Characterization of neuromas in peripheral nerves and their effects on heterotopic bone formation

Abstract

The formation of neuromas involves expansion of the cellular components of peripheral nerves. The onset of these disorganized tumors involves activation of sensory nerves and neuroinflammation. Particularly problematic in neuroma is arborization of axons leading to extreme, neuropathic pain. The most common sites for neuroma are the ends of transected nerves following injury; however, this rodent model does not reliably result in neuroma formation. In this study, we established a rodent model of neuroma in which the sciatic nerve was loosely ligated with two chromic gut sutures. This model formed neuromas reliably (∼95%), presumably through activation of the neural inflammatory cascade. Resulting neuromas had a disorganized structure and a significant number of replicating cells. Quantification of changes in perineurial and Schwann cells showed a significant increase in these populations. Immunohistochemical analysis showed the presence of β-tubulin 3 in the rapidly expanding nerve and a decrease in neurofilament heavy chain compared to the normal nerve, suggesting the axons forming a disorganized structure. Measurement of the permeability of the blood–nerve barrier shows that it opened almost immediately and remained open as long as 10 days. Studies using an antagonist of the β3-adrenergic receptor (L-748,337) or cromolyn showed a significant reduction in tumor size and cell expansion as determined by flow cytometry, with an improvement in the animal’s gait detected using a Catwalk system. Previous studies in our laboratory have shown that heterotopic ossification is also a result of the activation of neuroinflammation. Since heterotopic ossification and neuroma often occur together in amputees, they were induced in the same limbs of the study animals. More heterotopic bone was formed in animals with neuromas as compared to those without. These data collectively suggest that perturbation of early neuroinflammation with compounds such as L-748,337 and cromolyn may reduce formation of neuromas.

Outcomes of Patellar Replacement Vs Patellar Neurectomy in Total Knee Replacement

“…provided no evidence to support the routine resurfacing of the patella at a TKA for osteoarthritis. Controversy remains regarding whether the procedure should include patellar resurfacing or not (1,2,5,6) . This uncertainty has led to three approaches to patellar resurfacing in total knee replacement: always resurface, never resurface, or selectively resurface (12) .…”

“…This approach is used to reduce pain in the patella without removing it. By cutting the nerve, the patient may experience less pain in the patella area, although some loss of sensation may occur 5,6 . The outcomes of patellar replacement versus patellar neurectomy in TKR have been studied in several clinical trials and observational studies.…”

“…[4] There are two ways of correcting this patellar malt racking during TKR, firstly by removal of patellar osteophytes and secondly by LR release that can further prevent patellar subluxation or dislocation. [5] Some patients have a genetic predisposition to retinacular tightness and can have a laterally riding patellae. [6] Trauma to the patella is another important etiology for patellar misalignment which results in inflammation and fibrosis of the retinaculum pulling the patella off the track.…”

Role of adipose mesenchymal stem cells and secretome in peripheral nerve regeneration

“…This condition leading to the formation of a benign tumor, known as neuroma, due to a disorganized growth of cells associated with peripheral nerves when there is an injury, such as crush, stretch or transection. Neuroma may often cause increasing response of nerves and pain sensitization (allodynia), a pain response from stimuli that normally do not provoke pain [ 6 ].…”

“…4 ). First, secretomal strategies address cell survival after transplantation; second, secretome compounds fewer cell surface protein expression giving lower immunogenicity when compared to living cells and proliferative cells [ 53 ]; third, using the secretome as a ready-to-use product greatly reduces the immensely high cell counts for transplantation (7 × 10 [ 6 ] cells/kg), as well as the possible phenotypic changes and therapeutic potential due to the expansion of in vitro MSCs long before transplantation; fourth, higher rates of production are possible through the use of dynamically controlled laboratory conditions (eg bioreactors) [ 48 ], providing a suitable source of bioactive factors; fifth, in the form of conditioned media, the use of MSCs secretome is more economical and practical for clinical applications because it avoids invasive cell collection procedures; sixth, the MSCs secretome obtained for therapeutic applications can be modified as desired; seventh, the time and costs of developing and maintaining cultured stem cells can be greatly reduced and ready-to-use secretory therapies are readily available for therapy; eighth, MSCs secretomes can be evaluated for safety, dosage and potency in a manner similar to conventional pharmaceutical compounds; and lastly, the MSCs secretome can be stored safely without loss of its potency, regardless of the use of potentially toxic cryoprotectant agents [ 53 ].

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