transforming-growth-factor-beta and Hematoma

Recombinant human bone morphogenetic protein 2 (rhBMP-2) is a very potent osteogenic growth factor that has been used successfully in various spine fusions, obviating the need for autologous iliac crest bone graft harvest and therefore avoiding the associated morbidities.. In the past few years, a tremendous increase in rhBMP-2 usage was noted, and concerns regarding costs, benefits, and safety issues were raised by many. The goal of this work was to provide a comprehensive review of the adverse events and complications associated with use of rhBMP-2.. Literature review.. This is a review of the current literature on the reported adverse events, complications, and concerns associated with rhBMP-2 use.. This article discusses the wide spectrum of adverse outcomes related to rhBMP-2 use in the lumbar and the cervical spine; retrograde ejaculation, antibodies formation, postoperative radiculitis, postoperative nerve root injury, ectopic bone formation, vertebral osteolysis/edema, dysphagia and neck swelling, hematoma formation, interbody graft lucency, and wound healing complications are reviewed. Cost-related concerns, dosage considerations, carrier types, and theoretical carcinogenesis concerns were also presented.. Despite the excellent spinal fusion rates promoted by this powerful molecule, the increasingly reported adverse outcomes associated with bone morphogenetic protein usage have created real concerns. This article will provide the reader with a good understanding of the reported complications associated with rhBMP-2 use and ultimately help recognize its safety spectrum and limits for better clinical application.

Topics: Bone Morphogenetic Protein 2; Cervical Vertebrae; Dose-Response Relationship, Drug; Hematoma; Humans; Lumbar Vertebrae; Ossification, Heterotopic; Radiculopathy; Recombinant Proteins; Risk Factors; Spinal Fusion; Transforming Growth Factor beta

Intracerebral hemorrhage (ICH) is a severe neurological condition with high mortality and morbidity. Microglia activation and peripheral inflammatory cells infiltration play an important role in ICH prognosis. Previous studies demonstrated that regulatory T cells (Tregs) ameliorated neuroinflammation following experimental ICH. However, the molecular mechanism underlying such effects of Tregs remains unclear. The objective was to examine how Tregs recruitment induced by recombinant CC chemokine ligand 17 (rCCL17) influences microglia/macrophage polarization in an intrastriatal autologous blood injection ICH animal model, and to determine if TGFβ/TGFβ-R/Smad2/3 pathway was involved.. 380 adult CD1 mice (male, eight weeks old) were subjected to sham surgery or autologous blood injection induced ICH. A CD25-specific mouse antibody or isotype control mAb was injected intraventricular (i.c.v) 48 h prior to ICH induction to deplete Tregs. rCCL17, a CC chemokine receptor 4 (CCR4) ligand, was delivered intranasally at 1 h post-ICH. SB431542, a specific inhibitor of TGF-β was administered intraperitoneally 1 h before ICH induction. Following the ICH, neurobehavioral testing, brain edema, hematoma volume, hemoglobin content, western blotting, double immunofluorescence labeling, and immunohistochemistry were performed.. Endogenous expressions of CCL17, Tregs marker Foxp3, and the number of Tregs in perihematomal region increased following ICH. Tregs depletion with a CD25 antibody aggravated neurological deficits and brain edema, increased inflammatory cytokines, neutrophil infiltration, oxidative stress, and reduced the rate of hematoma resolution in ICH mice. rCCL17 treatment increased the number of Tregs in the brain, ameliorated neurological deficits and brain edema after ICH, and promoted microglia/macrophage polarization toward M2 phenotype which was reversed with CD25 antibody. Moreover, rCCL17 increased the expressions of brain TGF-β/phosphorylated-Smad2/3 which was abrogated with the selective TGFβ inhibitor SB431542.. rCCL17-mediated Tregs recruitment may be a potential therapeutic strategy to promote M2 microglia/macrophages polarization and alleviate early brain injury following ICH.

Topics: Animals; Brain Edema; Cerebral Hemorrhage; Chemokines, CC; Disease Models, Animal; Hematoma; Immunologic Factors; Ligands; Macrophages; Male; Mice; Microglia; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Topics: Contrast Media; Diagnosis, Differential; Hematoma; Humans; Laminectomy; Ligamentum Flavum; Magnetic Resonance Imaging; Male; Middle Aged; Signal Transduction; Tomography, X-Ray Computed; Transforming Growth Factor beta

In vivo and in vitro model.. Investigate soft-tissue inflammation caused by rhBMP-2.. Although rhBMP-2 produces excellent rates of fusion in the spine, dysphagia and respiratory compromise have occurred when used in the neck. The mechanism of the swelling and inflammatory response has yet to be fully elucidated.. ELISA kits (IL-6, IL-10, TNF-α) were used to measure cytokine levels at different concentrations of rhBMP-2. Absorbable collagen sponges were implanted with or without different concentrations of rhBMP-2 into the backs of rats subcutaneously (SC) and intramuscularly (IM). Magnetic resonance imaging was used to measure inflammation at 3 hours and 2, 4, and 7 days. The inflammatory volumes were measured and compared using MIPAV software. Rats were killed after 7 days and studied.. IL-6, IL-10, and TNF-α release was dose-dependent. Soft-tissue edema after rhBMP-2 implantation was also dose-dependent, peaking at 3 hours SC, after SC and IM implantations, and on day 2 IM after IM implantation. All formed a granuloma-type mass after SC insertion. The mass was much larger in the 10 and 20 μg/10 μL (high-concentration) groups. The inflammatory response did not diffuse across physiologic barriers (subcutaneous fascia). Both high-dose groups were associated with encapsulated hematomas and a significant increase in the inflammatory zone.. Swelling and inflammation after rhBMP-2 use are dose-dependent. Swelling may be due to direct contact as well as spread in the plane of access. The causes are a robust inflammatory reaction as well as sterile seroma and encapsulated hematoma formation.

Topics: Animals; Bone Morphogenetic Protein 2; Disease Models, Animal; Dose-Response Relationship, Drug; Hematoma; Inflammation; Neck; Rats; Rats, Inbred Lew; Recombinant Proteins; Rodentia; Seroma; Transforming Growth Factor beta

Topics: Adult; Aged; Aged, 80 and over; Benzophenones; Biocompatible Materials; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Plates; Cervical Vertebrae; Collagen Type I; Deglutition Disorders; Diskectomy; Drug Carriers; Female; Hematoma; Humans; Ketones; Male; Middle Aged; Orthopedic Fixation Devices; Polyethylene Glycols; Polymers; Postoperative Complications; Range of Motion, Articular; Recombinant Proteins; Safety; Seroma; Spinal Fusion; Titanium; Tomography, X-Ray Computed; Transforming Growth Factor beta; Treatment Outcome

Spinal fusion is a proven surgical tool for the treatment of degenerative, traumatic, neoplastic, and infectious conditions of the spine. Traditional grafting techniques using autogenous bone graft or allograft have inherent drawbacks including varying pseudoarthrosis rates and well recognized bone graft harvest site complications. Bone morphogenetic proteins (BMPs) offer the exciting prospect of enhanced union rates equal to or greater than autograft and potentially eliminate graft harvest site complications. Many studies have clearly demonstrated the efficacy of BMP products for various applications in spine surgery. BMP has proven effective in achieving union in anterior and posterior lumbar surgery and recently in anterior cervical surgery. Despite the reported success, the universal adoption of BMP is tempered by high costs and lingering safety concerns with reported complications specific to BMP use including vertebral osteolysis, ectopic bone formation, radiculitis and cervical soft tissue swelling. Ongoing clinical and basic-science research is focused on clearly defining guidelines for BMP use in spine surgery and on developing more affordable BMP formulations with dosing that predictably results in spine fusion yet minimizes the possible side effect profile.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Resorption; Bone Transplantation; Deglutition Disorders; Disease Models, Animal; Hematoma; Humans; Ilium; Middle Aged; Osteomyelitis; Plastic Surgery Procedures; Radiculopathy; Recombinant Proteins; Spinal Diseases; Spinal Fusion; Spine; Tissue and Organ Harvesting; Transforming Growth Factor beta

The goal in this study was to demonstrate the safety and efficacy of anterior cervical discectomy and fusion ([ACDF]; single- or multilevel procedure) performed using titanium plates and polyetheretherketone (PEEK) spacers filled with recombinant human bone morphogenetic protein-2 (rhBMP-2) impregnated in a type I collagen sponge to achieve fusion.. The authors retrospectively reviewed 200 patients who underwent a single- or multilevel ACDF with titanium plate fixation and PEEK spacer filled with a collagen sponge impregnated with low-dose rhBMP-2. Clinical outcomes were assessed using pre- and postoperative Nurick grades and the Odom criteria. Radiographic outcomes were assessed using dynamic radiographs and computed tomography (CT) scans.. The follow-up period ranged from 8 to 36 months (mean 16.7 months). A single-level ACDF was performed in 96 patients, 2-level ACDF in 62 patients, 3-level ACDF in 36 patients, and 4-level ACDF in 6 patients. Long-term follow-up was available for 193 patients. The Odom outcomes were rated as good to excellent in 165 patients (85%), fair in 24 (12.4%), and poor in 4 (2%). Among patients with myelopathy, Nurick grades improved from a preoperative mean of 1.42 to a postoperative mean of 0.26. All patients (100%) achieved solid radiographic fusion on dynamic radiographs and CT scans. Fourteen patients (7%) in this series experienced clinically significant dysphagia, and 4 (2%) required repeated operation for hematoma or seroma.. An ACDF performed using a PEEK spacer filled with rhBMP-2 leads to good to excellent clinical outcomes and solid fusion, even in multilevel cases and in patients who are smokers. The incidence of symptomatic dysphagia may be decreased with a lower dose of rhBMP-2 that is placed only within the PEEK spacer.

Topics: Adult; Aged; Aged, 80 and over; Benzophenones; Biocompatible Materials; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Plates; Cervical Vertebrae; Collagen Type I; Deglutition Disorders; Diskectomy; Drug Carriers; Female; Follow-Up Studies; Hematoma; Humans; Ketones; Longitudinal Studies; Male; Middle Aged; Orthopedic Fixation Devices; Polyethylene Glycols; Polymers; Postoperative Complications; Range of Motion, Articular; Recombinant Proteins; Retrospective Studies; Safety; Seroma; Spinal Fusion; Titanium; Tomography, X-Ray Computed; Transforming Growth Factor beta; Treatment Outcome

A sheep cervical spine interbody fusion model was used to determine the effect of combined insulin-like growth factor-I (IGF-I) and transforming growth factor-beta-1 (TGF-beta1) applied by a poly-(D,L-lactide) (PDLLA)-coated cage.. The purpose of this study was to determine the effect of a new PDLLA carrier system, and to evaluate the effect of combined IGF-I and TGF-beta1 application in a sheep cervical spine model.. Growth factors such as bone morphogenic protein-2 have been shown to promote spine fusion and to overcome the disadvantages of an autologous bone graft. The optimum growth factor for promoting spinal fusion and the optimum method for delivering such growth factors are still a matter of discussion.. In this study, 32 sheep underwent C3-C4 discectomy and fusion: Group 1 (autologous tricortical iliac crest bone graft; n = 8), Group 2 (titanium cage; n = 8), Group 3 (titanium cage coated with a PDLLA carrier; n = 8), and Group 4 (titanium cage coated with a PDLLA carrier including IGF-I [5% w/w] and TGF-beta1 [1% w/w; n = 8). Blood samples, body weight, and body temperature were analyzed. Radiographic scans were performed before and after surgery, then at 1, 2, 4, 8, and 12 weeks, respectively. At the same time points, the disc space height, intervertebral angle, and lordosis angle were measured. After 12 weeks, the animals were killed, and fusion sites were evaluated using functional radiographic views of the animals in flexion and extension. Quantitative computed tomographic scans were performed to assess bone mineral density, bone mineral content, and bony callus volume. Biomechanical testing of the motion segment C3-C4 was performed in flexion, extension, axial rotation, and lateral bending. The stiffness, range of motion, neutral zone, and elastic zone were determined. Histomorphologic and histomorphometric analysis was performed, and polychrome sequential labeling was used to determine the time frame of new bone formation.. There were no differences between the groups in terms of blood counts, body weight, and temperature. Over a 12-week period, cage Groups 2 to 4 showed significantly higher values for the intervertebral angle than for the bone graft. Functional radiographic assessment showed significantly lower residual flexion-extension movement in Group 4 than in any other group. The PDLLA-coated cages with IGF-I and TGF-beta1 showed significantly higher values for bone mineral density, bone mineral content, and bony callus volume. The average stiffness in rotation and bending was significantly higher, and the range of motion, neutral zone, and elastic zone in rotation were significantly lower in Group 4 than in any other group. Although only one animal in Group 4 demonstrated solid bony fusion after 12 weeks, histomorphometric evaluation showed a more progressed bone matrix formation in the group that had PDLLA-coated cages with IGF-I and TGF-beta1 than in any other group. Polychrome sequential labeling showed accelerated intervertebral bone matrix formation in Group 4.. The findings showed that PDLLA coating of cervical spine interbody fusion cages as a delivery system for growth factors was effective. Although IGF-I and TGF-beta1 application by a PDLLA-coated interbody cage was not able to achieve solid bony fusion during the 12-week follow-up period, these growth factors significantly increased the results of interbody bone matrix formation. Additional longer-term studies are required to determine whether combined IGF-I and TGF-beta1 application leads to a successful spinal fusion.

Topics: Absorbable Implants; Animals; Biocompatible Materials; Body Temperature; Body Weight; Bone Matrix; Cervical Vertebrae; Drug Carriers; Drug Therapy, Combination; Female; Hematoma; Insulin-Like Growth Factor I; Models, Animal; Neck; Polyesters; Reproducibility of Results; Sheep; Spinal Fusion; Spine; Tomography, X-Ray Computed; Transforming Growth Factor beta; Transforming Growth Factor beta1; Treatment Outcome

Clinical trauma suppresses immunity and experimental wound fluids have been shown to be immunosuppressive. To ascertain whether human wounds contain immunosuppressive cytokines, we assayed serum from fracture/soft-tissue hematomas (FSTH) of 22 patients for interleukin (IL)-10, transforming growth factor (TGF)-beta 1, and IL-4. Results were correlated to concurrent plasma cytokine concentrations in the same patients and in volunteer plasma. IL-10 was present in high concentration (1376 +/- 539 pg/mL) in all (7/7) FSTH < 24 h old. In FSTH > 24 h old, IL-10 was found intermittently and at lower levels (239 +/- 106 pg/mL, p = .011 vs. FSTH < 24 h old). IL-10 was rarely detectable in fracture patient plasma and never detectable (< 20 pg/mL) in normal plasma. No significant variations of IL-4 or total TGF-beta 1 were found in FSTH or plasma. FSTH are significant potential sources of IL-10 activity in trauma patients, which may be overlooked when only plasma is assayed. The potential for a relationship between cytokines found locally at sites of injury and clinical immune modulation in trauma requires further study.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Female; Femoral Fractures; Fractures, Bone; Hematoma; Humans; Interleukin-10; Interleukin-4; Internal Fixators; Male; Middle Aged; Pelvic Bones; Reference Values; Retrospective Studies; Tibial Fractures; Transforming Growth Factor beta