DLss: A Revolutionary Pain Biomarker Platform for Neuropathic Pain and Analgesic Development

Overview

DLss (Diode Laser Selective Stimulation) is a groundbreaking biomarker technology designed to assess and monitor pain thresholds in both preclinical and clinical settings. By leveraging the power of diode lasers, fiber-optic systems, and an understanding of sensory nerve fiber mechanisms, DLss offers a precise and reliable way to measure pain, including its neurogenic components, in patients with peripheral neuropathy. This platform integrates multiple biomarker measurements—pain and detection thresholds, axon reflex flare—making it one of the most versatile pain assessment tools available.

Core Technology Components

1. Diode Laser Technology
   
   

   The DLss platform uses diode lasers to produce highly controlled, repeatable light power, which is selectively absorbed by skin water content. This allows for uniform and deep heating, targeting both superficial and deep sensory nerve fibers. The diode laser provides two main advantages:

   • Highly reproducible power output for accurate pain threshold measurements.

   • Deep penetration capabilities, enabling selective activation of different nociceptive fibers, regardless of their depth within the skin.

   
   

   
   

2. Selective Activation of Pain Fibers
   
   

   DLss can precisely stimulate sensory nerve fibers, including C fibers (responsible for burning pain) and Aδ fibers (responsible for sharp pricking pain), as well as CMi fibers, which are crucial in neuropathic pain conditions. By adjusting the heat ramp and stimulation duration, DLss offers flexibility in stimulating these fibers selectively, making it ideal for cross-species studies and clinical assessments.

   
   

   
   

3. Mechanistic Biomarkers
   
   

   DLss biomarkers go beyond traditional subjective assessments like questionnaires. The biomarkers include:

   • Pain Thresholds: Determining the temperature at which subjects experience pain.

   • Detection Thresholds: Identifying the minimum heat stimuli detectable by the subject.

   • Axon Reflex Flare: Induced by activation of CMi fibers that release neuropeptides such as CGRP and Substance P, contributing to the characteristic neurogenic flare seen in conditions like diabetic neuropathy.

Foundation of DLss Technology

The DLss (Diode Laser Selective Stimulation) pain biomarker platform is built on these discoveries : TRPV1 receptors, diode laser technology, fiber optics, and universally constant skin water content across species.

1. TRPV1 Receptors - The Heat Sensor

   
   

   Discovered by David Julius and his team, TRPV1 receptors are activated by heat and spicy compounds like capsaicin. These receptors are shared across species with the same temperature of activation from humans to animals, making them ideal targets for pain research. This discovery earned a Nobel Prize in Physiology in 2021.

   
   

2. Diode Laser Technology - Precision Optical Power and Heat Delivery

   
   

   Diode laser emits light at a precise wavelength that is primarily absorbed in skin water, allowing for controlled, repeatable heating of the skin. This enables selective activation of pain fibers (polymodal C- or Aδ-fibers or C- mechano-insensitive fibers) and uniform skin heating from the epidermis to the dermis, two critical features of DLss. This discovery earned a Nobel Prize in Physics in 2000.

   
   

3. Fiber Optics - The Delivery Flexibility

   
   

   Fiber optics allowed flexible ways to deliver laser light and target any area of body skin in vivo and in vitro as well as activation of cells in a water solution. This discovery earned a Nobel Prize in Physics in 2009.

   
   

   
   

4. Skin Water Content - A Universal Equalizer

   
   

   The uniform water content in skin across species ensures that laser light is evenly absorbed and distributed, allowing for consistent activation of pain fibers, regardless of depth or species. This property enables the cross-species translatability of DLss and application of the same protocols in preclinical and clinical studies.
   
   
   

Cross-Species Translatability

One of the key strengths of DLss is its cross-species translatability. It has been tested in multiple species, including rodents, pigs, monkeys, and humans, ensuring its broad applicability for both preclinical and clinical trials. This allows for reliable comparisons of pain and analgesic responses across species, bridging the gap between animal models and human studies.

Applications in Pain Research and Clinical Trials

1. Neuropathic Pain Assessment
   
   

   DLss is particularly effective in neuropathic pain conditions, such as Diabetic Peripheral Neuropathy (DPN), Chemotherapy-Induced Peripheral Neuropathy (CIPN), and other painful peripheral neuropathies. By measuring C-fiber and Aδ-fiber pain thresholds, DLss can accurately differentiate between painful and painless neuropathy, that has failed traditional quantitative sensory testing methods (QST). DLss provides instrumental analysis of CMi fiber activation by inducing an axon reflex (aka neurogenic) flare that differentiates between painful and painless neuropathy.

   
   

2. Analgesic Development
   
   

   DLss has been incorporated into Merck's Pain Testing Platform to assess the efficacy of Nav sodium channel blockers and is also used to evaluate novel analgesic treatments, such as resiniferatoxin. It has proven to be a reliable tool for assessing analgesic response and treatment efficacy during preclinical studies and early-phase clinical trials.

   
   

   DLss biomarkers also have been tested with a wide spectrum of sodium blockers and lidocaine (ZT-Lido), that could be used in control arm in treatment efficacy validation. In both studies, significant changes in flare and pain thresholds were demonstrated. This makes DLss an ideal platform for evaluating new analgesic treatments in clinical settings.

   
   

Unique Advantages of DLss

• Precision and Reliability: DLss provides a highly reproducible and adjustable heat stimulation protocol that ensures consistent activation of nociceptive fibers.

  
  

• Selective Fiber Activation: Unlike traditional methods, DLss allows for the selective stimulation of Aδ or C fibers, including those responsible for neuropathic pain, and provides insight into the mechanisms of pain.

  
  

• Objective Measurement: DLss biomarkers are mechanistic and quantitative, providing clear, objective data on pain thresholds and neurogenic flare, unlike subjective assessments like VAS or self-report questionnaires.

  
  

• Cross-Species Compatibility: The DLss platform works across species—rodents, pigs, monkeys, and humans—making it ideal for both preclinical research and clinical development.

Applications in Preclinical and Clinical Trials

• Preclinical Research: DLss is currently used in preclinical trials to assess the efficacy of analgesic treatments, including novel compounds and devices aimed at modulating pain.

  
  

• Clinical Research: In clinical settings, DLss has been used to evaluate pain in patients with neuropathic conditions, monitor treatment efficacy, and help personalize treatment strategies.

Future Developments, Directions and FDA Approval

The long-term goal for the DLss platform is to achieve FDA recognition for its use as a validated pain response biomarker. This would allow DLss to be widely adopted as a clinical tool for pain assessment, enabling more accurate diagnoses, personalized treatments, and better evaluation of new analgesics.


Conclusion

DLss represents a revolutionary biomarker technology that provides highly reliable, reproducible, and mechanistic insights into pain mechanisms and treatment responses. With its broad applicability in preclinical and clinical settings, DLss is poised to become a key tool in the fight against chronic pain, providing critical data for drug development and patient management.

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