Advances in research on biomaterials and stem cell/exosome-based strategies in the treatment of traumatic brain injury

Abstract

Traumatic brain injury (TBI) is intricately linked to the most severe clinical manifestations of brain damage. It encompasses dynamic pathological mechanisms, including hemodynamic disorders, excitotoxic injury, oxidative stress, mitochondrial dysfunction, inflammation, and neuronal death. This review provides a comprehensive analysis and summary of biomaterial-based tissue engineering scaffolds and nano-drug delivery systems. As an example of functionalized biomaterials, nano-drug delivery systems alter the pharmacokinetic properties of drugs. They provide multiple targeting strategies relying on factors such as morphology and scale, magnetic fields, pH, photosensitivity, and enzymes to facilitate the transport of therapeutics across the blood-brain barrier and to promote selective accumulation at the injury site. Furthermore, therapeutic agents can be incorporated into bioscaffolds to interact with the biochemical and biophysical environment of the brain. Bioscaffolds can mimic the extracellular matrix environment, regulate cellular interactions, and increase the effectiveness of local treatments following surgical interventions. Additionally, stem cell-based and exosome-dominated extracellular vesicle carriers exhibit high bioreactivity and low immunogenicity and can be used to design therapeutic agents with high bioactivity. This review also examines the utilization of endogenous bioactive materials in the treatment of TBI.

Keywords: Biomaterial; Bioscaffold; Exosome; Extracellular matrix; Nano-drug delivery system; Regeneration; Stem cell; Traumatic brain injury.

Graphical abstract

Figure 1

Pathological mechanisms of TBI. Rupture of the BBB leads to edema and changes in ion balance. The release of intracellular components activates microglia and astrocytes, increasing oxidative stress, inflammation, and neural injury. An increase in extracellular Ca²⁺ and glutamate concentrations activates NMDAR receptors, and the mechanical activation and mechanoporation of NMDAR receptors result in increased Ca²⁺ concentrations. Excessive calcium uptake leads to neurotoxicity by decreasing the mitochondrial membrane potential, resulting in neural injury. The production of ROS increases, and after the destruction of the mitochondrial membrane structure, endotoxins and apoptotic factors are released into the cytoplasm, where they activate caspases and cause apoptosis. Simultaneously, the slow, chronic activation of calcium-permeable P2X7 purinergic receptors by a massive release of ATP leads to oligodendrocyte death, demyelination, and axonal injury. Microglia become highly activated and accordingly secrete large quantities of cellular inflammatory factors, which disrupt the BDNF–TrkB signaling pathway and allow circulating fibrocytes and other inflammation-related macrophages, leukocytes, and cytokines to enter brain tissue (Created with BioRender.com).

Figure 2

The stem cells rehabilitative schematic summarizes the mechanisms of TBI that lead to debilitating cellular and behavioral injuries and contrasts these with drug-stem cell-based interventions, which promote enhanced cellular survival and behavioral recovery (Reprinted with the permission from Ref. . Copyright © 2019 Neuropharmacology).

Figure 3

Mechanism of action of EVs in TBI treatment. (A) Schematic diagram of how EVs mediate neural repair and regeneration. After CCI injury, intravenous administration of NSC-EVs increases the expression of VEGF receptor-2 in the brain cortex and promotes the migration of endogenous NSCs and possibly newly generated neuroblast cells to the injury site. (Reprinted with the permission from Ref. . Copyright © 2023, Stem Cells Transl Med). (B) Schematic diagram of the mechanism by which EVs inhibit oxidative stress. Early administration of EVs derived from astrocytes after TBI can reduce tissue damage and motor and cognitive deficits by activating the Nrf2 signaling pathway, which has antioxidant effects (Reprinted with the permission from Ref. . Copyright © 2023, Stem Cells Transl Med).

Figure 4

Schematic diagram of the alleviation of neurodegeneration by Exos. The expression of miR-124-3p in microglia increases after TBI and miR-124-3p in Exos is subsequently transferred into hippocampal neurons to alleviate neurodegeneration by targeting the Rela/ApoE signaling pathway (Reprinted with the permission from Ref. . Copyright © 2020 Mol Ther).

Figure 5

PMNT/F@D-nanoparticles reduced reactive ROS accumulation in the cellular microenvironment, inhibited cell apoptosis, and simultaneously promoted PC12 cell proliferation and differentiation, thereby improving the microenvironment of the injured area to protect nerve cells from ischemic damage (Reprinted with the permission from Ref. . Copyright © 2022, J Am Chem Soc).

Figure 6

Schematic illustration of the manufacturing and in vivo experimental process of dendritic polymers. PAMAM nanodimers effectively delivered plasmid DNA encoding CCL20 and/or CCR6 to the brain and spleen, and treatment with shCCL20–CCR6 nanodimers reduced rTBI-induced neuroinflammation; combined treatment with shCCL20–CCR6 nanodimers and hMSCs increased BDNF expression and more effectively reduced TBI-related damage (Reprinted with the permission from Ref. . Copyright © 2020, Nanomedicine).

Figure 7

Schematic of the manufacturing and characterization of leukocyte nanoparticles and in vitro and in vivo experiments. Leukos were prepared by extracting membrane proteins from cultured leukocytes, characterized for their physicochemical and biomimetic properties, and then evaluated for targeting in a TBI mouse model through an in vivo imaging system and intravital microscopy as well as immunohistochemical techniques (Reprinted with the permission from Ref. . Copyright © 2021, Adv Funct Mater).

Figure 8

Bioscaffolds that provide physical support for the lesion site. Electrospun PLGA-functionalized sphingomyelin ceramide LysoGM1 formed a directional fiber network. The scaffold supported the growth of neuronal axons and protected neurons from pressure-related damage. (Reprinted with the permission from Ref. . Copyright © 2020, Acs Biomater Sci Eng).

Figure 9

Mechanisms by which implantable scaffolds exert therapeutic effects on TBI. (A) Bioscaffolds for cellular tissue regeneration. A chitosan-based fiber matrix supported morphologically mediated hESC differentiation; substrates made up of 400 nm- and 1.1 μm-diameter fibers increased the expression of neural cell markers, while substrates composed of 200 nm-diameter fibers increased the expression of bone and liver markers. (Reprinted with the permission from Ref. . Copyright ©2012, Macromol Biosci). (B) Bioscaffolds for TBI inflammation treatment. In situ injection of a HA hydrogel with galactose oxidase and horseradish peroxidase bioenzymes encapsulating BMSCs and NGF promoted the survival and proliferation of endogenous neural cells through the release of neurotrophic factors and modulation of neuroinflammation. (Reprinted with the permission from Ref. . Copyright © 2021, Mater Today Bio). (C) Bioscaffolds for vascular remodeling. A dual-affinity hydrogel with Hep-N cells with growth factor affinity and the lipid companion activity of albumin showed the potential to repair brain vessels. (Reprinted with the permission from Ref. . Copyright © 2018, Acs Biomater Sci Eng).