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Polynucleotides

Also known as: PN, polynucleotide, PDRN, polynucleotides

Polynucleotides are sterile, purified DNA fragments — often extracted from fish sperm in aesthetic products — injected intradermally for skin-quality aims. Regulatory classification is product-specific: the cited Plinest range is presented by its manufacturer as CE-marked Class III devices, not licensed medicines.

Evidence status

Manufacturer-supported

The 2025 systematic review found nine low-to-moderate-quality studies (219 patients) and called for rigorous trials, but failed to flag that a retracted 72-patient study supplied one-third of its sample. A randomised split-face comparison with HA (n=27) found no significant difference on global scales despite the authors’ positive conclusion, and placebo evidence is limited to two saline-controlled trials of 20 patients each from one group. Three aesthetic PN papers are retracted; mechanism evidence is in vitro or rodent, and reviews, consensus and post-market reports have declared Mastelli links.

What polynucleotides are, and how terms differ#

Polynucleotides (PN) and polydeoxyribonucleotide (PDRN) are purified, sterilised mixtures of DNA fragments. In aesthetic injectables the source is commonly sperm DNA from salmonid fish; the PDRN literature names Oncorhynchus mykiss and Oncorhynchus keta. Purification is intended to remove proteins and peptides that could provoke immune reactions.[3, 11][3]

The terms are not standardised. A 2025 narrative review notes that PN and PDRN have been used interchangeably, then proposes a molecular-weight cut-off of 1,500 kDa: PDRN below it and PN at or above it. That “Marques Polynucleotide Cutoff” is an author proposal, not an adopted scientific or regulatory definition, and several authors had commercial polynucleotide affiliations. Practitioners should identify the exact product, composition, source and intended use rather than infer clinical properties from the label.[5]

These products differ from hyaluronic-acid skin boosters, particulate collagen biostimulators and dermal fillers. An injected PN product may create transient fluid effects, but its intended claim is biorevitalisation rather than volumetric correction. Evidence from HA, PLLA, PCL or CaHA does not validate PN.

Fish-derived DNA is not the same as “salmon collagen”, an exosome or a genetic treatment. No primary evidence supports the common claim that similarity between fish and human DNA explains tolerance.

Use of polynucleotides in aesthetic practice#

Named polynucleotide products may be supplied as injectable medical devices. Classification, intended purpose and market route must be verified for the exact product rather than inferred from the PN label. Practice also requires material-origin consent, traceability, competence, complication recognition and appropriate medical support.

Mastelli describes its Plinest products as CE 0373 Class III medical devices for intradermal use and restricts a periocular product to authorised medical professionals in its documentation.[11] In Great Britain, market placement requires the applicable conformity route, MHRA registration and a UK Responsible Person for a non-UK manufacturer. MDD/AIMDD CE-marked devices remain acceptable only until the sooner of certificate expiry or 30 June 2028; MDR-compliant general devices may be accepted until 30 June 2030.[12]

Where the named product is correctly supplied as a medical device rather than a medicinal product, a prescription-only-medicine requirement is not inherent to that product route. This does not establish every PN product's classification or make competence, insurance, asepsis, medical oversight, complication access and local governance optional.[3, 11]

The cited English licensing consultation does not name polynucleotides, skin boosters or biostimulators, and “biorevitalisation injections” was defined there as hyaluronic acid with vitamins. Its proposed licensing scheme is not in force. Those documents therefore establish neither a PN-specific tier nor the complete legal and professional position on who may inject a named product. Scotland, Wales and Northern Ireland require separate current checks.[13][13]

Contraindications and cautions#

The current instructions for the exact device govern. Plinest documentation reproduced by a distributor lists hypersensitivity to product ingredients or a history of fish-product allergy as contraindications. It describes use in autoimmune disease, pregnancy, breastfeeding and under-18s as not recommended because clinical data are absent, and excludes infected or inflamed treatment areas. These are manufacturer positions for a named range, not automatically a class-wide evidence finding.[11]

Material origin is part of consent. “Purified DNA” should not be used to conceal that the source is fish gonads. The client may have allergy, ethical, religious or personal concerns even where a clinical allergy is not known.

Treatment requires verified product identity, batch, conformity certificate, MHRA registration route, UK Responsible Person, current instructions, sterile integrity and supply chain. A distributor’s marketing description is not a substitute for device documentation.

Caution is heightened around the periocular region and in anyone with active infection, inflammation, unexplained swelling, bleeding risk, impaired healing or a previous significant injectable reaction. Whether a condition is an absolute or relative contraindication is determined by the device instructions, medical assessment and professional scope—not by a generic online PN protocol.

Clinical uses and the evidence behind them#

Overall evidence. The only aesthetic-medicine systematic review identified nine low-to-moderate-quality studies involving 219 patients. It reported promising signals for wrinkles, texture and elasticity but found heterogeneous products and methods and called for rigorous high-quality studies. There was no meta-analysis or pooled effect estimate.[1] One included 72-patient trial had already been retracted in 2016, yet the review counted its patients and quoted its result without flagging the withdrawal.[1, 6]

The review declared no company grant or involvement, but one author was a Mastelli R&D steering-board member and tutor and another was a key opinion leader and trainer for Dermafocus, Mastelli's UK distributor. It is therefore not an independent synthesis of the manufacturer's evidence base.[1, 10, 8, 16]

Comparison with hyaluronic acid. A 27-person Korean randomised double-blind split-face study compared PN with non-cross-linked HA around the eyes. Improvements in visual analogue and Global Aesthetic Improvement Scale scores did not differ significantly. Roughness and pore-volume improvement rates favoured PN, while dermal-density change did not differ; no effect sizes or confidence intervals were reported in the abstract. Both sides received active injections, so the trial cannot separate either product from needling, fluid or expectation effects. Funding and conflict statements were unavailable in the accessible record.[2]

Placebo-controlled evidence. Two small saline-controlled randomised studies exist, both from the same Italian author group and each with 20 participants. In women with moderate-to-severe atrophic acne scars, PN-HPT showed significant within-group improvement at one and three months whereas saline did not; the report did not supply a clear between-group effect size, and funding and conflict statements were unavailable in the accessible record. In nasolabial folds, a split-face exploratory study reported early monotherapy changes before both sides later received HA; enrolment was expanded after favourable early outcomes, weakening inference. Its authors declared no funding, conflicts or industry relationships. These are real placebo-controlled data, but not a large or independently replicated evidence base.[8, 9, 14, 15]

Uncontrolled evidence. A 2026 post-market report included 66 adults and 106 treatment-area questionnaires, with subjective improvement and high satisfaction at three months. It had no control, randomisation or blinding; Mastelli paid publication costs while the paper declared no conflicts, and medical writing assistance was acknowledged.[8] A separate 42-person periorbital series found FACE-Q improvement to six months but likewise had no control; its authors declared no conflicts and no manufacturer funding was disclosed.[9]

Three aesthetic PN papers have been retracted. The 2014 Rejuran “phase III” comparison was withdrawn without a stated reason. A 2022 PN-HPT paper was retracted after unresolved duplication between baseline and post-treatment photographs. A large 2025 PCL-versus-PN study was retracted because the comparator filler had been misidentified; that error concerned the comparator rather than the PN arm but removes the dataset from reliable use.[6, 16, 7]

Selecting a polynucleotide injectable#

Selection starts with a named device rather than “PN” as a class. Relevant checks include:

  • manufacturer, authorised supply chain, batch and expiry;
  • DNA source, concentration and other components;
  • intended purpose, anatomical indication and route;
  • device class, conformity certificate, certificate validity and MHRA registration route;
  • UK Responsible Person for Great Britain where applicable;
  • complete current instructions, contraindications and adverse-incident route;
  • practitioner competence, indemnity and access to medical support.

The PN/PDRN label alone does not establish molecular weight, purity, biological equivalence or dose. The proposed 1,500 kDa distinction has not been linked to different clinical outcomes.[5]

Product claims must be matched to the actual evidence. A periorbital comparison does not validate neck, scalp or body use, and an acne-scar trial does not prove general rejuvenation.[2, 14] Consensus recommendations are not a substitute for trials: the 2021 PN-HPT board integrated limited evidence with opinion, had multiple member relationships with manufacturers, and Mastelli supported its logistics and publication.[10]

The available evidence does not establish a generic injection pattern, volume, interval or course. The named device instructions and appropriately governed training apply.

Adverse effects and their management#

Published studies describe mainly transient local swelling, erythema, pain, bruising, warmth or itching, and no serious adverse events in their small cohorts.[2, 8, 9] Those data are too small and too manufacturer-linked or uncontrolled to estimate rare-event rates.

Potential harms also arise from injection, sterility, anatomy, allergy and product quality rather than from the DNA fragment alone. Fish hypersensitivity is a manufacturer-stated contraindication, although no published anaphylaxis case in a fish-allergic PN recipient was located.[11] The absence of a case report does not prove absence of risk.

Severe or escalating pain, blanching or livedoid change, visual symptoms, breathing difficulty, widespread urticaria, rapidly increasing swelling, infection signs, tissue breakdown or neurological symptoms are outside routine local-reaction management and require urgent medical assessment. The clinic must have a complication and escalation pathway appropriate to injectable practice before treatment.

Suspected serious device incidents should be documented with product and batch details and reported through the manufacturer and MHRA vigilance routes where applicable.[12] Marketing descriptions such as “minimal downtime” do not alter incident duties.

Referral and scope boundaries#

Medical assessment is required when the indication or diagnosis is uncertain; there is active infection, inflammatory disease or an unexplained lesion; an allergy concern cannot be resolved; or comorbidity, medication or prior complication makes the risk unclear.

Urgent escalation is required for suspected vascular compromise, visual or neurological symptoms, anaphylaxis, severe infection, tissue necrosis or another rapidly progressive adverse event. An injectable practitioner must know the local emergency pathway and the limits of personal competence.

A Class III device can be non-prescription yet still demand advanced anatomical knowledge, asepsis, consent, complication recognition, insurance and access to medical care. “No prescription required” is a product-law statement, not a competence standard.

The evidence and legal discussion here establish Great Britain device market access and the current English licensing position only.[12, 13] They do not establish injector scope in Scotland, Wales or Northern Ireland. No specific JCCP, CPSA or national occupational competence standard for injectable polynucleotides was located; practitioners must therefore evidence competence and governance rather than treat regulatory silence as permission.[no source found]

We found no MHRA or GOV.UK publication addressing injectable polynucleotides specifically.[no source found]

Mechanism of action#

Two mechanisms are proposed: activation of adenosine A2A receptors after DNA breakdown and provision of nucleotides or nucleosides through the salvage pathway.[3]

The causal experiments are not clinical facial studies. In primary cultured human skin fibroblasts, PDRN increased proliferation and an A2 antagonist reduced the effect; the authors said receptor activation explained it only “in part” and also proposed nucleotide supply. This is in vitro, not injected living skin.[17]

A 2025 rat model used intraperitoneal PDRN in acetic-acid-induced colitis. An A2A antagonist abolished the measured effects, but the species, organ, disease model and administration route all differ from aesthetic intradermal use. One author reported National Research Foundation of Korea support and one co-author worked for a commercial contract-research organisation.[4] Animal and cell evidence supports biological plausibility, not proof that injected PN rebuilds collagen in human facial dermis.

No human histological study showing increased dermal collagen in living skin after injectable PN was located. Needling trauma, injected fluid volume and temporary hydration remain plausible contributors to visible change.[no source found]

Commonly misstated claims#

“Salmon DNA is almost identical to human DNA, so the body accepts it”

No primary source was located supporting a percentage-homology explanation. The literature instead describes purification intended to remove immunogenic proteins and peptides.[3] Supported statement: Tolerability is attributed to manufacturing and purification, not a verified fish-to-human DNA similarity percentage.

“Polynucleotides have been shown to rebuild collagen in human skin”

Mechanistic support comes from cultured fibroblasts and animal models, and no living-human injectable histology study was located.[4, 17] Supported statement: Collagen remodelling is biologically plausible but not demonstrated histologically in injected human skin.

“Polynucleotides outperform hyaluronic-acid skin boosters”

The 27-person split-face trial found no significant difference on visual analogue or global aesthetic scales.[2] Supported statement: PN and non-cross-linked HA both improved in a small active-comparator study, without demonstrated global superiority.

“Rejuran has phase III randomised evidence”

The study carrying that description was retracted in 2016 and should not support efficacy or safety claims.[6] Supported statement: The prominent phase III Rejuran paper is retracted; the remaining controlled evidence is small.

“CE marking proves clinical efficacy and makes the treatment prescription-only”

CE marking on the cited Plinest products supports device conformity and market access, not comparative efficacy; the manufacturer presents that named range as devices rather than licensed medicines. Supported statement: Verify the exact product's classification, conformity and registration separately from clinical benefit; a non-prescription device route does not remove competence or governance requirements.[11, 12]

Areas of remaining uncertainty#

  • Durable structural change in living human dermis has not been established, and most aesthetic follow-up is short; promise measured cosmetic improvement rather than permanent regeneration.
  • The proposed distinction between PN and PDRN at 1,500 kDa has no demonstrated clinical consequence; record the exact device rather than assigning efficacy from nomenclature.[5]
  • A2A-receptor activity is supported in cultured cells and animals, not injected human skin; present it as a proposed mechanism rather than a clinically proven pathway.[3, 4, 17]
  • Long-term safety of repeated fish-derived DNA injection and cross-product equivalence remain unknown; retain batch traceability and avoid transferring one manufacturer’s safety claims to another.
  • The English licensing tier is unassigned and the position in Scotland, Wales and Northern Ireland was not established here; verify the current jurisdiction-specific law, insurer requirements and oversight before practice.[13]
  • Removing retracted studies materially weakens an already small literature; do not quote pooled patient totals without disclosing that 72 of 219 patients came from a withdrawn trial.[1, 6]

Frequently asked questions#

Are polynucleotides dermal fillers?

They are injected devices, but the intended aesthetic role is skin-quality biorevitalisation rather than structural volume replacement. Product labelling and anatomy still govern.

Are they made from salmon sperm?

Commercial aesthetic PN/PDRN products commonly use purified DNA from salmonid fish gonads.[3, 11] The exact source must be checked for the named product and disclosed.

Do they need a prescription?

A named product supplied as a medical device rather than a medicine does not carry an inherent prescription-only-medicine requirement. The cited Plinest range is presented that way, but every product must be checked. This narrow distinction does not answer who is competent, insured or appropriately medically supported to inject.[11, 12]i

Are they better than hyaluronic-acid skin boosters?

Superiority has not been shown on the global scales in the only small randomised split-face comparison.[2]

Is the mechanism proven in people?

No. A2A-receptor and fibroblast findings come from cell culture and animals, while injected-human histological collagen evidence was not located.[3][4, 17]

References#

Each source is graded by evidence tier. Tier 4 material (manufacturer documents, expert consensus, practitioner experience) is useful for protocol and context, and is never presented as equivalent to independent clinical evidence.

  1. Lampridou S, Bassett S, Cavallini M, Christopoulos G. The Effectiveness of Polynucleotides in Esthetic Medicine: A Systematic Review. J Cosmet Dermatol. 2025 Feb;24(2):e16721. PMID 39645667. PMCID PMC11845969.Tier 1Supports: PROSPERO-registered (CRD42024588712) systematic review searching Embase, Medline and Cochrane for English-language primary research published 1 January 2010 – 1 January 2024; narrative synthesis reported to PRISMA, quality appraised with CASP checklists. Result: 'Nine studies, of low and moderate quality, were included in this review, describing a population of 219 patients receiving PN treatment.' Procedural characteristics (injection areas, techniques) varied. Findings: 'Polynucleotide injections have shown promising outcomes in reducing wrinkles, improving skin texture, and enhancing elasticity, with statistically significant results in several studies. While side effects are generally mild and transient, patient satisfaction is moderate to high.' Conclusion, verbatim: 'Polynucleotides offer promising potential in esthetic medicine; however, there is limited consensus regarding their optimal use. Rigorous, high-quality studies are essential to validate the effectiveness and safety of PN.' Scope limits: no meta-analysis, no pooled effect size, heterogeneous products and protocols, total pooled population of only 219 patients across nine low/moderate-quality studies. VERIFIER ADDITION — a material weakness the review does not disclose: two of the nine included studies are saline-placebo-controlled randomised trials (Araco and Araco 2021, acne scars; Araco, Araco and Raichi 2023, nasolabial folds), so the review's own evidence base is not purely uncontrolled. More seriously, included study [12] is Pak et al. (2014), the 'phase III' Rejuran trial retracted by the Journal of Korean Medical Science in January 2016 — it contributes 72 of the 219 patients (33%), and the review quotes its result ('Pak et al. observed a 95.7% improvement in crow's feet 12 weeks post treatment') without anywhere noting the retraction. The review also cites, as background reference [11], Cavallini et al. (2022) on PN-HPT in facial middle-third rejuvenation, which was itself retracted in 2024 for before/after image duplication — and Cavallini is a co-author of this review.Funding / interest: Declared conflicts: S. Lampridou none. S. Bassett is owner of Sian Aesthetics. M. Cavallini is an R&D steering board member and continuing-medical-education tutor for Mastelli Srl (Sanremo, Italy), the PN-HPT patent holder, and is employed by Centro Diagnostico Italiano. G. Christopoulos is employed by the Ghanem Clinic and is a Key Opinion Leader and clinical trainer for Dermafocus Ltd, the UK distributing company for Mastelli's polynucleotide (PN-HPT) medical devices. The authors state Dermafocus Ltd and Mastelli Srl were not involved in the research and no grants were received. Verifier note: the description of Mastelli as 'the PN-HPT patent holder' is not in this paper's own disclosure statement; it is taken from the 2021 consensus disclosure (source 10), which states it verbatim.
  2. Lee YJ, Kim HT, Lee YJ, Paik SH, Moon YS, Lee WJ, Chang SE, Lee MW, Choi JH, Jung JM, Won CH. Comparison of the effects of polynucleotide and hyaluronic acid fillers on periocular rejuvenation: a randomized, double-blind, split-face trial. J Dermatolog Treat. 2022 Feb;33(1):254-260. PMID 32248707.Tier 2Supports: 27 subjects, described in the title as 'randomized, double-blind, split-face' and in the abstract as 'randomized, pair-matched, and active-controlled'. Each subject received three filler injections at two-week intervals: polynucleotide filler on one periorbital side, non-cross-linked hyaluronic acid on the contralateral side. Primary comparative result, verbatim: 'Improvements in the visual analog scale and global esthetic improvement scale scores were not significantly different between the PN and HA groups.' Secondary: 'The improvement rates of skin elasticity and hydration decreased over time in both groups, with the PN group showing a higher improvement rate. The improvement rates of roughness and pore volume were higher in the PN group than in the HA group. The improvement rate of dermal density was not significantly different between the groups. No serious adverse events were reported.' The authors' own stated conclusion, which the sceptical reading must not omit, is verbatim: 'The PN filler injection is effective and safe for periorbital rejuvenation.' Scope limits: n=27, single centre, Korean population, active comparator only with no placebo or sham arm (so the shared improvement in both arms cannot be attributed to either product), no stated effect sizes or confidence intervals in the abstract, short follow-up. This trial is one of the nine studies in the 2025 systematic review (source 1).Funding / interest: No conflict-of-interest or funding statement is displayed in the PubMed record.
  3. Squadrito F, Bitto A, Irrera N, Pizzino G, Pallio G, Minutoli L, Altavilla D. Pharmacological Activity and Clinical Use of PDRN. Front Pharmacol. 2017 Apr 26;8:224. PMID 28491036. PMCID PMC5405115. (Erratum: Front Pharmacol. 2022 Nov 21;13:1073510.)Tier 4Supports: Definitional and mechanistic narrative review from the University of Messina. Verbatim: 'PDRN holds a mixture of deoxyribonucleotides with molecular weights ranging between 50 and 1,500 KDa, it is derived from a controlled purification and sterilization process of Oncorhynchus mykiss (Salmon Trout) or Oncorhynchus keta (Chum Salmon) sperm DNA. The procedure guarantees the absence of active protein and peptides that may cause immune reactions.' On mechanism, verbatim: 'In vitro and in vivo experiments have suggested that PDRN most relevant mechanism of action is the engagement of adenosine A2A receptors. Besides engaging the A2A receptor, PDRN offers nucleosides and nucleotides for the so called "salvage pathway." The binding to adenosine A2A receptors is a unique property of PDRN and seems to be linked to DNA origin, molecular weight and manufacturing process.' Also states 'PDRN is a proprietary and registered drug' with therapeutic use framed around regenerative medicine and diabetic foot ulcers. Scope limits: narrative review, not systematic; the mechanistic claims are attributed to in-vitro and animal ('in vivo') experiments, not to injected human skin; the clinical use discussed is wound care, not facial aesthetics. An erratum was published in 2022.Funding / interest: No conflict-of-interest or funding statement is displayed in the PubMed record. Note that PDRN is a commercially proprietary preparation and the authors' institution is in Italy, the home market of the principal manufacturer; readers should treat the absence of a disclosure statement as an absence of information, not as evidence of independence. Verifier addition: a 2015 PDRN paper from this same Messina group (Minutoli, Bitto, Irrera, Pizzino, Squadrito, Altavilla et al., 'Role of Inhibitors of Apoptosis Proteins in Testicular Function and Male Fertility: Effects of Polydeoxyribonucleotide Administration in Experimental Varicocele', Biomed Res Int 2015;2015:248976, PMID 26347229) was retracted in 2026 (retraction notice PMID 42047254). That does not impugn this 2017 review, but it is relevant context on the group's PDRN output.
  4. Lee J, Ko IG, Lee M, Hwang L, Kim SH, Jeon H, Shin HC, Lee S, Park SB, Choi HI, Joo KR, Cha JM, Shin HP, Jeon JW. Adenosine A(2A) receptor agonist polydeoxyribonucleotide ameliorates acetic acid-induced ulcerative colitis via modulating PI3K/Akt/VEGF signaling pathway. Eur J Pharmacol. 2025 Oct 15;1005:178072. PMID 40845959.Animal studyTier 3Supports: RAT MODEL, NOT HUMAN, AND NOT SKIN. Ulcerative colitis induced in rats by intracolonic 5% acetic acid (1.0 mL per animal). From day 3, treatment animals received intraperitoneal PDRN 8 mg/kg in 0.5 mL saline once daily for 10 days. PDRN reduced stool score, colonic wet weight, ulcer score and pro-inflammatory cytokine expression, suppressed PI3K/Akt signalling and increased cAMP and VEGF. Critical mechanistic result, verbatim: 'Combined treatment with PDRN and DMPX completely abolished the effect of PDRN on UC, indicating that the action of PDRN occurs through A2AR' (DMPX = 7-dimethyl-1-propargylxanthine, an A2A receptor antagonist, 8 mg/kg). VERIFIER CORRECTION: this was previously described as 'the cleanest available causal evidence' that PDRN acts via the A2A receptor. That overstated its standing. Antagonist-reversal experiments with DMPX are a long-standing feature of the PDRN literature — at least twenty indexed papers, running from Thellung et al. (1999) onwards, across wound healing, arthritis, periodontitis, spinal cord injury and colitis. It is more accurate to say this is a recent and methodologically explicit example of a well-replicated antagonist-reversal finding. Crucially, it remains a rodent colitis model with intraperitoneal dosing and says nothing directly about intradermal injection in human facial skin. The single most on-topic antagonist experiment is not this one but Thellung et al. (1999) in cultured human skin fibroblasts (source 17) — which is in-vitro, not in-vivo.Funding / interest: Jung Won Jeon reports financial support from the National Research Foundation of Korea. Remaining authors declare no competing interests. One co-author (L. Hwang) is affiliated to Orient Genia Inc (Team of Efficacy Evaluation), a commercial contract-research entity.
  5. Marques C, Porcello A, Cerrano M, Hadjab F, Chemali M, Lourenço K, Hadjab B, Raffoul W, Applegate LA, Laurent AE. From Polydeoxyribonucleotides (PDRNs) to Polynucleotides (PNs): Bridging the Gap Between Scientific Definitions, Molecular Insights, and Clinical Applications of Multifunctional Biomolecules. Biomolecules. 2025 Jan 19;15(1):148. PMID 39858543. PMCID PMC11764130.Tier 4Supports: Narrative review addressing terminology. States PDRNs and PNs are 'similar DNA-derived biopolymers' with molecular weight 'typically spanning from 50 to 1500 kDa', though recent studies extend the range 'to encompass fragments as small as 1 kDa and as large as 10,000 kDa'. Explicitly identifies the naming problem, verbatim: 'the interchangeable use of the terms "PDRN" and "PN" in the scientific literature (to describe polymers of varying lengths) has led to considerable confusion within the medical and scientific communities.' The paper then PROPOSES a new convention it names the 'Marques Polynucleotide Cutoff', set at 1500 kDa: 'the term "PDRN" should be exclusively reserved for small- and medium-chain polymers (MW < 1500 kDa), while the term "PN" should specifically be used to denote longer-chain polymers (MW ≥ 1500 kDa)'. Scope limits: this is an author-proposed nomenclature in a narrative review, not an adopted standard, not a regulatory definition, and not validated against clinical outcomes.Funding / interest: Heavy commercial affiliation. C. Marques, A. Porcello and K. Lourenço were employed by LOUNA REGENERATIVE SA (Geneva) during the study; M. Cerrano is a consultant for Louna Aesthetics (Poisy, France); F. Hadjab was employed by Albomed GmbH (Schwarzenbruck, Germany); A.E. Laurent was employed by LAM Biotechnologies SA (Epalinges) and TEC-PHARMA SA (Bercher). Remaining authors declare no conflicts. The proposed nomenclature therefore originates with authors commercially engaged in the polynucleotide market.
  6. Notice of Retraction: Pak CS, et al. A Phase III, Randomized, Double-Blind, Matched-Pairs, Active-Controlled Clinical Trial and Preclinical Animal Study to Compare the Durability, Efficacy and Safety between Polynucleotide Filler and Hyaluronic Acid Filler in the Correction of Crow's Feet: A New Concept of Regenerative Filler. J Korean Med Sci. 2016 Feb;31(2):330. PMID 26839493. Retracting: J Korean Med Sci. 2014 Nov;29(Suppl 3):S201-9, PMID 25473210.Tier 4Supports: Formal retraction notice, published January 2016, withdrawing the 2014 study most often cited as the pivotal trial for Rejuran (purified polynucleotide filler). The retracted paper had reported a 72-patient randomised split-face trial of Rejuran versus Yvoire-Hydro for crow's feet (three treatments at two-week intervals, 12 weeks' observation) alongside a 25-mouse preclinical study. FAIRNESS ADDITION: the same retracted paper reported POSITIVE preclinical results that a sceptical summary must not silently drop — verbatim, 'the Rejuran group showed the greatest elasticity and collagen composition, and a significant difference in skin surface roughness and wrinkle depth' in the mouse arm, and the authors concluded the product 'can be useful to reduce wrinkles'. Quoting only this paper's negative clinical result while suppressing its positive animal result would be selective use of a retracted source; in truth neither result should now be relied on. Notably, even before retraction the paper's own result was negative on the comparison: 'the primary and secondary objective efficacy outcome measure showed no statistical significance between the two groups.' One author of the retracted paper was affiliated to Pharmaresearch Products R&D Center — the manufacturer of Rejuran — while the paper's conflict statement asserted that all authors had no financial involvement with any organisation having a financial interest in the subject matter. The retraction notice itself states no reason. Scope limit: this source establishes that the trial has been withdrawn from the literature; it does not establish why. Verifier addition: despite the 2016 retraction, this study is still counted as one of the nine included studies in the 2025 systematic review (source 1), contributing 72 of its 219 patients.Funding / interest: Journal editorial action. The retracted underlying paper included an author from Pharmaresearch Products R&D Center, the Rejuran manufacturer.
  7. RETRACTION: A Randomized, Participant- and Evaluator-Blinded, Matched-Pair, Prospective Study Comparing the Safety and Efficacy Between Polycaprolactone and Polynucleotide Fillers in the Correction of Crow's Feet. J Cosmet Dermatol. 2026 Mar;25(3):e70794. PMID 41834780. Retracting: Choi SY, et al. J Cosmet Dermatol. 2025 Jan;24(1):e16576, PMID 39313949.Tier 4Supports: Retraction notice removing a 218-participant randomised evaluator-blinded split-face trial that used purified polynucleotide filler (Rejuran) as the active comparator against a PCL-based filler. Reason given verbatim: 'The retraction has been agreed following the authors' request. The authors informed the journal that a misidentification occurred regarding the dermal filler used in the clinical study. Specifically, the product DLMRO1 dermal filler was misidentified as containing pegylated polycaprolactone (PCL), whereas it is composed solely of pure PCL filler. Because pure PCL and pegylated PCL are distinct materials with different biocompatibility, viscosity, and biodegradation profiles, the misidentification significantly affects the reported methods and undermines the reliability of the study's findings.' Scope limit — important for fairness: the identified error concerns the COMPARATOR product, not the polynucleotide arm. It nonetheless removes the single largest randomised dataset in which polynucleotide filler appeared.Funding / interest: Journal editorial action; the retracted paper declared no conflicts of interest.
  8. Lanza E, Perna A, Bizzarri S, et al. A Real-Life Assessment of Injectable Polynucleotides High Purification Technology in Aesthetic Medicine for Skin Rejuvenation. J Cosmet Dermatol. 2026 Jan;25(1):e70532. PMID 41482668. PMCID PMC12759169.Tier 3Supports: Observational data collection within a post-market clinical follow-up (PMCF) framework — i.e. regulatory surveillance of a marketed device, not a controlled trial. 106 questionnaires from 66 adults (patients could be treated in more than one area), Fitzpatrick I–IV, excluding hypersensitivity to device components, pregnancy/breastfeeding, autoimmune disease and active dermatological conditions. Three sessions (T0; T1 at 2–3 weeks; T2 at 2–3 weeks after T1) with evaluation at 3 months after the final injection. Face (n=47): 53.5% noted improvement ranging from marked to excellent, 100% showed clinician-observed enhancement, 97% patient satisfaction. Neck (n=33): 87.8% moderate-to-marked improvement, 6.1% excellent, 96–100% satisfaction. Décolleté (n=26): 53.4% moderate improvement, over 34% rated 'very improved' or 'very much improved', 11.5% no change, 97–100% satisfaction. Safety: 'No serious AEs occurred'; transient light-severity swelling, erythema, pain, bruising, heat/itching, all resolving spontaneously. Scope limits: no control or comparator arm, no blinding, no randomisation, outcomes are subjective ratings by treating clinicians and patients, 3-month horizon only. Verified against the PMC full text: the PMCF framing, the 87.8%/6.1% neck figures and the 53.4%/34%/11.5% decollete figures are all verbatim. The paper also records that, as the product is a CE-marked medical device, 'no formal approval from an ethics committee was required under local regulations'.Funding / interest: Verbatim funding statement: 'This study was not supported by any external funding. Mastelli Srl covered only the publication costs.' Verbatim conflicts statement: 'The authors declare no conflicts of interest.' Flagged for readers: the manufacturer of the device under study paid the publication costs while the paper declares no conflicts. Also undisclosed in the conflicts statement but stated in the acknowledgements: 'Editorial assistance for the manuscript was provided by Osmosia, medical writing and scientific consultancy.' Verifier note on the citation: PubMed indexes these authors with given names in the surname field ('Eliana L, Anna P, Stefania B'); the PMC record confirms the correct forms are Lanza Eliana, Perna Anna, Bizzarri Stefania, so the citation as given here is right and the PubMed author string is the error.
  9. Ziade G, Keyrouz E, El Maalouf J, Swaidan D, Karam D, Daou D, Fidawi G. Prospective Observational Study of Polynucleotide Injections for Periorbital Rhytides. J Cosmet Dermatol. 2026 Feb;25(2):e70736. PMID 41689167. PMCID PMC12905022.Tier 3Supports: Prospective observational case series, 42 patients presenting for under-eye rejuvenation, treated with intradermal absorbable polynucleotides at 7.5 mg/mL (Pluryal Silk, MD Skin Solutions, Luxembourg), 2 mL total per session. Outcomes measured with validated FACE-Q patient-reported questionnaires at baseline and 1, 3 and 6 months; adverse events assessed 2 days after each session; paired t-tests. Result: 'Significant improvements in lower eyelid and crow's feet appraisal scores were observed at all follow-up time points compared with baseline (p < 0.001). The greatest improvements and highest patient satisfaction were observed at 3 months following two treatment sessions. Reported adverse events were minimal.' The authors' own framing is appropriately cautious: 'These findings support further controlled studies to confirm efficacy and refine treatment protocols.' Scope limits: single-arm, no control, no blinding, comparison is against the patient's own baseline only, so expectation effects, regression to the mean and the effect of needling and injected fluid volume cannot be separated from any drug effect. Also confirms the standard descriptive claim: 'Polynucleotides (PN), derived from salmon sperm DNA, are highly purified DNA fragments with reported tissue-repair and anti-inflammatory properties mediated through adenosine A2A receptor activation.'Funding / interest: The authors declare no conflicts of interest. No manufacturer funding is declared, though a named commercial product was used.
  10. Cavallini M, Bartoletti E, Maioli L, Massirone A, Palmieri IP, Papagni M, Priori M, Trocchi G; Polynucleotides HPT Priming Board (SIME, AGORÀ, SIES). Consensus report on the use of PN-HPT (polynucleotides highly purified technology) in aesthetic medicine. J Cosmet Dermatol. 2021 Mar;20(3):922-928. PMID 32799391. PMCID PMC7984045.Tier 4Supports: Expert consensus by eight Italian aesthetic-medicine clinicians. 'Recommendations' (defined as consensus greater than 80%) were reached for the face, periocular area, décolleté and neck, hands, scalp and stretch marks, covering technique, dosage, injected volumes, number of sessions and intervals. One item — the initial treatment cycle for the face — reached only 60% agreement and was downgraded to a 'Consensus statement' rather than a 'Recommendation'. This document is the origin of most protocol numbers repeated in UK training. Scope limits: opinion-based; the authors state they 'integrated the best available evidence and clinical judgment', and the underlying evidence base at that date was the same small, low-quality literature later catalogued by the 2025 systematic review. Consensus is not efficacy data. VERIFIER ADDITION: the first author, Maurizio Cavallini, had a subsequent PN-HPT paper — Cavallini M, De Luca C, Prussia G, Raichi M, 'PN-HPT (Polynucleotides Highly Purified Technology) in facial middle third rejuvenation. Exploring the potential', J Cosmet Dermatol 2022;21(2):615-624 — retracted in 2024 for duplication between reported baseline and post-treatment images (source 16). He is also a co-author of the 2025 systematic review (source 1).Funding / interest: Verbatim: 'All the members of Scientific Board variably received grants from several aesthetic medicine companies as consultants for research and development and/or continuing medical education activities and/or for participating as investigators to national and international clinical studies... Past sponsors of the members of the Board included Mastelli Srl., Sanremo, Italy, holder of the PN-HPT patents and producer of PN-HPT-based medical devices... Mastelli Srl. supported only the secretarial and logistic expenses of the Scientific Board and will financially support the publication costs of the Consensus after acceptance of the manuscript.'
  11. Mastelli S.r.l. Aesthetic Medicine (therapeutic areas) and Plinest product documentation. Mastelli S.r.l., Via Bussana Vecchia 32, 18038 Sanremo (IM), Italy.Tier 4Supports: Mastelli (Italian pharmaceutical company, founded 1952) describes its aesthetic polynucleotide products as 'intradermal skin rejuvenators' and states its regulatory class verbatim: 'Class III Medical Devices are products that require top quality standards: Mastelli's Class III Medical Devices are certified by the Italian Health Institute (CE 0373).' On origin, verbatim: DNA fragments 'obtained from fish gonads by means of a particular extraction method'. The Plinest Eye listing likewise states 'Medical device class III, CE 0373', manufacturer Mastelli S.r.l., composition aqua, polynucleotides, sodium chloride, sodium phosphate and disodium phosphate, 'for intradermal use in the periocular area', restricted to 'authorised medical professionals only' and 'not intended for self-administration'. Contraindication text, reproduced by a European distributor from the product documentation, verbatim: 'The use of PLINEST is contraindicated in patients with hypersensitivity to any product ingredients or with a history of allergy to fish products'; use is also 'not recommended' in autoimmune disease, pregnancy, breastfeeding and under-18s on the grounds of absent clinical data, and the product must not be used in areas with infection or inflammatory processes. Scope limits: the mastelli.com product pages themselves carry no contraindication list; the contraindication wording above was retrieved from a distributor reproduction (hyaloo.de), not from an official Mastelli Instructions For Use PDF, which could not be retrieved. CE 0373 identifies the notified body (Istituto Superiore di Sanità), and CE marking is an EU conformity mark — it is not evidence of comparative clinical efficacy.Funding / interest: Mastelli Srl is the manufacturer of the PN-HPT polynucleotide products (Plinest range) and holder of the PN-HPT patents. All statements here are the manufacturer's own commercial claims about its own product and carry a direct financial interest.
  12. Medicines and Healthcare products Regulatory Agency. Regulating medical devices in the UK (guidance). GOV.UK.Tier 1Supports: Establishes the GB framework a polynucleotide device sits inside. Primary legislation is the Medical Devices Regulations 2002 (SI 2002 No 618, as amended); the MHRA is the regulator, responsible for market surveillance and for designating approved bodies. UKCA marking is the Great Britain conformity mark. Transitional acceptance of EU marks, verbatim: 'general medical devices compliant with the EU MDD or EU AIMDD can be placed on the Great Britain market up until the sooner of expiry of certificate or 30 June 2028'; 'general medical devices, including custom-made devices, compliant with the EU MDR and IVDs compliant with the EU IVDR can be placed on the Great Britain market up until 30 June 2030'. Registration duty, verbatim: 'All medical devices, including IVDs, custom-made devices and systems or procedure packs must be registered with the MHRA before being placed on the Great Britain market.' Non-UK manufacturers must appoint a UK Responsible Person. Scope limits: this guidance governs the product's route to market. It says nothing about who may inject it and imposes no clinical training requirement.
  13. Department of Health and Social Care. The licensing of non-surgical cosmetic procedures in England: consultation document (consultation ran 2 September – 28 October 2023; government response published 7 August 2025). GOV.UK.Tier 1Supports: This is the only document that assigns individual procedures to the proposed green/amber/red tiers, and it is a PROPOSAL — the consultation is closed, the government response was published 7 August 2025, and no scheme is in force. Tier definitions, verbatim: green — 'procedures with the lowest risk of complications. All practitioners are eligible to perform licensed procedures where they meet agreed standards'; amber — 'procedures with medium risk of complications. Non-healthcare professionals must be licensed and have relevant oversight by a named regulated healthcare professional'; red — 'procedures with the highest risk of complications', to be brought into CQC regulation. Green includes microneedling, mesotherapy, IPL and LED, superficial chemical peels, 'no-needle' fillers, micropigmentation, non-ablative laser hair removal and photo rejuvenation. Amber includes botulinum toxin injections, semi-permanent dermal fillers (face only), biorevitalisation injections, vitamin and mineral injections, PRP, injection microsclerotherapy, weight-loss injections, carboxytherapy, cellulite subcision, cryolipolysis, HIFU, radiofrequency, plasma ablation, non-ablative lasers, medium-depth peels and electrocautery. Red includes all thread lifting, hair restoration surgery, body augmentation, dermal micro-coring, deep chemical peels, deep dermis-targeting lasers and intravenous injectables. CRITICALLY: the words 'polynucleotide', 'skin booster' and 'biostimulator' do not appear anywhere in the document. 'Biorevitalisation injections' is defined narrowly as 'The skin is injected with small doses of pure hyaluronic acid with vitamins', and mesotherapy — in green — is defined as injection of a 'cocktail' of active ingredients. The 6 August 2025 government announcement names only Brazilian butt lifts, botulinum toxin, lip fillers, facial dermal fillers and breast/genital fillers, assigns no procedures to tiers, and does not mention polynucleotides; a further public consultation on implementing secondary legislation was promised. VERIFIER CORRECTION: this entry previously stated the consultation ran from 9 September 2023. The GOV.UK content API for this consultation records opening_date 2023-09-02T09:00:00+01:00 and first_published_at 2023-09-02, with closing_date 2023-10-28T23:59:00+01:00. The correct window is 2 September to 28 October 2023. The change-history note 'Added the government's response to the consultation' is timestamped 2025-08-07, confirming the 7 August 2025 response date; the separate DHSC press release 'Crackdown on unsafe cosmetic procedures to protect the public' is timestamped 2025-08-05T23:00Z, i.e. 6 August 2025 UK time — so the entry's use of both dates for two different documents is correct, not a contradiction.
  14. Araco A, Araco F. Preliminary Prospective and Randomized Study of Highly Purified Polynucleotide vs Placebo in Treatment of Moderate to Severe Acne Scars. Aesthet Surg J. 2021 Jun 14;41(7):NP866-NP874. PMID 33755110.Tier 2Supports: ADDED BY VERIFIER — this source refutes a 'no-source-found' claim previously made in this package. A prospective, randomised, PLACEBO-CONTROLLED, double-blinded trial of injectable PN-HPT. Verbatim method: 'Ten patients (PN-HPT group) were treated with 4.0 mL of PN-HPT, and 10 patients (control) were treated with 4.0 mL of normal saline. All medical treatments were performed in a double-blinded manner; neither the injection doctor nor the patient knew if the PN-HPT or the placebo was being administered.' Population: women aged 30-50 with Goodman grade 3-4 moderate-to-severe atrophic acne scars. Result, verbatim: 'Only patients in the PN-HPT group improved significantly at 1 and 3 months after treatment compared with baseline.' Scope limits that matter: n=20 total (10 per arm), the indication is atrophic acne scarring rather than general facial rejuvenation, the reported result is a within-group change from baseline in each arm rather than a stated between-arm effect size, follow-up is 3 months, and the authors themselves call it preliminary. It is nonetheless a genuine double-blind saline-placebo-controlled randomised trial of injectable polynucleotide, and it is one of the nine studies included in the 2025 systematic review (source 1).Funding / interest: No conflict-of-interest or funding statement is displayed in the PubMed record. Both authors are from the Department of Aesthetic Medicine, University Tor Vergata, Rome. Treat the absence of a disclosure statement as absence of information, not as evidence of independence.
  15. Araco A, Araco F, Raichi M. Clinical efficacy and safety of polynucleotides highly purified technology (PN-HPT) and cross-linked hyaluronic acid for moderate to severe nasolabial folds: A prospective, randomized, exploratory study. J Cosmet Dermatol. 2023 Jan;22(1):146-155. PMID 35531796. PMCID PMC10084116.Tier 2Supports: ADDED BY VERIFIER — this source refutes a 'no-source-found' claim previously made in this package. A randomised split-face study in which the polynucleotide arm was compared against SALINE PLACEBO on the contralateral side. Verbatim: 'the selected right-side NLFs received 4 ml of PN-HPT intradermally in the initial priming phase ("NLF Rx group"); the selected left-side NLFs received 4 ml of saline (placebo) ("NLF Lx group").' 20 Caucasian women aged 40-65, 40 nasolabial folds, 6-month follow-up, objective assessment by Antera 3D and Vectra H2 imaging. After 3 and 6 weeks both sides then received cross-linked hyaluronic acid, so the clean placebo-controlled window is the first 6 weeks of PN monotherapy. Results, verbatim: 'The Antera 3D device demonstrated that wrinkles and skin texture significantly improved in the NLF Rx after 6 weeks (monotherapy phase) and 3 and 6 months (PN-HPT priming + HA phase) compared with baseline. HA levels, measured with the quantitative Vectra H2 assessment technology in the right NLFs, were significantly higher than contralaterally at both 3 and 6 months.' Scope limits: explicitly 'exploratory', enrolment was expanded mid-study 'because of the favorable early outcomes' from a planned maximum of 10 women to 20 — a post-hoc sample-size change that weakens inference; the headline wrinkle/texture readout is a within-side comparison against baseline rather than against the saline side; no blinding of assessors is stated; the authors conclude only that PN-HPT 'might be a valuable and effective option' and that 'well-designed trials in larger treatment groups will hopefully confirm these early promising results.'Funding / interest: Verbatim: 'The manuscript's authors state they have no conflict of interest related to the study, they received no funds, and they have no paid or unpaid relations with industry manufacturers, publishers, or other companies in some way related to their study.' Note that PN-HPT is Mastelli's proprietary technology and the paper uses its trademarked name throughout.
  16. RETRACTION [of] Cavallini M, De Luca C, Prussia G, Raichi M. PN-HPT (Polynucleotides Highly Purified Technology) in facial middle third rejuvenation. Exploring the potential. J Cosmet Dermatol. 2024 Jan;23(1):364. PMID 37495544. PMCID PMC11062035. Retracting: J Cosmet Dermatol. 2022 Feb;21(2):615-624, PMID 34791770.Tier 4Supports: ADDED BY VERIFIER — a third retracted polynucleotide paper in aesthetic medicine that the package had missed, and the most serious of the three in terms of stated reason. Retraction reason, verbatim: 'After publication, concerns were raised by a third party regarding possible duplication between the multipaneled images within Figures 3 and 4 - specifically, that they did not show the patients before and after treatment as reported. As part of the journal's investigation, the authors provided the raw, unmodified images for review. The analysis of the raw images resolved the issues for Figure 3. However, concerns remained about the duplication of images between the reported baseline and posttreatment images in Figure 4 that the authors were unable to provide a satisfactory explanation for. As a result, the conclusions reported in the article are no longer considered reliable.' Materiality: the first author, Maurizio Cavallini, is a Mastelli R&D steering board member, first author of the 2021 PN-HPT consensus (source 10) and a co-author of the 2025 systematic review (source 1), which cites this now-retracted paper without noting its status. Unlike the 2026 PCL retraction (source 7), this one concerns the polynucleotide arm itself and concerns before/after photographic evidence — the exact evidence type used to sell the treatment.Funding / interest: Journal editorial action by the Editor-in-Chief and Wiley Periodicals LLC.
  17. Thellung S, Florio T, Maragliano A, Cattarini G, Schettini G. Polydeoxyribonucleotides enhance the proliferation of human skin fibroblasts: involvement of A2 purinergic receptor subtypes. Life Sci. 1999;64(18):1661-74. PMID 10328526.In vitroTier 3Supports: ADDED BY VERIFIER — the most skin-relevant antagonist-reversal experiment in the PDRN literature, and the correct comparator for judging how strong the A2A mechanism story is. CULTURED HUMAN SKIN FIBROBLASTS, IN VITRO, NOT INJECTED SKIN. Verbatim: 'a polydeoxyribonucleotide (PDRN) and adenosine are able to increase, the growth rate of human skin fibroblasts in primary cultures. The proliferative activity exerted by PDRN was significantly counteracted by the A2 antagonist 3,7-Dimethyl-1-propargylxanthine (DMPX), but not by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine.' The authors' own interpretation is notably hedged and includes a competing mechanism, verbatim: 'our results suggest that PDRN may operate as a pro-drug providing the cultured cells with an effective amount of mitogenic deoxyribonucleotides, deoxyribonucleosides and bases; moreover, cell proliferation enhancement that has been induced by PDRN seems to be mediated, at least in part, by the activation of purinergic receptors of the A2 subtype.' Scope limits: primary cell culture, no tissue, no living human, 1999, and the effect is attributed only 'in part' to A2 receptors — the salvage-pathway explanation is offered in the same breath.Funding / interest: No conflict-of-interest or funding statement is displayed in the PubMed record (1999 predates routine disclosure). Institute of Pharmacology, University of Genova, Italy.