Heparin-Based Hydrogel Micropatches with Human Adipose-Derived Stem Cells: A Promising Therapeutic Approach for Neuropathic Pain Relief.

This study explores the therapeutic efficacy of heparin-based hydrogel micropatches containing human adipose-derived stem cells (hASCs) in treating neuropathic pain caused by nerve damage. Our results showed that hASCs exhibited neuroregenerative and pain-relieving effects when used with heparin-based hydrogel micropatches in the neuropathic pain animal model. The use of this combination also produced enhanced cell viability and nerve regeneration. We conducted various neurological behavioral tests, dynamic plantar tests, histological examinations, and neuroelectrophysiological examinations to confirm the therapeutic effect. Our findings suggest that this approach could maximize therapeutic efficacy and improve the quality of life for patients suffering from neuropathic pain.

Finite element analysis of a ball-and-socket artificial disc design to suppress excessive loading on facet joints: A comparative study with ProDisc.

Facet arthrosis at surgical level was identified as major complication after total disc replacement (TDR). One of the reasons for facet arthrosis after TDR has been speculated to be the hypermobility of artificial discs. Accordingly, the artificial disc that can constrain the hypermobility of ball-and-socket type artificial discs and reduce loading on facet joints is demanded. The proposed artificial disc, which is named as NewPro, was constructed based on the FDA-approved ProDisc but contained an interlocking system consisting of additional bars and grooves to control the range of motion (ROM) of lumbar spine in all anatomical planes. The three-dimensional finite element model of L1 to L5 was developed first, and the biomechanical effects were compared between ProDisc and NewPro. The ROM and facet contact force of NewPro were significantly decreased by 42.7% and 14% in bending and by 45.6% and 34.4% in torsion, respectively, compared with the values of ProDisc, thanks to the interlocking system. In addition, the ROM and facet contact force could be selectively constrained by modifying the location of the bars. The proposed artificial disc with the interlocking system was able to constrain the intersegmental rotation effectively and reduce excessive loading on facet joints, although wear and strength tests would be needed prior to clinical applications.

Biomechanical Effects of the Geometry of Ball-and-Socket Artificial Disc on Lumbar Spine: A Finite Element Study.

STUDY DESIGN: A three-dimensional finite element model of intact lumbar spine was constructed and four surgical finite element models implanted with ball-and-socket artificial discs with four different radii of curvature were compared. OBJECTIVE: To investigate biomechanical effects of the curvature of ball-and-socket artificial disc using finite element analysis. SUMMARY OF BACKGROUND DATA: Total disc replacement (TDR) has been accepted as an alternative treatment because of its advantages over spinal fusion methods in degenerative disc disease. However, the influence of the curvature of artificial ball-and-socket discs has not been fully understood. METHODS: Four surgical finite element models with different radii of curvature of ball-and-socket artificial discs were constructed. RESULTS: The range of motion (ROM) increased with decreasing radius of curvature in extension, flexion, and lateral bending, whereas it increased with increasing radius of curvature in axial torsion. The facet contact force was minimum with the largest radius of curvature in extension, flexion, and lateral bending, whereas it was maximum with the largest radius in axial torsion. It was also affected by the disc placement, more with posterior placement than anterior placement. The stress in L4 cancellous bone increased when the radius of curvature was too large or small. CONCLUSION: The geometry of ball-and-socket artificial disc significantly affects the ROM, facet contact force, and stress in the cancellous bone at the surgical level. The implication is that in performing TDR, the ball-and-socket design may not be ideal, as ROM and facet contact force are sensitive to the disc design, which may be exaggerated by the individual difference of anatomical geometry. LEVEL OF EVIDENCE: N/A.

Biomechanical Comparison of Spinal Fusion Methods Using Interspinous Process Compressor and Pedicle Screw Fixation System Based on Finite Element Method.

OBJECTIVE: To investigate the biomechanical effects of a newly proposed Interspinous Process Compressor (IPC) and compare with pedicle screw fixation at surgical and adjacent levels of lumbar spine. METHODS: A three dimensional finite element model of intact lumbar spine was constructed and two spinal fusion models using pedicle screw fixation system and a new type of interspinous devices, IPC, were developed. The biomechanical effects such as range of motion (ROM) and facet contact force were analyzed at surgical level (L3/4) and adjacent levels (L2/3, L4/5). In addition, the stress in adjacent intervertebral discs (D2, D4) was investigated. RESULTS: The entire results show biomechanical parameters such as ROM, facet contact force, and stress in adjacent intervertebral discs were similar between PLIF and IPC models in all motions based on the assumption that the implants were perfectly fused with the spine. CONCLUSION: The newly proposed fusion device, IPC, had similar fusion effect at surgical level, and biomechanical effects at adjacent levels were also similar with those of pedicle screw fixation system. However, for clinical applications, real fusion effect between spinous process and hooks, duration of fusion, and influence on spinous process need to be investigated through clinical study.

Early neuroprotective effect with lack of long-term cell replacement effect on experimental stroke after intra-arterial transplantation of adipose-derived mesenchymal stromal cells.

BACKGROUND AIMS: Adipose-derived mesenchymal stromal cells (AD-MSCs) have high proliferative capacity and ability to secrete trophic factors. Although intra-arterial (IA) transplantation of stem cells induces efficient engraftment to the host brain, it is unclear whether engrafted cells exert their long-term therapeutic effects through a bystander mechanism or a cell replacement mechanism. METHODS: After induction of ischemia in rats by middle cerebral artery occlusion, we transplanted human AD-MSCs into their carotid arteries with the use of a micro-needle, and we then investigated the therapeutic effects during the early and late phases of ischemia by means of in vivo magnetic resonance imaging, functional and histological analyses. RESULTS: During the early phase of cerebral ischemia, IA transplantation of AD-MSCs attenuated inflammation and enhanced endogenous neurogenesis. Transplanted animals showed a marked improvement in functional tests during the early phase of cerebral ischemia that was less prominent but still significant during the late phase of cerebral ischemia. Although the transplanted cells effectively migrated to the infarct area, only a small number of engrafted cells survived at 8 weeks after transplantation and differentiated into neuronal, glial and endothelial cells. CONCLUSIONS: IA transplantation of human AD-MSCs provides an effective therapeutic modality in a rodent model of stroke, of which the main effects are mediated by a bystander mechanism at the early phase of ischemia.

Enhanced spinal fusion using a biodegradable porous mesh container in a rat posterolateral spinal fusion model.

BACKGROUND CONTEXT: Posterolateral fusion (PLF) with an autogenous iliac bone graft is the most common procedure for treating various lumbar spinal diseases. However, the limited success and associated morbidity from an iliac crest graft demands new biologically competent graft enhancers or substitutes. PURPOSE: To investigate the feasibility of tubular mesh container made of bioabsorbable sutures (poly-1,4-dioxane-2-one, PDO) for spinal fusion. STUDY DESIGN: Experimental animal study. METHODS: A biodegradable PDO tubular mesh container was used to contain small pieces of bone grafts. Twenty Sprague-Dawley male rats underwent PLF between L4 and L5 transverse processes with bilateral iliac grafts. Experimental animals were assigned into two different groups: autograft-only group (N=10) that underwent PLF with autograft-only or mesh container group (N=10) that underwent PLF with tubular mesh container filled with autogenous bone grafts. The rats were sacrificed at 8 weeks postoperatively, and the lumbar spines were removed. Spinal fusion was evaluated by manual palpation, microcomputed tomography, three-point bending test, and histological examination. RESULTS: Solid fusion was achieved in all cases of the mesh container group, whereas the autograft-only group showed 60% of solid fusion. New bone mass was higher and more solidly fused in the mesh container group than the autograft-only group (p<.01). Volume of fusion mass and density of bone were significantly higher in the mesh container group (p<.05). In all cases, inflammatory response was minimal. CONCLUSIONS: This study demonstrated that a tubular mesh container made of bioabsorbable suture is useful to hold small pieces of bone grafts and to enhance spinal fusion.

Predictive value of circulating interleukin-6 and heart-type fatty acid binding protein for three months clinical outcome in acute cerebral infarction: multiple blood markers profiling study.

INTRODUCTION: There is no single blood marker for predicting the prognosis in ischemic stroke. A combination of multiple blood markers may enhance the ability to predict long-term outcome following ischemic stroke. METHODS: Blood concentrations of neuronal markers (neuron-specific enolase, visinin-like protein 1, heart type fatty acid binding protein (hFABP) and neuroglobin), astroglial markers (S100B and glial fibrillary acidic protein), inflammatory markers (IL-6, TNF-α, and C-reactive protein), blood-brain barrier marker (matrix metalloproteinase 9), and haemostatic markers (D-dimer and PAI-1) were measured within 24 hours after stroke onset. The discrimination and reclassification for favorable and poor outcome were compared after adding individual or a combination of blood markers to the clinical model of stroke outcome. RESULTS: In multivariate analysis, natural log-transformed (log) IL-6 (odds ratio (OR): 1.75, 95% CI: 1.25 to 2.25, P=0.001) and loghFABP (OR: 3.23, 95% CI: 1.44 to 7.27, P=0.005) were independently associated with poor outcome. The addition of a single blood marker to the clinical model did not improve the discriminating ability of the clinical model of stroke outcome. However, the addition of the combination of logIL-6 and loghFABP to the clinical model showed improved discrimination (area under receiver operating characteristic (AUROC) curve: 0.939 versus 0.910, P=0.03) and reclassification performance (net reclassification improvement index: 0.18, P=0.005). CONCLUSIONS: A combination of circulating IL-6 and hFABP level has an additive clinical value for the prediction of stroke outcome.

Mass-producible nano-featured polystyrene surfaces for regulating the differentiation of human adipose-derived stem cells.

In this study, we report an efficient and cost-effective method of fabricating polystyrene (PS) nano-featured substrates containing nanopore (NPo) and nanopillar (NPi) arrays based on hot embossing using nickel nano-stamps. We investigate the behavior of adipose-derived stem cells (ASCs), including adhesion, morphology, proliferation and differentiation, on the replicated PS surfaces. Compared to a flat substrate, NPo- and NPi-featured substrates do not alter the morphology of stem cells. However, both NPo- and NPi-featured substrates induce different integrin expression and lower formation of focal adhesion complexes. In addition, ASCs on the NPo-featured substrate exhibit greater adipogenic differentiation, while the NPi-featured substrate induces higher osteogenic differentiation.

Alteration of immunologic responses on peripheral blood in the acute phase of ischemic stroke: blood genomic profiling study.

OBJECTIVE: Peripheral blood cells and inflammatory mediators have a detrimental effect on brain during cerebral ischemia. We investigated the immunologic changes on peripheral blood in the acute phase of ischemic stroke using RNA microarray. METHODS: mRNA microarray and real time-polymerase chain reaction (RT-PCR) for genes of interest in microarray data were analyzed in 12 stroke patients and 12 controls. Plasma matrix metalloproteinase-9 (MMP-9) concentrations were measured in 120 stroke patients and 82 controls. RESULTS: In microarray analysis, a total of 11 genes of interest showed different expression in patients with ischemic stroke. The three most highly expressed genes were C19orf59 (chromosome 19 open reading frame 59), MMP9 and IL18RAP (interleukin-18 receptor accessory protein), whereas gene with the lowest expression was GNLY (granulysin). The expression patterns of three selected genes (MMP9, IL18RAP and GNLY) were validated by RT-PCR. The plasma concentration of MMP-9 was significantly elevated in the stroke patients, and showed a weakly positive correlation with infarct volume. Gene set enrichment analysis (GSEA) showed that gene sets related to immunity and defense, signal transduction, transport and cell adhesion were significant in acute ischemic stroke. CONCLUSIONS: In the peripheral blood, numerous genes of inflammatory mediators, including MMP9, IL18RAP and GNLY, are altered in the acute phase of ischemic stroke. This stroke-specific gene expression profiling provides valuable information about the role of peripheral inflammation to the pathophysiological mechanism of ischemic stroke.

Increase of chondrogenic potentials in adipose-derived stromal cells by co-delivery of type I and type II TGFß receptors encoding bicistronic vector system.

Stem cell therapy has been developing rapidly as a potential cure for repairing or regenerating the functions of diseased organs and tissues. Adipose-derived stromal cells (ASCs) are an attractive cell source for stem cell therapy because they can be isolated easily from fat tissue in significant numbers and exhibit multiple differentiation potential under appropriate in vitro culture conditions. However, ASCs derived from individual donors can show wide variations in differentiation potential. In addition, the regulatory mechanisms underlying stem cell differentiation remain unclear. Transforming growth factor ß (TGFß) is a well-known ASC chondrogenic differentiation factor that stimulates ASC signaling pathways by activating transmembrane type I and type II receptors. We hypothesized that the chondrogenic differentiation potential of ASCs is dependent upon the expression of TGFß receptors and could be improved by the co-delivery of type I (TGFßRI) and type II (TGFßRII) TGFß receptors. To prove this, heterogeneity within the chondrogenic potential of ASCs isolated from 10 donors was examined and their susceptibility to TGFß during the process of chondrogenic differentiation investigated. In addition, the results showed that co-delivery of the TGFßRI and TGFßRII genes increased the expression of TGFß receptor signaling in ASCs with low chondrogenic potential, resulting in increased chondrogenic differentiation. Monitoring and delivering TGFßRI and TGFßRII may, therefore, be a powerful tool for predicting the differentiation potential of stem cells and for enhancing their differentiation capacity prior to stem cell transplantation.

Effect of nucleus pulposus cells having different phenotypes on chondrogenic differentiation of adipose-derived stromal cells in a coculture system using porous membranes.

In this study, adipose-derived stem cells (ASCs) were cocultured with nucleus pulposus (NP) cells using a porous membrane to investigate the effect of NP cell phenotype on ASC chondrogenic differentiation. Human NP cells were collected from 14 patients and classified into two groups (normal vs. degenerative) depending on the level of type II collagen, aggrecan (AGG), type I collagen, and bax gene expression. Human ASCs were then cocultured with each group of NP cells on porous membranes in the absence of chondrogenic supplements. After 2 weeks, real-time-polymerase chain reaction results showed that ASCs cocultured with normal NP cells had much higher type II collagen and AGG gene expression than ASCs cocultured with degenerative NP cells. The production of AGG was also observed only in the group cocultured with normal NP cells. Additionally, coculture of ASC pellets with normal NP cells promoted the production of AGG as compared to coculture of ASC monolayer with normal NP cells. These data demonstrate that a coculture system using porous membranes can induce ASC differentiation into NP cells without chondrogenic supplements. Further, the phenotype of cocultured NP cells significantly influences the extent of ASC differentiation.

Effect of various surgical modalities in recurrent or persistent trigeminal neuralgia.

BACKGROUND/AIMS: In recurrent or persistent idiopathic trigeminal neuralgia (TN) after initial operation, additional surgical procedures may be required. There are numerous articles reporting the outcomes of additional surgical treatment and it is unclear how best to treat patients with recurrent or persistent TN. We evaluated the subsequent therapeutic options for recurrent or persistent TN. METHODS: The study was a retrospective study. The authors reviewed 29 patients (15 female/14 male) who underwent retreatments for recurrent or persistent symptoms after an initial operation. RESULTS: The mean follow-up duration was 56.4 months (range 12-78.7) from final treatment. Patients underwent a mean of 2.3 retreatments with a mean period of 26 months (range 1-72) between treatments. Final treatments were as follows: microvascular decompression (MVD) in 12 patients, percutaneous rhizotomy in 10, and radiosurgery in 7. Of the 29 patients, after final treatments, 9 patients (31%) achieved excellent results and 15 (52%) good results. Failure results were seen in 17% of patients with recurrent TN. CONCLUSION: In this study the authors demonstrate that percutaneous rhizotomy is recommended for most patients with recurrent pain after MVD, and MVD can be effective in patients with a history of failed percutaneous procedures. Radiosurgery can be utilized to treat those that have not responded to other surgical modalities.

Clinical and radiological findings of discogenic low back pain confirmed by automated pressure-controlled discography.

OBJECTIVE: Few studies on the clinical spectrum of automated pressure-controlled discography (APCD)-defined positive discs have been reported to date. Thus, the present study was undertaken to analyze clinical parameters critical for diagnosis of discogenic pain and to correlate imaging findings with intradiscal pressures and pain responses in patients with APCD-positive discs. METHODS: Twenty-three patients who showed APCD-positive discs were selected for analysis. CT discogram findings and the degrees of nuclear degeneration seen on MRI were analyzed in comparison to changes of intradiscal pressure that provoked pain responses; and clinical pain patterns and dynamic factors were evaluated in relation to pain provocation. RESULTS: Low back pain (LBP), usually centralized, with diffuse leg pain was the most frequently reported pattern of pain in these patients. Overall, LBP was most commonly induced by sitting posture, however, standing was highly correlated with L5/S1 disc lesions (p < 0.01). MRI abnormalities were statistically correlated with grading of CT discogram results (p < 0.05); with most pain response observed in CT discogram Grades 3 and 4. Pain-provoking pressure was not statistically correlated with MRI grading. However, it was higher in Grade 3 than Grade 4. CONCLUSION: APCD-positive discs were demonstrated in patients reporting centralized low back pain with diffuse leg pain, aggravated by sitting and standing. MRI was helpful to assess the degree of nuclear degeneration, yet it could not guarantee exact localization of the painful discs. APCD was considered to be more useful than conventional discography for diagnosis of discogenic pain.

Clinical relevance of pain patterns in osteoporotic vertebral compression fractures.

Few studies have been conducted to explain the pain patterns resulting from osteoporotic vertebral compression fractures (OVCF). We analyzed pain patterns to elucidate the pain mechanism and to provide initial guide for the management of OVCFs. Sixty-four patients underwent percutaneous vertebroplasty (N=55) or kyphoplasty (N=9). Three pain patterns were formulized to classify pains due to OVCFs: midline paravertebral (Type A), diffuse paravertebral (Type B), and remote lumbosacral pains (Type C). The degree of compression was measured using scale of deformity index, kyphosis rate, and kyphosis angle. Numerical rating scores were serially measured to determine the postoperative outcomes. As vertebral body height (VBH) decreased, paravertebral pain became more enlarged and extended anteriorly (p<0.05). Type A and B patterns significantly showed the reverse relationship with deformity index (p<0.05), yet Type C pattern was not affected by deformity index. Postoperative pain severity was significantly improved (p<0.05), and patients with a limited pain distribution showed a more favorable outcome (p<0.05). The improvement was closely related with the restoration of VBH, but not with kyphosis rate or angle. Thus, pain pattern study is useful not only as a guide in decision making for the management of patients with OVCF, but also in predicting the treatment outcome.

Diagnostic relevance of pressure-controlled discography.

Discogenic pain is a leading cause of chronic low back pain. The authors investigated the efficacy of pressure-controlled discography to determine its role in clinical decision-making for the management of patients with discogenic pain. Pressure-controlled discography was performed in 21 patients (51 discs) with pain-provocation, followed by post-discography computerized tomography scans. Pain response was classified as positive response and negative response, and measured with visual analog scale scores. Discographic findings were graded by the modified Dallas discogram scale. Elastance, pain provocation on intradiscal pressure, pressure and volume of initial pain response, and pain response intensity were statistically analyzed. Elastance showed significant differences between Grade 0 and Grade 4 and 5. Decreased elastance with positive pain response group was a good indicator to imply that disc degeneration presumably is a pain generator. Results of pain response were well correlated with intradiscal pressure but not with the amount of injected volume. Among 31 discs of Grade 4 and 5, 74% showed negative pain response and 26% showed positive response. It was concluded that pressure-controlled discography was useful to diagnose discogenic pain and excellent guide in decision-making for spinal operations.

Radiofrequency neurotomy of cervical medial branches for chronic cervicobrachialgia.

Chronic neck and arm pain or cervicobrachialgia commonly occurs with the degeneration of cervical spine. Authors investigated the usefulness of radiofrequency (RF) neurotomies of cervical medial branches in patients with cervicobrachialgia and analyzed the factors which can influence the treatment outcome. Demographic data, types of pain distribution, responses of double controlled blocks, electrical stimulation parameters, numbers and levels of neurotomies, and surgical outcomes were evaluated after mean follow-up of 12 months. Pain distribution pattern was not significantly correlated with the results of diagnostic blocks. Average stimulation intensity was 0.45 V, ranging from 0.3 to 0.69, to elicit pain response in cervical medial branches. The most common involvement of nerve branches was C4 (89%), followed by C5 (82%), C6 (75%), and C7 (43%). Among total of 28 patients, nineteen (68%) reported successful outcome according to outcome criteria after 6 months of followup (p=0.001), and eight (42%) of 19 patients reported complete relief (100%) of pain. Four patients showed recurrence of pain between 6 and 12 months. It was therefore concluded that cervical medial branch neurotomy is considered useful therapeutic modality for the management of cervicobrachialgia in selected patients, particularly in degenerative zygapophyseal disorders.