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Epidural adhesion or epidural fibrosis is the major reason for postoperative pain, which remains a clinically challenging problem. Current physical barriers fail to provide a satisfactory therapeutic outcome mainly due to their lack of adhesion, inability to prevent fluid leakage, and exhibiting limited antioxidant properties. Herein, we fabricated a cysteine-modified bioadhesive (SECAgel) with improved sealing and antioxidant properties for epidural adhesion prevention, inspired by the organism's antioxidant systems. The resulting SECAgel showed good injectability and in situ adhesion ability, effectively covering every corner of the irregular wound. Besides, it possessed efficient sealing properties (395.2 mmHg), effectively stopping blood leakage in the rabbit carotid artery transection model. The antioxidant experiments demonstrated that the SECAgel effectively scavenged various radicals and saved the cells from oxidative stress. Two animal models were used to show that the SECAgel effectively inhibited adhesion in both situations with and without cerebrospinal fluid leakage. The RNA sequencing analysis showed that SECAgel treatment effectively inhibited the expression of key genes related to adhesion development, inflammatory response, and oxidative stress. The SECAgel, together with good biocompatibility, can be a good candidate for preventing epidural adhesion in the clinic.

Epidural fibrosis (EF) is a chronic, progressive and severe disease. Histone deacetylase 6 (HDAC6) regulates biological signals and cell activities by deacetylating lysine residues and participates in TGF-β-induced epithelial-mesenchymal transition (EMT). Nevertheless, the effect and mechanism of HDAC6 in EF remain unclear. To investigate the effect and mechanism of HDAC6 inhibition on repressing epidural fibrosis. HDAC6 expression and α-smooth muscle actin (α-SMA) in normal human tissue and human EF tissue were assessed by quantitative real-time PCR (qRT-PCR) and western blotting. Human fibroblasts were treated with TGF-β ± HDAC6 inhibitors (Tubastatin) and fibrotic markers including collagen I, collagen III, α-SMA and fibronectin were assessed using western blotting. Then TGFβ1 receptor (TGFβ1-R), PI3K and Akt were analyzed using qRT-PCR and western blotting. Rats were undergone laminectomy± Tubastatin (intraperitoneally injection; daily for 7 days) and epidural scar extracellular matrix (ECM) expression was gauged using immunoblots. Increasing HDAC6 expression was associated with α-SMA enrichment. Tubastatin remarkably restrained TGF-β-induced level of collagen and ECM deposition in human fibroblasts, and the discovery was accompanied by decreased PI3K and Akt phosphorylation. Moreover, Tubastatin also inhibited TGF-β-mediated HIF-1α and VEGF expression. In the epidural fibrosis model, we found that Tubastatin weakened scar hyperplasia and collagen deposition, and effectively inhibited the process of epidural fibrosis. These results indicated that Tubastatin inhibited HDAC6 expression and decreased TGF-β/ PI3K/ Akt pathway that promotes collagen and ECM deposition and VEGF release, leading reduction of myofibroblast activation. Hence, Tubastatin ameliorated epidural fibrosis development.

Epidural fibrosis after lumbar laminectomy refers to a serious complication, and excessive proliferation of fibroblasts is considered the major factor. Interferon-alpha-2b (IFN-α-2b) can exert antiviral and antiproliferative effects, which has been suggested to effectively prevent several fibrotic diseases. However, the effect of IFN-α-2b on the prevention of epidural fibrosis (EF) and its possible mechanism remain unclear. In this study, in vitro and in vivo experiments were performed to examine the possible mechanism of IFN-α-2b for preventing EF. Cell counting kit-8 (CCK-8), cell cycle test, Edu incorporation, wound healing assay, transwell test, and Western blotting assay were performed to investigate the inhibitory effect of IFN-α-2b on the proliferation and migration of fibroblasts in vitro . As indicated from the results, IFN-α-2b was capable of inhibiting proliferation and migration of fibroblasts and inhibiting the activity of the transforming growth factor β (TGFβ)/Smad signaling pathway. In vivo , the effect of IFN-α-2b on the reduction of EF was determined by performing histological macroscopic evaluation and histological and immunohistochemical staining. As suggested from the results, IFN-α-2b significantly inhibited EF after laminectomy. As revealed from the mentioned results, IFN-α-2b may have a promising application for preventing EF in the future.

Objective: This present study aims to assess the effect of pirfenidone (PFD) on inhibiting fibroblast proliferation, migration or adhesion in vitro and reducing laminectomy-induced epidural fibrosis in vivo., Methods: The effect of PFD on proliferation inhibition was evaluated with flow cytometry, CCK-8, EdU and western-blotting assays. Altered properties in migration and adhesion were confirmed by wound-scratch, transwell, immunofluorescence (IF), cell adhesion and western-blotting assays. Additionally, fifty male healthy Sprague-Dawley rats were subjected to laminectomy and then treated with various concentrations of PFD. After 4 weeks, the degree of epidural fibrosis was evaluated by histological analysis., Results: In vitro, the results of flow cytometry, CCK-8, EdU and western-blotting assays showed that PFD reduced fibroblast proliferation by a dose-dependent manner. And the results of wound-scratch, transwell, IF, cell adhesion and western-blotting assays showed that the migration and adhesion of fibroblasts could be inhibited and the cytoskeleton could also be altered in a dose-dependent manner. And the inhibitory effect of PFD could be partially reversed in the PI3K overexpression experiment, which indicated that the capability of PFD to inhibit fibroblast proliferation, migration and adhesion might be through the PI3K/AKT signaling pathway. In vivo, an obvious reduction in epidural fibrosis was observed in groups topically treated with PFD., Conclusions: Topical PFD application obviously suppressed laminectomy-induced epidural fibrosis, possibly by inhibiting fibroblast proliferation, migration and adhesion via the PI3K/AKT signaling pathway. PFD may be a safe and effective pharmaceutical to reduce clinical epidural fibrosis., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: This study aims to investigate the effect of radial extracorporeal shock wave therapy (rESWT) treatment in the prevention of epidural fibrosis after laminectomy in rats., Materials and Methods: Eighteen 16-month-old male Sprague-Dawley rats weighing 300 g were used in this experimental study between November 2019 and February 2020. The rats were randomly divided into two groups as the control group (L3-L4 total laminectomy without any treatment) and the study group (L3-L4 total laminectomy plus rESWT). The rats were sacrificed at the postoperative sixth week and the lumbar spine was excised en bloc, fixed, and decalcified. Sections were stained with hematoxylin-eosin to evaluate epidural fibrosis, acute inflammation, chronic inflammation, and vascular proliferation., Results: The median value and standard deviations were obtained based on histological examinations. Accordingly, epidural fibrosis decreased significantly in the study group compared to the control group. There was no statistically significant difference between the groups in terms of acute and chronic inflammation response and vascular proliferation., Conclusion: The rESWT application immediately after surgery is effective in preventing epidural fibrosis after laminectomy in rats.

The potential paravertebral space includes spinal nerves, dorsal rami, rami communicants, and sympathetic chains. This study evaluated correlations between paravertebral spread of injectate and clinical efficacy in lumbar transforaminal block. We retrospectively analysed the data of 88 patients who received transforaminal blocks for lumbar radicular pain. We categorized patients into two groups: patients with ≥ 50% pain reduction on a numeric rating scale at 30 min following a block (responder group), and patients with < 50% pain reduction (non-responder group). Paravertebral spread of injectate was graded as limited to the anterior, middle, and posterior 1/3 of the anterolateral aspect of vertebral bodies; spread between the posterolateral margins of bodies and the posterior epidural space was considered no spread. Clinical and fluoroscopic data, perfusion index, temperature, and cold sensation were compared between the groups. Among 54 patients analysed, 26 (48.1%) experienced ≥ 50% and 28 (51.9%) < 50% pain reduction. Paravertebral spread occurred in 33 (61.1%) patients; 19 (57.6%) responders and 14 (42.4%) non-responders. On analysis, paravertebral spread, epidural spread patterns, perfusion index change ratios, temperature changes, and cold sensation changes showed no differences between responder and non-responder groups. Paravertebral spread occurred in 61.1%, with no correlation with the clinical efficacy of lumbar transforaminal block.

Background: Transforaminal (TF) lumbar injection is a commonly used minimally invasive intervention for management of chronic low back pain. TF injection can be performed using various approaches to inject the drug to the anterior epidural space (AES)., Objectives: To identify the volumes of contrast medium needed to reach the AES and other landmarks in the Kambin triangle (KB) and subpedicular (SP) approach of TF injection in patients with lumbosacral radicular pain., Study Design: Randomized controlled trial., Setting: Pain clinic and operating room of a tertiary care hospital., Methods: Seventy-five eligible patients were randomized to receive TF epidural injection either by SP (SP group; n = 38) or the KB (KB group; n = 37) approach under fluoroscopic guidance. After confirming the appropriate needle position, contrast medium was injected at 0.5 mL increments up to 2 mL under intermittent fluoroscopy. Contrast medium volumes needed to reach specific landmarks, that is, AES, medial to superior pedicle, medial to inferior pedicle, medial aspect of both the superior, and neural spread, were recorded. Following this, 4 mL of the drug (0.5% lidocaine 1 mL + methylprednisolone 80 mg + 1 mL normal saline solution) was injected. Patients were evaluated for Visual Analog Scale (VAS) and modified Oswestry Disability Questionnaire (MODQ) scores after epidural injections at 2 weeks, 1 month, and 2 months., Results: Average volume of contrast medium needed to reach AES was 1.10 ± 0.46 mL in the KB approach and 1.10 ± 0.38 mL in the SP approach. Contrast medium volume needed to reach other landmarks showed comparable results in both groups. AES was seen in 27.02% (10/37) patients in the KB group and 23.6% (9/38) patients in the SP group with 0.5 mL of contrast medium. This increased to 56.76% (21/37) and 77.7% (28/38) with 1 mL of contrast medium (P = 0.03, chi-square test). No anterior spread was seen even after 2 mL of contrast medium in 4 patients in the KB group and 2 patients in the SP group. Neural spread was seen in 100% of patients in the KB group after 0.5 mL of contrast medium, but in 34 (89.4%) patients in the SP group (P = 0.03, chi-square test). We did not note any contralateral spread. Short-term effectiveness in pain relief in terms of VAS for back pain and functional improvement in terms of MODQ score over time showed similar results in both groups. Intravascular needle puncture and needle paresthesia was comparable in both groups., Limitations: Small follow-up duration is one the limitations of this study. Future studies will be needed to assess any long-term differences in outcome between approach methods. Also, use of intermittent fluoroscopy might have limited detection of intravascular injections of the contrast medium in comparison to the continuous fluoroscopy., Conclusions: To conclude, our study revealed that average volume of contrast medium needed to reach AES and other landmarks were comparable with both approaches of TF injection., Key Words: Transforaminal injection, subpedicular approach, Kambin triangle approach, contrast medium spread, anterior epidural spread.

Objective: Epidural fibrosis represents a fatal stage of failed back surgery syndrome (FBSS) of known and idiopathic etiology, but no valid therapy is presently available. Previous evidence demonstrated that suberoylanilide hydroxamic acid (SAHA), a histone deacetylases inhibitor, has antifibrotic and anti-inflammatory potential. Current studies have proved that SAHA inhibits myofibroblast differentiation and increases fibroblast apoptosis to attenuate epidural fibrosis. The purpose of this study was to investigate the effect and mechanism of SAHA on repressing epidural fibrosis., Patients and Methods: First, the levels of acetylation of histone and α-tubulin in adult human fibroblasts (AHF) and human epidural fibroblasts (HEF) were analyzed following SAHA and transforming growth factor-β(TGF-β) treatment. Then, mRNA and protein obtained from human fibroblasts following TGF-β activation and SAHA treatment in vitro culture were used to test the influence of SAHA on the activation and apoptosis of fibroblasts, so as to further explore the related mechanism of SAHA. Then, a laminectomy model was established in rats to observe the therapeutic effect of SAHA on epidural scar tissue., Results: The present research proved that the increases of HDAC 3 and α-tubulin were observed in AHF and HEF after TGF-β administration, but SAHA decreased HDAC 3 and α-tubulin expressions. In addition, cell study demonstrated that SAHA inhibited fibroblast activation via decreasing TGF-β function and accelerated apoptosis by promoting cleaved-caspase-3. In the epidural fibrosis model, it was found that SAHA weakened scar hyperplasia and collagen deposition, and effectively inhibited the process of epidural fibrosis., Conclusions: These results indicated that SAHA inhibited HDAC 3 expression, decreased TGF-β effect, and enhanced caspase-3 in fibroblasts, leading reduction of myofibroblast activation and apoptosis elevation. Hence, SAHA ameliorated epidural fibrosis development.

Objective: To investigate the effect and mechanism of mocetinostat on diminishing epidural fibrosis. Dysregulated wound repair usually occurs after injury or surgery and is featured by excessive scar tissue contributed by fibrosis. Increasing researches demonstrated that histone acetylation, an epigenetic alteration, plays a crucial role in fibrosis. However, the mechanism of the complicated process remains unclear. In the current study, the effect of histone deacetylase (HDAC) inhibitor mocetinostat in a rat model of epidural fibrosis was detected, and it was discovered that mocetinostat suppressed myofibroblast activation and increased apoptosis by reducing Akt/GSK3b signaling., Patients and Methods: First, the levels of histone acetylation in the patients' epidural fibroblasts were analyzed. Then, mRNAs and proteins obtained from human fibroblasts following TGF-β activation and mocetinostat treatment in vitro were used to examine the influence of mocetinostat on the activation and survival of fibroblasts, so as to explore the related mechanism of mocetinostat. The laminectomy model was established in rats to observe the therapeutic effect of mocetinostat on epidural scar tissues., Results: In this research, it was found that the increase of HDAC1 in human dura scar was accompanied by the aggravation of fibrosis. In addition, cell assay demonstrated that mocetinostat inhibited fibroblast activation and accelerated apoptosis by inhibiting Akt/GSK3b pathway. In the rat model, mocetinostat weakened scar hyperplasia and collagen deposition and effectively inhibited the process of epidural fibrosis., Conclusions: The above results indicate that mocetinostat inhibits HDAC1 expression and decreases the conduction of the AKT/GSK3b pathway in fibroblasts, leading to myofibroblast activation and apoptosis elevation. Hence, mocetinostat ameliorates epidural fibrosis.

Purpose: Hyaluronic acid prevents tissue adhesion after different surgeries. Physical barriers and inflammatory regulation have been suggested to be involved in the mechanism of these clinical effects. However, the molecular mechanism by which hyaluronic acid prevents epidural adhesion has not yet been reported., Methods: In the current in vivo studies, we investigated cross-linked hyaluronic acid gel in the regulation of scar gene expression, the accumulation of fibroblasts in scar tissue, and the prevention of epidural adhesion. The effect of cross-linked hyaluronic acid gel on the secretion of inflammatory factors was observed in vitro. In addition, to ensure the accuracy and reliability of the in vivo gene expression results, we used a cell model to detect the target genes in vitro., Results: The expression levels of TGFβ1 and COL1A1 mRNA were decreased in the cross-linked hyaluronic acid gel-treated group, and the protein expression of levels TGFβ1 and COL1A1 were also reduced, as detected by Western blotting in vitro and in vivo (P < 0.05). Histomorphometry results demonstrated that the number of fibroblasts in the experimental group was significantly lower than that in the control group 2 weeks postoperatively. Micro-CT scans showed that the cross-linked hyaluronic acid gel could reduce adhesion in the epidural space after laminectomy. Additionally, the cross-linked hyaluronic acid gel could inhibit IL-6 secretion., Conclusions: These results indicate that cross-linked hyaluronic acid gel can prevent epidural adhesion by inhibiting inflammatory factors, such as IL-6, and downregulating TGFβ1 and COL1A1 mRNA expression. These slides can be retrieved under Electronic Supplementary Material.

Fibroblasts excessive proliferation was considered as a decisive reason for epidural fibrosis, which was known as a serious complication of lumbar laminectomy. As a traditional Chinese medicine, triptolide (TP) was used to be proved effective in preventing several fibrosis scar formation diseases. However, little is known about the effect of TP on preventing epidural fibrosis and its possible mechanism. Here, we performed in vitro and in vivo experiments to detect the possible mechanism of TP in preventing epidural fibrosis. In vitro, the effect of TP on impacting fibroblasts proliferation activities was detected by CCK-8, cell cycle assay and EdU incorporation assay. Also, the expressions of cell proliferation protein markers and the expressions of p-PI3K, p-AKT, p-mTOR were detect by Western blot. Besides, the effect of TP on inducing fibroblast apoptosis and autophagy was tested by Western blots, flow cytometry, TUNEL staining, Transmission electron microscope (TEM) analysis and LC3 immunofluorescent staining. The results suggested that TP could suppress the activation of PI3K/AKT/mTOR signaling pathway. Meanwhile, TP could inhibit fibroblast proliferation and induce fibroblast apoptosis as well as autophagy, which was known as two cellular self-destructions. Furthermore, we speculated the possible molecular pathway, through which that TP could inhibit fibroblast proliferation, induce fibroblast apoptosis and autophagy. We used PI3-kinase activator (740Y-P) to activate the PI3K/AKT/mTOR signaling. Activation of PI3K/AKT/mTOR signaling pathway increase the proliferation of fibroblasts and suppressed the autophagy and apoptosis induced by TP. In vivo, we built epidural fibrosis models in rats and locally applied TP of various concentrations. Hematoxylin-eosin (HE) and Masson's trichrome were used to detect the effect of TP on reducing epidural fibrosis. And the results showed that TP could significantly reduce the surgery-induced epidural fibrosis. In conclusion, the results above shown that TP could reduce epidural fibrosis formation, and the potential mechanism might through inhibiting fibroblast proliferation and stimulating apoptosis and autophagy via suppressing PI3K/AKT/mTOR signaling pathway. It might provide a novel thought for reducing surgery-induced epidural fibrosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Symptomatic lumbar spinal stenosis is a condition affecting a growing number of individuals resulting in significant disability and pain, leading to a multitude of interventions ranging from simple over the counter medication to opioids, and, finally, to complex surgical fusions. After failure of conservative treatment with drug therapy, physical therapy, and other conservative modalities including epidural injections, percutaneous adhesiolysis with targeted delivery of drugs into the epidural space can be offered in lumbar central spinal stenosis prior to minimally invasive surgical options or complex surgical fusions. To date there has been only one systematic review which has assessed the role of percutaneous adhesiolysis in treating central spinal stenosis, compared to post lumbar surgery syndrome which has multiple systematic reviews and randomized controlled trials (RCTs)., Study Design: A systematic review of RCTs and observational studies assessing the role of percutaneous adhesiolysis in managing lumbar central spinal stenosis., Objective: To evaluate the effectiveness of percutaneous adhesiolysis in managing central lumbar spinal stenosis, utilizing currently available literature., Methods: This systematic review was performed utilizing Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for literature search, Cochrane review criteria, Interventional Pain Management techniques - Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB), and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR) to assess methodologic quality assessment and qualitative analysis utilizing best evidence synthesis principles, and meta-analysis.PubMed, Cochrane library, US National Guideline Clearinghouse, Google Scholar, and prior systematic reviews and reference lists were utilized in the literature search from 1966 through June 2019. The evidence was summarized utilizing principles of the best evidence synthesis on a scale of 1 to 5., Outcome Measures: The primary outcome or hard endpoint was defined as the proportion of patients with 50% pain relief and improvement in functionality, whereas the secondary outcome measures or soft endpoints were pain relief and/or improvement in functionality. Short-term effectiveness was defined as improvement of 6 months or less, whereas long-term effectiveness was defined as more than 6 months., Results: Based on search criteria, 9 manuscripts were identified and considered for inclusion with final inclusion of 2 RCTs and 4 observational studies in this systematic review and 5 studies for single arm meta-analysis. The results showed Level II evidence for short-term and long-term improvement in pain and function with application of percutaneous adhesiolysis in managing central lumbar spinal stenosis., Limitations: There was a significant paucity of evidence assessing the role of percutaneous adhesiolysis in managing lumbar central spinal stenosis, leading to Level II or strong evidence., Conclusion: Overall, the present analysis shows Level II (moderate) evidence for percutaneous adhesiolysis in managing lumbar central spinal stenosis based on relevant high quality RCTs and observational studies., Key Words: Lumbar central spinal stenosis, percutaneous adhesiolysis, randomized controlled trials, systematic reviews, neuroplasty.

Background: Laminectomy is usually classed as a common orthopedic surgery, but postoperative epidural fibrosis often leads to less-than-desirable clinical outcomes. As demonstrated by prior studies, emodin (EMO) exerts an anti-fibrotic effect. Here, we carried out investigation into the inhibitory effect created by EMO application on epidural fibrosis after laminectomy in rats., Methods: The paper conducts a series of experiment. In vitro, we observed the effect of EMO on fibroblasts by Cell Counting Kit-8 (CCK-8) assay. Apoptosis of fibroblasts induced by EMO was detected by western blot, TUNEL assay, and flow cytometry. The results revealed that EMO was capable of inducing fibroblast apoptosis, and the proteins of PERK pathway also changed accordingly. In vivo, the effect of EMO on epidural fibrosis in 12 male Sprague-Dawley rats was observed by histological staining., Results: CCK-8 assay indicated that EMO was effective in reducing fibroblast viability in a time- and a dose-dependent manner. TUNEL assay and flow cytometry analysis have demonstrated that the apoptotic rate of fibroblasts increased as the EMO concentration rose. Western blot analysis proved that EMO promoted the relative expression of p-perk and p-eIF2α and that the expression of its downstream proteins CHOP and GRP78 was also enhanced. The expression of apoptotic protein Bax and cleaved PARP was upregulated, whereas the expression of anti-apoptotic protein Bcl-2 was downregulated. In addition, histological and immunohistochemical analysis demonstrated that EMO functioned to inhibit epidural fibrosis and increase GRP78 expression in fibrous tissue by promoting apoptosis of fibroblasts., Conclusions: EMO could have inhibitory effect on epidural fibrosis in a concentration-dependent manner. The potential mechanism might be through PERK signaling pathway to promote fibroblast apoptosis. It has a possibility to be taken as a novel method for the treatment of epidural fibrosis.

Objective: To evaluate the effect of interleukin-19 (IL-19) treatment on epidural fibrosis and its mechanism of action with transforming growth factor β (TGF-β)., Materials and Methods: Initially, IL-19 (10, 20, 50 and 100 ng/L) was used to pretreat rat fibroblasts. TGF-β (10 μg/L) was then applied to activate fibroblasts. The protein expression levels of TGF-β receptor, extracellular-signal-regulated kinase (Erk) and p-38 were measured by Western blotting. In addition, we performed laminectomy at T10 vertebral plate in rats, followed by injection of IL-19 in caudal vein one week after injury. Furthermore, IL-19, TGF-β and fibrosis indexes were measured by quantitative Real-time polymerase chain reaction (qRT-PCR) and Western blotting at 7 and 28 days after injury, respectively., Results: Concentration-dependent IL-19 significantly down-regulated TGF-β receptor expression and inhibited phosphorylated Erk (p-Erk) and phosphorylated p38 (p-p38). In vivo, IL-19 reduced the expressions of TGF-β and connective tissue growth factor (CTGF) at 7 days. Furthermore, IL-19 significantly suppressed extracellular matrix productions formation, including α smooth muscle actin (α-SMA) and collagen-1 (COL-1), and fibronectin at 28 days., Conclusions: IL-19 inhibited TGF-β expression via Erk and p38 pathway. Moreover, it decreased CTGF expression to suppress α-SMA, COL-1 and fibronectin in scar tissues, thereby preventing spinal cord from compression of scar tissues.

Background: Failed back surgery syndrome (FBSS) is a common complication after the laminectomy. Epidural fibrosis is the major cause of lower back pain and other complications. Numerous studies have shown that apigenin (API) could treat various fibrotic diseases by regulating various signaling pathways, whereas no study has discussed whether API can inhibit fibroblast proliferation and reduce epidural fibrosis after the laminectomy by regulating Wnt3a/β-catenin signaling pathway., Methods: Human fibroblasts were cultured and treated with API in different concentrations for 24 h. CCK-8 detection and EdU incorporation assay were performed to detect cell viability and cell proliferation. Western blotting analysis was applied to detect expressions of proliferative proteins, Wnt3a, and its downstream proteins. Moreover, the Wnt3a gene was overexpressed in fibroblasts to define the relationship between Wnt3a/β-catenin signaling pathway and fibroblast proliferation. Wnt3a overexpressed fibroblasts were treated with API to verify if it could reverse the effects of API treatment. Twenty-four Sprague-Dawley rats were randomly divided into four groups. Laminectomy was performed and the rats were gavaged with different doses of API or 5% sodium carboxyl methyl cellulose (CMC-Na) solution for 1 month. The abilities of API to inhibit fibroblast proliferation and to reduce epidural fibrosis were evaluated using histological and immunohistochemical analysis., Results: CCK-8 detection and EdU incorporation assay demonstrated that API could inhibit the viability and proliferation rate of fibroblasts in a concentration-dependent manner. The Western blotting analysis revealed that API could inhibit the expressions of PCNA, cyclinD1, Wnt3a, and its downstream proteins. The overexpression of Wnt3a in fibroblasts could upregulate the expressions of proliferative proteins such as PCNA and cyclinD1. The inhibitory effect of API on PCNA, Wnt3a, and its downstream proteins was partially reversed by overexpression of Wnt3a. Moreover, the results of the histological and immunohistochemical analysis revealed that API could reduce the epidural fibrosis in rats by inhibiting fibroblast proliferation in a dose-dependent manner., Conclusions: API can inhibit fibroblast proliferation and reduce epidural fibrosis by suppressing Wnt3a/β-catenin signaling pathway, which can be adopted as a new option to prevent epidural fibrosis after the laminectomy.

Caudal block has limited injectate distribution to the desired lumbar level due to the relatively long distance from the injection site and reduction in the volume of injectate due to leakage into the sacral foramen. The objective of this study was to investigate the influence of needle gauge on fluoroscopic epidural spread and to assess the correlation between the spread level and analgesic efficacy in patients undergoing caudal block. We retrospectively analyzed data from 80 patients who received caudal block for lower back and radicular pain. We categorized patients based on the epidural needle gauge used into group A (23 gauge), group B (20 gauge), and group C (17 gauge). Fluoroscopic image of the final level of contrast injected through the caudal needle and pain scores before the block and 30 minutes after the block recorded using a numerical rating scale, were evaluated. Of the 80 patients assessed for eligibility, 7 were excluded. Thus, a total of 73 patients were finally analyzed. Age, sex, body mass index, diagnosis, lesion level, lesion severity, and duration of pain did not differ among the 3 groups. All patients showed cephalic spread of contrast. Contrast spread beyond L5 was seen in 26.9% of patients in group A, 41.7% in group B, 39.1% in group C, and 35.6% overall; there was no significant difference among the groups (P = .517). Analgesic efficacy was not significantly different among the groups (P = .336). The needle gauge did not influence the level of epidural spread or analgesic efficacy in caudal block.

BACKGROUND This study compared combined spinal-epidural anesthesia (CSEA) and single-shot spinal anesthesia (SSSA) by performing a meta-analysis. MATERIAL AND METHODS An electronic search of relevant studies was done through 2017. Primary endpoints included duration of surgery, and time for (1) sensory recovery to thoracic vertebra (T10), (2) maximal sensory, (3) motor blockade, and (4) motor recovery. Secondary endpoints were the adverse effects. RevMan 5.3 analytical software was used with odds ratios (OR) and 95% confidence intervals (CIs) as the analytic parameters. Standard deviation and mean were used to evaluate data by weighted mean differences (WMDs) with 95% CI. RESULTS A total of 370 patients were analyzed. A similar duration of surgery was observed with CSEA and SSSA (WMD: 0.24, 95%CI: -3.41-3.89; P=0.90). Time to maximal sensory blockade (WMD: 0.96, 95%CI: -2.91-4.83), time to maximal motor blockade (WMD: 0.25, 95%CI: -2.46-2.96), time for complete motor recovery (WMD: -6.28, 95%CI: -29.42-16.86), and time for sensory recovery to T10 vertebra (WMD: 0.42, 95%CI: -11.07-11.91) were not significantly different. Adverse effects such as hypotension (OR: 1.49, 95%CI: 0.27-8.31), pruritus (OR: 0.23, 95%CI: 0.03-2.18), nausea/vomiting (OR: 0.84, 95%CI: 0.12-5.99). and shivering (OR: 0.53, 95%CI: 0.11-2.56) were also similar with CSEA and SSSA. CONCLUSIONS CSEA was not associated with significantly different maximal duration of sensory/motor blockade, complete motor recovery, sensory regression to T10, or adverse drug events compared to SSSA. Hence, both should be considered effective in cesarean delivery.

Competing Interests: Competing interests: None declared.

Purpose: To evaluate the hyaluronic acid (HA) inflammatory reaction, fibroblasts, fibrosis and duration of effect in the dorsal region of tobacco-exposed rats., Methods: Ten Wistar rats were divided into two groups: tobacco-exposed-group (TEG;n=5) and air-control-group (CG;n=5). The TEG animals were tobacco-exposed twice a day, 30-minutes/session, during 60 days. After this period, all animals received 0.1 mL HA subcutaneous injection in the dorsal area. The volume of HA was measured immediately after HA injection and weekly using a hand-caliper in nine weeks. After this period, all the animals were euthanized, and a specimen of was collected to evaluate inflammatory cells, fibroblasts, and fibrosis by HE., Results: This study showed a higher inflammatory reaction in TEG than CG: inflammatory cell-count (CG: 1.07±0.9; TEG: 8.61±0.36, p<0.001); fibroblast count (CG: 2.92±0.17; TEG: 19.14±0.62, p<0.001), and fibrosis quantification (CG: 2.0; TEG: 3.75, p<0.001). The analysis of the HA volume in nine weeks in the dorsal region did not show a difference between groups (p=0.39)., Conclusions: This study suggested that the HA injection in the TEG caused an increase in inflammatory cell count, fibroblast, and fibrosis quantification when compared to the CG. There was no difference in the duration of effect of HA between the groups.

Background: Epidural fibrosis is a major problem after spine surgery, with some patients having recurrent symptoms secondary to excessive formation of scar tissue resulting in neurologic compression. We used a rat laminectomy model to determine if topical application of boric acid could be helpful in the prevention of epidural fibrosis., Methods: Rats were randomly assigned to 2 control and 2 experimental groups (n = 8 for each group). The negative control group received no surgery, and the positive control group underwent laminectomy only. Experimental groups were classified according to the study agents applied onto the dura mater after laminectomy at the L3 level: 2.5% boric acid solution and 5% boric acid solution. The extent of epidural fibrosis was assessed 4 weeks later macroscopically and histopathologically., Results: Boric acid reduced epidural fibrosis in rats after laminectomy. The effect of 5% boric acid solution was more pronounced (P < 0.05) compared with the 2.5% solution., Conclusions: The antifibrotic effect of boric acid solution for the prevention of epidural fibrosis suggests that boric acid should be further evaluated in future studies for the prevention of epidural fibrosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Study Design: The effect of cetuximab on the development of epidural fibrosis (EF) was assessed using immunohistochemical methods as well as antibodies for CD105 and osteopontin (OPN)., Objective: The goal of this study was to assess of EGFR inhibition for the postoperative treatment of fibrosis., Summary of Background Data: EF is one of most common causes of failed back surgery syndrome, which occurs after laminectomy. Numerous causes and mechanisms have been proposed to explain its development after laminectomy. Many agents have been tested to prevent the development of EF. EGFR, a multi-functional transmembrane glycoprotein, causes cell growth, proliferation, and EF by interacting with epidermal growth factor and TGF-β1. The inhibition of postoperative fibrosis using cetuximab, an epidermal growth factor receptor blocker, is theoretically possible. However, this has not been tested to date., Methods: Sixteen Wistar-Albino rats were divided into two groups, namely, control and cetuximab groups. L1-2 laminectomy alone was performed in both groups, and topical cetuximab was applied to the treatment group. After 6 weeks, rats were sacrificed and examined histopathologically and immunohistochemically; EF tissue was also graded. Statistical significance was accepted at P < 0.05., Results: Fibroblast counts and fibrosis density, determined by histopathologic examination, and EF, according to immunohistochemical assessment based on CD105, were found to be higher in the treatment group than in the control group, and this was statistically significant (P < 0.001). Based on OPN staining, the results were consistent with classical methods, and no significant difference was detected among the groups (P = 0.358)., Conclusion: Our study revealed that cetuximab inhibits the development of EF and that CD105, and not OPN, is a reliable marker for grading EF. In addition, cetuximab did not result in toxic, systemic side effects in surrounding tissues., Level of Evidence: N/A.

Aim: To clarify the effects of topical application of curcumin on the prevention of epidural fibrosis., Material and Methods: Twenty-one rats were randomly divided into three equal groups (control, spongostan, local curcumin) and a laminectomy procedure was performed between T11 and L1 in all rats. Subsequently, spongostan soaked with curcumin (100 mg/kg) was applied topically. After four weeks, the vertebral column from T9 to L3, which included the paraspinal muscles and epidural scar tissue, was removed as a single piece and the epidural fibrosis and arachnoidal scarring were graded and histopathological analysis carried out accordingly. Kruskal-Wallis and Pearson Chi-Square tests were used for statistical analysis. A p-value of less than 0.05 was considered to be significant., Results: The grading of epidural fibrosis was far lower in the experimental group with curcumin compared to the control and spongostan groups, but the difference was not statistically significant., Conclusion: The findings of this study show that local curcumin decreases the formation of epidural fibrosis and this effect of curcumin is thought to be mediated by reducing the functions of inflammatory cells such as macrophages, neutrophils and fibroblasts, and the anti-inflammatory and antioxidant effects.

In infants and small children, ultrasound (US) guidance provides ample anatomical information to perform neuraxial blocks. We can measure the distance from the skin to the epidural space in the US image and can refer to it during needle insertion. We may also visualize the needle or a catheter during real-time US-guided epidural catheterization. In cases where direct needle or catheter visualization is difficult, US allows predicting successful puncture and catheterization using surrogate markers, such as dura mater displacement, epidural space widening due to drug injection, or mass movement of the drug within the caudal space. Although many experienced anesthesiologists still prefer to use conventional techniques, prospective randomized controlled trials using US guidance are providing increasing evidence of its advantages. The use of US-guided regional block will gradually become widespread in infants and children.

Background and Objectives: The retrolaminar block (RB) is used for truncal analgesia, but its mechanism of neural blockade remains obscure. We sought to learn the pattern of local anesthetic spread after thoracic RB using cadaveric models., Methods: In 8 fresh cadavers, an ultrasound-guided T4 RB was performed with 20 mL of methylene blue 1% and bupivacaine 0.5%. For comparison, an RB at T9 in 1 cadaver and a T4 thoracic paravertebral block in another cadaver were performed. Subsequently, posterior and anterior thoracic dissections were performed to examination where the dye spread., Results: After T4 RB, dye was noted to spread in the ipsilateral retrolaminar plane (all 8 cadavers, median cephalad spread 3.5 cm, caudad spread 10.7 cm, lateral spread 2.5 cm), the contralateral retrolaminar plane (6 cadavers), the paravertebral space (5 cadavers, median of 3 segments, T3-T5), the intercostal space (5 cadavers, median of 3.5 cm laterally), the T4 epidural space (6 cadavers), and the intervertebral foramina (4 cadavers, median of 2 segments, T4-T5). After T9 retrolaminar injection, dye was noted in the ipsilateral retrolaminar plane (5.5 cm cephalad, 13.5 cm caudad, and 2.5 cm lateral), the contralateral retrolaminar plane, and the epidural space. Dye after T4 traditional paravertebral block spread to T1-T6 paravertebral space with 15-cm lateral spread., Conclusions: Injectate spread to the paravertebral space, epidural space, intercostal space, and intervertebral foramina is possible in the RB but is quite variable. In comparison to the thoracic paravertebral block, injectate spread within the paravertebral space is more limited.

Objective: In this experimental study, PRF (Platelet Rich Fibrin), HA (Hyaluronic Acid) gel and ADCON® Gel were compared in terms of preventing epidural fibrosis., Methods: Twenty-eight Sprague-Dawley rats (mean weight, 400-450 g) were divided into 4 groups. L3-L4 laminectomy was performed in each group. Following laminectomy, Adcon® Gel, HA gel and PRF were applied onto the surgery site locally in Group 1, 2 and 3, respectively. Group 4 was maintained as control without any local application. After five weeks, L3-L4 vertebrae were removed totally and taken to histopathological evaluation for epidural fibrosis, acute inflammatory cell density, chronic inflammatory cell density, hemorrhage, angiogenesis and new bone formation., Results: Acute inflammation cell density, angiogenesis, and new bone formation levels were comparable among the study groups (p > 0.05). However, new bone formation was higher in the PRF group. Epidural fibrosis and chronic inflammatory cell density were significantly lower in the PRF group (p < 0.05)., Conclusion: We concluded that PRF contributed to hemostasis and prevented epidural fibrosis., (Copyright © 2018 Turkish Association of Orthopaedics and Traumatology. All rights reserved.)

Objective: To investigate the relationship between epidurographic contrast dispersal patterns and both immediate and short-term clinical effectiveness of lumbar transforaminal epidural steroid injections (TFESIs) in patients with radicular back pain., Methods: A digital database of 64 patients who underwent single-level lumbar TFESI for unilateral lumbar radicular pain was scanned. The type of contrast pattern was analyzed by 1 physiatrist and defined as follows: type 1 (tubular appearance), type 2 (nerve root visible as a filling defect), or type 3 (cloud-like appearance). Pain was evaluated with a visual analog scale (VAS) and recorded before injection and 2 days, 2 weeks, and 3 months after injection., Results: The mean age was 45.9 ± 13.5 years (range, 22-80 years), and the mean duration of symptoms was 5.7 ± 4.2 months. Contrast distribution patterns were as follows: type 1 in 33 patients (51.6%), type 2 in 18 patients (28.1%), and type 3 in 13 patients (20.3%). Mean decrease in VAS scores at all time points was statistically significant in 3 types of contrast dispersal patterns (P < 0.05). Differences in improvements of VAS scores obtained at any assessment period and success rates were not statistically significant between groups. However, the ratio of patients who achieved 50% or greater reduction in pain scores was higher in type 1 and type 2 than type 3 at each follow-up point., Conclusions: TFSEIs have a beneficial effect in managing lumbar radicular pain regardless of contrast pattern type. Success rates were higher in type 1 and type 2 than type 3., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The best technique to identify the epidural space for labor analgesia is still unclear despite the publication of various randomized controlled studies and meta-analyses. Our aim was to assess the superiority of the saline loss of resistance (SLOR) technique over the air loss of resistance (ALOR) technique with respect to the quality of the block., Methods: Consenting parturients admitted to our obstetric suite for spontaneous or induced labor were randomized to receive epidural analgesia using either the ALOR or SLOR technique. Our primary outcome was to compare the impact of the SLOR and ALOR technique on pain score improvement measured 30 minutes after administration of epidural block. Our secondary outcomes included the density of motor blockade and analgesic efficacy measured at 30 minutes. Primary and secondary outcomes were compared using the Student t test and Mann-Whitney U test. Statistical significance was set at P < .017 for primary and secondary outcomes, considering Bonferroni correction for multiple comparisons. Other comparisons were considered exploratory., Results: Four hundred parturients were included; 24 were excluded from the final analysis. After 30 minutes, pain score reduction (ALOR, 4.7 ± 2.9/10; SLOR, 4.9 ± 3.0/10; P = .49), motor block (ALOR, 1.4 ± 0.8; SLOR, 1.3 ± 0.8; P = .27), and efficacy of the block (ALOR, 1.0 ± 0.7; SLOR, 1.0 ± 0.6; P = .87) did not differ significantly between groups., Conclusions: Pain score reduction after 30 minutes and onset of the block were not affected by the technique used to locate the epidural space.

Objective: To investigate the effect of interlaminar epidural steroid injection (ESI) for management of central cervical spinal stenosis-induced posterior neck pain., Methods: This retrospective study recruited 45 patients with posterior neck pain caused by central cervical spinal stenosis. For the ESI procedure, a 21-gauge Touhy needle was inserted into the epidural space between C7 and T1, and 20 mg (40 mg/mL) of dexamethasone with 4 mL of normal saline was injected. The effect of the procedure was evaluated using a numerical rating scale at 1, 2, and 3 months after the procedure. Successful pain relief was defined as reduction in numerical rating scale score of ≥50% compared with before treatment. At 3 months after treatment, patient satisfaction levels were examined; patients who reported very good (score = 7) or good results (score = 6) were considered to be satisfied with the procedure., Results: Posterior neck pain was significantly reduced at follow-up evaluation 1, 2, and 3 months after ESI (P < 0.001, repeated measures 1-factor analysis). At 3 months after the procedure, 58% of the patients achieved a successful response (≥50% pain reduction), and 56% were satisfied with treatment results., Conclusions: Cervical interlaminar ESI appears to be a good treatment method for managing chronic posterior neck pain induced by central cervical spinal stenosis, especially when pain is refractory to oral medication., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: To evaluate bevacizumab for epidural fibrosis (EF) treatment in an experimental rat model using histopathology as well as immunohistochemical staining for CD105 and osteopontin (OPN)., Material and Methods: Sixteen Wistar Albino rats underwent either laminectomy alone to induce EF (group I, control) or laminectomy plus local bevacizumab treatment (group II). The degree of EF was compared between groups using the current histopathological grading method as well as immunohistochemistry for CD105 and OPN. In addition, the consistency of EF staging using CD105 and OPN expression was compared to that using histopathology., Results: The grade of EF was significantly lower in group II than in group I based on the fibroblast count and fibrosis density determined using histopathology, as well as by CD105 expression determined using immunohistochemistry. In contrast, OPN expression was not a reliable marker for EF evaluation because it did not show a significant difference between the two groups., Conclusion: Bevacizumab prevents EF development as assessed using both histopathology and CD105 expression. CD105 is a potentially reliable marker for the immunohistochemical grading of EF, in contrast to OPN.

Aim: To investigate the effects of local and systemic administration of etanercept on the formation of epidural fibrosis., Material and Methods: Twenty-eight rats were randomly divided into four equal groups (Control, SpongostanTM, Local etanercept and Systemic etanercept) and laminectomy was performed between T11 and L1 in all rats. SpongostanTM was soaked with saline (0.1 mg/kg), local etanercept (300 ?g/kg) was applied with SpongostanTM and systemic etanercept (300 ?g/kg/week) was applied subcutaneously. Four weeks later, the vertebral column from T9 to L3, including the paraspinal muscles and epidural scar tissue, was removed en bloc, and epidural fibrosis and arachnoidal involvement were graded and evaluated histopathologically., Results: The grading of epidural fibrosis was statistically significantly lower in systemic and local administration of etanercept groups compared to the control group (p < 0.005), but systemic etanercept administration was more effective., Conclusion: Systemic administration of etanercept can be effective in reducing epidural fibrosis in rats after laminectomy.

Surgery-induced epidural fibrosis after laminectomy often results in poor clinical outcomes. Fibroblasts proliferation is considered to be one of the major causes of epidural fibrosis formation. Previously, there was no research about the effect of Homoharringtonine(HHT) on inhibiting fibroblast proliferation and reducing epidural fibrosis. Here, we performed in vitro and in vivo experiments to explore the effect of HHT on inhibiting fibroblast proliferation, inducing fibroblast apoptosis and preventing epidural fibrosis formation. In vitro, the effect of HHT on inhibiting fibroblasts was detected by CCK-8 assay. Besides, the effect of HHT on causing fibroblast apoptosis was investigated via Western blots, flow cytometry and TUNEL assay. Results suggested that HHT could inhibit fibroblasts proliferation and induce apoptosis. And the marker proteins of endoplasmic reticulum (ER) stress were also changed positively. In vivo, histological macroscopic assessment, hydroxyproline content analysis and histological staining were used to detect the effect of HHT on reducing epidural fibrosis. The results showed that HHT had positive suppressive effects on epidural fibrosis following laminectomy in rats. TUNEL assay in epidural tissue suggested that HHT could obviously induce fibroblasts apoptosis. Immunohistochemistry staining showed that the expression of two important ER stress markers(78-kDa glucose-regulated protein and C/EBP homologous protein) were also increased. In conclusion, this research showed that HHT could reduce epidural fibrosis formation after laminectomy, and the potential mechanism might through inhibiting fibroblasts proliferation and inducing fibroblasts apoptosis via ER stress signaling pathway. It might provide a novel agent for reducing epidural fibrosis after laminectomy surgery., (Copyright © 2017. Published by Elsevier B.V.)

Post-operative epidural fibrosis is a biological response after laminectomy that may lead to clinical symptoms, such as radicular pain. An ideal material for prevention of epidural fibrosis should be able to inhibit fibroblast adhesions and reduce formation of scar tissue. An injectable hydrogel would be the material of choice for this purpose, since it could fill an irregular surgical defect completely, gelate in situ and be delivered in a minimally-invasive manner. The objective of this study was to evaluate, in vitro and in vivo, the cytocompatibility and anti-adhesive effect of an oxidised hyaluronic acid/adipic acid dihydrazide (oxi-HA/ADH) hydrogel. Different cell types present in the spine were used to test the cytocompatibility of the hydrogel. The hydrogel extraction medium had no deleterious effects on neural cells (PC-12), but reduced fibroblasts viability (NIH/3T3). Although the hydrogel did not change the release of lactate dehydrogenase from myoblasts (C2C12) and Schwann cells (RSC96), the extraction medium concentration slightly affected the mitochondrial activity of these two cell types. qPCR showed that the hydrogel down-regulated S100a and P4hb expression in NIH/3T3 cells, supporting the hypothesis that the hydrogel might inhibit fibroblast activity. The animal study showed a reduction of scar tissue formation as well as severity of adhesion between scar tissue and the dura mater in a rat laminectomy model. Superficially, the peel-off test showed significantly decreased tenacity. In conclusion, the oxi-HA/ADH hydrogel is a promising injectable and thermosensitive material for prevention of post-operative epidural fibrosis.

Epidural volume extension, a modification of combined spinal-epidural anaesthesia, involves the epidural injection of saline in order to increase the spread of drugs given intrathecally. Results from individual studies have so far been contradictory and we aimed to gather the available evidence for this technique. We performed a systematic literature search for randomised, controlled trials comparing epidural volume extension after spinal injection with a control group without epidural injection in patients undergoing surgery. Conventional meta-analyses, trial sequential analyses and meta-regression were performed, with the Grading of Recommendations on Assessment, Development and Evaluation (GRADE) approach used to express reliability of outcome estimates. We included 15 studies with 1177 participants. Meta-analyses for the primary outcomes, such as maximum sensory height (6 studies, 274 participants, mean difference (MD) (95%CI) -0.59 (-1.24 to 0.07) dermatomes, low-quality evidence) and hypotension (10 studies, 683 participants, risk ratio (95%CI) 0.84 (0.66-1.07), low-quality evidence), did not differ significantly between the two treatment arms, but trial sequential analysis suggested insufficient evidence to be certain of these findings. Meta-regression suggested a volume-dependent effect, with higher volumes causing a higher spread of intrathecal drugs and a higher incidence of hypotension. A sub-group analysis indicated a pronounced effect on motor block recovery time when a lower anaesthetic dose plus epidural volume extension was compared with a higher anaesthetic dose without epidural volume extension, the MD (95%CI) being -66.75 (-76.0 to -57.5) min, with trial sequential analysis suggesting the evidence was sufficient to draw this conclusion. In trials using the same anaesthetic mixture in the epidural volume extension and the control groups, motor block recovery time did not differ between groups, with a MD (95%CI) of -1.06 (-5.48 to 3.36) min, although trial sequential analysis suggested insufficient evidence. In summary, there is not enough evidence to draw definite conclusions on the effect of epidural volume extension. The quality of the current evidence is low for both efficacy (maximum sensory height) and safety (hypotension). However, there may be a significantly shorter motor block recovery time when different anaesthetic mixtures are used in epidural volume extension and control groups; this warrants further investigation., (© 2017 The Association of Anaesthetists of Great Britain and Ireland.)

Objective: To describe and to analyze cervical epidural contrast patterns seen in antero-posterior (AP), contralateral oblique (CLO), and lateral view. To identify factors that might help in predicting contrast distribution pattern and extent., Method: Spread of contrast in the cervical epidural space was prospectively studied in AP, lateral, and three CLO views., Results: CLO view showed contrast spread of variable thickness with its posterior margin overlying the ventral interlaminar line (VILL). In the lateral view, the spread was also of variable thickness, but the posterior margin of the contrast lay on the spinolaminar line in only 10 of 24 patients. Ventral contrast spread was not visualized in any patient. In the AP view, bilateral spread was seen in 14 of 24 subjects, and nerve root spread was seen in 16 of 24 subjects. No association of the pattern of spread or dispersion was seen to patient age, volume injected, or needle location., Conclusions: The CLO view provides a consistent radiological landmark for the posterior margin of contrast in the dorsal epidural space; the lateral view fails to provide such a consistent landmark. The thickness of the spread is variable, both in the CLO and in the lateral view. Thick spread extending into the foramen in the CLO view and over the articular pillars in the lateral view is frequent and should not be misconstrued as subdural or intrathecal spread. In contradistinction to previous studies, true ventral spread was not seen in any patient. When using low volumes, contrast spread is independent of patient age, volume injected, or needle tip location in the AP view., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objective: To design a new controlled-release MMC-PLA film and explore whether and how this film could prevent epidural scar hyperplasia and adhesion in a post-laminectomy rat model., Materials and Methods: All procedures were performed under the approval and supervision of the Institutional Animal Care and Use Committee (IACUC) of Nanjing Medical University. A total of 120 Sprague-Dawley (SD) rats were randomly placed into four groups after laminectomy (each group=30 rats). In Group I, the laminectomy area was flushed with saline as a control; in Group II, 25 mg of PLA film was applied to the dura mater in the laminectomy area; in Group III, a cotton pad soaked with 0.01% MMC solution was kept on the laminectomy area; and in Group IV, 25 mg of PLA film containing 0.01% MMC was implanted on the laminectomy area. Magnetic resonance imaging (MRI), hematoxylin-eosin (HE) staining and Masson staining were used to evaluate scar adhesion and collagen deposition one month after the operation. Autophagy-related proteins, including autophagy-related gene 5 (ATG5), beclin 1, light chain-3B-2/1 (LC3B-2/1) and protein 53 (p53), were detected by Western blotting. A microRNA microarray analysis was performed to screen for scar tissue miRNAs, especially those associated with autophagy, and changes in expression were confirmed by reverse transcription-polymerase chain reaction (RT-PCR)., Results: A total of 112 rats recovered uneventfully from the surgery. MRI showed that the scar adhesion and scar area of the MMC-PLA group were significantly reduced compared with those of the PLA, MMC, and saline groups. Accordingly, scar adhesion and the deposition of collagen in the rats treated with MMC-PLA were also significantly reduced, as indicated by HE and Masson staining. In the scar tissue, the levels of autophagy-related proteins (ATG5, beclin 1, LC3B-2/1 and p53) were significantly elevated in the MMC-PLA group. Additionally, in the MMC-PLA group, the expression levels of miR-34a, miR-146a and miR-200 were significantly increased, while the levels of miR-16, miR-221 and miR-378a were significantly decreased., Conclusions: The controlled-release MMC-PLA film could alleviate epidural scar hyperplasia after laminectomy; this outcome might be associated with increased autophagy and altered expression of miRNAs in the scar tissue.

Lumbar laminectomy is one of the most common treatments for lumbar disc herniation and other lumbar disorders with serious complications, such as failed back surgery syndrome, mainly caused by epidural fibrosis (EF). The developing fibrosis causes radicular pain after the laminectomy or discectomy. Methotrexate (MTX) is a folic acid antagonist that has shown anti-proliferative effects in previous studies. The aim of our experiment is to study whether MTX has positive effects on the outcome of the laminectomy in rats. Our finding first demonstrated the beneficial effect of topical application of MTX in laminectomy models. As the results of a macroscopic scoring system, hydroxyproline content analysis, histological evaluation, the number of fibroblasts and immunohistochemistry showed that MTX suppressed the EF compared with the control group, and the inhibiting effect was in a dose-dependent manner. Furthermore, we hypothesized that the endoplasmic reticulum (ER) stress mediated the suppression effect of the EF. To verify this point of view, fibroblast cells cultured from epidural scar tissues of rats were used. CCK-8 assay, Western blot (for apoptotic genes, such as cleaved PARP) and annexin V-FITC/PI double-labelling showed that MTX could induce cell apoptosis. The expression of CHOP and GRP78 and the activation of ER stress-associated genes strongly suggested that ER stress mediated the apoptotic signalling pathway; immunohistochemistry of GRP78 and CHOP further verified this. Our findings indicate that topical application of MTX could indeed reduce EF, and the application of MTX could induce apoptosis through ER stress in rats., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aim: The aim of this experimental study was to investigate whether spinal epidural 4% glucose polymer solution is effective in the prevention of postoperative fibrosis., Material and Methods: Twenty eight adult Wistar albino rats were randomly divided into two equal groups, including treatment and control. Both groups underwent L1 vertebral total laminectomy to expose the dura. Topical treatment group received 4% icodextrin. Four weeks later, epidural fibrosis was examined in both groups histologically, biochemically and macroscopically., Results: Topical use of 4% icodextrin prevented significantly epidural fibrosis following the laminectomy operation., Conclusion: Topical 4% icodextrin application inhibits postoperative epidural fibrosis with various mechanisms and prevents adhesions by playing barrier role between tissue surfaces through flotation. Our study is first to present evidence of experimental epidural fibrosis prevention with 4% icodextrin.

Fused real-time ultrasound and magnetic resonance imaging (MRI) may be used to improve the accuracy of advanced image guided procedures. However, its use in regional anesthesia is practically nonexistent. In this randomized controlled crossover trial, we aim to explore effectiveness, procedure-related outcomes, injectate spread analyzed by MRI, and safety of ultrasound/MRI fusion versus ultrasound guided Suprasacral Parallel Shift (SSPS) technique for lumbosacral plexus blockade. Twenty-six healthy subjects aged 21-36 years received two SSPS blocks (20 mL 2% lidocaine-epinephrine [1 : 200,000] added 1 mL diluted contrast) guided by ultrasound/MRI fusion versus ultrasound. Number (proportion) of subjects with motor blockade of the femoral and obturator nerves and the lumbosacral trunk was equal (ultrasound/MRI, 23/26 [88%]; ultrasound, 23/26 [88%]; p = 1.00). Median (interquartile range) preparation and procedure times (s) were longer for the ultrasound/MRI fusion guided technique (686 [552-1023] versus 196 [167-228], p < 0.001 and 333 [254-439] versus 216 [176-294], p = 0.001). Both techniques produced perineural spread and corresponding sensory analgesia from L2 to S1. Epidural spread and lidocaine pharmacokinetics were similar. Different compartmentalized patterns of injectate spread were observed. Ultrasound/MRI fusion guided SSPS was equally effective and safe but required prolonged time, compared to ultrasound guided SSPS. This trial is registered with EudraCT (2013-004013-41) and ClinicalTrials.gov (NCT02593370)., Competing Interests: None of the authors have any potential conflicts of interests to declare.

Objective: Spinal epidural fibrosis is a clinical condition that develops after laminectomy and can compress the spine. Many agents have been tried for the treatment, but none has entered clinical use at present. Pegaptanib sodium is an antiangiogenetic drug that prevents the development of new vessels and thus adhesion by inhibiting the effect of VEGF., Material and Method: 20 Wistar rats were used in this study. The rats were divided into 2 different groups as the control and pegaptanib sodium group. Three levels of laminectomy were performed. Only laminectomy was performed in the control group. A cotton ball soaked with 3 mg/kg Pegaptanib sodium diluted 1: 10 with 0.9 % NaCl was topically applied to the dura in the surgical field for 5 minutes in the pegaptanib sodium group. The rats were sacrificed 3 weeks later and histopathologically examined. The epidural fibrosis was graded., Results: The epidural fibrosis grade in the pegaptanib sodium was significantly lower than in the control group c2 = 11,65; (p = 0.004)CONCLUSION: Pegaptanib sodium blocked the VEGF through its anti-VEGF effect and decreased spinal epidural fibrosis in rats that had undergone laminectomy (Tab. 2, Fig. 3, Ref. 53).

Aim: Lumbar epidural fibrosis is increasingly recognized as a cause of persistent back pain. The aim of this study was to examine the effect Ankaferd Blood Stopper on epidural fibrosis following laminectomy in rat models., Material and Methods: Twenty Sprague-Dawley male rats were randomly allocated to 2 groups of 10 each. The dura mater and nerve root were exposed after L1 unilateral laminectomy. Close attention was paid not to traumatize the dura, the nerve roots, or the dissected muscles. Immediate muscle and skin closure was made in sham group. In the Ankaferd Blood Stopper group, cotton wool soaked with 1 mL Ankaferd Blood Stopper was applied to the exposure site for 5 minutes, and muscle and skin closure was then made. Histological analysis was performed at four weeks postoperatively., Results: Epidural fibrosis formation evaluation and fibroblastic activity evaluation revealed that there was a significant difference between the sham and the Ankaferd Blood Stopper treated groups (p = 0.011, p = 0.009). Severe epidural adhesions were observed in the Ankaferd Blood Stopper group. Dissection of these epidural adhesions was difficult and accompanied by bleeding and disruption of the dura mater., Conclusion: The results of this study showed that there was no positive effect of Ankaferd Blood Stopper on the prevention of epidural fibrosis, which is one of the most significant problems following spinal surgery, and the epidural fibrosis actually increased.

Background and Objective: Liposomal prostaglandin E1 (Lipo-PGE1) can inhibit platelet aggregation and vasodilatation and has been found to be therapeutic in ischemia and spinal diseases including stenosis. However, the neurologic safety of epidural administration of lipo-PGE1 requires further study. We investigated the neurotoxicity of epidurally administered lipo-PGE1 agonist in rats., Methods: Twenty-seven rats were randomly divided into three groups: Epidural isotonic sodium chloride solution administration (negative control, group N, n = 9); epidural lipo-PGE1 agonist (group L, n = 9); and epidural alcohol (positive control, group A, n = 9). A single 3-mL injection of lipo-PGE1 agonist (0.3 mL, 0.15 μg/kg), 40% ethanol, or isotonic sodium chloride solution was administered. Neurologic assessments were performed 3, 7, and 21 days after the injection. Histopathologic data were evaluated by one pathologist via light microscopy., Results: All rats in groups N and L, except one rat in group L, demonstrated normal response to neurologic assessments. Histopathologic findings showed no evidence of degenerative myelopathy, chromatolysis, or myelin loss in group N or L at any time point. However, all rats in group A revealed sensory and motor deficits as well as histopathologic abnormalities., Conclusion: Liposomal prostaglandin E1 agonist did not cause any apparent neurologic abnormalities in the spinal cord or dorsal root ganglion, suggesting it is neurologically safe for epidural injection in this species. Additional mammalian study is warranted.

Caudal epidural block is a commonly used technique for surgical anesthesia in children and chronic pain management in adults. It is performed by inserting a needle through the sacral hiatus to gain entrance into the sacral epidural space. Using conventional blind technique, the failure rate of caudal epidural block in adults is high even in experienced hands. This high failure rate could be attributed to anatomic variations that make locating sacral hiatus difficult. With the advent of fluoroscopy and ultrasound in guiding needle placement, the success rate of caudal epidural block has been markedly improved. Although fluoroscopy is still considered the gold standard when performing caudal epidural injection, ultrasonography has been demonstrated to be highly effective in accurately guiding the needle entering the caudal epidural space and produce comparative treatment outcome as fluoroscopy. Except intravascular and intrathecal injection, ultrasonography could be as effective as fluoroscopy in preventing complications during caudal epidural injection. The relevant anatomy and techniques in performing the caudal epidural block will be briefly reviewed in this article., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Background: Epidural fibrosis often causes serious complications in patients after lumbar laminectomy and discectomy and is associated with the proliferation of fibroblasts. Suramin is known to have an obvious inhibitory effect on the coactions of many growth factors and their receptors, but little was previously known about the effect of suramin on fibroblast proliferation and the progress of epidural fibrosis., Methods: We illustrated the effect of suramin on cultured fibroblasts of rats with different concentrations (0, 200, 400, 600 mg/l). The proliferation of suramin-treated fibroblasts was evaluated by CCK-8 and western blot analysis. Additionally, in a rat model of laminectomy, different concentrations of suramin (100, 200, and 300 mg/ml) and saline were applied to the laminectomy sites locally. The effect of suramin on preventing epidural fibrosis was detected by the Rydell classification, hydroxyproline content, histological analysis, and collagen density analyses., Results: The results of CCK-8 shown that suramin could significantly inhibit fibroblasts proliferation in a dose-dependent manner. The western blotting shown that the expression levels of the cell proliferation markers such as cyclin D1, cyclin E, and PCNA were down-regulated. Moreover, in a rat model, we found that suramin could reduce epidural fibrosis as well as inhibit fibroblast proliferation, and 300 mg/ml suramin had better effect., Conclusions: Topical application of suramin could reduce epidural fibrosis after laminectomy, and the application of suramin could inhibit the proliferation of fibroblasts in rats. This study indicates that suramin is a potent antifibrotic agent that may have therapeutic potential for patients with epidural fibrosis.

OBJECTIVE The complication profile of epidural triamcinolone acetonide use during lumbar decompression surgery is not known. However, isolated reports of increased risk of delayed CSF leakage with the use of triamcinolone acetonide in adult spinal surgery patients have been published. The purpose of this study was to determine the safety of epidural triamcinolone acetonide use in conjunction with lumbar decompression surgery in pediatric patients. METHODS The medical records of all patients who underwent lumbar decompression surgery with or without discectomy between July 1, 2007, and July 31, 2015, were retrospectively reviewed. RESULTS During the study period, 58 patients underwent 59 spine procedures at Texas Children's Hospital. There were 33 female and 25 male patients. The mean age at surgery was 16.5 years (range 12-24 years). Patients were followed for an average of 38.2 months (range 4-97 months). Triamcinolone acetonide was used in 28 (of 35 total) cases of discectomy; there were no cases of delayed symptomatic CSF leaks (0%) in the minimally invasive and open discectomies. On the other hand, triamcinolone acetonide was used in 14 (of 24 total) cases of multilevel laminectomy, among which there were 10 delayed CSF leaks (71.4%) requiring treatment. The use of triamcinolone acetonide in patients who underwent multilevel laminectomy was significantly associated with an increased risk of delayed CSF leaks or pseudomeningoceles (Fisher's exact test, p < 0.001). CONCLUSIONS There was an unacceptable incidence of delayed postoperative CSF leaks when epidural triamcinolone acetonide was used in patients who underwent multilevel laminectomy.

Background: Epidural fibrosis is a common complication after laminectomy. It is associated with intractable lower back pain and additional complications. To date, no study has evaluated whether the local application of rapamycin (RAPA) can inhibit fibroblast proliferation and reduce epidural scar adhesion after laminectomy. The results of the present study showed that the local application of RAPA reduces epidural fibrosis after laminectomy in rats., Methods: In this study, 32 male Sprague-Dawley rats were randomly divided into four groups (0.2 mg/ml RAPA-treated group, 0.1 mg/ml RAPA-treated group, 0.05 mg/ml RAPA-treated group and physiological saline group). Laminectomy was performed at the level of lumbar segment 1 to 2, and different concentrations of RAPA or saline were applied to the laminectomy sites for 10 min. Four weeks after laminectomy, the rats were sacrificed, and the degrees of epidural adhesion in each group were evaluated. Macroscopic assessment, analysis of hydroxyproline content, and histological analysis were used to determine the therapeutic effect of the local application of RAPA on the inhibition of fibroblast proliferation and the reduction of epidural fibrosis after laminectomy. Next, we cultured fibroblasts from epidural scar tissues of rats that had undergone laminectomy. Fibroblasts were exposed to the indicated concentrations of RAPA, and western blotting and TUNEL assays were used to assess the effects of RAPA on inhibiting fibroblasts proliferation and promoting fibroblast apoptosis., Results: The results of macroscopic assessments, analysis of hydroxyproline content, and histological analyses indicated that RAPA significantly inhibited fibroblast proliferation and reduced epidural fibrosis in the treated groups in the rat model. The western blotting results indicated that the expression levels of the pro-apoptotic proteins cleaved-PARP and Bax were up-regulated, whereas those of Bcl-2 were reduced. TUNEL assay indicated that the apoptosis rates of fibroblasts were significantly increased after exposure to the indicated concentrations of RAPA., Conclusions: The local application of RAPA reduced epidural fibrosis after laminectomy by inhibiting the proliferation of fibroblasts, stimulating their apoptosis, and decreasing collagen synthesis. This protocol may be used in new clinical treatment strategies to reduce epidural fibrosis after laminectomy.

The formation of fibrous tissue is part of the natural healing response following a laminectomy. Severe scar tissue adhesion, known as epidural fibrosis, is a common cause of failed back surgery syndrome. In this study, by combining the advantages of drug treatment with a physical barrier, an ibuprofen-conjugated crosslinkable polygalacturonic acid and hyaluronic acid hydrogel was developed for epidural fibrosis prevention. Conjugation was confirmed and measured by 1D(1)H NMR spectroscopy.In vitroanalysis showed that the ibuprofen-conjugated polygalacturonic acid-hyaluronic acid hydrogel showed low cytotoxicity. In addition, the conjugated ibuprofen decreased prostaglandin E2production of the lipopolysaccharide-induced RAW264.7 cells. Histological data inin vivostudies indicated that the scar tissue adhesion of laminectomized male adult rats was reduced by the application of our ibuprofen-conjugated polygalacturonic acid-hyaluronic acid hydrogel. Its use also reduced the population of giant cells and collagen deposition of scar tissue without inducing extensive cell recruitment. The results of this study therefore suggest that the local delivery of ibuprofenviaa polygalacturonic acid-hyaluronic acid-based hydrogel reduces the possibility of epidural fibrosis., (© The Author(s) 2016.)

Background: The aim of this experimental study was to investigate the effectiveness of intramuscular pentoxifylline in the prevention of postoperative fibrosis., Material/methods: We divided 16 adult Wistar albino rats into 2 equal groups: treatment and control. Both groups underwent L1 vertebral total laminectomy to expose the dura. The intramuscular treatment group received pentoxifylline. Four weeks later, epidural fibrosis was studied in both groups using electron microscopy, light microscopy, histology, biochemistry, and macroscopy., Results: The evaluation of epidural fibrosis in the 2 groups according to macroscopic (p<0.01) assessment and light microscopy revealed that epidural scar tissue formation was lower in the treatment group compared to the control group (p<0.001) and the number of fibroblasts was also decreased significantly in the pentoxifylline-treated group (p<0.05). More immature fibers were demonstrated in the treatment group by electron microscopy in comparison with the control group. In biochemical analysis, a statistically significant decrease was detected in hydroxyproline, which indicates fibrosis and myeloperoxidase activity, and shows an inflammatory response (P<0.001)., Conclusions: Systemic pentoxifylline application prevents postoperative epidural fibrosis and adhesions with various mechanisms. Our study is the first to present evidence of experimental epidural fibrosis prevention with pentoxifylline.