Autologous bone marrow mononuclear cell therapy for severe traumatic brain injury
Autologous bone marrow mononuclear cells (BMMNCs) infused for severe traumatic brain injury treatment have shown promise for treating the injury.
Key points
Mechanism of Action: Autologous BMMNCs are believed to exert their effects through various mechanisms, including the release of growth factors, anti-inflammatory properties, and the potential to differentiate into various cell types that can contribute to tissue repair.
Clinical Trials: Some clinical trials have been conducted to evaluate the safety and efficacy of autologous BMMNC therapy for severe traumatic brain injury. These trials typically involve collecting bone marrow from the patient, isolating the mononuclear cell fraction, and then administering the cells back to the patient, often through intravenous (IV) or intra-arterial (IA) injection.
Outcomes: Results from clinical trials have been mixed, with some studies reporting potential benefits in terms of neurological improvement and reduced disability, while others have not shown significant effects. The field is still evolving, and further research is needed to establish the optimal cell types, dosages, and delivery methods for maximizing therapeutic benefits.
Challenges and Considerations: Traumatic brain injury is a complex condition with varying degrees of severity and diverse clinical presentations. Factors such as the timing of intervention, the type of cells used, and the patient population can influence the outcomes. Additionally, the safety and ethical considerations of such therapies are crucial and require careful evaluation.
While the use of autologous BMMNC therapy for severe traumatic brain injury is an area of active research
Cox et al. evaluated their impact on children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural central nervous system preservation with improved outcomes. They performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at 2 children's hospitals in Houston, TX, and Phoenix, AZ, USA (NCT01851083). Patients 5-17 years of age with severe traumatic brain injury (Glasgow Coma Scale ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation, and infusion were completed by 48 hours post-injury. Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between 2 doses. Primary endpoints were quantitative brain volumes using magnetic resonance imaging and microstructural integrity of the corpus callosum (CC; diffusivity and edema measurements) at 6 months and 12 months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days, and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring, and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1 year in the BMMNC group was significantly preserved compared to placebo (decrease of 19891 vs 40491, respectively; mean difference of -20600, 95% CI: -35868 to -5332; P = 0.01), and the number of CC streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved CC connectivity in the treated groups (-431 streamlines placebo vs. -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 hours after severe traumatic brain injury is safe and feasible. The data show that BMMNC infusion led to 1) shorter intensive care duration and decreased ICU intensity; 2) white matter structural preservation; and 3) enhanced CC connectivity and improved microstructural metrics 1).
A retrospective cohort design comparing pediatric patients in 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).
Setting: 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.
Patients: Study patients were 5-14 years old with post-resuscitation Glasgow Coma Scale scores of 5-8.
Interventions: 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 identically, per standard of care, guided by our traumatic brain injury management protocol, derived from American Association of Neurological Surgeons guidelines.
Measurements and main results: The primary measure was the Pediatric Intensity Level of Therapy scale used to quantify the treatment of elevated intracranial pressure. Secondary measures included the Pediatric Logistic Organ Dysfunction score and days of intracranial pressure monitoring as a surrogate for the 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.
Conclusions: 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 2).
Ten children aged 5 to 14 years with a post-resuscitation Glasgow Coma Scale of 5 to 8 were treated with 6×10 autologous BMMNCs/kg body weight delivered intravenously within 48 hours after TBI. To determine the safety of the procedure, systemic and cerebral hemodynamics were monitored during bone marrow harvest; infusion-related toxicity was determined by pediatric logistic organ dysfunction (PELOD) scores, hepatic enzymes, Murray lung injury scores, and renal function. Conventional magnetic resonance imaging (cMRI) data were obtained at 1 and 6 months postinjury, as were neuropsychological and functional outcome measures.
Results: All patients survived. There were no episodes of harvest-related depression of systemic or cerebral hemodynamics. There was no detectable infusion-related toxicity as determined by PELOD score, hepatic enzymes, Murray lung injury scores, or renal function. cMRI imaging comparing gray matter, white matter, and CSF volumes showed no reduction from 1 to 6 months postinjury. Dichotomized Glasgow Outcome Score at 6 months showed 70% with good outcomes and 30% with moderate to severe disability.
Bone marrow harvest and intravenous mononuclear cell infusion as treatment for severe TBI in children is logistically feasible and safe 3).
Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI.
The potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model.
Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7 days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function accompanied the combined therapy, which was either moderately or short-lived in the monotherapy conditions. These results suggest that combined treatment rather than monotherapy appears optimal for abrogating histophalogical and motor impairments in chronic TBI 4).