Doctors' Commentary: Improvement of Atopic Disease? Exosome treatment and how to perform and inject the treatment

The contents of this column do not "assert" that "exosomes" can cure atopic dermatitis. It is only a reference to the possibility of treatment.

They say exosomes will probably help with atopy, is that true?"
What kind of treatment is exosomes anyway?"
'How are exosomes different from IVs and dermapens?'

Hello, I am a doctor at Smart Skin Clinic.

Exosomes" have been a hot topic in the cosmetic medicine industry in recent years, but do you know what they are?

Exosomes originally attracted attention and research in the field of regenerative medicine,Recently, the effects of exosomes may be effective in chronic inflammatory skin diseases such as atopic dermatitisWe are beginning to understand that this is not the case.

Exosomes are offered in combination with a variety of procedures in the cosmetic medicine industry, but there have not been many detailed explanations of the features and differences that exist in each procedure.

For those who are considering exosome therapy for their atopic problems, here is a simple explanation from a physician's point of view.

What is an exosome?

Extracellular vesicles (EV = exosome)
A general term for particles released from cells, surrounded by a lipid bilayer, and unable to replicate. In this study, it refers to small extracellular vesicles (also called exosomes) released from late endosomes. EV stands for Extracellular Vesicle.

reference
RIKEN　Illuminating the Trajectory of Extracellular Vesicles - Contributing to the Elucidation of the Mechanism of Extracellular Vesicle Uptake into Target Cells

To explain this a little more clearly, we can say the following.

Exosomes are microscopic pouch-like structures released primarily from stem cells that carry bioactive molecules such as RNA, proteins, and growth factors in their pouch. They transmit information by presenting the molecules in this pouch to other cells.

Stem cells are known as specialized cells that have the ability to generate a variety of cells in the body. Since exosomes have the same properties as the stem cells from which they are derived, they are believed to be able to repair damaged tissues and stimulate the generation of new cells.

Are exosomes effective for atopy?

Conclusion,The effect of exosomes on atopic disease is promising."It is considered to be a

I will explain the specific effects that support this conclusion and the medical evidence for these effects on the next page.

Three reasons why exosomes are expected to be effective for atopy

Exosomes are effective for atopy because of the following three benefits of exosomes

1. anti-inflammatory effect
2. Immunomodulating Effects
3. Tissue repair promotion effect
   

Let's take a closer look at each of these.

1) Anti-inflammatory effect

It was mentioned earlier that exosomes have a variety of signaling molecules inside them, but the presence of cytokines, a component of cytokines, is particularly important. Cytokines are essential for intercellular communication and the regulation of immune responses, and are known to have a wide variety of roles.

Some cytokines (such as IL-10 and TGF-β) have an inhibitory effect on inflammation. These cytokines have the effect of reducing the excessive inflammatory response triggered in the body and also play a role in preventing the negative effects of persistent inflammation on the body.

In atopic dermatitis, there is persistent inflammation of the skin of a part of the body.These anti-inflammatory properties of exosomes may help alleviate the inflammation associated with atopic dermatitis, which in turn may contribute to the improvement of symptoms.

Below are excerpts from two medical papers describing the anti-inflammatory effects of exosomes, with a few key passages.

If you are interested, please read up to the actual literature.

Exos could inhibit the inflammatory responses by reducing the expression of inflammatory factors TNF-α and IL-1β, while promoting the expression of anti-inflammatory factor IL-10. The overexpression of exosomal miR-181c effectively reduced the inflammatory factors secreted by macrophages stimulated by lipopolysaccharide, inhibited the TLR-4 and NF-κB/p65 signaling pathways, and suppressed the inflammation caused by burns. Therefore, Exos may promote skin repair by regulating the inflammatory responses.

(Japanese translation)Exosome (Exosome) was found to suppress inflammatory responses by down-regulating the expression of inflammatory factors TNF-α and IL-1β while promoting the expression of anti-inflammatory factor IL-10.Overexpression of exosomal miR-181c effectively reduced inflammatory factors secreted by macrophages stimulated by lipopolysaccharides, inhibited TLR-4 and NF-κB/p65 signaling pathways, and suppressed burn-induced inflammation.Thus, Exos may promote skin repair by modulating the inflammatory response.

reference
Exosomes for Regenerative Medicine Applications

4.8. Skin Diseases
Inappropriate responses by cells of the skin immune system can cause chronic skin diseases [129]. Cho et al. reported that EVs from human AD-MSCs decreased serum levels of pro-inflammatory cytokines (IL-4, IL-31, IL-23, and TNF-α) in the NC/Nga mouse model of atopic dermatitis. The serum IgE level and the number of eosinophils also decreased [130]. In another study, AD-MSC-derived EVs showed anti-inflammatory effects in the hairless SKH-1 mouse model in which atopic dermatitis was induced.
-- (omitted) --
The EVs also induced secretion of IL-10 by human skin organ cultures, suggesting that Lactobacillus plantarum-derived EVs have therapeutic potential The EVs also induced secretion of IL-10 by human skin organ cultures, suggesting that Lactobacillus plantarum-derived EVs have therapeutic potential [132]. Moreover, human BM-MSC- and human jaw BM-MSC-derived EVs promoted M2 polarization of human monocytes in vitro and accelerated cutaneous wound healing in vivo [133].
(Japanese translation) 4.8. skin diseases
Inappropriate reactions by cells of the skin immune system can cause chronic skin diseases. such as Cho,Human AD (adipocyte)-MSC (mesenchymal stem cell) We reported that EVs (extracellular vesicles ≈ exosomes) reduced serum levels of pro-inflammatory cytokines (IL-4, IL-31, IL-23, and TNF-α) in a NC/Nga mouse model of atopic dermatitis.Serum IgE levels and eosinophil counts also decreased.In another study, EVs (≈exosomes) derived from AD-MSCs showed anti-inflammatory effects in a hairless SKH-1 mouse model of induced atopic dermatitis.
- (omitted) - (omitted)
Also,EV also induces IL-10 secretion by human skin organ cultures, suggesting that EV from Lactobacillus plantarum has therapeutic potential in skin inflammation.Furthermore, EVs derived from human BM-MSCs and human jaw BM-MSCs promoted M2 polarization of human monocytes in vitro and skin wound healing in vivo.

reference
Therapeutic Applications of Exosomes in Inflammatory Diseases

(2) Effects of immunomodulation

One of the main factors in atopic dermatitis is the activation of Th2 cells, which are widely recognized to produce cytokines that promote allergic reactions and give rise to excessive immune responses. Exosomes contain cytokines (e.g., IFN-γ, IL-2) that normalize immune balance. These cytokines are expected to increase the number and activity of immune-regulating Treg cells, thereby alleviating the hypersensitive response of the entire immune system and reducing the symptoms of atopic dermatitis.

The following are excerpts from two medical papers describing the immunomodulatory effects of exosomes.
In the first paper,Exosomes "increase and activate Tregs."The second paper shows thatTregs regulate the immune response."This will be an indication that
If you are interested, please read the actual literature.

Exosomes from MDSC has also been shown to carry TGF-β1 which participates in the inhibition of NK-cells . Further research also showed that exosomes from MDSC, in vitro, promoted Treg differentiation and proliferation from CD4+ T cells in the presence of TGF- β and inhibited CD4+ cell proliferation .
(Japanese translation)Exosomes from MDSCs have also been shown to carry TGF-β1 , which is implicated in NK cell inhibition. Further studies have also shown that MDSC-derived exosomes promote Treg differentiation and proliferation from CD4+ T cells in vitro in the presence of TGF-β and inhibit CD4+ cell proliferation.

reference
Exosomes for Regulation of Immune Responses and Immunotherapy

In this study, focusing on the relationship between skin barrier function and Tregs, we created a mouse model of skin barrier failure by repeated application of surfactant (SDS) and analyzed its skin. The results showed that the epidermis was thickened and infiltrated by Tregs due to the skin barrier disruption treatment, and that the Tregs were also infiltrated by the epidermis at this time.Tregs were found to produce the inhibitory cytokines IL-10 *5 and Transforming Growth Factor (TGF)-β *6.
-- (omitted) -- (omitted)
From the above results,It was suggested that IL-33 is released from epidermal keratinocytes upon skin barrier disruption and maintains skin homeostasis by infiltrating and accumulating Tregs to prevent inflammation from occurring.

reference
Elucidating the mechanisms that suppress inflammation and maintain skin homeostasis - Role of regulatory T cells in the disruption of the skin barrier

In other words,Exosomes → increase Treg → increased regulation of immune response → improvement of atopyThe process may occur such as

(iii) Tissue repair promotion effect

Exosomes are rich in cytokines and growth factors produced by stem cells, which stimulate cell proliferation, migration, and differentiation.

This property of exosomes to support tissue regeneration has led to their potential use in the field of regenerative medicine.

The skin of atopic patients is easily penetrated by external stimuli and allergens, causing inflammation. It is speculated that the tissue regeneration-promoting ability of exosomes may accelerate the recovery of damaged skin and increase the likelihood that this situation will improve.

The following is an excerpt from a medical article describing the tissue repair-promoting effects of exosomes.
Interested parties should also read the actual literature.

Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed that exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) attenuate AD-like symptoms by AD-like symptoms by reducing multiple inflammatory cytokine levels.
-- (omitted) -- (omitted)
Collectively, our results suggest that ASC-exosomes effectively restore epidermal barrier functions in AD by facilitating the de novo synthesis of ceramides, resulting in a promising cell-free therapeutic option for treating AD.
 (Atopic dermatitis (AD) is a multifactorial heterogeneous disease with epidermal barrier disruption and severe systemic inflammationWe have been in the market for a long time. Earlier, we,Exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) have been shown to reduce AD-like symptoms by decreasing multiple inflammatory cytokine levels.
-- (omitted) -- (omitted)
In summary, our results are,We suggest that ASC exosomes effectively restore epidermal barrier function in AD by promoting new ceramide synthesis, and thus represent a promising option for cell-free therapy in the treatment of AD.

reference
Exosomes derived from human adipose tissue-derived mesenchymal stem cells promote epidermal barrier repair by inducing new ceramide synthesis in atopic dermatitis

Disadvantages of exosomes

So far we have described the positive aspects of exosomes. We believe that you have only seen the advantages of exosomes, so we will describe the disadvantages neutrally as well.

Three disadvantages of exosomes include the following

1. Expensive
2. It takes time to achieve the desired effect
3. No longer able to donate blood or have a blood transfusion

(1) Expensive

Exosome infusion is offered as an unrestricted treatment and is not covered by insurance.

The cost per treatment isApprox. 50,000-200,000 yenand is more expensive than other intravenous therapies. This price is due to the use of rare materials and the sophisticated technology and manufacturing costs involved in the extraction and purification of exosomes from specific cells.

In addition, regular treatments may be required to maintain ongoing effectiveness, which can be a significant financial burden.

(2) It takes time to achieve the desired effect.

Although the main purpose of exosome therapy is to promote cell repair and tissue regeneration, these cellular-level effects are not immediately visible. Therefore, if you expect immediate and noticeable improvement, you may find that you do not feel the effects.

(iii) No longer be able to donate blood or have blood transfusions.

Exosome therapy involves the use of human-derived stem cell culture supernatants, and this often restricts blood donations and transfusions. Because exosomes contain components of biological origin and current testing methods cannot adequately confirm the presence or safety of unknown viruses in these components, it is recommended that blood donations after treatment be discouraged.

While there are some disadvantages to exosomes, there are also advantages that outweigh them.
If you are concerned about exosome treatment, please consult with us at the clinic.

How to inject exosomes

Now let's talk about how to actually inject the exosomes.

In this article, we will compare the different methods of injecting exosomes, with the premise that they can be compared in order to "improve the skin quality or constitution of atopic patients".

There are six injection methods

First, I will try to give you a broad overview with a comparison chart.

Comparison of different injection methods when undergoing exosome treatment for atopic skin improvement

	injection	intravenous drip	direct injection	Vital Injector	dermapen	ultrasonic waves
site of action	Whole (body)	Whole (body)	local	local	local	local
Effect	Anti-inflammatory Immunoregulation Skin repair promotion Rejuvenation of the whole body Prevention of thinning and hair loss Increased immunity and physical strength	Anti-inflammatory Immunoregulation Skin repair promotion Rejuvenation of the whole body Prevention of thinning and hair loss Increased immunity and physical strength	Anti-inflammatory Immunoregulation Skin repair promotion	Anti-inflammatory Immunoregulation Skin repair promotion	Anti-inflammatory Immunoregulation Skin repair promotion	Anti-inflammatory Immunoregulation Skin repair promotion
ease	★★★★	★★★★	★★★	★	★	★★★★
Price (per transaction)	★★★ (40,000-80,000 yen)	★ (50,000-150,000 yen)	★★★ (40,000-50,000 yen)	★★★ (40,000-50,000 yen)	★★★ (40,000-50,000 yen)	★★★★ (20,000-30,000 yen)
Down time	★★★★	★★★★	★★★	★	★	★★★★
Atopic active phase Permissibility of treatment on skin	Possible	Possible	not allowed	not allowed	not allowed	Possible

Broadly speaking,Dermapen and hydroxyapatite injections for the face," and "intravenous infusions for the whole body."This may be a good idea.

We have given you an overview in the table, so if you would like to know more details, please read the following as well.

injection

• Since exosomes are injected into blood vessels, they can be injected in larger quantities than in procedures that act on the skin. The price is higher because a larger amount is injected.

intravenous drip

• The basic effects and characteristics are the same as those of "injections. The amount that can be injected is greater than that of injections. Therefore, the cost is the highest.

direct injection

• Injection" here refers to a manual injection in which the needle is inserted into the middle to dermal layer of the skin (1 to 2 mm from the skin surface) rather than into a blood vessel. Pain is present at the time of puncture and at the time of injecting the drug solution.
• One advantage is that the doctor can adjust the range, amount, and depth of the injection accordingly after checking the skin condition. The disadvantages, however, include the fact that only a few clinics use this procedure because it is performed by a skilled physician, and the degree of pain varies depending on the physician's skill level.

Vital Injector

• Aqueous light injections are a method of injecting a chemical solution into the skin by using a special machine with nine ultra-fine needles that are inserted into the skin like a stamp. A certain amount of drug can be injected at a specific depth (1 to 2 mm from the skin surface). Although the pain felt varies from person to person, it is accompanied by a prickling pain at the time of puncture.
• After the procedure, the skin will be left with needle holes and may require 2-3 days of downtime.
• The microscopic wounds created by the needles have the secondary effect of activating the skin's self-repair mechanism, like a dermapen, and promoting the production of collagen and elastin.

dermapen

• The dermapen is a machine with 16 ultrafine needles of 0.2 mm that vibrates at an ultrahigh speed of approximately 120 times per second to make microscopic holes in the epidermis of the skin.
• The effect of the Dermapen alone is to improve skin texture by promoting the skin's natural regenerative power to heal wounds by applying the Dermapen to healthy skin.
• By applying the chemical solution during the treatment, the active ingredients penetrate deep into the subcutaneous layer through the holes created, resulting in a synergistic effect.
• Although it may sound similar to the hydrophotonic injections, the difference is that hydrophotonic injections "inject" the drug solution, whereas the Dermapen "penetrates through the holes".
• A high-speed, fine needle repeatedly pierces the skin, causing constant pain.
• After the procedure, the skin will be left with needle holes and may require several days to a week of downtime.

For more information on the synergistic effects of atopy and dermapen, please refer to this article.

ultrasonic waves

• This procedure uses ultrasonic vibrations to temporarily open a gap in the skin's surface barrier to promote penetration of the drug solution. Since no needle is used, the procedure is painless and is the easiest of the injection methods used in this project.
• Since it does not damage the skin, exosomes can be directly absorbed into the skin even during the active phase of atopy.

These are the injection methods explained above. Were there any injection methods that you were interested in?

There are many things to worry about when choosing a treatment method.
We hope that they will make their choice while considering their budget and the frequency with which they can visit the clinic.

For exosome treatment, go to Smart Skin Clinic.

At Smart Skin Clinic,

• Exosome infusion
• Exosome x Dermapen

The company handles the following

We use a Japanese exosome infusion of 991 TP3T purity derived from umbilical cord. We also use the official Dermapen exosome induction solution.

If you are interested, please feel free to contact us.

Reference

・RIKEN

・Exosomes for Regenerative Medicine Applications

・Therapeutic Applications of Exosomes in Inflammatory Diseases

・Exosomes for Regulation of Immune Responses and Immunotherapy

・Elucidating the mechanisms that suppress inflammation and maintain skin homeostasis - Role of regulatory T cells in the disruption of the skin barrier

・Exosomes derived from human adipose tissue-derived mesenchymal stem cells promote epidermal barrier repair by inducing new ceramide synthesis in atopic dermatitis