Traumatic Brain Injury: Novel Experimental Approaches and Treatment Possibilities
Abstract
:1. Introduction
2. The Role of Precision Medicine in the Traumatic Brain Injury Management
3. Cell-Based Therapies for the Treatment of Traumatic Brain Injury: Neuroprotective and Regenerative Potential of Stem and Progenitor Cells
Type of Stem Cells | Main Results | Reference |
---|---|---|
Amnion-derived neural stem-like cells (AM-NSCs) | AM-NSC transplantation significantly improved neurological function and brain tissue morphology in a rat TBI model compared to AMSC and Matrigel controls. Effect was associated with enhanced expression of neurotrophic factors, despite low graft survival and minimal differentiation into neural-like cells. | [30] |
Embryonic stem cell (ESC)-derived NSCs | Transplantation of human ESC-derived NSCs into immunodeficient TBI rats led to long-term cognitive improvement (≥2 months), particularly in hippocampal-dependent spatial memory, despite no change in lesion volume. Surviving NSCs (9–25%) differentiated into neurons, astrocytes, and oligodendrocytes, and cognitive recovery correlated with increased host hippocampal neuron survival. | [32] |
Induced pluripotent stem cells (iPSC)-derived neurons | Mild stretch injury modeling mild TBI in human iPSC-derived neurons triggered amyloidogenic processing of APP, disrupting axonal transport and leading to accumulation of amyloid-related components associated with Alzheimer’s disease. Pharmacological inhibition of APP cleavage, as well as expression of the Alzheimer’s disease-protective A673T variant, prevented these stretch-induced transport defects, suggesting a potential strategy to reduce Alzheimer’s disease risk following mTBI. | [33] |
Neural stem cells (NSCs) | Intracranial transplantation of clinical-grade fetal human NSCs in athymic rats with penetrating TBI showed no evidence of tumorigenicity or oncogenic tissue necrosis after six months, supporting the safety of human NSC therapy. Despite robust human NSC engraftment and predominantly neuronal differentiation of human NSCs into immature neurons, lesion size remained unchanged in athymic rats, highlighting a potential role of thymus-derived immune cells in modulating post-traumatic inflammation and tissue repair. | [34] |
ESC-derived cerebral organoids | Transplantation of 8-week-old human embryonic stem cell-derived cerebral organoids (hCOs) in a mild TBI mouse model reduced neuronal death, enhanced neurogenesis and angiogenesis, and promoted repair of damaged cortical and hippocampal regions. hCO treatment improved cognitive function post-injury, supporting its therapeutic potential for neuronal dysfunction through cortical reconstruction and hippocampal neurogenesis. | [35] |
iPSC-derived neural stem/progenitor cells (NS/PCs) | Genome-edited human iPSC-derived NS/PCs expressing yCD–UPRT enhanced motor recovery and reduced secondary brain injury, atrophy, and ventricle enlargement in a TBI mouse model. The yCD–UPRT/5-FC system enabled selective ablation of undifferentiated cells, preventing tumorigenesis while preserving surrounding neuronal tissue, improving the safety of iPSC-based therapy. | [36] |
NSCs genetically modified to express human L-myc gene | Intranasally delivered L-myc-expressing human NSC (LMNSC008) migrated along white matter tracts to both primary and secondary injury sites in a rat TBI model. LMNSC008 treatment modulated gene expression by downregulating inflammatory pathways and microglial activation, supporting neuroprotection and tissue regeneration. | [37] |
4. Nanomedicine in Traumatic Brain Injury: The Use of Nanomaterials for Targeted Drug Delivery, Neuro-Regeneration, and Tissue Engineering
4.1. Use of Nanomaterials for Targeted Drug Delivery
4.2. Nanoparticles: Polymeric and Metallic Nanoparticles and Nanogels
4.3. Lipid Nanoparticles
4.4. Exosomes
4.5. Carbon Dots and Carbon Quantum Dots
5. Innovations in Traumatic Brain Injury Rehabilitation: Brain–Machine Interfaces and Virtual Rehabilitation Interventions
5.1. Brain–Machine Interface-Driven Approaches in Traumatic Brain Injury Rehabilitation
5.2. Virtual Rehabilitation Interventions in Neurorehabilitation
Technology Type | Definition and Key Features | Clinical Applications in Healthcare | Application in Brain Injury Rehabilitation |
---|---|---|---|
Virtual Reality (VR) | Creates a fully immersive digital environment that replaces the real world. Users interact with this environment through headsets, controllers, and other devices that track body movements and provide sensory feedback. | Widely used for motor skill retraining, cognitive therapy, and psychological interventions. | [132,134,135,141,142,143,144,145,146,147,148,149,150,151,152,153] |
Augmented Reality (AR) | Overlays digital elements—such as images, videos, or 3D models—onto the real-world environment. Enhances reality without fully replacing it and is typically accessed through smartphones, tablets, or AR glasses. | Particularly useful for providing real-time guidance during physical therapy exercises or offering visual cues to improve motor coordination. It has also been used in cognitive training by overlaying interactive tasks onto physical spaces. | [130,137,138,145,154] |
Video Capture VR | Uses cameras and software to track user movements without requiring physical markers on the body. The user’s image is embedded into a virtual environment, enabling natural interaction with animated graphics. | Useful for balance training, motor skill recovery, and functional movement exercises. | [155] |
Interactive Video Gaming | Employs commercial gaming systems or custom-designed games to engage patients in therapeutic activities. | Often used for home-based rehabilitation, providing accessible and engaging platforms for motor skill training, cognitive exercises, and physical activity. | [156,157,158,159] |
Tele-Rehabilitation | Uses high-speed networking to connect patients with therapists remotely. This enables virtual therapy sessions and real-time monitoring of rehabilitation progress. | Facilitates access to therapy for patients in remote areas or those with limited mobility. It can include virtual environments combined with haptic devices, video conferencing, and data analytics tools. | [136,160,161] |
Behavior Change Techniques | Integrated into VRIs to promote behavior modification through structured interventions, such as goal setting, adaptability, feedback mechanisms, and competition. | Used within VR environments to enhance motor recovery by tailoring tasks to individual needs and providing explicit feedback on performance. | [162] |
Wearable Sensors | Wearable devices equipped with sensors measure physiological responses such as movement patterns, muscle activity, or heart rate during rehabilitation exercises. | Provide real-time feedback and data collection for both therapists and patients, enabling personalized adjustments to therapy protocols. | [163,164,165] |
Extended Reality (XR) | Encompasses VR, AR, and mixed reality, offering hybrid environments that combine digital elements with the physical world. | Increasingly used in rehabilitation to provide immersive yet contextually relevant environments for motor skill training, cognitive exercises, and social interaction. | [138,139,166] |
Haptic Feedback Devices | Simulate tactile sensations by applying force or vibrations to the user’s skin or muscles. | Enhance the realism of virtual environments by providing physical feedback during tasks such as grasping objects or navigating virtual spaces. | [167,168] |
Metaverse-Based Rehabilitation | Integrates hardware (e.g., XR devices) and software platforms (e.g., rendering tools) to create interconnected virtual spaces for rehabilitation. | Collaborative therapy sessions, gamified exercises, and continuous follow-ups post-discharge from clinical care. | [140] |
5.3. Application of Neuromodulation Techniques in Brain Injury Recovery
5.4. Ethical and Regulatory Challenges Facing Brain–Machine Interface and Virtual Rehabilitation Interventions in Brain Trauma Care
6. Conclusions and Future Considerations
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Abbreviations
AI | Artificial intelligence |
APP | Amyloid precursor protein |
APOE | Apolipoprotein E |
AR | Augmented reality |
BBB | Blood–brain barrier |
BDNF | Brain-derived neurotrophic factor |
BMI | Brain–machine interfaces |
CT | Computed tomography |
CTE | Chronic traumatic encephalopathy |
DTI | Diffusion tensor imaging |
FDA | U.S. Food and Drug Administration |
GFAP | Glial fibrillary acidic protein |
ICP | Intracranial pressure |
iPSCs | Induced pluripotent stem cells |
mTBI | Mild TBI |
ML | Machine learning |
MRI | Magnetic resonance imaging |
MSCs | Mesenchymal stem cells |
NPs | Nanoparticles |
NfL | Neurofilament light chain |
NSCs | Neural stem cells |
NS/PCs | Neural stem/progenitor cells |
QDs | Quantum dots |
siRNA | Small interfering RNA |
TBI | Traumatic brain injury |
VR | Virtual reality |
VRIs | Virtual rehabilitation interventions |
UCH-L1 | Ubiquitin carboxyl-terminal hydrolase L1 |
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Function/Use | Type | References |
---|---|---|
Carriers | Small molecules | [54,55] |
Large molecules | [56,57,58,59,60,61] | |
Chemicals | [62,63,64,65] | |
Coding and non-coding | [66,67,68,69,70] | |
Nucleic acid molecules | [71] | |
Gasses data | [72,73,74,75,76,77] | |
Drugs | [70] | |
Stem cells | [78,79] | |
Scaffold | [80] | |
Sealant | [66,81,82,83,84,85,86] | |
Intrinsic effect | [87,88] | |
Diagnostics | Serum markers’ detection | [86,89,90,91,92] |
Imaging | [54,55] |
Nanomaterial | Surface Functionalization | Main Results | Reference |
---|---|---|---|
Polymeric nanoparticles (NP) | Poly (butyl cyanoacrylate) (PBCA) | PBCA NPs effectively deliver large molecules, such as HRP or EGFP, across the BBB 4 h post-TBI. | [57] |
PBCA NPs deliver β-NGF factor and promote the neurite outgrowth and reduce mortality after TBI in rats. | [54] | ||
Poly (lactic-co-glycolic acid) (PLGA) | Transplantation of PLGA scaffolds combined with MSCs/MSC and NGF enhances neural function and restores brain tissue structure in after TBI. | [79] | |
PLGA with SOD1 and CAT reduce ROS post-TBI. | [60] | ||
PLGA based DOPA-NGF microunits improve neuronal recovery and decrease neuronal loss, astrocytic and microglial activation. | [55] | ||
Poly (ethylene) glycol (PEG) | PEG hydrophilic carbon cluster ameliorates neuronal loss, oxidative stress and repairs BBB. | [84] | |
PEG prolongs RNA NPs’ half-life in blood in order to knockdown TNF-α cytokine, increase nanoparticle stability, reduce of protein adsorption and uptake by the reticuloendothelial system. | [67] | ||
Xenon-containing microbubbles functionalized with PEG reduce BBB disruption. | [71] | ||
PEG-azide modifies clotting cascade in in vivo response and increases neuronal survival in TBI rats. | [62] | ||
PLGA–PEG | PLGA-PEG NPs encapsulating isoliquiritigenin can replicate the effects of intracranial isoliquiritigenin administration in lowering serum COX-2 levels. | [75] | |
PLGA–polysorbate (PLGA–PS) | Tau siRNA–loaded PS-NPs silence tau expression in vivo early and late after TBI. | [68] | |
Metallic NP | Cerium oxide NPs, coated with 6-aminocaproic acid and polyvinylpyrrolidone, show antioxidant properties and improve recovery post-TBI. | [63] | |
Anti-S100 B labeled gold NPs can be used to determine concentration of S100B in human serum. | [87] | ||
Gold NPs in an optical microfiber interface increase sensitivity of ultralow concentrations of GFAP in human serum post-TBI. | [88] | ||
Superparamagnetic iron oxide NPs can serve as an MRI contrast agent for labeling MSCs, enabling non-invasive, real-time in vivo tracking following intranasal delivery post-TBi in mice. | [92] | ||
Nanogel | PEG hydrogel containing dexamethasone-conjugated hyaluronic acid improves motor function, and reduces lesion volume and inflammation after mild and moderate TBI. | [74,76] | |
Hyaluronic acid-based hydrogels based and gelatin combined with salvianolic acid B and VEGF, used as sealants, reduce the lesion volume site. | [61] | ||
Hyaluronic acid hydrogels encapsulating bone MSCs and nerve growth factor may enhance neurotrophic support and mitigate neuroinflammation, thereby facilitating neurological recovery and functional restoration post-TBI in mice. | [70] | ||
Hydrophobic methyl-acrylated gelatin mitigates TBI-induced mortality, neurological deficits, and cerebral edema while modulating iron-related toxicity via PI3K/PKC-α signaling. | [80] | ||
Lipid NPs (LNPs) | PEG | LNPs are a promising non-viral gene therapy platform for treating TBI and PEG-LNPs prolong blood half-time after i.v. administration. | [69] |
Fluorescently dyed lipid nano droplets can be used to track nanocarriers in brains of TBI mice and are able to cross the BBB by endothelial transcytosis into the penumbra and are later internalized by neurons. | [90] | ||
A lipoprotein nanocarrier can deliver cyclosporine A to damaged brain sites, effectively reducing neuronal damage, alleviating neuroinflammation, and rescuing memory deficits post-TBI. | [73] | ||
Liposomes | Baicalein encapsulated in liposomes decreases brain edema, reduces inflammatory cytokine serum levels and improves motor function outcomes. | [65] | |
Dexamethasone encapsulated in liposomes can specifically affect the damaged brain, decreasing lesion size, neuronal loss, astrogliosis, pro-inflammatory cytokine release, and microglial activation predominantly in male mice acutely post-TBI. | [72] | ||
Liposome encapsulated with 20-hydroxyeicosatetraenoic acid inhibitor, applied i.v., reduces lesion volume, neuronal degeneration, microglial activation and ameliorates neurological outcome. | [77] | ||
Delayed application of intranasal liposomes with anti-inflammatory protein IL-4 preserves the structural and functional integrity of white matter via oligodendro-genesis, and facilitates long-term sensorimotor recovery. | [59] | ||
Liposomes applied i.v. can be used as imaging agents due to their ability to carry contrast agent and target inflamed brain area. Empty liposomes also reduce lesion volume and show therapeutic effect after experimental TBI in mice. | [86] | ||
VCAM-1 liposome nanocarrier concentrate in the brain at higher levels than untargeted IgG controls after intravenous injection. | [58] | ||
Leukosomes | Leukosomes, applied i.v., serve as effective imaging agents by delivering contrast agents, specifically targeting inflamed brain regions. Additionally, empty liposomes have higher adherence affinity to lesion blood vessels and reduce lesion size following experimental TBI in mice. | [86] | |
Exosomes | Exosomes from human platelet concentrates’ supernatants show a strong anti-inflammatory effect by decreasing GFAP and TNFα mRNA levels after TBI in mice. | [81] | |
Exosomes from umbilical cord MSCs enhance neurological recovery of TBI rats by NF-κB pathway inhibition. | [85] | ||
Exosomes derived from neural stem cells preconditioned with IFN-γ supports the regeneration of damaged neural tissue and enhances endogenous neurogenesis. | [56] | ||
I.v. application of exosomes from human umbilical cord MSCs can improve neurological repair after TBI in rats by inhibiting apoptosis, promoting neurogenesis and reducing inflammation. | [66] | ||
Intranasal administration of exosomes from human adipose-derived stem cells 48 h after injury alleviates motor and cognitive deficits following TBI in rats. | [83] | ||
I.v. injected microglial exosomes are absorbed by injured brain neurons, delivering miR-124-3p to hippocampal neurons, mitigating neurodegeneration and ameliorating cognitive recovery after rmTBI in mice. | [82] | ||
Carbon dots and carbon quantum dots | I.v. application of PEG-capped silver indium selenide-based quantum dots enables precise hemorrhage diagnostics after TBI in mice. | [89] | |
I.v. applied carbon dots, functionalized with herbal medicine, ameliorate neurological functions and reduce brain edema, neuronal damage and BBB permeability. | [64] | ||
Fluorescently labeled quantum dots enable imaging-guided treatment of TBI while exhibiting antioxidant activity due to uniform Mn atom distribution. | [91] |
Technique | Common Uses in Neurorehabilitation | Application in Brain Injury Rehabilitation |
---|---|---|
Non-Invasive Neuromodulation Techniques | ||
Transcranial Direct Current Stimulation (tDCS) | Applies low direct current to modulate cortical excitability. Used in stroke, cognitive rehab, and depression. | [180,181,182,183,184,185,186] |
Transcranial Magnetic Stimulation (TMS/rTMS) | Uses magnetic fields to induce electric currents in the brain. Can excite or inhibit specific areas. Repetitive TMS (rTMS) is common in stroke and depression rehab. | [187,188,189,190,191] |
Transcranial Alternating Current Stimulation (tACS) | Similar to tDCS but uses an alternating current. Targets neural oscillations (brain wave frequencies). | [192] |
Transcranial Random Noise Stimulation (tRNS) | Applies random frequencies of current. Thought to increase cortical excitability and plasticity. Used for sensory-motor rehab, cognition. | [193] |
Invasive or Semi-Invasive Neuromodulation | ||
Deep Brain Stimulation (DBS) | Surgically implanted electrodes. Often used in Parkinson’s, dystonia, and other movement disorders. | [194] |
Epidural Cortical Stimulation | Electrodes placed over the dura (outer brain covering). Investigated in stroke recovery and epilepsy. | [195] |
Vagus Nerve Stimulation (VNS) | Stimulates the vagus nerve (implanted or non-invasive versions exist). Used in epilepsy and increasingly in post-stroke motor recovery. | [196] |
Emerging or Combined Techniques | ||
Closed-loop Neuromodulation | Real-time feedback systems that adjust stimulation based on brain activity (could be considered a bridge between neuromodulation and BMIs). | [197] |
Paired Associative Stimulation (PAS) | Combines peripheral nerve stimulation with brain stimulation to boost synaptic plasticity. Used for motor learning and post-stroke. | [198] |
Molecular Strategies | Technology-Based Strategies | Mechanisms/Applications | Key Advancements |
---|---|---|---|
Gene Therapy | Nanoparticle Delivery | Delivering genes to modulate neuroprotection/regeneration | Nanoparticles cross the blood–brain barrier, enabling targeted gene delivery with reduced immune response |
Stem Cell Therapy | Biomaterial Scaffolds | Enhancing stem cell survival and integration via 3D matrices | Hydrogels and nanocarriers improve stem cell engraftment, reducing inflammation and promoting repair |
Exosome-based Therapy | Nanocarriers | Transporting exosomes or drugs to mitigate oxidative stress | Carbo-genic nanozymes and engineered exosomes show efficacy in modulating neuroinflammation |
Precision Medicine | Brain–Computer Interfaces (BCI) | Using biomarkers (e.g., genomics) to tailor treatments | BCI enables neurofeedback for personalized cognitive rehabilitation, aligning with biomarker-guided plans |
Treatment Approach | Readiness Level | Key Findings and Limitations |
---|---|---|
Nanomaterials for Targeted Delivery/Neuro-regeneration | Preclinical | Nanoparticles demonstrate efficacy in animal models for targeted drug delivery and neuroprotection but remain still in preliminary research phases for TBI. Clinical translation is limited due to scalability issues challenges in manufacturing (low reproducibility, high cost) and safety concerns (potential off-target accumulation in liver and lungs) and long-term toxicity concerns [206,209]. |
Cell-Based Therapies (Stem/Progenitor Cells) | Clinical (Phase I/II Trials) | Autologous bone marrow-derived MSCs show safety and efficacy in early-stage clinical trials, with improvements in consciousness and motor function observed in subacute TBI patients. Limitations include donor variability, risk of tumorigenicity, poor survival/engraftment, and high costs of autologous cell processing [207,210,211,212,213]. |
Precision Medicine | Preclinical/Early Clinical | Genetic risk factors (e.g., APOE, BDNF, Tau polymorphisms) are under investigation for patient stratification. No targeted therapies have reached late-stage clinical trials [7]. Limiting factors are that there are no TBI-specific biomarkers for patient stratification, the polygenic nature of TBI, and the fact that there are no approved therapies targeting genetic risk factors (e.g., APOE) [1]. |
Brain–Machine Interfaces (BMI) and Virtual Rehabilitation | Clinical (Pilot Trials) | Implantable BMI systems are in active clinical trials for restoring communication in patients with motor impairments (e.g., ALS, stroke). Virtual rehabilitation lacks TBI-specific clinical data but is emerging as an adjunct. Implementation issues are related different factors: signal drift/noise in chronic BMI use, limited TBI-specific validation for virtual rehab protocols, and high costs of BMI hardware/software [208]. |
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Pilipović, K.; Janković, T.; Rajič Bumber, J.; Belančić, A.; Mršić-Pelčić, J. Traumatic Brain Injury: Novel Experimental Approaches and Treatment Possibilities. Life 2025, 15, 884. https://doi.org/10.3390/life15060884
Pilipović K, Janković T, Rajič Bumber J, Belančić A, Mršić-Pelčić J. Traumatic Brain Injury: Novel Experimental Approaches and Treatment Possibilities. Life. 2025; 15(6):884. https://doi.org/10.3390/life15060884
Chicago/Turabian StylePilipović, Kristina, Tamara Janković, Jelena Rajič Bumber, Andrej Belančić, and Jasenka Mršić-Pelčić. 2025. "Traumatic Brain Injury: Novel Experimental Approaches and Treatment Possibilities" Life 15, no. 6: 884. https://doi.org/10.3390/life15060884
APA StylePilipović, K., Janković, T., Rajič Bumber, J., Belančić, A., & Mršić-Pelčić, J. (2025). Traumatic Brain Injury: Novel Experimental Approaches and Treatment Possibilities. Life, 15(6), 884. https://doi.org/10.3390/life15060884