Topical Co-application of Hyaluronan with Transdermal Drug Delivery Enhancers Attenuates Inflammatory and Neuropathic Pain

#1

The paper is behind a paywall.

https://journals.lww.com/pain/fulltext/2023/12000/topical_coapplication_of_hyaluronan_with.4.aspx

If someone has access could you post a copy?

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How to Stop or Reverse Skin Aging (2026)
#2

Joseph, the full paper is here and is open access: Topical Co-application of Hyaluronan with Transdermal Drug Delivery Enhancers Attenuates Inflammatory and Neuropathic Pain - PMC

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#3

Here is a short summary of the paper. It is very interesting that they were able to drive High Molecular weight Hyaluronon using DSMO and other reagents. Seems like a potential application for skin health and longevity (that could be investigated more or tried). I dig deeper into how this protocol might be used for skin health and longevity in the later half of this post.

The “Mole Rat” Molecule Goes Topical: High-Molecular Weight Hyaluronan Reverses Neuropathic Pain Without Needles

In a significant advance for pain management and longevity biotechnology, researchers at the University of California, San Francisco (USA) have developed a non-invasive, topical delivery system for High Molecular Weight Hyaluronan (HMW-HA). Published in the journal PAIN, this study demonstrates that HMW-HA—the same polymer responsible for the cancer resistance and extraordinary longevity of Naked Mole Rats—can successfully penetrate the skin when paired with specific enhancers (DMSO, Protamine, or Terpenes) to reverse chronic inflammatory and neuropathic pain.

The “Big Idea” here is the democratization of a potent biologic. Historically, HMW-HA’s large size (500–1200 kDa) prevented skin penetration, limiting its use to invasive intra-articular injections for osteoarthritis. By unlocking transdermal delivery, this study opens a new therapeutic window for Chemotherapy-Induced Peripheral Neuropathy (CIPN)—a debilitating condition affecting ~40% of cancer survivors with no FDA-approved cure. The researchers found that topical HMW-HA engages the CD44 receptor on nociceptors (pain neurons) to silence pain signaling. Crucially, the effect is sexually dimorphic; while effective in males, females require the inhibition of the estrogen receptor GPR30 to experience relief, highlighting a critical variable for future human translation. For the longevity biohacker, this represents a potential “healthspan” intervention: a method to leverage the anti-inflammatory, cytoprotective properties of HMW-HA systemically or locally without injections.

Impact Evaluation: The impact score of this journal is 5.9, evaluated against a typical high-end range of 0–60+ for top general science, therefore this is a High impact journal (ranking in the top quartile of Anesthesiology and Pain Medicine).

Mechanistic Deep Dive

  • Longevity Pathway (ECM & CD44): The intervention directly leverages the **Extracellular Matrix (ECM)**signaling pathway. HMW-HA is a known “youth signal.” In Naked Mole Rats, abundant HMW-HA prevents cellular senescence and cancer (via early contact inhibition). In this study, HMW-HA acts as a ligand for CD44 on sensory neurons.
  • Pathway Action: Unlike Low Molecular Weight HA (which is pro-inflammatory and signals tissue damage), HMW-HA induces an anti-hyperalgesic, anti-inflammatory state. It likely downregulates downstream cAMP/PKA and PKCΔ signaling pathways in nociceptors.
  • Organ-Specific Priority: Peripheral Nervous System (PNS) and Skin. The ability to quell neuroinflammation topically suggests a “skin-to-nerve” signaling axis that could be exploited for other neuro-dermatological conditions.

Novelty

  • Transdermal HMW-HA: The dogma was that HA >500 kDa cannot penetrate the stratum corneum. This study proves that using 75% DMSO, Protamine, or Terpenes as carriers allows functional HMW-HA to reach nociceptors in the dermis.
  • GPR30 Sexual Dimorphism: The finding that estrogen signaling (via GPR30) actively blocks the analgesic effect of HMW-HA in females is a novel, critical insight for personalized medicine.

Critical Limitations

  • Translational Gap: Rats have different skin permeability than humans. DMSO enhances penetration in both, but human skin is thicker; the efficacy depth profile is unknown.
  • Effect-Size Uncertainty: The “pain reversal” was measured in grams of force (Randall-Selitto test). While statistically significant, translating mechanical withdrawal thresholds in rats to subjective pain relief in humans is notoriously difficult (Level D evidence).
  • Short Duration: The analgesic effect lasted only ~1-2 hours post-application (though it could be prolonged with repeated dosing). This is not a “cure,” but a transient management tool.

The Translational Protocol (Rigorous Extrapolation)

  • Compound: High Molecular Weight Hyaluronic Acid (500–1,200 kDa).
  • Vehicle: Dimethyl Sulfoxide (DMSO) 75% solution (Pharma Grade).
  • Human Equivalent Dose (HED):
    • Note: BSA scaling is imperfect for topical local effects, but provides a safety baseline.
    • Animal Dose: ~60 ”g total per paw (~200 ”g/kg for a 300g rat).
    • HED Calculation: 0.2 mg/kg×(6/37)≈0.032 mg/kg.
    • Human Target: For a 70kg human, systemic equivalent is ~2.24 mg. However, for topical local application, concentration matters more.
    • Actionable Concentration: The study used 2 mg/mL (0.2%) HMW-HA in 75% DMSO. A similar concentration should be the target for a compound cream.

Pharmacokinetics (PK/PD)

  • Bioavailability: HMW-HA is typically <1% bioavailable topically without enhancers. With 75% DMSO, local dermis penetration is high, but systemic absorption is likely low to moderate.
  • Half-Life: HA in tissue has a half-life of <1 day (rapidly degraded by hyaluronidases). This aligns with the study’s finding that effects wore off in 2 hours, necessitating multiple daily applications.

Safety & Toxicity Check

  • DMSO:
    • NOAEL: Varies, but FDA limits residual DMSO in drugs to 5000 ppm (Class 3 solvent). Direct topical application of 75% is high.
    • Risks: Skin irritation, erythema, “garlic breath” (metabolite dimethyl sulfide), and transport of surface impurities (toxins/bacteria) into the blood. Clean skin is non-negotiable.
  • HMW-HA: Very safe; no LD50 established (biologically inert polymer).
  • Contraindications:
    • Liver/Kidney: DMSO is metabolized by the liver and excreted by kidneys; caution in organ failure.
    • Pregnancy: DMSO is category C.

Feasibility & ROI

  • Sourcing:
    • HMW-HA Powder: Readily available (~$40–$80/100g). Ensure >1,000 kDa or “High Molecular Weight.”
    • Pharma Grade DMSO: Essential to avoid industrial impurities (benzene/heavy metals).
  • Cost: Extremely low. <$10/month for DIY preparation.

Q: Why did the effect wear off after 2 hours?

  • A: Hyaluronidases in the skin degrade HA rapidly. The study showed that repeated applications extended the duration, suggesting a saturation effect is needed.

Q: How do I ensure I have “High Molecular Weight” HA?

  • A: Check the Certificate of Analysis (CoA) from the supplier. Look for Dalton size >1,000,000 Da (1 MDa). Cosmetic “penetrating” HA is often hydrolyzed (bad for this purpose).

Q: What about the “female problem” (GPR30)? Can women use this?

  • A: Based on this rat data, it may be ineffective in women with normal estrogen levels unless GPR30 is blocked. There is no safe, approved topical GPR30 antagonist for humans currently.

Q: Does DMSO damage the skin barrier over time?

  • A: Yes. DMSO disrupts lipid bilayers to allow penetration. Chronic use can lead to dry, scaly skin and dermatitis. Rotate application sites and use emollients after the DMSO has fully absorbed and the area is washed (hours later).

Q: Will 75% DMSO cause systemic toxicity if used daily?

  • A: Unlikely to be toxic, but side effects are real. Long-term human use of 50%+ DMSO (e.g., for interstitial cystitis) is safe but associated with skin irritation and strong body odor. Monitor liver enzymes (ALT/AST) periodically.

Q: Can I use “Low Molecular Weight” HA (LMW-HA) since it absorbs better?

  • A: NO. The study explicitly states LMW-HA is pro-nociceptive (causes pain) and pro-inflammatory. You must use HMW-HA (500–1200 kDa) to trigger the CD44 anti-hyperalgesic pathway.

Additional Prompt:

What is the scientific and clinical evidence that this same approach be used to drive HMW-HA deeper into the skin, for hand or foot skin health and rejuvenation benefits, for example?

Gemini Pro Response:

There is no direct clinical evidence (Level A or B) that 75% DMSO + HMW-HA rejuvenates healthy human hands or feet for cosmetic purposes. However, there is Level C (Observational/Case Series) evidence from the treatment of Scleroderma and Ischemic Digital Ulcers where high-concentration DMSO (50–70%) was used on human fingers and hands to improve skin flexibility, reduce fibrosis, and heal ulcers.

This suggests the “Hand/Foot” application is significantly more viable than the face due to the Stratum Lucidum—the extra, toughened layer of skin on palms and soles. While the facial skin is too fragile for this solvent, the hands and feet are evolutionary designed to withstand mechanical and chemical stress, making them a plausible target for this “chemical drilling” technique. The trade-off remains the systemic “garlic” odor and the potential for solvent-induced dermatitis.

1. The Clinical Precedent: Scleroderma & Ischemia

Evidence Level: C (Case Studies & Old Clinical Reports)

Unlike the face, we have human data on driving compounds into the hands using DMSO:

  • Scleroderma Protocols: Historically, 50–70% DMSO topically was used to treat localized scleroderma (hardening of the skin). Patients reported “softening” of the collagen matrix and improved range of motion.
    • Relevance: This validates that DMSO can penetrate thick, fibrotic skin and modulate the Extracellular Matrix (ECM) deep in the dermis.
  • Ischemic Ulcers: Studies on digital ulcers (fingertips) utilized DMSO for its vasodilatory and penetrative properties to restore tissue health.
    • Mechanism: DMSO increases local blood flow (vasodilation) and reduces inflammation (ROS scavenging), creating a fertile environment for HMW-HA to act if co-applied.

2. Scientific Rationale for Hands/Feet

  • The “Barrier” Challenge: The palms and soles have a thick Stratum Corneum and a unique Stratum Lucidum. Standard creams (molecular weight >500 Da) cannot penetrate this “armor.”
  • The DMSO Solution: DMSO is one of the few agents capable of disrupting the lipid bilayers of this thick skin transiently.
  • HMW-HA Synergy: Once inside, HMW-HA (via CD44) promotes Type III Collagen (youthful collagen) and inhibits myofibroblast differentiation (scarring/stiffness). This is particularly relevant for “bony” hands where skin thinning reveals tendons/veins.

3. The Critical “Dealbreakers” (Safety)

Even if it works, you must accept two physiological realities:

  1. Systemic “Garlic” Odor:
  • Applying DMSO to your feet will make your breath smell like garlic/oysters within 20–30 minutes. The solvent enters the bloodstream, metabolizes to dimethyl sulfide, and is exhaled from your lungs. There is no way to block this.
  1. Solvent “Drag” Effect:
  • Feet are often exposed to floor bacteria, sock lint, and shoe dyes. DMSO will drag any surface contaminant into your bloodstream. Sterile preparation is non-negotiable.

4. Actionable Intelligence: The Protocols

If you choose to experiment with this for hand/foot rejuvenation, you must follow a strict “Medical” protocol, not a “Cosmetic” one.

Option A: The “Scleroderma” Protocol (DMSO + HMW-HA)

High Risk / High Reward

  • Compound: Pure HMW-HA Powder (>1 MDa) dissolved in sterile water.
  • Carrier: Ph. Eur. / USP Grade DMSO (diluted to 50–70%). Do not use 99% pure on skin; it generates heat (exothermic) and damages tissue.
  • Prep:
    1. Scrub hands/feet with Hibiclens (Chlorhexidine) to sterilize.
    2. Apply HMW-HA serum first.
    3. Apply DMSO solution over the HA (paint it on).
    4. Wait 15 mins: Let it absorb fully.
    5. Wash: Rinse thoroughly to remove surface residue before touching anything or putting on socks.
  • Frequency: 1–2x per week max. Monitor for peeling.

Option B: The “Biohacker Standard” (Microneedling)

Evidence Level: B (Superior Safety) Instead of “melting” the barrier with solvent, mechanically bypass it.

  • Tool: Derma Stamp or Roller (0.5mm for hands, 1.0mm–1.5mm for soles/heels).
  • Protocol:
    1. Stamp the area to create thousands of micro-channels.
    2. Apply sterile HMW-HA immediately.
    3. Why it wins: No garlic breath, no systemic toxicity risk, and the “micro-injury” itself stimulates collagen more potently than DMSO.

Option C: The “Poor Man’s DMSO” (Urea 40%)

Evidence Level: A (Dermatological Standard) If the goal is “baby soft” feet/hands and driving hydration deep:

  • Mechanism: Urea at >20% is a “keratolytic” (dissolves the glue holding dead skin cells) and a penetration enhancer.
  • Protocol: Mix HMW-HA into a 40% Urea cream (commercially available for cracked heels).
  • Result: It strips the armor (Stratum Corneum) allowing the HA to penetrate the viable epidermis without the systemic solvent risks of DMSO.

Summary Table: DMSO vs. Alternatives for Extremities

Feature DMSO (50-70%) Microneedling (0.5-1.5mm) Urea (40%)
Penetration Depth High (Dermis/Systemic) Adjustable (Epidermis/Dermis) Medium (Epidermis)
Primary Risk Systemic Toxin Transport Infection (if non-sterile) Irritation / Peeling
Side Effects Garlic Breath, Erythema Redness, Pinpoint Bleeding Mild Stinging
Biohacker Verdict Use only for “Pathology” (Stiff joints/Fibrosis) Best for “Rejuvenation”(Thin skin/Veins) Best for “Texture”(Calluses/Dryness)
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