four stages of reparative healing, with some key differences. The key difference is that compared with reparative healing, the inflammatory response in regenerative healing is attenuated. Many of the cells involved in both innate and adaptive immunity, such as mast cells, macrophages, and neutrophils, are not yet differentiated or are not responsive to the wound where regenerative healing occurs. Therefore, levels of inflammatory cytokines and chemokines are reduced or absent in regenerative healing.

Increased expression of anti-inflammatory cytokine IL-10 in postnatal regenerative healing helps decrease the inflammatory response. Adipose mesenchymal stem cells are a key source of the IL-10 secreted into the skin, and thus promoting regenerative healing. A number of studies suggests that IL-10 not only indirectly modulates fibrosis via its anti-inflammatory properties but may also stimulate fetal-like fibroblast behavior and thus fetal-like ECM production. If scar tissue is to be of normal structure, regenerative healing must take place. The secretion of IL-10 from AMSCs is key to inducing regenerative healing in adult skin. One mechanism to explain the ability of IL-10 to inhibit inflammation is that it inhibits NF-κB activity by inhibiting nuclear translocation of NF-κB by blocking IκBα degradation in response to TNF stimulation.

Collagen Production in Wound Healing – Inflammation Degrades Collagen, Not Produce It

Collagen production in the skin to aid in healing, is mainly derived from fibroblasts, but also by keratinocytes. Fibroblasts have evolved to regulate their synthesis of collagen and other extracellular matrix proteins in response to mechanical tension. Fibroblasts are also induced to secrete collagen by the molecules released from AMSCs. It’s not inflammation that stimulates the production of collagen. Tissue damage caused by inflammation from an infection or an autoimmune disease triggers degradation of collagen in the extracellular matrix (ECM), which further enhances inflammation. So inflammation is degrading collagen, not producing it. Also know that dermal collagen has a half-life of about 15 years, a very long-lived protein, a feature that predisposes collagen to accumulate lesions such as advanced glycosylation end products (AGE), which have damaging effects on the molecules they bind. So with much collagen in the skin lasting for decades, accumulating damage through inflammation is occurring. The secretome from AMSCs can protect these long-lived collagen proteins from inflammatory damage, while also helping to replace damaged collagen. 

Non-Inflammatory Immune Cells, M2 Macrophages are Anti-inflammatory and Pro-Regenerative

Often, the delay in tissue healing results from the inflammatory phase of the wound healing. Non-healing wounds result from chronic inflammation, characterized by an overload of inflammatory immune cells, inflammatory cytokines, and proteolytic enzymes. Chronic wounds share certain common features, including excessive levels of proinflammatory cytokines, proteases, ROS, senescent cells, persistent infection, and a deficiency of stem cells and their released molecules that are often also dysfunctional. Chronic wounds are defined as wounds stalled in a constant and excessive inflammatory state. For example, much evidence has revealed that chronic wounds are closely associated with impaired phenotype transition of pro-inflammatory macrophages (M1) to anti-inflammatory phenotypes (M2) in wounds. The secretome from AMSCs biases the macrophage phenotype from an inflammatory M1 to an anti-inflammatory, pro-regeneration M2 phenotype, and greatly aids in wound healing. An example of the pro-healing effects is that M2 macrophages induced the expression of the proteins required for the assembly of collagen fibrils, and macrophages themselves secrete some forms of collagen. A shift towards M2 in the M1/M2 balance improves not only the quantity but also the quality of collagen fibrils, leading to a non-fibrotic scar. M2 macrophages induce the expression of the proteins required for the assembly of collagen fibrils,

From: Horiba et al (2023)

In wounds, the continued infiltration of pro-inflammatory immune cells and production of pro-inflammatory molecules attract additional inflammatory immune cells, exacerbating the inflammation. Thus, inflammation is preventing wound healing. If you think inflammation is needed to clear debris in a wound, including “sterile inflammation,” think again. During the resolution of inflammation, macrophages are predominantly polarized to an M2 phenotype (non-inflammatory), which can suppress proinflammatory cytokine production, clear debris, and restore tissue homeostasis. Yes, M2 macrophages are phagocytic – meaning they eat debris. Again, wounds don’t need inflammation to heal, whether it’s an infected wound, or “sterile inflammation” where debris is present without infection.

The Inflammatory NK-kB Pathways Are Pro-Inflammatory and Impede Wound Healing

Recent studies have found the genes and pathways involved in the induction of inflammation, called, NF-kB, and that these genes and pathways are also involved in aging and many disease processes. The NF-kB pathways underlying inflammation, diseases, and aging (inflammasome) are different from the genes and pathways that are activated during injury and responsible for regenerative healing.

Leung et al (2013) at Stanford did a nice study separating out the two pathways involved in adult healing, i.e. the NF-kB pathways. They found that hypochlorite (HOCl) reversibly inhibited the expression of CCL2 and SOD2, two NF-κB–dependent genes. In radiation dermatitis, topical HOCl (aka Bleach) inhibited the expression of NF-κB–dependent genes, decreased disease severity, and prevented skin ulceration. Additionally, skin of aged HOCl-treated mice acquired enhanced epidermal thickness and proliferation, comparable to skin in juvenile animals. In other words, inhibiting inflammation helped to heal the skin when injured through irradiation or aging.

Platelets, Bone Marrow Mesenchymal Stem Cells, and Their Molecules Induce Inflammation

This is why you don’t want to use a platelet extract or PRP on your skin, because platelets and their molecules induce inflammation. It’s also why you don’t want to use bone marrow mesenchymal stem cell derived molecules because they too are pro-inflammatory and can induce, through IL-7, autoimmunity and tissue destruction. Both of these cell types only appear transiently in open wounds through the blood supply and serve to induce inflammation to fight infection, and to induce high rates of fibrotic scarring to close the wound rapidly (see Maguire, 2022).

Adipose Mesenchymal Stem Cells and Their Molecules Reduce Inflammation

There’s another safe and effective means to inhibit the inflammatory pathways associated with NF-kB, and that is the secretome from AMSCs, which is contained in the S2RM Technology of NeoGenesis. González-Cubero et al (2022) in Spain found that in inflamed human cells from connective tissue, like that found in the skin, when exposed to the molecules released from AMSCS, NF-κB activation was blocked. Thus, the secretome from AMSCs blocked inflammation by blocking the NF-kB pathways. Adipose mesenchymal stem cells and their released molecules act in many other ways in addition to inhibiting NF-kB to reduce inflammation.

Chronic Inflammation

So the adipose mesenchymal stem cells reduce inflammation and this is critical for autoimmunity. Tregs control other T cells from over activating and causing damaging inflammation. It is important to keep Treg cell functioning because they tend to lose their regulatory capacity under chronic severe inflammatory conditions. If a patient’s Treg cell function is compromised or defective, their immune system can become excessively activated, leading to systemic autoimmune inflammation. So AMSCs controlling inflammation in turn controls Treg cell function and reduces T cell mediated autoimmune inflammation.

Summary – Inflammation is Unwanted in Wound Healing and Adipose Mesenchymal Stem Cells Deactivate Inflammation and Activate Regenerative Healing

In summary, inflammation does not heal the skin and does not produce collagen. Inflammation is unwanted in the skin unless their is an infection and the pathogens need to be destroyed. Unfortunately, in the process of killing the pathogens, the inflammation also damages your cells and connective tissues. To effectively and safely decrease inflammation and activate regenerative wound healing, use NeoGenesis Recovery which is loaded with the molecules released from AMSCs that reduce inflammation and activate pro-healing regenerative mechanisms.

Human Platelet Extract: Some People Want You to Apply Blood Clotting, Cancer-Causing Factors to Your Face

In the land of where some people will do nearly anything for money, a company is selling “human platelet extract” as a topical cosmetic product for daily use on normal skin. Can you say, “Gee, let’s clot our skin’s blood supply, induce inflammation, and induce cancer at the same time?” Yes, extended use of a platelet extract product is likely carcinogenic (Carr et al, 2014; Sabrkhany et al, 2021).  To be clear, platelet lysate (extract) triggers an inflammatory response in stem cells in the skin and induces the secretion of factors maintaining immune cells (macrophages) in a proinflammatory state thus enhancing inflammation (Ulivi et al, 2014), and long term inflammation is dangerous.

First, platelet extract does not contain exosomes as some are claiming. The company Plated uses the term “Renewosome”” to fool people. It’s marketing hype that the hysterical mass media has been repeating. They even put a trademark after this silly name. Lol. Platelet-derived exosomes (PLT-Exos) are the main subtype of extracellular vesicles secreted by platelets, which carry proteins, nucleotides, lipids, and other substances to acceptor cells, playing an important role in intercellular communication.” Notice the term “secreted.” Exosomes are actively secreted from living platelets, and an extraction process of platelets will not yield any exosomes. None. I introduced the concept of and actual products containing exosomes to skin care over a decade ago. Many people criticized me at the time, and never bothered to read my peer-reviewed work on the subject, including my scientific book on the subject. But over a decade later following my introduction of exosomes to skin care, the word is out and people are making false claims to have exosomes in their products. Again, exosomes must be released (secreted) and cannot be collected through cellular extraction processes.

BTW, if you want to buy some human platelet extract (lysate is the scientific term for extract), here’s the source:

You can also purchase the platelet extract without fibrinogen. The company has removed the fibrinogen to reduce clotting because fibrinogen is one of the clotting factors.

So, what are platelets? Platelets are anucleated red blood cells that circulate in blood. They are small because they’re anucleated and can therefore squeeze into small places. Platelets are called into action when a wound occurs and blood is spewing. Their job is to close the wound fast by clotting to stop blood leakage, and by inducing high rates of cellular proliferation and inducing an inflammatory response to fight infection. Thus, quoting from Scherlinger et al (2023) in a Nature review article, “platelets produce soluble factors and directly interact with immune cells, thereby promoting an inflammatory phenotype. Furthermore, platelets participate in tissue injury and promote abnormal tissue healing, leading to fibrosis.” Inflammation, fibrosis, abnormal tissue healing with an abnormal matrix, and proliferation are hallmarks of cancer. Tumors are wounds that don’t heal, and applying platelet extract on your face mimics a wound that doesn’t heal. Platelets don’t live long in humans, about 7-10 days, nor would you want them to. They’ve evolved to flux into an area rapidly, secrete all of their inflammatory, clotting, and proliferative factors, close the wound, and then die before before they cause too much damage. If the platelets didn’t die, but instead stayed around for a long time secreting their inflammatory, clotting, and proliferative factors, it would be similar to applying platelet extract to your skin on daily basis. Chronic inflammation, clotting and fibrosis with tumorigenesis would result.

If we consider platelet rich plasma (PRP), a less concentrated form of platelet extract, an inflammatory response in fibroblasts is induced that leads to the formation of ROS (reactive oxygen species) and activation of oxidative stress pathways. It does not promote regeneration. Recent studies have found, “Treatment with PRP increased reticular dermis thickness with a fibrotic aspect. In the long term, the presence of inflammation and microangiopathy caused by PRP injection could lead to trophic alteration of the skin and the precocious aging process.” In other words, platelets cause fibrosis and advanced aging of the skin. Why someone would want to use platelet extract on their skin is beyond me.

According to epidemiologists, “A growing body of laboratory research has shown the direct involvement of platelets with cancer.: Cancer follows a high platelet count. Signaling by platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial–mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. In other words, the extract of platelets will be high in PDGF and when applied daily will enhance the probability of cancer.

Recent studies have found that over-active PDGF signaling is implicated in several types of human malignancies, in one way by promoting proliferation, survival and invasion of tumour cells directly, and in another way by changing the tumor stroma (matrix) in a manner that promotes tumorigenesis. If we look at a product called Regranex, which is a topical product containing 0.01% PDGF, the label includes a warning, “Malignancies distant from the site of application have occurred in REGRANEX users in a clinical study and in postmarketing use.” Thus, using a platelet extract, loaded with PDGF, on a daily basis may be asking for trouble, specifically tumorigenesis.

Let’s look at the ingredients of the platelet extract product used in a “clinical study” of the platelet extract product (from their website):

“purified water, glycerin, pentylene glycol, trideceth-9, panthenol, human platelet extract™, PEG-5 isononanoate, polyacrylate crosspolymer-6, hyaluronic acid, caprylyl glycol, 1,2-hexanediol, hydrolyzed gelatin, arginine, silanetriol, saccharide isomerate, menthyl lactate, carnosine, citric acid, sodium citrate.”

Question – If the “human platelet extract” is so good, why do they need to include all of those other actives?

Answer- because the platelet extract doesn’t work well on its own. At NeoGenesis, we don’t have to add anything to our S2RM adult stem cell-based technology containing exosomes because it really works.

Let’s look at a study published by the company selling platelet extract. The study is:

This study is for short term results in treated skin, not long term results in normal skin. The study suffers from a poor experimental design, conflicts of interest, and the results are underwhelming,

First, the study was not conducted at Mayo Clinic as some people have said in social media. Rather the study was performed for payment from the company to a plastic surgeon named Steve Dyan, and the authors included those employed by the company. So Steve Dyan put his name on the paper for money – this is common, and is called ghostwriting. This is where a physician puts their name on a paper when others have done the work. He was paid to put his name on this published paper. This is a conflict of interest, and is one of the reasons why most medical research and clinical trials cannot be believed.

Look at the study design, and find the problem with the design:

Treatment Group – Before Procedure:   “A 7-day pre-procedure facial skincare regimen for subjects randomized to the HPE treatment group included Cetaphil cleanser (or equivalent) twice daily morning and evening, with application of HPE once daily, and EltaMD (Colgate-Palmolive, New York, NY) UV Daily Broad-Spectrum SPF 40 (or equivalent) in the morning, with reapplication throughout the day as needed.”
Treatment Group – Post-Procedure: 

 “Post-procedure skincare (until the skin was fully healed at 7–10 days) in the treatment group included application of HPE three times daily (morning, mid-day, and before bedtime) followed by Vanicream (PSI, Rochester, MN) Moisturizing Ointment as needed for dryness, applied 15 min after HPE CALM. Post-healing when were they [sic] determined “healed” skincare in the HPE treatment group included Cetaphil (Galderma, Fort Worth, TX) cleanser twice daily, application of HPE three times daily, sunblock, and Vanicream.” 

Control Group: “Post-procedure skincare in the control group (until the skin was fully healed) included application of silicone gel twice daily and application of Vanicream Moisturizing Ointment as needed for dryness. After complete healing, the control group used Cetaphil cleanser twice daily and application of sunblock.”

Do you see the problems?

A proper study design will make the control and experimental groups the same except for the one variable, which is the test product.


Did the study do this?

No, the treatment group received extra care in the form of 7-day pre-procedure care.


Are the results convincing?

No, look at the pictures and the data – the improvement is minimal if at all.


Why didn’t the study use an active comparator?
Basically this is a study of platelet extract versus doing nothing. A good study would have compared the platelet extract to something that is known to improve post-procedure healing, something like, say, NeoGenesis Recovery. The company decided to compare their product to doing nothing, and even when compared to doing nothing, the results are poor.

I could have formulated a product using platelet extract years ago, but decided not to because it is not good for the skin (inflammation and fibrosis) and is dangerous (tumorigenesis). So, if you want clotted blood vessels in your skin, tumorigenesis, fibrosis, and inflammation, go ahead and do as some company wants you to do, apply platelet extract to your face daily. Halloween is coming in a couple of months, and if you start now, you won’t need a costume.