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Palackdkharry CS, Wottrich S, Dienes E, Bydon M, Steinmetz MP, Traynelis VC. The leptomeninges as a critical organ for normal CNS development and function: First patient and public involved systematic review of arachnoiditis (chronic meningitis). PLoS One 2022; 17:e0274634. [PMID: 36178925 PMCID: PMC9524710 DOI: 10.1371/journal.pone.0274634] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 08/31/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND & IMPORTANCE This patient and public-involved systematic review originally focused on arachnoiditis, a supposedly rare "iatrogenic chronic meningitis" causing permanent neurologic damage and intractable pain. We sought to prove disease existence, causation, symptoms, and inform future directions. After 63 terms for the same pathology were found, the study was renamed Diseases of the Leptomeninges (DLMs). We present results that nullify traditional clinical thinking about DLMs, answer study questions, and create a unified path forward. METHODS The prospective PRISMA protocol is published at Arcsology.org. We used four platforms, 10 sources, extraction software, and critical review with ≥2 researchers at each phase. All human sources to 12/6/2020 were eligible for qualitative synthesis utilizing R. Weekly updates since cutoff strengthen conclusions. RESULTS Included were 887/14286 sources containing 12721 DLMs patients. Pathology involves the subarachnoid space (SAS) and pia. DLMs occurred in all countries as a contributor to the top 10 causes of disability-adjusted life years lost, with communicable diseases (CDs) predominating. In the USA, the ratio of CDs to iatrogenic causes is 2.4:1, contradicting arachnoiditis literature. Spinal fusion surgery comprised 54.7% of the iatrogenic category, with rhBMP-2 resulting in 2.4x more DLMs than no use (p<0.0001). Spinal injections and neuraxial anesthesia procedures cause 1.1%, and 0.2% permanent DLMs, respectively. Syringomyelia, hydrocephalus, and arachnoid cysts are complications caused by blocked CSF flow. CNS neuron death occurs due to insufficient arterial supply from compromised vasculature and nerves traversing the SAS. Contrast MRI is currently the diagnostic test of choice. Lack of radiologist recognition is problematic. DISCUSSION & CONCLUSION DLMs are common. The LM clinically functions as an organ with critical CNS-sustaining roles involving the SAS-pia structure, enclosed cells, lymphatics, and biologic pathways. Cases involve all specialties. Causes are numerous, symptoms predictable, and outcomes dependent on time to treatment and extent of residual SAS damage. An international disease classification and possible treatment trials are proposed.
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Affiliation(s)
| | - Stephanie Wottrich
- Case Western Reserve School of Medicine, Cleveland, Ohio, United States of America
| | - Erin Dienes
- Arcsology®, Mead, Colorado, United States of America
| | - Mohamad Bydon
- Department of Neurologic Surgery, Orthopedic Surgery, and Health Services Research, Mayo Clinic School of Medicine, Rochester, Minnesota, United States of America
| | - Michael P. Steinmetz
- Department of Neurological Surgery, Cleveland Clinic Lerner College of Medicine Neurologic Institute, Cleveland, Ohio, United States of America
| | - Vincent C. Traynelis
- Department of Neurosurgery, Rush University School of Medicine, Chicago, Illinois, United States of America
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Yang L, Liu S, Wang Y. Role of bone morphogenetic protein-2/4 in astrocyte activation in neuropathic pain. Mol Pain 2019; 15:1744806919892100. [PMID: 31726923 PMCID: PMC6886276 DOI: 10.1177/1744806919892100] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background Bone morphogenetic protein-2/4 (BMP2/4) has been recognized as promoters of astrocyte activity. Substantial evidence suggests that BMP2/4 may be elevated and plays a critical role in astrocyte activation upon spinal cord injury. Although neuropathic pain is similarly associated with astrocyte activation, the participation of BMP2/4 in this regard still remains unclear. Methods A rat model of neuropathic pain achieved by spinal nerve ligation at L5 was used to evaluate the expression of glial fibrillary acidic protein and BMP2/4 in the spinal cord in days 1, 4, 7, 10, and 14. Next, normal rats received intrathecal exogenous BMP2/4 and the antagonist Noggin to assess the effect of BMP2/4 on astrocyte activation. In both experiments, von Frey filaments were used to evaluate the changes in paw withdrawal threshold. In addition, Western blotting and immunofluorescence were performed to assess the expression of glial fibrillary acidic protein, BMP2/4, p-Smad 1/5/8, and phospho-signal transducer and activator of transcription-3 (p-STAT3) in the spinal cord. Results Firstly, spinal nerve ligation caused a significant increase in the expression of BMP4, while BMP2 levels remained unchanged. Secondly, exogenous BMP4 but not BMP2 induced a significant decrease in paw withdrawal threshold, along with the upregulation of glial fibrillary acidic protein. Moreover, exogenous BMP4 stimulated both p-Smad 1/5/8 and p-STAT3, while BMP2 only upregulated p-Smad 1/5/8. Finally, exogenous Noggin alleviated the decrease in paw withdrawal threshold induced by BMP4 and reduced astrocyte activation, as well as p-STAT3 upregulation. Conclusions Our results indicate only BMP4—and not BMP2—intervened in allodynia in rats by eliciting glial activation probably through both p-Smad 1/5/8 and p-STAT3 signaling.
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Affiliation(s)
- Lin Yang
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Province Center for Clinical Anesthesia and Anesthesiology, Research Institute of Central South University, Changsha, China
| | - Shuxin Liu
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Province Center for Clinical Anesthesia and Anesthesiology, Research Institute of Central South University, Changsha, China
| | - Yaping Wang
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Province Center for Clinical Anesthesia and Anesthesiology, Research Institute of Central South University, Changsha, China
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Abstract
STUDY DESIGN We developed a spinal nerve root wrapping rodent model to evaluate the relationship between recombinant human bone morphogenetic protein 2 (rhBMP-2) dosage and the degree of inflammation. OBJECTIVE To investigate the direct effects of recombinant human bone morphogenetic protein 2 (rhBMP-2) dosage and the degree of inflammation in rodent spinal nerve roots. SUMMARY OF BACKGROUND DATA rhBMP-2 is commonly used in clinical practice to augment spinal fusion. However, complications such as postoperative leg pain, and a higher rate of postoperative neurologic deficits have been reported. These may be attributable to the exposure of adjacent nerve roots to high doses of rhBMP-2. METHODS Eighteen rats were randomized into three groups as follows: Group 1: absorbable collagen sponge (ACS) + 10 μg rhBMP-2, Group 2: ACS + 1 μg rhBMP-2, and Group 3 ACS with 20 μL saline. The ACS containing rhBMP-2 or saline were then wrapped around the L5 nerve root and secured loosely with nonabsorbable sutures. At 1-week postoperation, the rats were sacrificed, and the L5 nerve root and dorsal root ganglion harvested for reverse transcription polymerase chain reaction (RT-PCR), histology and immunohistochemical staining. RESULTS In our study, 10 μg rhBMP-2 induced a 10-fold increase in seroma compared with 1 μg group. Using RT-PCR, macrophage markers MIP3-α, and CD-68 were upregulated by 8- and 2-fold respectively in comparison with the saline group. Haematoxylin and eosin (H&E) images demonstrated disruption of nerve structures in the high dose 10 μg rhBMP-2, but not at 1 μg rhBMP-2 and with saline. CONCLUSION High doses of rhBMP-2 induced neuroinflammation in a dose dependent manner, resulting in higher seroma volume, macrophage marker gene expressions, and higher proportions of immunohistochemically stained TNF-alpha and more macrophage infiltration. LEVEL OF EVIDENCE 2.
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Lykissas M, Gkiatas I. Use of recombinant human bone morphogenetic protein-2 in spine surgery. World J Orthop 2017; 8:531-535. [PMID: 28808623 PMCID: PMC5534401 DOI: 10.5312/wjo.v8.i7.531] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 02/05/2017] [Accepted: 04/20/2017] [Indexed: 02/06/2023] Open
Abstract
Bone morphogenetic proteins are osteoinductive factors which have gained popularity in orthopaedic surgery and especially in spine surgery. The use of recombinant human bone morphogenetic protein-2 has been officially approved by the United States Food and Drug Administration only for single level anterior lumbar interbody fusion, nevertheless it is widely used by many surgeons with off-label indications. Despite advantages in bone formation, its use still remains a controversial issue and several complications have been described by authors who oppose their wide use.
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Mitchell K, Shah JP, Dalgard CL, Tsytsikova LV, Tipton AC, Dmitriev AE, Symes AJ. Bone morphogenetic protein-2-mediated pain and inflammation in a rat model of posterolateral arthrodesis. BMC Neurosci 2016; 17:80. [PMID: 27905881 PMCID: PMC5134101 DOI: 10.1186/s12868-016-0314-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 11/24/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Bone morphogenetic protein-2 (BMP-2) is a pleiotropic, secreted molecule with diverse effects. The potent ability of BMP-2 to stimulate bone growth prompted its widespread clinical use for arthrodesis (spine fusion). However, elevated post-operative pain in patients treated with BMP-2 has been increasingly reported. Determining whether BMP-2 induces pain directly or whether it induces neuroinflammation, which could lower the threshold for pain, is important for developing therapeutic interventions. We therefore modeled the clinical use of BMP-2 for posterior lumbar fusion by implanting absorbable collagen sponges soaked with either recombinant human BMP-2 (rhBMP-2) or vehicle above the L4-L5 transverse processes of rat spine. RESULTS Using microarray analysis we found that implantation of rhBMP-2-soaked absorbable collagen sponges resulted in altered expression of numerous pro-inflammatory genes in the adjacent dorsal root ganglia (DRG) showing that implantation of rhBMP-2/absorbable collagen sponges triggers potent neuroinflammatory responses in the DRG-2. Interestingly, direct BMP-2 treatment of DRG explants resulted in changes in gene expression that were not specifically pro-inflammatory. Rats implanted with rhBMP-2 in absorbable collagen sponges also exhibited a transient change in thermal and mechanical sensitivity indicating that rhBMP-2 applied to the lumbar spine could increase pain sensitivity. Immunohistochemical analysis indicated macrophage infiltration in the DRG and spinal nerve in rats implanted with rhBMP-2/absorbable collagen sponges or absorbable collagen sponges alone, but not in rats that underwent surgery without implantation of the absorbable collagen sponges suggesting that the sponges contributed to the biological response. Indeed, analysis of DRGs taken from rats implanted with absorbable collagen sponges without rhBMP-2 showed a significant change in gene expression distinct from DRGs from rats undergoing surgery only. CONCLUSIONS Our data indicate that implantation of rhBMP-2/absorbable collagen sponges on the lumbar spine triggers potent neuroinflammatory responses in the DRG. Importantly, however, these BMP-2 effects may be partially mediated through a response to the absorbable collagen sponges.
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Affiliation(s)
- Kendall Mitchell
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA
| | - Jill P Shah
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA
| | - Clifton L Dalgard
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, MD, USA
| | - Lyubov V Tsytsikova
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA
| | - Ashley C Tipton
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA
| | - Anton E Dmitriev
- Department of Surgery, Uniformed Services University, Bethesda, MD, USA.,Department of Orthopaedic Surgery, Walter Reed National Military Medical Center, Bethesda, MD, 20814, USA.,Division of Applied Mechanics, CDRH/OSEL, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
| | - Aviva J Symes
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
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Ishida W, Elder BD, Holmes C, Lo SFL, Witham TF. Variables Affecting Fusion Rates in the Rat Posterolateral Spinal Fusion Model with Autogenic/Allogenic Bone Grafts: A Meta-analysis. Ann Biomed Eng 2016; 44:3186-3201. [PMID: 27473706 DOI: 10.1007/s10439-016-1701-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 07/21/2016] [Indexed: 01/14/2023]
Abstract
The rat posterolateral spinal fusion model with autogenic/allogenic bone graft (rat PFABG) has been increasingly utilized as an experimental model to assess the efficacy of novel fusion treatments. The objective of this study was to investigate the reliability of the rat PFABG model and examine the effects of different variables on spinal fusion. A web-based literature search from January, 1970 to September, 2015, yielded 26 studies, which included 40 rat PFABG control groups and 449 rats. Data regarding age, weight, sex, and strain of rats, graft volume, graft type, decorticated levels, surgical approach, institution, the number of control rats, fusion rate, methods of fusion assessment, and timing of fusion assessment were collected and analyzed. The primary outcome variable of interest was fusion rate, as evaluated by manual palpation. Fusion rates varied widely, from 0 to 96%. The calculated overall fusion rate was 46.1% with an I 2 value of 62.4, which indicated moderate heterogeneity. Weight >300 g, age >14 weeks, male rat, Sprague-Dawley strain, and autogenic coccyx grafts increased fusion rates with statistical significance. Additionally, an assessment time-point ≥8 weeks had a trend towards statistical significance (p = 0.070). Multi-regression analysis demonstrated that timing of assessment and age as continuous variables, as well as sex as a categorical variable, can predict the fusion rate with R 2 = 0.82. In an inter-institution reliability analysis, the pooled overall fusion rate was 50.0% [44.8, 55.3%], with statistically significant differences among fusion outcomes at different institutions (p < 0.001 and I 2 of 72.2). Due to the heterogeneity of fusion outcomes, the reliability of the rat PFABG model was relatively limited. However, selection of adequate variables can optimize its use as a control group in studies evaluating the efficacy of novel fusion therapies.
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Affiliation(s)
- Wataru Ishida
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
| | - Benjamin D Elder
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA.
| | - Christina Holmes
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
| | - Sheng-Fu L Lo
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
| | - Timothy F Witham
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
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Tian H, Li CS, Scott TP, Montgomery SR, Phan K, Lao L, Zhang W, Li Y, Hayashi T, Takahashi S, Alobaidaan R, Ruangchainikom M, Zhao KW, Brochmann EJ, Murray SS, Wang JC, Daubs MD. Secreted phosphoprotein 24 kD inhibits nerve root inflammation induced by bone morphogenetic protein-2. Spine J 2015; 15:314-21. [PMID: 25264179 DOI: 10.1016/j.spinee.2014.09.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 08/10/2014] [Accepted: 09/17/2014] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Bone morphogenetic protein-2 (BMP-2) has been used to successfully promote spine fusion, but side-effects including nerve inflammation have been observed. PURPOSE To investigate the direct neurotoxic effects of BMP-2 and test the hypotheses that the use of BMP binding proteins, such as secreted phosphoprotein 24 kD (Spp24), can reduce or eliminate these effects. STUDY DESIGN In vitro experiments and in vivo analysis in a rodent model. METHODS In vitro, dorsal root ganglion cells were cultured in the presence of BMP-2 with and without Spp24 and calcitonin gene-related peptide and Substance P, markers of neuroinflammation, were measured by immunohistochemistry. In vivo, rats underwent a left-sided laminotomy at L5 to expose the S1 nerve root and were randomized into four different groups according to the intervention at the laminotomy site: collagen sponge only (no BMP-2 or Spp24), BMP-2 in a collagen sponge only, BMP-2 in a collagen sponge+an empty collagen sponge to act as a barrier, and BMP-2 in a collagen sponge+Spp24 in a collagen sponge to act as a barrier. Functional evaluation was done using the Basso, Beattie, and Bresnahan scale and immunohistochemical analyses were performed using calcitonin gene-related peptide and Substance P staining. RESULTS The neuroinflammatory effects of BMP-2 in vitro were ameliorated by the addition of Spp24. Similarly, in vivo, Spp24 reduced the expression of markers on neuroinflammation in animals treated with BMP-2 and also improved the function after BMP-2 administration. CONCLUSIONS These results confirm that BMP binding proteins have great potential as adjuvant therapies to limit BMP-2 related side-effects in spine surgery.
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Affiliation(s)
- Haijun Tian
- Department of Orthopaedic Surgery, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Rd., Shanghai, 200003, P.R. China; Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA.
| | - Chen-Shuang Li
- Department of Orthodontics, Peking University School and Hospital of Stomatology, 22 South Zhongguancun St., Beijing 100081, P.R. China
| | - Trevor P Scott
- Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Scott R Montgomery
- Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Kevin Phan
- Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Lifeng Lao
- Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Wei Zhang
- Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Yawei Li
- Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Tetsuo Hayashi
- Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Shinji Takahashi
- Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Raed Alobaidaan
- Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Monchai Ruangchainikom
- Department of Orthopaedic Surgery, University of California, 675 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Ke-Wei Zhao
- Research Service, VA Greater Los Angeles Healthcare System, 16111 Plummer St., North Hills, CA 91343, USA
| | - Elsa J Brochmann
- Research Service, VA Greater Los Angeles Healthcare System, 16111 Plummer St., North Hills, CA 91343, USA; Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, 16111 Plummer St., North Hills, CA 91343, USA; Department of Medicine, University of California, 650 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Samuel S Murray
- Research Service, VA Greater Los Angeles Healthcare System, 16111 Plummer St., North Hills, CA 91343, USA; Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, 16111 Plummer St., North Hills, CA 91343, USA; Department of Medicine, University of California, 650 Charles E. Young Dr. S., Los Angeles, CA 90024, USA
| | - Jeffrey C Wang
- Department of Orthopaedic Surgery, Keck School of Medicine of USC, 1520 San Pablo, HCT Suite 2000, Los Angeles, CA 90033, USA
| | - Michael D Daubs
- Division of Orthopaedic Surgery, Department of Surgery, University of Nevada School of Medicine, 2040 W Charleston Blvd, Suite 601, Las Vegas, NV 89102, USA
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Wilson CG, Martín-Saavedra FM, Padilla F, Fabiilli ML, Zhang M, Baez AM, Bonkowski CJ, Kripfgans OD, Voellmy R, Vilaboa N, Fowlkes JB, Franceschi RT. Patterning expression of regenerative growth factors using high intensity focused ultrasound. Tissue Eng Part C Methods 2014; 20:769-79. [PMID: 24460731 DOI: 10.1089/ten.tec.2013.0518] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Temporal and spatial control of growth factor gradients is critical for tissue patterning and differentiation. Reinitiation of this developmental program is also required for regeneration of tissues during wound healing and tissue regeneration. Devising methods for reconstituting growth factor gradients remains a central challenge in regenerative medicine. In the current study we develop a novel gene therapy approach for temporal and spatial control of two important growth factors in bone regeneration, vascular endothelial growth factor, and bone morphogenetic protein 2, which involves application of high intensity focused ultrasound to cells engineered with a heat-activated- and ligand-inducible gene switch. Induction of transgene expression was tightly localized within cell-scaffold constructs to subvolumes of ∼30 mm³, and the amplitude and projected area of transgene expression was tuned by the intensity and duration of ultrasound exposure. Conditions for ultrasound-activated transgene expression resulted in minimal cytotoxicity and scaffold damage. Localized regions of growth factor expression also established gradients in signaling activity, suggesting that patterns of growth factor expression generated by this method will have utility in basic and applied studies on tissue development and regeneration.
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Affiliation(s)
- Christopher G Wilson
- 1 Department of Periodontics and Oral Medicine, Center for Craniofacial Regeneration, University of Michigan School of Dentistry , Ann Arbor, Michigan
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Lykissas MG, Aichmair A, Sama AA, Hughes AP, Lebl DR, Cammisa FP, Girardi FP. Nerve injury and recovery after lateral lumbar interbody fusion with and without bone morphogenetic protein-2 augmentation: a cohort-controlled study. Spine J 2014; 14:217-24. [PMID: 24269858 DOI: 10.1016/j.spinee.2013.06.109] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Accepted: 06/29/2013] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Despite common use of intraoperative electrophysiologic neuromonitoring, injuries to the lumbar plexus during lateral lumbar interbody fusion (LLIF) have been reported. Emerging data suggest that recombinant human bone morphogenetic protein-2 (rhBMP-2) use during an anterior or transforaminal lumbar interbody fusion may be associated with an increased risk of neurological deficit. Clinical data on the sequelae of rhBMP-2 implantation in close proximity to the lumbosacral plexus during LLIF remains to be understood. PURPOSE The purpose of this study was to compare the incidence of neurologic deficits and pain in patients undergoing LLIF with and without rhBMP-2. STUDY DESIGN/SETTING Retrospective outcome analysis in controlled cohorts undergoing the lateral exposure technique for LLIF with and without rhBMP-2. METHODS The electronic medical records of patients undergoing LLIF with and without supplemental posterior fusion for degenerative spinal conditions were retrospectively reviewed over a 6-year period. Patients with previous lumbar spine surgery or follow-up of less than 6 months were excluded. Patients were divided into 2 groups, Group 1 (rhBMP-2 use; n=72) and Group 2 (autograft/allograft use; n=72), and were matched according to the age at the time of surgery, gender, weight, body mass index, side of approach, total number of treated spinal segments, use of supplemental posterior fusion, and length of follow-up. RESULTS Immediately after surgery, a sensory deficit was recorded in 33 patients in Group 1 and 35 patients in Group 2 (odds ratio [OR] 0.895; 90% confidence interval [CI] 0.516-1.550; p=.739). At last follow-up, a persistent sensory deficit was identified in 29 patients whose LLIF procedure was supplemented by rhBMP-2 and 20 patients in whom autograft/allograft was used (OR 1.754; 90% CI 0.976-3.151; p=.115). A motor deficit was recorded in 37 patients immediately after the rhBMP-2 procedure and 28 patients treated with autograft/allograft (OR 1.661; 90% CI 0.953-2.895; p=.133). A persistent motor deficit was recorded in 35 and 17 patients in Groups 1 and 2, respectively, at last follow-up (OR 3.060; 90% CI 1.681-5.571; p=.002). During the first postoperative examination, 37 patients in Group 1 and 25 patients in Group 2 complained of anterior thigh or groin pain (OR 1.987; 90% CI 1.133-3.488; p=.045). At last follow-up, there was a significantly higher number of patients in Group 1 who complained of persistent anterior thigh or groin pain than Group 2 (8 vs. 0 patients) (OR 16.470; 90% CI 1.477-183.700; p=.006). CONCLUSIONS Our results provide evidence of an increased rate of postoperative neurologic deficit and anterior thigh/groin pain after LLIF using rhBMP-2, when compared with matched controls without rhBMP-2 exposure. This study suggests a potential direct deleterious effect of rhBMP-2 on the lumbosacral plexus.
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Affiliation(s)
- Marios G Lykissas
- Department of Orthopedic Surgery, Spine and Scoliosis Service, Hospital for Special Surgery, Weill Cornell Medical College, 535 E. 70th St, New York, NY 10021, USA.
| | - Alexander Aichmair
- Department of Orthopedic Surgery, Spine and Scoliosis Service, Hospital for Special Surgery, Weill Cornell Medical College, 535 E. 70th St, New York, NY 10021, USA
| | - Andrew A Sama
- Department of Orthopedic Surgery, Spine and Scoliosis Service, Hospital for Special Surgery, Weill Cornell Medical College, 535 E. 70th St, New York, NY 10021, USA
| | - Alexander P Hughes
- Department of Orthopedic Surgery, Spine and Scoliosis Service, Hospital for Special Surgery, Weill Cornell Medical College, 535 E. 70th St, New York, NY 10021, USA
| | - Darren R Lebl
- Department of Orthopedic Surgery, Spine and Scoliosis Service, Hospital for Special Surgery, Weill Cornell Medical College, 535 E. 70th St, New York, NY 10021, USA
| | - Frank P Cammisa
- Department of Orthopedic Surgery, Spine and Scoliosis Service, Hospital for Special Surgery, Weill Cornell Medical College, 535 E. 70th St, New York, NY 10021, USA
| | - Federico P Girardi
- Department of Orthopedic Surgery, Spine and Scoliosis Service, Hospital for Special Surgery, Weill Cornell Medical College, 535 E. 70th St, New York, NY 10021, USA
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Mitchell K, Shah JP, Tsytsikova LV, Campbell AM, Affram K, Symes AJ. LPS antagonism of TGF-β signaling results in prolonged survival and activation of rat primary microglia. J Neurochem 2013; 129:155-68. [DOI: 10.1111/jnc.12612] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 10/18/2013] [Accepted: 11/18/2013] [Indexed: 01/08/2023]
Affiliation(s)
- Kendall Mitchell
- Department of Pharmacology; Uniformed Services University of the Health Sciences; Bethesda Maryland USA
| | - Jill P. Shah
- Department of Pharmacology; Uniformed Services University of the Health Sciences; Bethesda Maryland USA
| | - Lyubov V. Tsytsikova
- Department of Pharmacology; Uniformed Services University of the Health Sciences; Bethesda Maryland USA
| | - Ashley M. Campbell
- Department of Pharmacology; Uniformed Services University of the Health Sciences; Bethesda Maryland USA
| | - Kwame Affram
- Department of Pharmacology; Uniformed Services University of the Health Sciences; Bethesda Maryland USA
- Program in Neuroscience; Uniformed Services University of the Health Sciences; Bethesda Maryland USA
| | - Aviva J. Symes
- Department of Pharmacology; Uniformed Services University of the Health Sciences; Bethesda Maryland USA
- Program in Neuroscience; Uniformed Services University of the Health Sciences; Bethesda Maryland USA
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11
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Rangasamy SB. Locomotor recovery after spinal cord hemisection/contusion injures in bonnet monkeys: footprint testing--a minireview. Synapse 2013; 67:427-53. [PMID: 23401170 DOI: 10.1002/syn.21645] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 02/01/2013] [Indexed: 12/12/2022]
Abstract
Spinal cord injuries usually produce loss or impairment of sensory, motor and reflex function below the level of damage. In the absence of functional regeneration or manipulations that promote regeneration, spontaneous improvements in motor functions occur due to the activation of multiple compensatory mechanisms in animals and humans following the partial spinal cord injury. Many studies were performed on quantitative evaluation of locomotor recovery after induced spinal cord injury in animals using behavioral tests and scoring techniques. Although few studies on rodents have led to clinical trials, it would appear imperative to use nonhuman primates such as macaque monkeys in order to relate the research outcomes to recovery of functions in humans. In this review, we will discuss some of our research evidences concerning the degree of spontaneous recovery in bipedal locomotor functions of bonnet monkeys that underwent spinal cord hemisection/contusion lesions. To our knowledge, this is the first report to discuss on the extent of spontaneous recovery in bipedal locomotion of macaque monkeys through the application of footprint analyzing technique. In addition, the results obtained were compared with the published data on recovery of quadrupedal locomotion of spinally injured rodents. We propose that the mechanisms underlying spontaneous recovery of functions in spinal cord lesioned monkeys may be correlated to the mature function of spinal pattern generator for locomotion under the impact of residual descending and afferent connections. Moreover, based on analysis of motor functions observed in locomotion in these subjected monkeys, we understand that spinal automatism and development of responses by afferent stimuli from outside the cord could possibly contribute to recovery of paralyzed hindlimbs. This report also emphasizes the functional contribution of progressive strengthening of undamaged nerve fibers through a collateral sprouts/synaptic plasticity formed in partially lesioned cord of monkeys.
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Affiliation(s)
- Suresh Babu Rangasamy
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, 60612, USA.
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