Evolutionary Regenerative Medicine that Activates Cellular Repair Capabilities

Secretome therapy is a novel regenerative medicine approach that utilizes various active components secreted by cells (cytokines, growth factors, exosomes, etc.) to enhance the body's intrinsic repair capabilities.

The secretome comprises the array of naturally secreted therapeutic substances from cells, frequently characterized as a "cellular healing soup." For instance, stem cells release hundreds of different types of substances into their surrounding environment during their proliferation and activity.

It contains growth factors that promote tissue growth and repair, cytokines that regulate immune function, exosomes (small, capsule-shaped vesicles released by cells) that transmit messages to other cells, among others.

These components function synergistically to promote the repair of damaged cells or to convey essential instructions to other cells, thus enabling the body's self-healing processes.

The Role of the Secretome in Body Repair and Regeneration

When the human body sustains damage from injury or disease, it initiates repair and regeneration through substances secreted by its own cells (secretome). For instance, in cases of a fall resulting in a scrape, growth factors are secreted from cells in the vicinity of the affected area, directing the synthesis of new skin.

Simultaneously, anti-inflammatory cytokines are released, reducing swelling and pain at the wound site. Additionally, small exosome-like vesicles, acting as "messengers," convey essential information to the injured area, prompting other cells to initiate repair processes.

In this way, the secretome plays a pivotal role in the body's innate healing abilities, and serves as a lubricant for cells to cooperate in tissue repair and regeneration.

Fundamental Mechanism of Secretome Therapy

Secretome therapy is a novel regenerative medicine approach that artificially utilizes a cocktail of therapeutic factors derived from these cells to enhance the body's regenerative capacity.

In traditional regenerative medicine, it is common practice to transplant the stem cells themselves into the body. However, in secretome therapy, the stem cells themselves are not utilized. Instead, only the active components released by the stem cells (secretome) are extracted and administered to the patient.

In other words, rather than introducing cells, consider administering therapeutic agents produced by cells. Through this mechanism, we aim to achieve the inherent tissue repair and immunomodulatory effects, even without directly transplanting the stem cells themselves. As the cells themselves are not utilized, the risk of immune rejection (the body's rejection response to allogeneic cell introduction) and tumorigenicity is reduced, enhancing overall safety.

Furthermore, the complex process of cultivating and managing stem cells can be streamlined, thereby attracting attention as a method with relatively lower costs and reduced patient burden.

Secretome Mechanism

How Secretome Works in the Body

The administered secretome circulates systemically, targeting areas of need. For instance, in damaged or inflamed tissues, local distress signals are emitted, leading to the preferential accumulation of secretome components at these sites.

Accumulated growth factors and cytokines promote cell proliferation and migration at the site, initiating repair. Within injured tissue, new cells are generated, blood vessels are regenerated, and damaged tissue is gradually replaced.

Furthermore, the anti-inflammatory components within the secretome attenuate excessive inflammatory responses, thereby reducing edema and discomfort while accelerating the healing process. Essentially, the secretome operates by precisely modulating key biological pathways, activating the body's intrinsic repair mechanisms and providing a supportive impetus for regeneration.

Function of Bioactive Substances such as Growth Factors and Exosomes

Let us examine in more detail the key functions of the bioactive substances contained within the secretome. Firstly, growth factors, which are substances that promote cell growth and division, and aid in tissue regeneration.

For instance, when the liver is damaged, growth factors act on liver cells to promote the regeneration of new hepatocytes. Cytokines are signaling molecules secreted by immune cells, serving as an immune command center.

In the event of injury or infection, necessary immune cells are recruited; conversely, when inflammation is excessive, it is attenuated to balance the immune response. Exosomes are minute extracellular vesicles, approximately 50-100 nm in diameter, encapsulating proteins and genetic information (such as RNA).

Exosomes deliver messages from their parent cells, and upon internalization by target cells, they modify cellular function. For instance, when exosomes are taken up by damaged cells, the encapsulated messages serve as 'initiate repair' instructions.

In this manner, diverse elements such as growth factors, cytokines, and exosomes work in concert to orchestrate complex processes including tissue repair and immunomodulation.

Benefits of Secretome Therapy (Tissue Repair, Immune Modulation, Anti-Inflammatory Effects, etc.)

Secretome therapy offers significant advantages, primarily its potent ability to support the body's inherent healing capabilities. The primary effects are as follows:

• Promosi Perbaikan Jaringan:Promotes cell regeneration of damaged tissues or organs, accelerating wound healing. This can shorten the recovery period from injury or surgery, or the expected period for organ function recovery.
• Penyesuaian Imun:By suppressing an excessive immune response or enhancing an insufficient one, immune balance is adjusted. For example, alleviating reactions that attack the body itself, such as autoimmune diseases, or increasing resistance to infections.
• Efek Anti-Inflamasi:Calming chronic inflammation, reducing swelling and pain. By relieving inflammation, the progression of tissue damage can be halted, leading to symptom improvement.

A key therapeutic advantage of secretome therapy is the overall enhancement of the body's healing and regenerative capabilities. Furthermore, by not utilizing the cells themselves but rather extracting only their intrinsic "healing power," the therapy presents minimal side effects. Its versatility in application across a wide range of conditions can also be considered a significant benefit.

The difference between Secretome and Stem Cell Transplantation / Immune Cell Therapy

Secretome therapy differs from stem cell transplantation or immune cell therapy (e.g., NK cell therapy) in that it does not involve the use of the cells themselves. Let's clarify this distinction.

• The Differences of Stem Cell Therapy:
  In stem cell therapy, live stem cells are transplanted into the patient's body. The transplanted stem cells function in the body by differentiating into new cells or continuously secreting necessary substances, providing a therapeutic effect.
• Differences from NK Cell Therapy:
  NK cell therapy is a treatment where NK cells are taken from the patient's own blood, expanded outside the body, highly activated, and then returned to the body. The activated NK cells function within the body to directly attack cancer cells, boosting immune strength.

The secretome is derived from these cells but does not include the cells themselves. Because it does not utilize the cells themselves, even when allogeneic cells are used, the likelihood of an immune rejection reaction is reduced, and there is no risk of unintended stem cell proliferation.

Application of Secretome Therapy

Expected Diseases and Symptoms from Secretome Therapy

Secretome therapy is anticipated to be applicable across diverse diseases and conditions, owing to its pro-regenerative, anti-inflammatory, and immunomodulatory effects. Representative examples are as follows:

• Pengobatan Kanker:Secretome therapy does not directly cure cancer itself, but is gaining attention as an adjuvant therapy that supports the body in fighting cancer by boosting immune strength or by aiding recovery from the side effects of cancer treatment (surgery or chemotherapy). Research is ongoing to enhance the effectiveness of standard treatments by improving the immune microenvironment around tumors using secretomes derived from immune cells.
• Penyakit Saraf:Applications in the treatment of neurodegenerative diseases such as Parkinson's or Alzheimer's, or post-stroke sequelae are expected. Components in the secretome can help neuronal survival, alleviate inflammation in the brain, thereby suppressing symptom progression or promoting functional recovery. Indeed, reports from animal experiments show that secretome administration in Parkinson's models led to improved motor function.
• Anti-Aging (Anti-Penuaan):Secretome therapy is hoped to be an approach for cellular rejuvenation addressing the decline in bodily function associated with aging or cosmetic concerns. Applications include promoting skin regeneration for the improvement of wrinkles and folds, or hair regrowth treatment using exosomes to restore hair thickness and volume. There are also cases where people receive periodic secretome transfusions as an anti-aging treatment to enhance fatigue recovery and energy.
• Difficult-to-heal wounds and tissue damage:In cases such as burns or refractory ulcers (wounds that are difficult to heal) due to diabetes, where conventional treatment takes a long time to heal, secretome therapy is expected to accelerate wound healing. Components that promote tissue regeneration allow for the smooth formation of wound granulation and skin regeneration, potentially shortening the treatment period and reducing scarring.
• Penyakit Inflamasi Kronis:The application is also considered for diseases such as rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease, which cause symptoms due to chronic inflammation. By alleviating the inflammation itself through the anti-inflammatory effects of the secretome, the progression of tissue damage can be halted, leading to pain reduction and an improved quality of life.

Thus, research and therapeutic applications of secretome are ongoing across a very broad range of fields. Its flexibility for optimal utilization, tailored to the specific pathological conditions of each individual patient, also constitutes one of its primary appeals.

Expected Effects (Tissue Regeneration, Inflammation Suppression, Immune Enhancement, Anti-Aging Benefits)

As mentioned above, the anticipated effects of secretome therapy are diverse, but can generally be categorized into the following:

• Promosi Regenerasi Jaringan:Accelerates the repair of damaged organs or tissues, promoting the regeneration of new cells. This can lead to faster recovery from injuries or surgery, or an expected improvement in declining organ function.
• Penekanan Peradangan:Calming chronic inflammatory reactions, reducing swelling and tissue pain. By alleviating inflammation, the cessation of tissue damage can be achieved, leading to symptom improvement.
• Peningkatan Fungsi Imun:Enhances immune cell function, strengthening the body's ability to fight off infections and diseases. With increased immune strength, expected effects include a reduced likelihood of contracting illnesses or a faster recovery from illness.
• Perawatan Anti-Aging (Efek Anti-Penuaan):Secretome activates the function of old cells, helping to maintain whole-body youthfulness. This can result in improvements in skin radiance and elasticity, increased hair thickness and volume, reduction in chronic fatigue, etc., leading to the alleviation of discomforts associated with aging.

Notwithstanding individual variability, the combination of these effects can be expected to improve quality of life (QOL) and alleviate symptoms. However, given that the manifestation and onset time of effects vary depending on symptoms and individual constitution, it is crucial to establish realistic targets in consultation with a physician.

Secretome Therapeutic Method

Workflow from Secretome Collection to Administration

A number of steps precede the availability of secretome therapy to patients. The fundamental process is outlined below:

• Kultur Sel:First, the cells that form the basis of the secretome are prepared. In the case of stem cell origin, stem cells taken from a donor or the patient's own stem cells are cultured. In the case of immune cell origin, immune cells taken from blood (such as NK cells) are expanded. When these cells are grown in a special culture medium for a period of time, they increase in number and simultaneously release various useful components into the culture medium.
• Pemisahan Supernatan Kultura:After a certain culture period, we proceeded to separate the culture fluid from the cells. The culture fluid was transferred to a centrifuge or filtered to remove the cells. The clear liquid obtained in this way (supernatant or culture supernatant) contains abundant growth factors, cytokines, exosomes, etc., released by the cells.
• Pemurnian dan Konsentrasi Komponen:From the separated culture supernatant, remove unnecessary substances for therapeutic purposes, and concentrate the active components. Since the culture fluid contains waste products released by cells during culture (such as ammonia and lactic acid), and these may be present even in trace amounts, use special filters or membranes to remove them. At the same time, proteins and exosomes, which are the active components, are collected at the highest possible concentration. Through this process, a high-quality and safe secretome product is created. The product can be stored as a liquid by freezing or by lyophilization (dried into a powder) for storage.
• Giving to Patient:The secretome product is ready for patient administration and is actually introduced into the body. As explained later, there are various administration methods, but the secretome is introduced into the body via intravenous (IV) administration or direct injection to specific locations, depending on the treatment objective. After administration, the secretome works within the body as described above, providing tissue repair and immune modulation effects.

Outlined above is the fundamental workflow of secretome therapy. While it necessitates advanced laboratory equipment and specialized expertise, at the point of patient administration, it is delivered in a simple form, such as a transfusion or injection. Behind the scenes, these processes are performed to create an extract that serves as the seed for regeneration.

Administration Method Options (Transfusion, Local Injection)

The optimal administration method for products derived from secretome therapy is selected based on the patient's condition and therapeutic objectives. Key administration methods include:

• Pemberian IV (Transfusi IV):This method dilutes the secretome product with physiological saline solution or similar, and slowly introduces it into the bloodstream via transfusion. Since the active components can spread throughout the body, this method is suitable for cases where a systemic effect is desired (such as increased immune strength or whole-body anti-aging). The procedure is usually performed by transfusion from an arm vein, and the administration takes approximately 30 minutes to 1 hour.
• Injeksi Lokal:When the treatment area is well-defined, there is a method to inject secretome directly into that area. For example, to promote joint regeneration, it is injected into the joint, or when the goal is skin rejuvenation, it is finely injected into the dermis (the inner layer of the skin). Because highly concentrated active components can be delivered to where they are needed, this method is used when a strong local restorative effect is desired. Depending on the location of the procedure, local anesthesia can be used to reduce pain.

Thus, secretome therapy enables the selection of an administration route aligned with the therapeutic objective. The attending physician will evaluate the patient's condition and recommend the most effective and safest method; therefore, please do not hesitate to consult regarding any concerns you may have.

Treatment Duration and Procedure Schedule (Frequency and Number Individualized for the Patient)

The duration of treatment and the schedule for secretome therapy procedures are individually tailored to each patient's specific needs and symptoms. For instance, in relatively mild cases, such as for anti-aging or general health enhancement, a regimen involving monthly transfusions over several months may be considered.

On the other hand, when the objective is to treat specific diseases or injuries, an intensive dosing regimen involving multiple administrations over a short period (e.g., once weekly for 1-2 months) is sometimes employed to enhance the therapeutic effect.

Typically, during the initial consultation, the physician confirms the patient's current health status and the desired therapeutic outcomes, then recommends a suitable treatment regimen with appropriate frequency and duration. Progress can be observed once therapy commences, and the regimen can be flexibly adjusted as required.

In many cases, the therapeutic effects of secretome emerge gradually. Therefore, optimal results are better achieved through a series of periodic procedures, rather than a single intervention.

Additionally, some patients undergo secretome therapy procedures in conjunction with other treatments (e.g., rehabilitation or medication therapy). In such cases, the medical team also supports its implementation at a manageable pace without discomfort. Therefore, please confidently establish your treatment plan.

Safety of Secretome Therapy

Fundamental Safety Information for Secretome Therapy (Risks of Adverse Effects and Management)

Secretome therapy is considered to have relatively high safety among regenerative therapies.
The biggest reason is, as mentioned before, "the cell itself" is not used but only "the substance made by the cell" is used.

The risk of rejection (when foreign cells are introduced, the immune system attacks them) or unpredictable behavior of transplanted cells, both of which are concerns when transplanting live cells, is very low in secretome therapy.
The components included are proteins and vesicles native to the human body, making them easily adaptable to the human body, and serious side effects are unlikely to occur.

Of course, as a medical procedure, it cannot be said that the risk is completely zero. In very rare cases, temporary fever or fatigue may occur after the procedure, or the injection site might swell and redden.
However, these symptoms usually subside within a short time (1-2 days), and with appropriate treatment such as taking fever-reducing medication or getting rest, improvement is not an issue.

Also, there is a possibility of small internal bruising due to the transfusion needle or mild pain, symptoms accompanying a regular transfusion or injection, may occur, but these also disappear naturally over time.
At our clinic, we carefully explain the safety of secretome therapy beforehand, and if symptoms indicating side effects appear, we have also taken steps to address them.

By assessing patient conditions, performing procedures within appropriate parameters, and diligently monitoring post-procedure progress, we strive to ensure that patients receive safe treatment.

Comparison with Other Cell Therapies (e.g., Stem Cell Therapy, NK Cell Therapy)

Let us compare the safety and therapeutic characteristics of secretome therapy with other representative cell therapies.

• Comparison with Stem Cell Therapy:As mentioned previously, in stem cell therapy, live stem cells themselves are infused. This allows the stem cells to function within the body for a long period. However, on the other hand, the risk of unwanted cell proliferation (carcinogenesis) is rare but cited, and in the case of stem cells derived from another person, there is a risk of immune rejection. Conversely, because secretome therapy only uses components extracted from stem cells, these risks can be further reduced. Furthermore, while stem cell therapy sometimes requires surgery or procedures to harvest and culture cells from the patient themselves, secretome therapy simply involves administering a finished product via transfusion, etc., thus the reduced burden on the body is an advantage.
• Comparison with NK Cell Therapy:NK cell therapy is an immune treatment that is gaining attention, especially for cancer, by expanding NK cells taken from the patient and reinfused to directly attack cancer cells. This is a very powerful treatment, but because the patient's own cells are processed, it requires time and cost, and temporary immune reactions such as fever can occur after transfusion. In contrast, secretome therapy (including those derived from immune cells) aims more to enhance overall immunity rather than the direct attack power of immune cells. Side effects are minimal and it is more easily repeatable, but on the other hand, it does not have the same effect as NK cell therapy in directly and powerfully eliminating tumors. For this reason, in cancer treatment, secretome therapy tends to be used in conjunction with standard treatments or other immune therapies to modulate the body's condition, rather than being used alone.

In this regard, compared to other cell therapies, secretome therapy offers superior safety and convenience, despite its gentle therapeutic effects and primarily supportive role. Every therapy possesses unique strengths and weaknesses, making it essential to select and integrate the optimal methods tailored to the patient's condition and objectives. The physician will recommend a treatment plan that maximizes benefits based on these choices.

**Secretome:** The complete set of molecules (e.g., proteins, lipids, nucleic acids, metabolites) actively secreted by a cell, tissue, or organism into its extracellular environment. **Exosome:** A specific subtype of extracellular vesicle (typically 30-150 nm in diameter) originating from the endosomal pathway and released by cells. Exosomes are a component of the secretome, playing crucial roles in intercellular communication and cargo delivery. **Platelet-Rich Plasma (PRP):** An autologous blood product prepared by concentrating platelets from a patient's own blood. PRP contains a high concentration of growth factors and other bioactive molecules released by activated platelets (many of which are part of the platelet secretome), used therapeutically for tissue regeneration and healing.

In the field of regenerative medicine, there are three treatment methods:Secretome, Exosome, dan PRP (Platelet-Rich Plasma)We compared the characteristics of each.

The secretome comprises all bioactive substances secreted by cells, such as exosomes, growth factors, cytokines, and proteins, which are broadly involved in tissue repair, regeneration, and immune modulation.

Exosomes are components of the secretome, and the secretome provides a more comprehensive therapeutic effect.

Exosomes and PRP are effective in their individual applications, but considering the treatment's persistence and broad spectrum of action, secretome emerges as the superior choice. Particularly for chronic conditions or those seeking long-term therapeutic solutions, secretome offers considerably greater benefits.

Choosing the Right Secretome Therapy

Secretome therapy is a safe, affordable treatment with the potential for numerous benefits. However, improper selection can not only prevent the realization of desired effects but also lead to harm.

Derived from Wharton's Jelly Stem Cells

Non-Wharton's Jelly stem cells contain significantly fewer growth factors and cytokines, resulting in lower therapeutic efficacy. Wharton's Jelly stem cells are abundant in essential factors that promote tissue repair and regeneration, and their application in regenerative medicine and reverse aging is expanding.

Extracted from Stem Cell Culture Supernatant, not Supernatant Fluid.

Stem cell culture supernatant is a culture fluid used when culturing stem cells, and was originally waste that was discarded after removing the stem cells.
Therefore, the concentration of growth factors and active components is low, and the therapeutic effect is not as expected.

Conversely, components precisely extracted from stem cells enhance cellular activation and repair capabilities, enabling more effective treatments. Therefore, it is recommended to select specifically extracted components.

Manufactured in a facility compliant with Global Safety Standards

Regulations regarding the cultivation and extraction of stem cells vary by country, and there are facilities that do not meet strict standards.
Therefore, it is very important to ensure which facilities produce the product.
By choosing products manufactured in facilities that have obtained international cGMP or cGPTs, the safety and quality of high-quality products can be ensured.

Without processing such as lyophilization

Many secretomes or exosomes are available on the market, as well as lyophilized stem cell culture supernatants to improve ease of storage and transport.
However, during this processing, active components such as growth factors and cytokines are reduced due to the effects of heat and drying, potentially lowering the original therapeutic effect. From the perspective of regenerative medicine and secretome therapy, it is better to choose those that are unprocessed and in a fresh state.

Secretome therapy is next-generation regenerative medicine that utilizes growth factors and exosomes secreted by stem cells. As it does not involve cell transplantation, high safety is anticipated, and various effects such as inflammation suppression, tissue repair, and immune modulation are expected.

Currently, research is underway in the fields of joint diseases, neurological diseases, and anti-aging, with the expectation of future indication expansion driven by technological innovation. Additionally, as safety and efficacy verification advances, it is anticipated that these will be established as viable treatment options.

Secretome therapy is gaining attention as a novel therapeutic method that plays a new role in the field of regenerative medicine.