Dataset Information

Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.

ABSTRACT: Preclinical studies using bone marrow derived cells to treat traumatic brain injury have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe traumatic brain injury demonstrated safety and potentially a central nervous system structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and potential treatment effect size of structural preservation/inflammatory biomarker mitigation in adults to guide Phase 2 clinical trial design. Adults with severe traumatic brain injury (Glasgow Coma Scale 5-8) and without signs of irreversible brain injury were evaluated for entry into the trial. A dose escalation format was performed in 25 patients: 5 controls, followed 5 patients in each dosing cohort (6, 9, 12 ×106 cells/kg body weight), then 5 more controls. Bone marrow harvest, cell processing to isolate the mononuclear fraction, and re-infusion occurred within 48 hours after injury. Patients were monitored for harvest-related hemodynamic changes, infusional toxicity, and adverse events. Outcome measures included magnetic resonance imaging-based measurements of supratentorial and corpus callosal volumes as well as diffusion tensor imaging-based measurements of fractional anisotropy and mean diffusivity of the corpus callosum and the corticospinal tract at the level of the brainstem at 1 month and 6 months postinjury. Functional and neurocognitive outcomes were measured and correlated with imaging data. Inflammatory cytokine arrays were measured in the plasma pretreatment, posttreatment, and at 1 and 6 month follow-up. There were no serious adverse events. There was a mild pulmonary toxicity of the highest dose that was not clinically significant. Despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest that correlated with functional outcomes. Key inflammatory cytokines were downregulated. Treatment of severe, adult traumatic brain injury using an intravenously delivered autologous bone marrow mononuclear cell infusion is safe and logistically feasible. There appears to be a treatment signal as evidenced by central nervous system structural preservation, consistent with previous pediatric trial data. Inflammatory biomarkers are downregulated after cell infusion. Stem Cells 2016 Video Highlight: https://youtu.be/UiCCPIe-IaQ Stem Cells 2017;35:1065-1079.

SUBMITTER: Cox CS

PROVIDER: S-EPMC5367945 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.

Cox Charles S CS Hetz Robert A RA Liao George P GP Aertker Benjamin M BM Ewing-Cobbs Linda L Juranek Jenifer J Savitz Sean I SI Jackson Margaret L ML Romanowska-Pawliczek Anna M AM Triolo Fabio F Dash Pramod K PK Pedroza Claudia C Lee Dean A DA Worth Laura L Aisiku Imoigele P IP Choi Huimahn A HA Holcomb John B JB Kitagawa Ryan S RS

Stem cells (Dayton, Ohio) 20161123 4

Preclinical studies using bone marrow derived cells to treat traumatic brain injury have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe traumatic brain injury demonstrated safety and potentially a central nervous system structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and poten ...[more]

PMID: 27800660

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Project description:The devastating effect of traumatic brain injury is exacerbated by an acute secondary neuroinflammatory response, clinically manifest as elevated intracranial pressure due to cerebral edema. The treatment effect of cell-based therapies in the acute post-traumatic brain injury period has not been clinically studied although preclinical data demonstrate that bone marrow-derived mononuclear cell infusion down-regulates the inflammatory response. Our study evaluates whether pediatric traumatic brain injury patients receiving IV autologous bone marrow-derived mononuclear cells within 48 hours of injury experienced a reduction in therapeutic intensity directed toward managing elevated intracranial pressure relative to matched controls.The study was a retrospective cohort design comparing pediatric patients in a phase I clinical trial treated with IV autologous bone marrow-derived mononuclear cells (n = 10) to a control group of age- and severity-matched children (n = 19).The study setting was at Children's Memorial Hermann Hospital, an American College of Surgeons Level 1 Pediatric Trauma Center and teaching hospital for the University of Texas Health Science Center at Houston from 2000 to 2008.Study patients were 5-14 years with postresuscitation Glasgow Coma Scale scores of 5-8.The treatment group received 6 million autologous bone marrow-derived mononuclear cells/kg body weight IV within 48 hours of injury. The control group was treated in an identical fashion, per standard of care, guided by our traumatic brain injury management protocol, derived from American Association of Neurological Surgeons guidelines.The primary measure was the Pediatric Intensity Level of Therapy scale used to quantify treatment of elevated intracranial pressure. Secondary measures included the Pediatric Logistic Organ Dysfunction score and days of intracranial pressure monitoring as a surrogate for length of neurointensive care. A repeated-measure mixed model with marginal linear predictions identified a significant reduction in the Pediatric Intensity Level of Therapy score beginning at 24 hours posttreatment through week 1 (p < 0.05). This divergence was also reflected in the Pediatric Logistic Organ Dysfunction score following the first week. The duration of intracranial pressure monitoring was 8.2 ± 1.3 days in the treated group and 15.6 ± 3.5 days (p = 0.03) in the time-matched control group.IV autologous bone marrow-derived mononuclear cell therapy is associated with lower treatment intensity required to manage intracranial pressure, associated severity of organ injury, and duration of neurointensive care following severe traumatic brain injury. This may corroborate preclinical data that autologous bone marrow-derived mononuclear cell therapy attenuates the effects of inflammation in the early post-traumatic brain injury period.

Project description:Combinations of biomaterials and cells can effectively target delivery of cells or other therapeutic factors to the brain to rebuild damaged nerve pathways after brain injury. Porous collagen-chitosan scaffolds were prepared by a freeze-drying method based on brain tissue engineering. The scaffolds were impregnated with rat bone marrow mesenchymal stem cells. A traumatic brain injury rat model was established using the 300 g weight free fall impact method. Bone marrow mesenchymal stem cells/collagen-chitosan scaffolds were implanted into the injured brain. Modified neurological severity scores were used to assess the recovery of neurological function. The Morris water maze was employed to determine spatial learning and memory abilities. Hematoxylin-eosin staining was performed to measure pathological changes in brain tissue. Immunohistochemistry was performed for vascular endothelial growth factor and for 5-bromo-2-deoxyuridine (BrdU)/neuron specific enolase and BrdU/glial fibrillary acidic protein. Our results demonstrated that the transplantation of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds to traumatic brain injury rats remarkably reduced modified neurological severity scores, shortened the average latency of the Morris water maze, increased the number of platform crossings, diminished the degeneration of damaged brain tissue, and increased the positive reaction of vascular endothelial growth factor in the transplantation and surrounding areas. At 14 days after transplantation, increased BrdU/glial fibrillary acidic protein expression and decreased BrdU/neuron specific enolase expression were observed in bone marrow mesenchymal stem cells in the injured area. The therapeutic effect of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds was superior to stereotactic injection of bone marrow mesenchymal stem cells alone. To test the biocompatibility and immunogenicity of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds, immunosuppressive cyclosporine was intravenously injected 12 hours before transplantation and 1-5 days after transplantation. The above indicators were similar to those of rats treated with bone marrow mesenchymal stem cells and collagen-chitosan scaffolds only. These findings indicate that transplantation of bone marrow mesenchymal stem cells in a collagen-chitosan scaffold can promote the recovery of neuropathological injury in rats with traumatic brain injury. This approach has the potential to be developed as a treatment for traumatic brain injury in humans. All experimental procedures were approved by the Institutional Animal Investigation Committee of Capital Medical University, China (approval No. AEEI-2015-035) in December 2015.

Project description:ImportanceThere are limited data on which factors affect the critical and complex decision to withdraw life-supporting treatment (LST) in patients with severe traumatic brain injury (sTBI).ObjectiveTo determine demographic and clinical factors associated with the decision to withdraw LST in patients with sTBI.Design, setting, and participantsThis retrospective analysis of inpatient data from more than 825 trauma centers across the US in the American College of Surgeons Trauma Quality Improvement Program database from January 2013 to December 2015 included adult patients with sTBI and documentation of a decision regarding withdrawal of LST (WLST). Data analysis was conducted in September 2019.Main outcomes and measuresFactors associated with WLST in sTBI.ResultsA total of 37931 patients (9817 women [25.9%]) were included in the multivariable analysis; 7864 (20.7%) had WLST. Black patients (4806 [13.2%]; odds ratio [OR], 0.66; 95% CI, 0.59-0.72; P < .001) and patients of other race (4798 [13.2%]; OR, 0.83; 95% CI, 0.76-0.91; P < .001) were less likely than white patients (26 864 [73.7%]) to have WLST. Patients from hospitals in the Midwest (OR, 1.12; 95% CI, 1.04-1.20; P = .002) or Northeast (OR, 1.23; 95% CI, 1.13-1.34; P < .001) were more likely to have WLST than patients from hospitals in the South. Patients with Medicare (OR, 1.55; 95% CI, 1.43-1.69; P < .001) and self-pay patients (OR, 1.36; 95% CI, 1.25-1.47; P < .001) were more likely to have WLST than patients with private insurance. Older patients and those with lower Glasgow Coma Scale scores, higher Injury Severity Scores, or craniotomy were generally more likely to have WLST. Withdrawal of LST was more likely for patients with functionally dependent health status (OR, 1.30; 95% CI, 1.08-1.58; P = .01), hematoma (OR, 1.19; 95% CI, 1.12-1.27; P < .001), dementia (OR, 1.29; 95% CI, 1.08-1.53; P = .004), and disseminated cancer (OR, 2.82; 95% CI, 2.07-3.82; P < .001) than for patients without these conditions.Conclusions and relevanceWithdrawal of LST is common in sTBI and socioeconomic factors are associated with the decision to withdraw LST. These results highlight the many factors that contribute to decision-making in sTBI and demonstrate that in a complex and variable disease process, variation based on race, payment, and region presents as a potential challenge.

Dataset Information

Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.

Publications

Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.

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