Human birth tissue products as a non-opioid medicine to inhibit post-surgical pain

Reviewer #1 (Public review):

Summary:

Opioids and related drugs are powerful analgesics that reduce suffering from pain. Unfortunately, their use often leads to addiction and there is an opioid-abuse epidemic that affects people worldwide. This study represents an ongoing effort to develop non-opioid analgesics for pain management. The findings point to an alternative approach to control post-surgical pain in lieu of opioid medications.

Strengths:

(1) The study responds to the urgent need for the development of non-opioid analgesics.

(2) The study demonstrates the efficacy of Clarix Flo (FLO) and HC-HA/PTX3 from the human amniotic membrane (AM) in reducing pain in a mouse model without the adverse effects of opioids.

(3) The study further explored the underlying mechanisms of how HC-HA/PTX3 produces its effects on neurons, suggesting the molecules/pathways involved in pain relief.

(4) The potential use of naturally derived biologics from human birth tissues (AM) is safe and sustainable, compared to synthetic pharmaceuticals.

(5) The study was conducted with scientific rigor, involving purification of active components, comparative analysis with multiple controls, and mechanistic explorations.

Weaknesses:

(1) It should be cautioned that while the preclinical findings are promising, these results still need to be translated into clinical settings that are complex and often unpredictable.

(2) The study shows the efficacy of FLO and HC-HA/PTX3 in one preclinical model of post-surgical pain. The observed effect may be variable in other pain conditions.

Reviewer #2 (Public review):

Summary:

This is an outstanding piece of work on the potential of FLO as a viable analgesic biologic for the treatment of postsurgical pain. The authors purified the HC-HA/PTX3 from FLO and demonstrated its potential as an effective non-opioid therapy for postsurgical pain. They further unraveled the mechanisms of action of the compound at cellular and molecular levels.

Strengths:

Prominent strengths include the incorporation of behavioral assessment, electrophysiological and imaging recordings, the use of knockout and knockdown animals, and the use of antagonist agents to verify biological effects. The integrated use of these techniques, combined with the hypothesis-driven approach and logical reasoning, provides compelling evidence and novel insight into the mechanisms of the significant findings of this work.

Weaknesses:

I did not find any significant weaknesses even with a critical mindset. The only minor suggestion is that the Results section may focus on the results from this study and minimize the discussions of background information.

Reviewer #3 (Public review):

Summary:

Non-opioid analgesics derived from human amniotic membrane (AM) product represents a novel and unique approach to analgesia that may avoid the traditional harms associated with opioids. Here, the study investigators demonstrate that HC-HAPTX3 is the primary bioactive component of the AM product FLO responsible for anti-nociception in mouse-model and in-vitro dorsal root ganglion (DRG) cell culture experiments. The mechanism is demonstrated to be via CD44 with an acute cytoskeleton rearrangement that is induced that inhibits Na+ and Ca++ current through ion channels. Taken together, the studies reported in the manuscript provide supportive evidence clarifying the mechanisms and efficacy of HC-HAPTX3 antinociception and analgesia.

Strengths:

Extensive experiments including murine behavioral paw withdrawal latency and Catwalk test data demonstrating analgesic properties. The breadth and depth of experimental data are clearly supporting mechanisms and antinociceptive properties.

Weaknesses:

A few changes to the text of the manuscript would be recommended but no major weaknesses were identified.