Covering the proximal nerve stump with chondroitin sulfate proteoglycans prevents traumatic painful neuroma formation by blocking axon regeneration after neurotomy in Sprague Dawley rats

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>Neuropathic pain caused by traumatic neuromas is an extremely intractable clinical problem. Disorderly scar tissue accumulation and irregular and immature axon regeneration around the injury site mainly contribute to traumatic painful neuroma formation. Therefore, successfully preventing traumatic painful neuroma formation requires the effective inhibition of irregular axon regeneration and disorderly accumulation of scar tissue. Considering that chondroitin sulfate proteoglycans (CSPGs) can act on the growth cone and effectively inhibit axon regeneration, the authors designed and manufactured a CSPG-gelatin blocker to regulate the CSPGs’ spatial distribution artificially and applied it in a rat model after sciatic nerve neurectomy to evaluate its effects in preventing traumatic painful neuroma formation.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Sixty female Sprague Dawley rats were randomly divided into three groups (positive group: no covering; blank group: covering with gelatin blocker; and CSPG group: covering with the CSPG-gelatin blocker). Pain-related factors were evaluated 2 and 8 weeks postoperatively (n = 30). Neuroma growth, autotomy behavior, and histological features of the neuromas were assessed 8 weeks postoperatively (n = 30).</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Eight weeks postoperatively, typical bulb-shaped neuromas did not form in the CSPG group, and autotomy behavior was obviously better in the CSPG group (p &lt; 0.01) than in the other two groups. Also, in the CSPG group the regenerated axons showed a lower density and more regular and improved myelination (p &lt; 0.01). Additionally, the distribution and density of collagenous fibers and the expression of α–smooth muscle actin were significantly lower in the CSPG group than in the positive group (p &lt; 0.01). Regarding pain-related factors, c-fos, substance P, interleukin (IL)–17, and IL-1β levels were significantly lower in the CSPG group than those in the positive and blank groups 2 weeks postoperatively (p &lt; 0.05), while substance P and IL-17 remained lower in the CSPG group 8 weeks postoperatively (p &lt; 0.05).</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>The authors found that CSPGs loaded in a gelatin blocker can prevent traumatic neuroma formation and effectively relieve pain symptoms after sciatic nerve neurotomy by blocking irregular axon regeneration and disorderly collagenous fiber accumulation in the proximal nerve stump. These results indicate that covering the proximal nerve stump with CSPGs may be a new and promising strategy to prevent traumatic painful neuroma formation in the clinical setting.</jats:p></jats:sec>

Traumatic neuromas of peripheral nerves: Diagnosis, management and future perspectives

“…Rats are the most common species studied in animal models of traumatic neuroma, for the anatomy of rat nerves is well-established and similar to human anatomy ( 58 , 86 , 106 – 109 ). Besides, the model has a large number of standardized functional tests, making the experimental results easy to evaluate ( 110 , 111 ).…”

“…According to the research, the sciatic nerve, saphenous nerve ( 48 ), sural nerve ( 119 ), and tibial nerve ( 120 , 121 ) can be used for modeling. Among these nerves, the sciatic nerve has gradually become the most common site for the animal model of a traumatic neuroma given the fact that the sciatic nerve is easy to expose and observe, while others are rarely used now ( 58 , 86 , 106 , 107 ). After exposure of the sciatic nerve and its trifurcation under the microscope, the nerve is sharply dissected 3–10 mm distal from the trifurcation ( 108 , 113 , 114 ).…”

“…After exposure of the sciatic nerve and its trifurcation under the microscope, the nerve is sharply dissected 3–10 mm distal from the trifurcation ( 108 , 113 , 114 ). To prevent spontaneous regeneration of the distal nerve stump, at least 10 mm of the distal nerve stumps should be removed and discarded ( 106 – 108 ). Finally, the presence or absence of a traumatic neuroma was determined by gross observation, ultrasound, hematoxylin-eosin staining, and immunofluorescence ( 106 , 122 ).…”

Chondroitin sulfate-based composites: a tour d’horizon of their biomedical applications

“…As a result, this study implied that the fabricated scaffolds Coll/HA and Coll/CS/HA were suitable candidates for brain TE therapy. 275 Some other composites and scaffolds for neural regeneration and tissue engineering are CS-A/GAGs for axonal growth in embryonic, adult, and injured rat brains, 276 CSPG loaded in GEL blocker for neuroma formation, 277 Col/CS/HA for embryonic nerve cell engineering, 278 and CS/GAG for post-traumatic brain injury. 279 3.2.5.…”

Magnesium‐Encapsulated Injectable Hydrogel and 3D‐Engineered Polycaprolactone Conduit Facilitate Peripheral Nerve Regeneration

“…[ 1 ] However, this approach is limited by restricted autograft availability and other drawbacks, such as donor‐site morbidity, sensation loss, and neurological pain. [ 2 ] Thus, a current research focus is to develop various biocompatible scaffolds using tissue engineering strategies. [ 3 , 4 ]…”