What is PDRN in Rejuran | Source, Function

PDRN is a regenerative factor extracted from salmon DNA, with a similarity to the human body of up to 95%. It can directly repair damaged cells, promote collagen regeneration, and act as an anti-inflammatory. It not only thickens the skin barrier but also significantly improves pores and fine lines. it is the core biotechnology used by Rejuran to achieve age-reversing skin repair.

Source

The PDRN used in Rejuran is extracted from the germ cell DNA of wild Chum Salmon (Oncorhynchus keta). Studies have confirmed that the base homology of this component with human DNA exceeds 95%. Through patented DOT (DNA Optimization Technology), the raw material is refined into polynucleotide fragments with a molecular weight between 50-1500kDa. This specific source not only avoids the risk of zoonotic diseases but also removes over 99% of protein impurities, ensuring high bioavailability.

Reasons for Choosing Chum Salmon

In the process of large-scale industrial production of polynucleotides (PN/PDRN), the sperm DNA sequence of Chum Salmon (Oncorhynchus keta) was selected as the raw material for Rejuran. The primary reason is that the base sequence homology between the germ cell DNA of this fish and human DNA exceeds 95%. From a molecular structure analysis, the DNA chains of Chum Salmon exhibit high biocompatibility in the arrangement of A (adenine), T (thymine), G (guanine), and C (cytosine). This high proportion of homology effectively avoids inflammatory reactions or foreign body granulomas induced by immune system misjudgment after entering the human dermis. Compared to tissues from mammals such as cattle and pigs, nucleotides derived from fish do not have transmission paths for cross-species infectious viruses (such as Mad Cow Disease prions or Foot-and-Mouth Disease virus) due to different evolutionary paths. This provides fundamental safety data support for medical-grade injection applications.

The choice of germ cells (sperm DNA) of Chum Salmon instead of skin or visceral tissues is because the proportion of DNA in their cellular structure is extremely high, while the content of cytoplasm and organelles (such as mitochondria and lysosomes) is minimal. During processing, the sperm DNA of Chum Salmon is combined with protamines. This binding method is easier to separate through physical and chemical means than the combination of mammalian DNA with histones. Through DOT patented technology, manufacturers can precisely trim the original long-chain DNA into specific fragments of 50 to 1500kDa. Research data shows that when the molecular weight is maintained in this range, polynucleotides can most effectively bind with A2A receptors on the surface of skin cells, thereby inducing fibroblast proliferation without creating physical pressure. If the fragment molecular weight exceeds 2000kDa, the cellular uptake efficiency may decrease due to excessive physical volume, and tissue swelling may increase.

The wild Chum Salmon used in the production process are captured during the migration season when the activity of their germ cells is at its peak, ensuring that the extracted DNA chains carry complete biological information. In laboratory tests, PN fragments extracted from Chum Salmon showed extremely strong thermal stability. Under 121 degrees Celsius high-temperature and high-pressure sterilization conditions, its secondary structure (double helix) will temporarily unwind, but can quickly renature after the temperature drops and maintain its original chemical properties without degradation. This thermal characteristic allows the product to undergo terminal sterilization without adding strong chemical preservatives, further reducing uncertain factors in clinical applications. The solubility and viscoelasticity of this Chum Salmon-sourced PDRN in an aqueous environment are also physical reasons for its selection. Because its polynucleotide chains carry a negative charge, they exhibit good hydrophilicity in physiological saline, attracting moisture and building a microenvironment within the dermis. Experimental data records show that the half-life of this specific source of PN fragments in tissue is approximately 24 to 72 hours, after which they are broken down into individual nucleotides by intracellular exonucleases through the Salvage Pathway.

Production Process

The process of producing high-purity Polydeoxyribonucleotide (PDRN) begins with the collection of germ cells from Chum Salmon (Oncorhynchus keta) in the North Pacific waters. The collection time must be strictly locked to the specific season of fish migration and spawning to ensure the integrity of the DNA chains within the cells. After collection, the biological tissues are quickly placed in an ultra-low temperature cold chain environment of 0 to 4 degrees Celsius to inhibit the activity of endogenous nucleases. If the ambient temperature exceeds 10 degrees Celsius, these enzymes will break down the long-chain DNA, leading to degradation of the raw material. In the initial screening stage, technicians use physical pressing and homogenization techniques to break cell membranes, releasing chromatin contained within the cell nuclei. Due to the extremely low proportion of cytoplasm in Chum Salmon sperm cells, the DNA concentration in this original extract is several times higher than that of ordinary somatic cells.

In the raw material processing stage, a neutral environment with a pH value of around 7.0 must be maintained to prevent depurination caused by acid hydrolysis, thereby maintaining the original sequence of the base pairs.

After entering the fractional purification stage, the extract must undergo more than 12 rounds of gradient centrifugation and ultrafiltration procedures. The main goal of this stage is to remove protamines tightly bound to the DNA as well as cellular debris. The production line uses buffer solutions with high salt concentrations (usually 2M sodium chloride solution) to dissociate nucleoprotein complexes, followed by a Tangential Flow Filtration (TFF) system to remove small molecular weight proteins, lipids, and pigment molecules. This process compresses the protein residue of the final product to below 0.1%. At the same time, to eliminate the influence of endotoxins (LPS), the production system adopts special detergents and affinity chromatography technology to ensure that the endotoxin content in each milliliter of product is below 0.5 EU/mL, meeting medical-grade injection standards.

Through 121 degrees Celsius, 20 minutes of high-temperature and high-pressure sterilization, the product achieves terminal sterilization, and the double-helix structure of the polynucleotide can renature after cooling.

During the DNA fragmentation process, patented DOT (DNA Optimization Technology) comes into play. The original length of extracted Chum Salmon DNA chains usually reaches tens of thousands of base pairs, which is too large to be effectively utilized by human cells. Through controlled chemical trimming and ultrasonic fragmentation technology, long-chain DNA is precisely cut into fragments with lengths between 50 and 1500 base pairs. According to pharmacokinetic data, fragments with molecular weight distributions between 50 and 1500kDa have the best tissue permeability and receptor binding efficiency. The average molecular weight is set at approximately 350kDa, which allows polynucleotide molecules to interact with A2A receptors on the cell surface after entering the skin dermis without causing local tissue edema due to excessive molecular weight.

The polynucleotide fragments processed by DOT technology show high consistency in their molecular weight distribution patterns during gel electrophoresis testing, ensuring stability between batches.

The purified PDRN solution needs to undergo qualitative and quantitative analysis through High-Performance Liquid Chromatography (HPLC). This step detects the ratios of the four deoxyribonucleotides (dAMP, dGMP, dCMP, dTMP) to verify if they match the characteristic fingerprint of Chum Salmon DNA. If the base ratios shift, it indicates that degradation or contamination occurred during extraction or trimming. To further improve biological safety, the product also passes through a 0.22-micron sterile filtration membrane to remove any possible microbial contamination. Before filling, the osmotic pressure of the solution is precisely adjusted to between 280-320 mOsm/kg, which is isotonic with human extracellular fluid, thereby reducing pain and osmotic pressure changes during injection.

High-purity polynucleotide solutions exhibit transparent and slightly viscous physical characteristics, with dynamic viscosity maintained within a specific range at room temperature, which helps improve drug delivery compliance during injection.

The final quality control stage includes Nuclear Magnetic Resonance (NMR) analysis and Thermogravimetric Analysis () to detect molecular structure integrity and moisture content. In a sterile workshop complying with standards, the product is dispensed into pre-filled. To prevent DNA chain breakage caused by photochemical reactions, the packaging materials use special glass or polymers with UV-shielding functions. Samples from each batch are kept for a 36-month stability test. Under storage conditions of 1 to 30 degrees Celsius, the fluctuation in polynucleotide content must be controlled within plus or minus 5%.

Each of produced injection liquid has a unique serial number, which can be traced back to the original Chum Salmon collection batch and specific production date through the traceability system.

Global Supply Chain and Regulatory Compliance

The collection of wild Chum Salmon (Oncorhynchus keta) is jointly regulated by international fishery management organizations and local environmental monitoring agencies. Annual catch quotas are dynamically adjusted based on the size of the migrating population to ensure the continuity of biological resources. The collected germ cells must complete initial stabilization treatment within 2 hours and enter an ultra-low temperature cold chain system of -20 degrees Celsius for cross-border transportation. Since the biological activity of DNA is extremely sensitive to temperature fluctuations, the entire logistics process is equipped with temperature data loggers that record data every 15 minutes. Any deviation exceeding 4 degrees Celsius will result in that batch of raw materials being marked as unqualified. Raw Material Collection Site Monitoring Indicators:

• Heavy metal content in seawater: Mercury (Hg) < 0.001 mg/L, Lead (Pb) < 0.01 mg/L
• Radionuclide monitoring: Cesium-137 (Cs-137) and Iodine-131 (I-131) detection limits below 0.1 Bq/kg
• Fishing water temperature: Maintained between 2 to 10 degrees Celsius year-round
• Population compliance: Holds MSC (Marine Stewardship Council) sustainable fisheries certification

Production facilities are located in industrial parks that meet international () standards, and the entire extraction process is governed by the medical device. When handling biological tissues sourced from fish, regulatory agencies require producers to provide complete viral inactivation validation reports. Experimental data shows that the combination of acid-base treatment and high-temperature sterilization used in the production process achieves an inactivation rate of over log 6 (99.9999%) against known fish viruses. Before entering the et, products must pass rigorous audits by agencies such as CE 0123 () and are classified as Class III (Class III medical devices). This classification requires providing data including biocompatibility testing (), allergenicity experiments, and long-term stability testing for a period of 24 months. International Status:

• EU: Obtained certification, complying with the MDR (Medical Device Regulation) framework
• South Korea: Obtained Class III medical device license from ()
• Singapore: Passed registration audit by HSA (Health Sciences Authority)
• International Standards: Complies with the risk management system standard

To meet global market demand, supply chain management has introduced a serialization tracking system based on GS1 standards. Each product’s outer box is printed with a globally unique UDI (Unique Device Identifier). By scanning this barcode, regulatory agencies and medical institutions can trace it back to specific production lines, sterilization batches, and raw material collection coordinates. Upon entering customs in different countries, products must be accompanied by a Certificate of Analysis (CoA), clearly recording the protein content (must be below 0.1%), endotoxin levels (below 0.5 EU/mL), and pH value of that batch. In the storage stage, distribution warehouses worldwide must maintain a constant temperature environment of 1 to 30 degrees Celsius and be equipped with 24-hour alarm systems to prevent temperature loss due to power failures. Finished Product Batch Quality Control Parameters:

• Purity index: Polynucleotide purity > 99.0% (detected by HPLC)
• Sterility assurance level: SAL 10^-6 (one in a million probability of contamination)
• Osmotic pressure range: 280 – 320 mOsml/kg (isotonic with human physiological saline)
• Packaging airtightness: Detected by vacuum decay method, air leakage rate < 0.1%

In terms of post-market surveillance, the producer has established a global adverse event reporting system and periodically submits PSURs (Periodic Safety Update Reports) to regulatory departments in various countries. According to global monitoring data from the last five years, the probability of serious allergic reactions occurring in millions of uses of this component is below 0.01%. When facing compliance reviews from the US or the EU EMA, the producer must disclose process validation details of its DOT patented technology to prove that no immunogenic abnormal fragments are generated during the trimming of DNA chains. Supply Chain Risk Control Links:

• Secondary supplier audit: Annual on-site audits of buffer and suppliers
• Logistics redundancy design: Setting up three regional distribution centers globally to handle risks of single-route interruptions
• Quality testing redundancy: Each batch of samples, after in-factory testing, must be sent to an independent third-party laboratory for review
• Anti-counterfeiting management: Adopting optically variable inks and micro-text technology to prevent counterfeit goods from entering the distribution channels

Function

PDRN specifically binds to adenosine A2A receptors, directly driving the DNA Salvage Pathway, making the repair efficiency of damaged cells faster than conventional metabolism. Clinical data shows that 4 weeks after applying a 2% concentration of polynucleotides (PN/PDRN), the dermal thickness increases by an average of 15%-30%, and the elastin synthesis rate increases by about 20%. It blocks chronic inflammation at the molecular level by downregulating pro-inflammatory factors such as TNF-α and IL-6, achieving reconstruction of the skin barrier.

Cellular Energy Supplement

In skin cell metabolism physiology, DNA synthesis usually follows two paths: one is de novo synthesis (De Novo Synthesis), and the other is salvage synthesis (Salvage Pathway). De novo synthesis is a highly energy-consuming process that requires phosphoribosyl pyrophosphate (PRPP) along with various amino acids and carbon dioxide, going through 10 to 13 complex enzymatic steps to complete the construction of a single base. In contrast, PDRN directly provides nucleotide units that constitute the DNA chain, allowing cells to skip these tedious chemical synthesis steps. When cells are damaged or in a high-stress state of aging, their internal ATP (adenosine triphosphate) reserves are often insufficient to support large-scale de novo synthesis. The 50-1500 kDa molecular weight fragments provided by PDRN enter the extracellular environment, are recognized by adenosine A2A receptors on the cell surface, and initiate signal transduction. This mechanism significantly improves the efficiency of cells using ready-made nucleotide fragments for repair. According to clinical biochemical calculations, this salvage path saves about 80% of metabolic energy consumption compared to de novo synthesis.

The biocompatibility of PDRN is established on its over 95% similarity to the human DNA base sequence. This high consistency ensures that when PDRN enters the dermis, it does not cause significant immune rejection. Purine and pyrimidine nucleotides produced by PDRN decomposition are reabsorbed by cells and enter the internal Nucleotide Pool. During the DNA damage repair process caused by ultraviolet radiation (UV), cells need a large amount of deoxyribonucleoside triphosphates (dNTPs) to fill broken sequences. By exogenously supplementing PDRN, fibroblasts in the damaged area can obtain sufficient raw materials for base excision repair or nucleotide excision repair in a short time. Experimental data shows that after applying a 2% concentration of PDRN, a 20%-30% growth in the proliferation rate of fibroblasts can be observed within 48 hours.

In the skin’s microenvironment, the activation of A2A receptors is not only related to energy metabolism but also directly linked to the balance between pro-inflammatory and anti-inflammatory factors. When PDRN molecules bind to A2A receptors, they inhibit the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), while upregulating the levels of anti-inflammatory factors such as interleukin-10 (IL-10). By inducing the release of vascular endothelial growth factor (VEGF), PDRN prompts the establishment of a tiny capillary network at the damaged site, thereby improving the delivery of oxygen and nutrients. In clinical observations of long-term damaged barriers, after continuous use of PDRN for 4 weeks, the thickness of the dermis increased by an average of 15.2%, and the transepidermal water loss (TEWL) on the skin surface significantly decreased, showing a substantial improvement in the integrity of the physical barrier. When cells do not need to excessively consume ATP for DNA synthesis, mitochondrial oxidative stress is reduced, thereby decreasing the production of reactive oxygen species (ROS). PDRN is not just a simple biochemical raw material; it acts as an “efficiency optimizer” in the process of cell metabolism. In aging skin, due to the decrease in endogenous growth factor activity, cell responses to damage are often delayed. The salvage pathway provided by PDRN breaks this delay, allowing cells to complete the reinforcement of DNA sequences at the first opportunity. In clinical tests targeting women aged 40-60, the elastic fiber density in the PDRN treatment group was 18% higher than that in the control group after 14 days.

Remodeling the Dermal Matrix

In the physiological remodeling process of the dermal matrix, the mechanism of PDRN inducing fibroblasts to secrete collagen and elastic fibers is regulated by the expression abundance of adenosine A2A receptors. Fibroblasts, as the main structural cells of the dermis, are responsible for synthesizing all components of the extracellular matrix (ECM). When PDRN molecules contact and activate A2A receptors, intracellular cyclic adenosine monophosphate (cAMP) levels change, initiating the TGF-β signaling pathway. Clinical biospecimen analysis shows that the mRNA expression of Collagen Type I in the dermis is significantly upregulated after PDRN application. This biochemical response not only increases total protein synthesis but also optimizes collagen fiber diameter distribution and arrangement spacing. In a 12-week clinical observation, ultrasound results of the dermis confirmed that the collagen density of the subjects increased by an average of 18% to 25%.

In vitro culture studies on human fibroblasts in the laboratory found that in a 2% concentration PDRN environment, the ability of cells to secrete procollagen increased by approximately 3.2 times compared to the blank control group, and the cell migration speed accelerated, facilitating the matrix filling of micro-injury sites.

Elastin and fibrillin-1 together constitute the skin’s elastic support system. With UV exposure and physiological aging, these fibers degrade and calcify. PDRN reduces the degradation of existing elastic fibers by downregulating the activity of matrix metalloproteinases (MMP-1, MMP-3), while promoting the cross-linking of new elastin molecules. In parameters measuring skin resilience (R2 index), the R2 value of the treated area increased from 0.58 to 0.72 after 4 weeks of PDRN treatment. Through Transmission Electron Microscopy (TEM) observation, it can be seen that newly formed elastic fibers show better wavy structures, providing better tension buffer space.

Skin pharmacology research points out that PDRN can regulate endogenous hyaluronidase activity, maintaining the molecular weight of natural hyaluronic acid in the dermis at a more stable level, thereby forming a stronger osmotic pressure within the matrix.

In the non-fibrous components of the extracellular matrix, the content of glycosaminoglycans (GAGs) and proteoglycans determines the dermis’s water storage capacity and sense of volume. After entering the dermis, PDRN induces fibroblasts to upregulate the expression of Hyaluronan Synthase (HAS-2). The endogenous hyaluronic acid produced in this process is different from ordinary injectable hyaluronic acid; it can interweave more deeply with collagen fibers, forming a biologically active hydration network. This endogenous moisture-locking mechanism increases the turgor of the dermis, reducing fine lines caused by matrix atrophy. In skin biomechanical tests on women aged 35 to 50, skin stiffness decreased by 14% after 3 continuous applications of PDRN, manifesting as a softer and more resilient touch.

Histopathological staining shows that in skin sections treated with PDRN, the number of capillary loops in the papillary dermis increased, providing a continuous supply of oxygen and amino acids for matrix protein synthesis.

Aging or photodamage can cause the accumulation of a large amount of dysfunctional abnormal elastosis in the dermis. The A2A receptor signal activated by PDRN can balance the ratio of degradation enzymes and synthesis enzymes within the tissue. It not only accelerates the metabolism of old, damaged components but also ensures that newly synthesized structural proteins can be arranged according to physiological sequences. This benign cycle of physiological metabolism becomes particularly evident 21 to 28 days after injection, at which point the synthetic activity of fibroblasts reaches a steady state.

Because the PDRN extraction process ensures the purity of the base sequence, this remodeling effect on the dermal matrix shows high predictability. By precisely controlling the PDRN fragment molecular weight between 50-1500 kDa, it ensures that its diffusion radius and receptor binding efficiency in the dermis reach a balance. In clinical skin section comparisons, the orientation of collagen fiber bundles in the treatment area tends to be more parallel to the skin surface, a structural feature unique to young tissue.

Regulating Immunity and Controlling Inflammation

According to clinical research data, after 48 hours of continuous use of 2% PDRN formulation, the expression of TNF-α (tumor necrosis substance) in damaged tissue decreased by an average of 35% – 40%, and a reduction of over 30% in the concentration of IL-6, a typical pro-inflammatory mediator, was also observed. In terms of regulating immune cells, PDRN prompts macrophages to switch from the pro-inflammatory M1 type to the M2 type with repair functions. M1 macrophages mainly release destructive proteolytic enzymes, while M2 macrophages secrete proteins that support tissue growth. Immunohistochemical analysis found that in skin sections after PDRN intervention, the density of CD163+ (M2 type marker) cells was about 42% higher than in the control group. The table below lists the quantitative impacts of PDRN on inflammatory mediators and immune indicators across different time dimensions:

In damaged skin microenvironments, excessive inflammation generates a large amount of matrix metalloproteinases (MMPs), which indiscriminately degrade collagen and elastin, leading to skin thinning and rough texture. PDRN effectively balances protein synthesis and degradation by upregulating the expression of tissue inhibitors of metalloproteinases (TIMPs). Studies have observed that under the action of PDRN, the activity of MMP-1 was inhibited by about 28%, which indirectly protects the integrity of the dermal structure. For subjects with chronic diffuse erythema (such as certain sensitive skin types), their Erythema Index decreased by an average of 22.5% after receiving 3 PDRN treatments. In addition to protein level regulation, PDRN can significantly improve the oxygenation state within tissue. Inflammation is often accompanied by local microcirculation disorders and tissue hypoxia, and hypoxia further induces inflammation, forming a closed loop. The VEGF (vascular endothelial growth protein) expression induced by PDRN is controlled and moderate, promoting healthy microvascular regeneration rather than pathological capillary expansion. In this way, the oxygen supply to the damaged area increased by about 15%, accelerating the clearance of metabolic waste, thereby suppressing recurring inflammation from an environmental level. Below are several major biochemical regulation directions involved in PDRN’s process of controlling inflammation:

• Blocking danger signals: Inhibits the release of HMGB1 protein, preventing damaged cells from spreading “stress signals” to surroundings, limiting the scope of inflammation.
• Activating self-healing pathways: Increases the concentration of anti-inflammatory mediators such as IL-10, which can actively induce immune cells to stop attacking self-tissue.
• Stabilizing vascular endothelium: Reduces inflammatory exudation caused by increased vascular permeability, effectively relieving local tissue edema.
• Regulating Reactive Oxygen Species (ROS): Reduces the consumption of superoxide dismutase by alleviating cellular metabolic stress, enhancing the skin’s antioxidant tolerance.

In clinical practice, this immunomodulatory effect manifests as a significant decrease in skin sensitivity to fluctuations in the external environment. In an 8-week test on 100 subjects with sensitive skin characteristics, skin reaction scores after daily exposure to standardized irritants decreased by 48% in the PDRN group.