Postoperative Epidural Fibrosis: Challenges and Opportunities - A Review.

Postoperative epidural fibrosis (EF) is still a major limitation to the success of spine surgery. Fibrotic adhesions in the epidural space, initiated via local trauma and inflammation, can induce difficult-to-treat pain and constitute the main cause of failed back surgery syndrome, which not uncommonly requires operative revision. Manifold agents and methods have been tested for EF relief in order to mitigate this longstanding health burden and its socioeconomic consequences. Although several promising strategies could be identified, few have thus far overcome the high translational hurdle, and there has been little change in standard clinical practice. Nonetheless, notable research progress in the field has put new exciting avenues on the horizon. In this review, we outline the etiology and pathogenesis of EF, portray its clinical and surgical presentation, and critically appraise current efforts and novel approaches toward enhanced prevention and treatment.

Metformin-grafted polycaprolactone nanoscaffold targeting sensory nerve controlled fibroblasts reprograming to alleviate epidural fibrosis.

Epidural fibrosis (EF), associated with various biological factors, is still a major troublesome clinical problem after laminectomy. In the present study, we initially demonstrate that sensory nerves can attenuate fibrogenic progression in EF animal models via the secretion of calcitonin gene-related peptide (CGRP), suggesting a new potential therapeutic target. Further studies showed that CGRP could inhibit the reprograming activation of fibroblasts through PI3K/AKT signal pathway. We subsequently identified metformin (MET), the most widely prescribed medication for obesity-associated type 2 diabetes, as a potent stimulator of sensory neurons to release more CGRP via activating CREB signal way. We copolymerized MET with innovative polycaprolactone (PCL) nanofibers to develop a metformin-grafted PCL nanoscaffold (METG-PCLN), which could ensure stable long-term drug release and serve as favorable physical barriers. In vivo results demonstrated that local implantation of METG-PCLN could penetrate into dorsal root ganglion cells (DRGs) to promote the CGRP synthesis, thus continuously inhibit the fibroblast activation and EF progress for 8 weeks after laminectomy, significantly better than conventional drug loading method. In conclusion, this study reveals the unprecedented potential of sensory neurons to counteract EF through CGRP signaling and introduces a novel strategy employing METG-PCLN to obstruct EF by fine-tuning sensory nerve-regulated fibrogenesis.

Evaluation of the Efficacy of Caudal Epidural Neuroplasty in Patients With Lumbar Epidural Fibrosis.

Introduction Lumbar and leg pain can be caused by many factors, including scar tissue in the epidural space. Epidural fibrosis may cause chronic radicular low back pain. Adhesions in the epidural space may occur due to surgical or non-surgical reasons. Epidural adhesiolysis, i.e., neuroplasty, eliminates the pain-causing effects of scar tissue by releasing the nerve from the scar tissue or decompressing the nerve. In light of this information, this study was conducted to evaluate the effectiveness of percutaneous epidural neuroplasty interventions performed in the algology clinic in patients with lumbar epidural fibrosis who have and have not undergone lumbar surgery. Methods The sample of this retrospective study consisted of 72 patients with chronic radicular low back pain, finding fibrosis in the epidural region on contrast-enhanced magnetic resonance imaging (MRI), filling defect after epidurogram, and caudal epidural neuroplasty. Patients' visual analog scale (VAS) and Oswestry disability index (ODI) scores, pregabalin, duloxetine, and opioid doses were evaluated before and one month and six months after having neuroplasty. Results The VAS and ODI scores and pregabalin, duloxetine, and opioid doses decreased significantly in patients who had had caudal epidural neuroplasty at post-procedure endpoints compared to before the procedure (p<0.001). The paired temporal comparisons of the data of the patients who underwent epidural neuroplasty procedures before the procedure, one month after the procedure, and six months after the procedure revealed significant differences in the VAS and ODI scores (p<0.001). Additionally, the analysis of patients' VAS scores revealed that the pre-procedure VAS scores decreased significantly more one month after the procedure in patients without a history of lumbar surgery than in patients with a history of lumbar surgery. Conclusions The findings of our study demonstrated that fluoroscopy-guided percutaneous epidural neuroplasty alleviated pain and improved physical functions and quality of life. In conclusion, percutaneous epidural neuroplasty is a safe and effective treatment method for patients with lumbar epidural fibrosis.

Cinnamaldehyde has Antifibrotic Effects on Rats with Epidural Fibrosis.

BACKGROUND: Laminectomy is a widely employed surgical procedure for the treatment of spinal stenosis, but it may lead to epidural fibrosis (EF) and failed back surgery syndrome. Cinnamaldehyde, a phenylpropanoid found in cinnamon, has demonstrated antioxidant and anti-inflammatory properties. In the present study, we hypothesized that topical application and systemic administration of cinnamaldehyde could be helpful in the prevention of EF in a rat laminectomy model. METHODS: The rats were randomly assigned to control, local, and systemic Tween-80 and local and systemic cinnamaldehyde experimental groups (n = 6, per group). In the control group, just laminectomy was performed. In local treatment groups, applications were done just after the laminectomy onto dura. In systemic treatment groups, intraperitoneal administrations were performed following skin suturing. The degree of epidural fibrosis was evaluated macroscopically and histopathologically 4 weeks later. RESULTS: Macroscopic assessment revealed decreased EF with both topical and systemic cinnamaldehyde application, whereas microscopic examination results were not significant. CONCLUSIONS: Our findings provide the first experimental evidence of cinnamaldehyde's potential protective effects against EF.

The effectiveness of organic vegetable oils with high biocompatibility in preventing epidural fibrosis: An experimental study.

Background and purpose:

Epidural fibrosis after all spinal surgeries is an important surgical issue. Various biological and non-biological materials have been tried to inhibit epidural fibrosis, which is deemed to be the most important cause of pain after spinal surgery. Olive oil, nigella sativa oil and soybean oil employed in oral nutrition in clinics involving liquid fatty acids, palmatic acid, linoleic acid, stearic acid and palmitoleic acid. The effectiveness of olive oil, nigella sativa oil and soybean oil on epidural fibrosis was researched on for the first time in laminectomy model.

Fifty adult male Wistar albino rats weighing between 300 and 400 grams were used in the research. A total of 5 groups were formed: sham (Group I) (n = 10), no application was created; Group II (n = 10) 1 cc saline; Group III (n = 10) 1 cc olive oil; Group IV (n = 10) 1 cc nigella sativa oil; Group V (n = 10); 1 cc soybean oil was applied topically to the epidural region after laminectomy. The total spine of the rats was dissected, histopathological and immuno­chemical measurements were conducted. Neuro-histopathological results were scored semi-quantitatively in terms of vascular modification, neuron degeneration, gliosis and bleeding criteria.

The lowest level of fibrosis and connective tissue proliferation was observed in the group where nigella sativa oil was used after the operation, followed by the group treated with olive oil and lastly with the group given soybean oil.

Nigella sativa oil and olive oil are very efficient for lowering the degree of epidural fibrosis and adhesions following laminectomy and can be employed as a simple, inexpensive and highly biocompatible material in clinical practice.

High-Frequency Bipolar Coagulation Limits Epidural Fibrosis in Lumbar Microdiscectomy.

BACKGROUND AND AIM: We propose a vast study to examine the effect of high-frequency bipolar coagulation used in the operating room to prevent the development of epidural fibrosis after lumbar microdiscectomy. MATERIALS AND METHODS: A total of 1004 participants were divided into two groups: no high-frequency bipolar coagulation (NC group) and high-frequency bipolar coagulation (C group). Postoperative epidural fibrosis, infection rates, reoperation status, and dural injury complications during the operation were recorded. RESULTS: Considering the epidural fibrosis rates of the two groups, epidural fibrosis was seen in 10.6% of the patients in the NC group. In contrast, it was seen in only 6.2% of the patients in the C group. CONCLUSION: The complication of epidural fibrosis that develops after lumbar microsurgery operations both impairs patient comfort and brings with it the complications of reoperation. After performing hemostasis with bipolar, coagulating the annulus may effectively reduce epidural fibrosis and prevent reoperation.

Medical ozone treatment on prevention of epidural fibrosis in the rat model.

Background/Aim: Epidural fibrosis is one of the problems that can be seen after spinal surgery. The aim of this study was to investigate the possible preventive role of medical ozone (O) treatment on epidural fibrosis. Materials and Methods: Twenty-four Sprague Dawley rats were randomly split into four groups: control (C), O, laminectomy (L), and L+O groups. Animals in the C group were sacrificed at the beginning of the experiment. The L and L+O groups had L procedure, while O treatment was supplied for the O and O+L groups. After 42 days of follow-up, for histological evaluation and biochemical measurements, the ratio of epidural fibrosis and catalase (CAT) with malondialdehyde (MDA) levels in serum, respectively, were analyzed in terms of statistical differences. Results: Histologically, a distinct difference was o bserved in the epidural space after O treatment. A significant difference in epidural fibrosis areas is found to be between the O, L, and O+L groups (P < 0,0001). There was no statistically significant difference between CAT and MDA levels that were obtained by spectrophotometric analysis. Conclusion: Histological results suggest that medical O treatment after L can be used as an alternative method to prevent epidural fibrosis. Further studies with wide cohorts and interval measures are required to detail the effects of doses.

Is Tranexamic Acid an Effective Prevention in the Formation of Epidural Fibrosis? Histological Evaluation in the Rats.

OBJECTIVE: The present study aimed to determine the topical and systemic efficacy of tranexamic acid (TXA) on epidural fibrosis in a rat laminectomy model. METHODS: Thirty-two 12-month-old adult Sprague-Dawley rats were used in this study. Each rat underwent bilateral laminectomy at the L1 and L2 vertebral levels. Rats were divided into four groups : in group I (control group, n=8), a laminectomy was performed and saline solution was applied into the surgical space. In group II (topical group, n=8), laminectomy was performed and 30 mg/ kg TXA was applied to the surgical site before skin closure. In group III (systemic group, n=8), 30 mg/kg TXA was administered intravenously via the tail vein in the same session as the surgical procedure. In group IV (topical and systemic group, n=8), TXA was administered 30 mg/kg both topical and intravenous. The rats were sacrificed at 4 weeks postoperatively. Masson's trichrome and hematoxylin and eosin were used to assess acute inflammatory cells, chronic inflammatory cells, vascular proliferation, and epidural fibrosis. RESULTS: Epidural fibrosis, acute inflammation, chronic inflammation, and sum histologic score value were significantly lower in the systemic TXA group, systemic and topical TXA groups than in the control group (p<0.05). In addion, the sum histologic score was significantly lower in the topical TXA group than in the control group (p<0.05). CONCLUSION: In this study, epidural fibrosis formation was prevented more by systemic application, but the topical application was found to be effective when compared to the control group. As a result, we recommend the systemic and topical use of TXA to prevent epidural fibrosis during spinal surgery.

MicroRNA-29a Mitigates Laminectomy-Induced Spinal Epidural Fibrosis and Gait Dysregulation by Repressing TGF-ß1 and IL-6.

Spinal epidural fibrosis is one of the typical features attributable to failed back surgery syndrome, with excessive scar development in the dura and nerve roots. The microRNA-29 family (miR-29s) has been found to act as a fibrogenesis-inhibitory factor that reduces fibrotic matrix overproduction in various tissues. However, the mechanistic basis of miRNA-29a underlying the overabundant fibrotic matrix synthesis in spinal epidural scars post-laminectomy remained elusive. This study revealed that miR-29a attenuated lumbar laminectomy-induced fibrogenic activity, and epidural fibrotic matrix formation was significantly lessened in the transgenic mice (miR-29aTg) as compared with wild-type mice (WT). Moreover, miR-29aTg limits laminectomy-induced damage and has also been demonstrated to detect walking patterns, footprint distribution, and moving activity. Immunohistochemistry staining of epidural tissue showed that miR-29aTg was a remarkably weak signal of IL-6, TGF-ß1, and DNA methyltransferase marker, Dnmt3b, compared to the wild-type mice. Taken together, these results have further strengthened the evidence that miR-29a epigenetic regulation reduces fibrotic matrix formation and spinal epidural fibrotic activity in surgery scars to preserve the integrity of the spinal cord core. This study elucidates and highlights the molecular mechanisms that reduce the incidence of spinal epidural fibrosis, eliminating the risk of gait abnormalities and pain associated with laminectomy.

Pharmacotherapies to prevent epidural fibrosis after laminectomy: a systematic review of in vitro and in vivo animal models.

BACKGROUND CONTEXT: Excessive production of epidural fibrosis in the nerve root can be a pain source after laminectomy. Pharmacotherapy is a minimally invasive treatment option to attenuate epidural fibrosis by suppressing proliferation and activation of fibroblasts, inflammation, and angiogenesis, and inducing apoptosis. PURPOSE: We reviewed and tabulated pharmaceuticals with their respective signaling axes implicated in reducing epidural fibrosis. Additionally, we summarized current literature for the feasibility of novel biologics and microRNA to lessen epidural fibrosis. STUDY DESIGN/SETTING: Systematic Review. METHODS: According to the PRISMA guidelines, we systematically reviewed the literature in October 2022. The exclusion criteria included duplicates, nonrelevant articles, and insufficient detail of drug mechanism. RESULTS: We obtained a total of 2,499 articles from PubMed and Embase databases. After screening the articles, 74 articles were finally selected for the systematic review and classified based on the functions of drugs and microRNAs which included inhibition of fibroblast proliferation and activation, pro-apoptosis, anti-inflammation, and antiangiogenesis. In addition, we summarized various pathways to prevent epidural fibrosis. CONCLUSION: This study allows a comprehensive review of pharmacotherapies to prevent epidural fibrosis during laminectomy. CLINICAL SIGNIFICANCE: We expect that our review would enable researchers and clinicians to better understand the mechanism of anti-fibrosis drugs for the clinical application of epidural fibrosis therapies.

Substance P promotes epidural fibrosis via induction of type 2 macrophages.

In response to spinal surgery, neurons secrete a large amount of substance P into the epidural area. Substance P is involved in macrophage differentiation and fibrotic disease. However, the specific roles and mechanisms of substance P in epidural fibrosis remain unclear. In this study, we established a mouse model of L1-L3 laminectomy and found that dorsal root ganglion neurons and the macrophages infiltrating into the wound area released sphingolipids. In vitro experiments revealed that type 1 macrophages secreted substance P, which promoted differentiation of type 1 macrophages towards a type 2 phenotype. High-throughput mRNA-seq analysis revealed that the sphingolipid metabolic pathway may be involved in the regulation of type 2 macrophages by substance P. Specifically, sphingomyelin synthase 2, a component of the sphingolipid metabolic pathway, promoted M2 differentiation in substance P-treated macrophages, while treating the macrophages with LY93, a sphingomyelin synthase 2 inhibitor, suppressed M2 differentiation. In addition, substance P promoted the formation of neutrophil extracellular traps, which further boosted M2 differentiation. Blocking substance P with the neurokinin receptor 1 inhibitor RP67580 decreased the number of M2 macrophages in the wound area after spinal surgery and alleviated epidural fibrosis, as evidenced by decreased fibronectin, α-smooth muscle actin, and collagen I in the scar tissue. These results demonstrated that substance P promotes M2 macrophage differentiation in epidural fibrosis via sphingomyelin synthase 2 and neutrophil extracellular traps. These findings provide a novel strategy for the treatment of epidural fibrosis.

Spinal epidural fibrosis following hemostatic agent employment.

OBJECTIVE: Failed Back Surgery Syndrome (FBSS) refers to a subset of patients who have new or persistent pain after spinal surgery for back or leg pain. Epidural fibrosis (EF) is a common cause of FBSS. Many agents aiming to prevent EF have been tested. However, hemostatic agents are readily available at hospitals, easy to reach and frequently used. For these reasons, oxidized regenerated cellulose, polysaccharide hemostat, hemostatic thrombin-gelatin matrix and chitosan linear polymer were evaluated for their effects on epidural fibrosis on rats after laminectomy. METHODS: 40 Sprague-Dawley rats were randomly divided into 5 equal groups including the control group where only the laminectomy was performed. The other 4 groups received hemostatic agents after laminectomy. The rats were euthanized 45 days later and were assessed by a blinded observer to grade the fibrosis level. RESULTS: The study revealed that oxidized regenerated cellulose, polysaccharide hemostat and hemostatic thrombin-gelatin matrix lowered the epidural fibrosis grade which was statistically significant (p < 0.001). Although chitosan linear polymer created fibrosis similar to the control group it was not proven to be statistically significant (p = 0.8999). However, when compared with other hemostatic agents it resulted in a higher fibrosis grade (p < 0.001). CONCLUSION: The results obtained from this experimental study revealed that Pahacel, Sealfoam and Surgiflo, were effective in reducing epidural fibrosis after laminectomy in rats.

Effect of Ozone Therapy on Epidural Fibrosis in Rats.

OBJECTIVE: To demonstrate the effect of medical ozone therapy on the development of epidural fibrosis. METHODS: A total of 25 Sprague-Dawley male rats were randomly divided into 3 groups: a control group (L3-L4 laminectomy only), a systemic ozone therapy (SOT) group (L3-L4 laminectomy only + intraperitoneal 15 mL [30 µg/mL] ozone), and a local ozone therapy (LOT) group (L3-L4 laminectomy only + subcutaneous 15 mL [30 µg/mL] ozone). Ozone therapy was administered 4 times on a 3-day interval during the wound-healing process, with the first dose immediately administered after surgery. The effects of ozone therapy on vascular endothelial growth factor, inflammation, and epidural fibrosis between groups were evaluated. RESULTS: Staining with vascular endothelial growth factor was significantly less in the group that received SOT compared with the control group (P = 0.021). When the groups were compared in terms of inflammation, it was found that inflammation was less common in the SOT and LOT groups compared with the control group (SOT vs. control: P = 0.004 and LOT vs. control: P = 0.024), whereas inflammation was found to be significantly less in the SOT group compared with the LOT group (P = 0.008). In the histopathologic evaluation of epidural fibrosis, there was no significant difference between the SOT and LOT groups but less epidural fibrosis was observed in both groups compared to the control group (LOT vs. control: P = 0.037; SOT vs. control: P = 0.018). CONCLUSIONS: Medical ozone therapy may be an alternative method that can be used effectively and safely in the prevention of epidural fibrosis after laminectomy.

Artificial lamina after laminectomy: Progress, applications, and future perspectives.

In clinical practice, laminectomy is a commonly used procedure for spinal decompression in patients suffering from spinal disorders such as ossification of ligamentum flavum, lumbar stenosis, severe spinal fracture, and intraspinal tumors. However, the loss of posterior column bony support, the extensive proliferation of fibroblasts and scar formation after laminectomy, and other complications (such as postoperative epidural fibrosis and iatrogenic instability) may cause new symptoms requiring revision surgery. Implantation of an artificial lamina prosthesis is one of the most important methods to avoid post-laminectomy complications. Artificial lamina is a type of synthetic lamina tissue made of various materials and shapes designed to replace the resected autologous lamina. Artificial laminae can provide a barrier between the dural sac and posterior soft tissues to prevent postoperative epidural fibrosis and paravertebral muscle compression and provide mechanical support to maintain spinal alignment. In this paper, we briefly review the complications of laminectomy and the necessity of artificial lamina, then we review various artificial laminae from clinical practice and laboratory research perspectives. Based on a combination of additive manufacturing technology and finite element analysis for spine surgery, we propose a new designing perspective of artificial lamina for potential use in clinical practice.

Protective and Therapeutic Effects of Bovine Amniotic Fluids Collected in Different Trimesters on the Epidural Fibrosis After Experimental Laminectomy in Rats.

BACKGROUND: The aim of this study was to investigate the protective and therapeutic effects of bovine amniotic fluid (BAF) on the inhibition of epidural fibrosis (EF) after experimental laminectomy. METHODS: Forty female Sprague Dawley rats were used. The amniotic fluids were collected from each trimester of a pregnant cow. The rats were divided into 5 groups. Whereas no laminectomy was applied to the control group, animals in the sham group underwent laminectomy. Laminectomy was performed in the animals in other groups and the operation area was closed by dripping 1 mL of BAF collected in 3 trimesters of pregnancy. Animals were killed 28 days after the operation. RESULTS: Compared with control, VEGF gene expression levels were downregulated approximately 5-fold in BAF-2. Whereas IL-6 was upregulated approximately 8-fold in the sham, it was downregulated 5-fold and 3-fold in BAF-1 and BAF-2, respectively. There was downregulation in BAF-2 and BAF-3 in terms of CD105 gene expression levels. TGFß1 was upregulated approximately 2-fold in the sham group and downregulated in BAF-1 and BAF-2. Although histopathologic alterations including EF grade and fibroblast cell density were found to increase in the sham group, all BAF treatment decreased those of alterations. The highest CD105 immunoreactivity was detected in the sham group. All BAF treatment markedly aggravated fibrosis via decreasing CD105 immunoreactivity. In terms of grading parameters, almost the closest grades to the control were determined in the BAF-2. BAF collected in the second trimester is most effective in healing of scar tissue and preventing fibrosis via decreasing microvessel and fibroblast densities. CONCLUSIONS: The results indicate that BAF may be used as a potential protective agent to prevent EF.

The Effect of Amniotic Tissue on Spinal Interventions: A Systematic Review.

BACKGROUND: Amniotic membrane tissue has been thought to potentiate healing in many soft tissue conditions. Specifically, recent studies have shown its therapeutic potential for treatment in the setting of spinal pathologies. The purpose of this study is to thoroughly review the existing scientific literature and evidence concerning the clinical use of amniotic membrane-derived biologic agents on postoperative outcomes following spinal surgery. METHODS: A systematic review was conducted following preferred reporting items for systematic reviews and meta-analyses guidelines using PubMed, Embase, and Cochrane databases up to December 2020 to identify animal and clinical studies examining the therapeutic potential for amniotic membrane tissue in the setting of spinal pathologies (including disc herniation, prevention of epidural fibrosis, and spinal fusion). Studies were broken down into 2 categories: experimental model type and the type of amnion product being analyzed. RESULTS: A total of 12 studies (4 clinical studies and 8 studies utilizing animal models) met inclusion criteria. Additionally, the major types of amnion product were divided into cryopreserved/freeze-dried amniotic membrane, human amniotic fluid, human amniotic membrane, cross-linked amniotic membrane, and amnion-derived epithelial cells. While heterogeneity of study design precludes definitive specific results reporting, most studies showed positive benefits on healing/outcomes with amniotic augmentation. Specifically, amnion products have shown promising effects in reducing epidural adhesions and scar tissue after spine surgery, improving spinal fusion rate and postoperative pain scores, and promoting better functional outcomes after spine surgery. CONCLUSIONS: A review of the limited number of reported studies revealed a wide variety of amniotic membrane preparations, treatment regimens, and indications, which limit definitive conclusions. To date, while there is no definitive clinical proof that amniotic tissues enhance tissue repair or regeneration, the aggregate results demonstrate promising basic science and outcomes potential in spinal surgery. Further study is warranted to determine whether this application is appropriate in the clinical setting. CLINICAL RELEVANCE: This systematic review provides a summary of the existing literature regarding the use of amniotic membrane preparations, treatment regimens, and indications within spinal surgery. With the growing popularity and utilization of biologic agents such as amniotic membrane-derived products in orthopedic and neurologic surgery, this systematic review gives physicians a concise summary on the outcomes and indications associated with amniotic membrane products.

Laminin α1 as a target for the treatment of epidural fibrosis by regulating fibrotic mechanisms.

Excessive proliferation and migration of fibroblasts in the lumbar laminectomy area can lead to epidural fibrosis, eventually resulting in failed back surgery syndrome. It has been reported that laminin α1, a significant biofunctional glycoprotein in the extracellular matrix, is involved in several fibrosis­related diseases, such as pulmonary, liver and keloid fibrosis. However, the underlying mechanism of laminin α1 in epidural fibrosis remains unknown. The present study aimed to explore the effect and mechanism of laminin α1 in fibroblast proliferation, apoptosis and migration, and epidural fibrosis. Following the establishment of a laminectomy model, hematoxylin and eosin, Masson's trichrome and immunohistochemical staining were performed to determine the degree of epidural fibrosis, the number of fibroblasts, collagen content and the epidural expression levels of laminin α1, respectively. Furthermore, a stable small interfering RNA system was used to knock down the expression of laminin α1 in fibroblasts. The transfection efficiency was confirmed by reverse transcription­quantitative PCR and immunofluorescence staining. Western blot analysis, scratch wound assay, EdU incorporation assay, flow cytometric analysis and Cell Counting Kit 8 assay were performed to assess the proliferation, apoptosis, migration and viability of fibroblasts, as well as the expression levels of the AKT/mechanistic target of rapamycin (mTOR) signaling­related proteins. In vivo experiments revealed that laminin α1 was positively and time­dependently associated with epidural fibrosis. In addition, laminin α1 knockdown attenuated cell proliferation, viability and migration, and promoted apoptosis. Furthermore, the results revealed that the activation of the AKT/mTOR signaling pathway was involved in the aforementioned processes. Overall, the current study illustrated the positive association between laminin α1 and epidural fibrosis, and also verified the effect of laminin α1 on fibroblast proliferation, apoptosis and migration. Furthermore, the results suggested that the AKT/mTOR signaling pathway may serve a significant role in regulating the behavior of laminin α1­induced fibroblasts.

Histopathological Study of the Effects of Dura Adhesive Agents Used in Spinal Surgery Practice on Spinal Epidural Fibrosis in Experimental Animal Model.

Objective: Histopathological examination of the effects of Tisseel, Cova, Glubran and Coseal, which are used for sealing purposes in spinal surgery practice, on epidural fibrosis is aimed. Methods: Forty Sprague Dawley rats were randomly divided into five groups in our study as Group 1 (n=8) control group (Laminectomy); Group 2 (n=8) Cova group (Laminectomy + Cova); Group 3 (n=8) Tissel group (Laminectomy + Tisseel); Group 4 (n=8) Coseal group (Laminectomy + Coseal); and Group 5 Glubrane group (Laminectomy + Glubrane). Control group was only applied laminectomy. After laminectomy to other groups, Cova was applied to the 2nd group, Tissel to the 3rd group, Coseal to the 4th group and Glubran to the 5th group in surgical fields. After the rats were monitored in separate cages for 6 weeks after the operation, the relevant spinal level was extracted and the samples were examined histopathologically and the results were evaluated statistically. Results: It was found that there was a statistically significant difference in Tisseel and Glubran groups in terms of fibrosis grading compared to the control group, and this had a positive effect on fibrosis. Compared to the control group, there was no statistically significant difference on fibrosis in Cova and Coseal groups. Conclusion: As dura adhesive agents used in spinal surgery practice did not increase spinal epidural fibrosis statistically significantly, we concluded that these products can be used safely during spinal surgery if necessary.

Continuous release of mefloquine featured in electrospun fiber membranes alleviates epidural fibrosis and aids in sensory neurological function after lumbar laminectomy.

Recurrent low back pain after spinal surgeries, such as lumbar laminectomy, is a major complication of excessive epidural fibrosis. Although multiple preclinical and clinical methods have been aimed at ameliorating epidural fibrosis, their safety and efficacy remain largely unclear. Single implanted electrospun fibrous membranes provide physical barriers that can decrease tissue fibrosis after surgery; however, they also trigger local inflammation due to the implantation of a foreign body, thus subsequently attenuating their anti-fibrosis properties. Here, we designed a strategy that permits easy incorporation of mefloquine into polylactic acid membranes, and stable long-term mefloquine release, to potentially improve anti-fibrosis effects and relieve or prevent low back pain. The electrospun fibrous membranes grafted with mefloquine showed a well-controlled early temporary peak release, and secondary drug release occurred smoothly over several weeks. Histopathological and histomorphometric results indicated that the drug-loaded membranes had excellent anti-fibrosis effects after laminectomy in rats. Inflammation and neovascularization at the surgical site indicated that the mefloquine-grafted electrospun fibrous membranes provided sustained anti-inflammatory outcomes while effectively alleviating associated neuropathic pain hypersensitivity. In summary, our study indicated that polylactic acid-mefloquine grafted electrospun fibrous membranes may be a potential local agent to mitigate epidural fibrosis and support sensory neurological function after laminectomy, thereby potentially improving patients' postoperative outcomes.

The Comparative Effects of Dexamethasone, Nanocurcumin, and Coenzyme Q10 Against Lumbar Laminectomy-Induced Epidural Fibrosis in a Rat Model.

BACKGROUND: One of the major problems in neurosurgical procedures is fibrosis formation. Therefore, the prevention of fibrosis is an important issue in spinal cord injury that needs to be addressed. No approved therapy has yet been found, and epidural fibrosis (EF) is a huge treatment challenge. In this regard, new drugs that can effectively prevent EF are still being considered. Hence, this study aimed to investigate the effects of dexamethasone (DEX), nanocurcumin (Nano-CUR), and coenzyme Q10 (CoQ10) on the prevention of EF in a rat laminectomy model. METHODS: Thirty-five Sprague-Dawley male rats were randomly divided into 5 groups: sham group, laminectomy group, laminectomy + DEX group, in which 0.5 ml DEX (8 mg/ml) was applied locally on the laminectomy area, laminectomy + Nano-CUR group, in which 100 mg/kg Nano-CUR was administered intraperitoneally once a day for 7 days, and laminectomy + CoQ10 group, in which 30 mg/kg CoQ10 was administered once daily intraperitoneally for 7 days. After 4 weeks, the vertebral columns were removed from L1 and L3 and prepared for histopathological assays. RESULTS: The local administration of DEX could not improve the histological parameters, and EF was induced by laminectomy after 4 weeks. On the other hand, Nano-CUR could ameliorate EF at the laminectomy site compared to the laminectomy group, but the difference was not statistically significant. CoQ10 significantly reduced EF (P < 0.05), collagen density (P < 0.01), and inflammation in the arachnoid layer (P < 0.01). CONCLUSIONS: Our findings showed that Nano-CUR and CoQ10 had the potential to be used for treatment of EF.