Safety of intradiscal injection and biocompatibility of polyester amide microspheres in a canine model predisposed to intervertebral disc degeneration.
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ABSTRACT:
SUBMITTER: Willems N
PROVIDER: S-EPMC6690078 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Intervertebral disc herniation (IVDH) is an important pathology in humans and also in dogs. While the molecular disease mechanisms are well investigated in humans, little is known about the inflammatory mediators in naturally occurring canine IVDH. The objective of this study was to investigate whether the involved proinflammatory cytokines in human IVDH are also key cytokines in canine IVDH and thus to elucidate the suitability of the dog as a model for human trials. 59 samples from 25 dogs with surgically confirmed thoracolumbar IVDH were collected and classified in three subgroups: herniated (H), affected non-herniated (NH) disc, and adjacent non-affected (NA) disc. Discs from 11 healthy dogs acted as controls (C). Samples were analyzed for IL-1, IL-6, IL-8, and TNF-? expression (qPCR/ELISA) as well as cell infiltration and activation of the MAP kinase pathways (immunohistochemistry). Gene and protein expression of all key cytokines could be detected in IVDH affected dogs. Canine IVDH was significantly associated with a higher gene expression of IL-6 (H?>?C, NH?>?C) and TNF-? (H?>?C, NH?>?C, NA?>?C) and a significant down-regulation of IL-1? (H?<?C). Dogs with spontaneous pain had significantly higher IL-6 mRNA compared to those with pain arising only upon palpation. An inter-donor comparison (H and HN relative to NA) revealed a significant increase of IL-6 gene expression (H?>?NA, NH?>?NA). IL-8 (H?>?C, NA?>?C) and TNF-? (NH?>?C) protein levels were significantly increased in diseased dogs while inversely, IL-6 protein levels were significantly higher in patients with better clinical outcome. Aside from resident IVD cells, mostly monocytes and macrophages were found in extruded material, with concomitant activation of extracellular signal-regulated kinase p38 in the majority of samples. Dogs with spontaneous IVDH might provide a useful model for human disc diseases. Although the expression of key cytokines found in human IVDH was also demonstrated in canine tissue, the inflammatory mechanisms accompanying canine IVDH diverges partially from humans, which will require further investigations in the future. In dogs, IL-6 seems to play an important pathological role and may represent a new potential therapeutic target for canine patients.
| S-EPMC5723024 | biostudies-literature
Project description:Knowledge of the prognosis of acute spinal cord injury is critical to provide appropriate information for clients and make the best treatment choices. Acute intervertebral disc extrusions (IVDE) are a common cause of pain and paralysis in dogs with several types of IVDE occurring. Important prognostic considerations are recovery of ambulation, return of urinary and fecal continence, resolution of pain and, on the negative side, development of progressive myelomalacia. Initial injury severity affects prognosis as does type of IVDE, particularly when considering recovery of continence. Overall, loss of deep pain perception signals a worse outcome. When considering Hansen type 1 IVDE, the prognosis is altered by the choice of surgical vs. medical therapy. Concentration of structural proteins in the plasma, as well as inflammatory mediators, creatine kinase, and myelin basic protein in the cerebrospinal fluid (CSF) can provide additional prognostic information. Finally, cross-sectional area and length of T2 hyperintensity and loss of HASTE signal on MRI have been associated with outcome. Future developments in plasma and imaging biomarkers will assist in accurate prognostication and optimization of patient management.
| S-EPMC7725764 | biostudies-literature
Project description:Background: Canine intervertebral disc disease (IVDD) represents a significant clinical problem in veterinary medicine, with similarities to the human pathology. Host-derived damage-associated molecular patterns like fibronectin fragments (FnF) that develop during tissue dysfunction may be of specific relevance to IVD pathologies by inducing an inflammatory response in resident cells. Aim: This project aimed to determine the presence and pathobiological role of FnF during IVD herniation in dogs, with a focus on inflammation. Methods: Herniated nucleus pulposus (NP) material from five dogs as well as non-herniated adjacent NP material from three dogs was collected during spinal surgery required due to acute IVD herniation. The presence of different types of FnF were determined by Western blot analysis. NP cells isolated from six herniated canine IVDs were then exposed to 30 kDa FnF. NP cell inflammation and catabolism was examined by investigating the expression of IL-1β, IL-6, IL-8, and COX-2, as well as MMP-1 and MMP-3 by qPCR (all targets) and ELISA (IL-6, PGE2). Results: Amongst multiple sized FnF (30, 35, 45, and >170kDa), N-terminal fragments at a size of ~30 kDa were most consistently expressed in all five herniated IVDs. Importantly, these fragments were exclusively present in herniated, but not in non-herniated IVDs. Exposure of canine NP cells to 500 nM 30 kDa FnF caused a significant upregulation of IL-6 (62.5 ± 79.9, p = 0.032) and IL-8 (53.0 ± 75.7, p = 0.031) on the gene level, whereas IL-6 protein analysis was inconclusive. Donor-donor variation was observed in response to FnF treatment, whereby this phenomenon was most evident for COX-2, with three donors demonstrating a significant downregulation (0.67 ± 0.03, p = 0.003) and three donors showing upregulation (6.9 ± 5.5, p = 0.21). Co-treatment with Sparstolonin B, a TRL-2/TRL-4 antagonist, showed no statistical difference to FnF treatment alone in all tested target genes. Conclusion: Given the presence of the 30 kDa FnF in canine herniated IVDs and the proinflammatory effect of 30 kDa FnF on NP cells, we concluded that the accumulation of FnF may be involved in the pathogenesis of canine IVDD. These results correspond to the findings in humans with IVDD.
| S-EPMC7701143 | biostudies-literature
Project description:IntroductionChemonucleolysis with condoliase (chondroitin sulfate ABC endolyase) has been used to treat patients with lumbar disc herniation (LDH) in Japan since 2018. In this study, we retrospectively investigated clinical outcomes in patients who received an intradiscal condoliase injection for LDH and sought to identify significant predictors of good outcome.MethodsIndications for treatment were as follows: (1) unilateral leg pain with or without back pain, (2) nerve root compression caused by LDH confirmed on magnetic resonance imaging (MRI), and (3) leg pain resistant to at least 1 month of conservative treatment, including medication, nerve root block, or physical therapy. Patients with motor weakness or a history of severe allergy were excluded, as were those with the foraminal or sequestrated type of LDH. The injection was defined as effective if the numeric rating scale score for leg pain improved by ≥50% at 6 months post-treatment.ResultsA total of 52 patients (mean age, 45.0 years) were enrolled and classified according to whether the injection was effective (E group, n=40, 76.9%) or less effective (L group, n=9, 17.3%). Three patients (5.8%) underwent herniotomy for residual pain within 6 months of the injection. There were no severe adverse events. Reduction of herniation was seen on MRI more often in the E group than in the L group. The effectiveness in patients with transligamentous LDH was similar to that in patients with subligamentous LDH. High-intensity signal change in the area of LDH on pretreatment T2-weighted MRI was a significant predictor of successful leg pain relief.ConclusionsAn intradiscal condoliase injection was a safe and effective treatment for painful radiculopathy caused by LDH. Leg pain was more likely to improve in patients with high-intensity signal change in the area of LDH before treatment.
| S-EPMC9200423 | biostudies-literature
Project description:Intervertebral disc degeneration(IVDD) is a common spinal condition with limited effective treatments available. This study aims to investigate the impact of poly(lactic-co-glycolic acid)/Bradykinin (PLGA/BK) microspheres on IVDD and its underlying mechanisms. We collected nucleus pulposus samples from both healthy and degenerated human intervertebral discs and conducted immunohistochemical analyses, revealing reduced BK expression in degenerated tissues. Subsequently, we used BK to treat nucleus pulposus cells and conducted Bulk RNA sequencing (RNA-seq), identifying BK's involvement in cellular senescence, extracellular matrix metabolism, and the PI3K signaling pathway. Further experiments using tert-butyl hydroperoxide (TBHP)-induced cell senescence showed that BK treatment reduced senescence, enhanced extracellular matrix synthesis, and inhibited degradation, along with activation of the PI3K pathway. These effects were mediated through B2R (BK receptor 2) and the downstream PI3K pathway. Following this, we developed sustained-release BK microspheres with an optimized manufacturing process. In vitro co-culture experiments showed no observable toxicity. We established an IVDD model in rat tail vertebrae through fine needle puncture, administering local injections of BK sustained-release microspheres. Using various experimental methods, including X-ray, MRI, histopathology, and immunohistochemistry, we found that these microspheres could slow the progression of IVDD. This study highlights the potential of injectable PLGA/BK microspheres to regulate cellular senescence and extracellular matrix metabolism via the B2R and PI3K pathways, ultimately delaying IVDD.
2024-09-21 | GSE277600 | GEO
Project description:Introduction: Canine interverterbral disc (IVD), although physiologically acellular, displays an inflammatory cell population consisting almost exclusively of macrophages (M?) when acutely herniated. M? encompass a heterogenous cell population, roughly divided into classically (M1) or alternatively activated (M2)M?. Polarization into M1 M? leads to strong antimicrobial activity and pro-inflammatory response. In contrast, M2M? exibit anti-inflammatory function and regulate wound healing. The purpose of this study was to characterize the phenotype of the M? population present in naturally occurring IVD herniation. Materials and Methods: IVD material of dogs with IVD disease was collected during standard decompressive surgery. A negative control consisting of IVD material of dogs without IVD degeneration and a positive control consisting of canine liver and lymph node samples were also included. All samples were embedded in OCT and shock frozen. Eight micrometer cryostat sections were prepared, air dried and immunostained without prefixation or permeabilization. CD14 was used as marker M?, MHCII for M1M? and CD206 for M2M?. Results: Fifteen samples of dogs with IVD herniation, 10 negative, and 5 positive control samples were obtained. No positive cell was found in the negative control group. The positive control group displayed several MHCII and CD206 positive cells, all of them being simultaneously positive to CD14. All herniated samples displayed a mixed population of M1M? and M2M?, and some sparse M? displaying markers for both M1 and M2M? simultaneously. Conclusion: The mixed phenotype encountered shows the plasticity and dynamism of M? and evidences the chronic component of IVD disease despite its acute clinical presentation.
| S-EPMC7005589 | biostudies-literature
Project description:Study designSystematic review and meta-analysis.ObjectivesWe performed this meta-analysis to evaluate whether intradiscal Platelet Rich Plasma(PRP) injection has any beneficial role in the management of lumbar disc disease.MethodsWe conducted independent and duplicate electronic database searches including PubMed, Embase, and Cochrane Library till September 2020 for studies investigating the role of intradiscal PRP in the management of lumbar disc disease. The analysis was performed in the R platform using OpenMeta[Analyst] software.Results13 studies including 2 RCTs, 5 prospective, and 6 retrospective studies involving 319 patients were included in the meta-analysis. A single-arm meta-analysis of the included studies showed a beneficial effect of the intervention in terms of pain relief outcomes like VAS score (p < 0.001), pain component of SF-36 (p = 0.003) while such improvement was not seen in functional outcome measures like ODI score (p = 0.071), the physical component of SF-36 (p = 0.130) with significant heterogeneity noted among the included studies. No structural improvement in magnetic resonance imaging was observed (p = 0.106). No additional procedure-related adverse events were noted in the included studies (p = 0.662).ConclusionThere is a paucity of high-quality studies to give conclusive evidence on the benefits of intradiscal PRP for lumbar disc disease. Although intradiscal PRP injection has shown some beneficial effect in controlling pain for lumbar disc disease, we could not find structural or functional improvement from the included studies. Hence, we recommend large double-blind double-arm randomized controlled studies to analyze the benefits of the intervention being analyzed.
| S-EPMC9121148 | biostudies-literature
Project description:The most common reason that adults in the United States see their physician is lower back or neck pain secondary to degenerative disc disease. To date, approaches to treat degenerative disc disease are confined to purely mechanical devices designed to either eliminate or enable flexibility of the diseased motion segment. Tissue engineered intervertebral discs (TE-IVDs) have been proposed as an alternative approach and have shown promise in replacing native IVD in the rodent tail spine. Here we demonstrate the efficacy of our TE-IVDs in the canine cervical spine. TE-IVD components were constructed using adult canine annulus fibrosis and nucleus pulposus cells seeded into collagen and alginate hydrogels, respectively. Seeded gels were formed into a single disc unit using molds designed from the geometry of the canine spine. Skeletally mature beagles underwent discectomy with whole IVD resection at levels between C3/4 and C6/7, and were then divided into two groups that received only discectomy or discectomy followed by implantation of TE-IVD. Stably implanted TE-IVDs demonstrated significant retention of disc height and physiological hydration compared to discectomy control. Both 4-week and 16-week histological assessments demonstrated chondrocytic cells surrounded by proteoglycan-rich matrices in the NP and by fibrocartilaginous matrices in the AF portions of implanted TE-IVDs. Integration into host tissue was confirmed over 16 weeks without any signs of immune reaction. Despite the significant biomechanical demands of the beagle cervical spine, our stably implanted TE-IVDs maintained their position, structure and hydration as well as disc height over 16 weeks in vivo.
| S-EPMC5650136 | biostudies-literature
Project description:The intervertebral disc (IVD) is a highly hydrated tissue, the rich proteoglycan matrix imbibes water, enabling the disc to withstand compressive loads. During aging and degeneration increased matrix degradation leads to dehydration and loss of function. Aquaporins (AQP) are a family of transmembrane channel proteins that selectively allow the passage of water in and out of cells and are responsible for maintaining water homeostasis in many tissues. Here, the expression of all 13 AQPs at gene and protein level was investigated in human and canine nondegenerate and degenerate IVDs to develop an understanding of the role of AQPs during degeneration. Furthermore, in order to explore the transition of notochordal cells (NCs) towards nucleus pulposus (NP) cells, AQP expression was investigated in canine IVDs enriched in NCs to understand the role of AQPs in IVD maturation. AQP0, 1, 2, 3, 4, 5, 6, 7, and 9 were expressed at gene and protein level in both nondegenerate and degenerate human NP tissue. AQP2 and 7 immunopositivity increased with degeneration in human NP tissue, whereas AQP4 expression decreased with degeneration in a similar way to AQP1 and 5 shown previously. All AQP proteins that were identified in human NP tissue were also expressed in canine NP tissue. AQP2, 5, 6, and 9 were found to localize to vacuole-like membranes and cell membranes in NC cells. In conclusion, AQPs were abundantly expressed in human and canine IVDs. The expression of many AQP isotypes potentially alludes to multifaceted functions related to adaption of NP cells to the conditions they encounter within their microenvironment in health and degeneration. The presence of AQPs within the IVD may suggest an adaptive role for these water channels during the development and maintenance of the healthy, mature IVD.
| S-EPMC6686802 | biostudies-literature
Project description:Cell-based therapy was a promising treatment method for disc degenerative diseases. Wharton's jelly cell (WJC) has been explored to cure various human diseases, while it still remains unknown about this MSC for disc repair. In our prior work, WJCs could differentiate into nucleus pulposus (NP)-like cells by co-culturing with NP cells in vitro. Thence, the aim of this study was further to investigate the survival and function of WJCs in vivo after transplantation into degenerated canine discs.WJCs were isolated from human umbilical cords and labeled with EGFP. The degeneration of L4-5, L5-6, and L6-7 discs of beagles was induced by aspirating the NP tissues. Four weeks after the operation, the injured discs were left to be no treatment at L4-5 (DS group), injected with 0.9 % saline at L5-6 (FS group), and transplanted with EGFP-labeled WJCs at L6-7 (TS group). In all animals, the intact disc L3-4 served as a control (CS group). The animals were followed up for 24 weeks after initial operation. Spine imaging was evaluated at 4, 8, 12, and 24 weeks, respectively. Histologic, biomechanics and gene expression analyses were performed at 24 weeks. Immunohistochemistry for aggrecan, types II collagen, SOX-9 was employed to investigate the matrix formation in the NP.The TS group showed a significantly smaller reduction in the disc height and T2-weighted signal intensity, and a better spinal segmental stability than DS and FS groups. Histologic assay demonstrated that WJCs were specifically detected in TS group at 24 weeks and the discs of TS group maintained a relatively well preserved structure as compared to the discs of DS and FS groups. Furthermore, real-time PCR and immunohistochemistry demonstrated that expressions of disc matrix genes, aggrecan, type II collagen, and SOX-9, were up-regulated in TS group compared to DS and FS groups.WJCs could not only survive in the degenerate IVDs, but also promote the disc matrix formation of aggrecan and type II collagen in the degenerate IVDs. It may have value in cell-based therapy for degenerative disc disease.
| S-EPMC4551525 | biostudies-literature