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Engineering of Electrospun Nanofiber Scaffolds For Repairing Brain Injury
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1. Introduction
The central nervous system (CNS) plays a vital part in health and well-being, and the brain is the most vulnerable organ of the CNS [1]. Brain interposes input from the external environment and processes information to support operational repair. Currently, brain injury is one of the most serious public health problems, which mainly includes traumatic brain injury (TBI), ischemic brain injury (IS), hemorrhagic brain injury, etc. In the acute stage, the clinical treatment of brain injury is mainly surgical. However, the brain has a limited regenerative capacity [2,3], and tissue damage or neurological damage caused by disease or traumatic brain injury is permanent, leading to cognitive, motor, and neurological dysfunction, among others. In response, most current clinical treatment strategies are based on drug therapy to reduce further tissue loss and/or alleviate other symptoms such as inflammation, coupled with postoperative maintenance of motor function through rehabilitation, etc. However, these approaches often result in poor outcomes due to narrow time windows and the limited penetration of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) with conventional oral or intravenous therapeutic agents [4,5]. The BBB prevents the entry of potentially harmful substances to the brain from the blood [6] while the BCSFB controls the transfer of molecules from the blood to the cerebrospinal fluid before entering the brain [7], [8], [9]. These subtle mechanisms control the homeostatic state within the brain but also limit the passage of various therapeutic molecules. Thus, after a systemic administration (e.g., intravenous injection) of therapeutic cells or molecules, only moderate concentrations of these therapeutic drugs can reach the brain, resulting in unsatisfactory treatment outcomes. In this case, high or frequent doses of therapeutic agents are often necessary to achieve the desired therapeutic effect, which may exacerbate systemic toxicity [10]. For example, the use of N-acetylcysteine (NAC) drugs for TBI requires an increased systemic dose, which can lead to adverse effects such as increased blood pressure [11], and the use of chemotherapeutic drugs to treat brain tumors can cause toxicity to cells throughout the body upon entering the circulation [12,13].
To resolve this paradox, the most often used methods include disruption of the BBB and invasive drug delivery to maximize drug concentrations at the target site while minimizing drug exposure to surrounding tissues. Disruption of the BBB was proposed in the 1960s [14] and can be achieved with hypertonic solutions such as mannitol, drugs, or focused ultrasound [15]. Additionally, an invasive procedure to create a hole a few millimeters into the skull allows therapeutic drugs to be injected directly into the brain through this channel. Unfortunately, these invasive strategies not only can induce further neuronal damage and inflammatory responses, but also ignore the balance of the internal environment in the brain tissue. For example, drugs that increase the permeability of the BBB, such as histamine, tend to induce inflammatory effects due to sudden changes in the chemical composition of the internal environment [16]. Thus, to avoid these adverse influences, developing sophisticated brain tissue engineering strategies show great promise to repair and further regenerate brain tissues at the site of damage through reconstructing the cellular microenvironment, ultimately achieving functional reconstruction [17].
The brain consists of interconnected neurons that interact with the extracellular matrix (ECM) to form a complex network [18]. Cell loss following nerve injury can adversely affect brain function by disrupting the connectivity and signaling between neurons. In addition, progressive degeneration usually activates astrocytes, microglia, or macrophages and oligodendrocyte precursor cells, which facilitate the formation of glial scarring and leads to the formation of desmoplastic cavities in the lesion site [19,20]. Cell therapy is expected to replace apoptotic neurons and/or prevent further degradation by introducing exogenous cells, promoting the expression of relevant trophic factors, guiding axon growth and promoting angiogenesis [21]. In the process of tissue regeneration, neurotrophic factors can promote the survival of neurons and the establishment of connections between neurons to achieve the re-establishment of functional neural networks. Common trophic factors include glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). In animal models of Parkinson's disease (PD) [22], [23], [24], Huntington's disease [25,26], and TBI, increasing the expression of these neurotrophic factors can accelerate the promotion of cell survival and integration [27], so as to realize tissue regeneration.
The creation of a microenvironment for cells growth is essential not only in promoting normal cell growth to reduce inflammation, supporting the survival of neurons (endogenous or derived from exogenous cells), and reconstructing the vascular network at the site of injury, but also in avoiding further damaging tissue surrounding lesion site as the support structure [28,29]. Thereby it can be good support for drug therapy and cell therapy. Electrospun nanofiber scaffolds are well received in various tissue engineering [30], especially in neural tissues [31], [32], [33], due to special properties that simulate the structure of the ECM. Electrospun nanofibers scaffolds can guide axons extension of neurons and modulate the phenotype and function of cells associated with brain injury. Different cues can be combined or integrated with electrospun nanofibers [34], involving physical cues like gradient structures and fiber diameters, biochemical cues like growth factors, exogenous cells like stem cells [35], and other support materials like hydrogels or nanoparticles [30].
In this review, we firstly discuss the mechanisms of several common brain injuries including TBI, ischemic brain injury, and hemorrhagic brain injury, and then summarize the recent development of the functionalization of electrospun nanofiber scaffolds. Afterwards, we discuss the recent and representative development in the application of electrospun nanofiber scaffolds in brain injury repair. In the end, we raise the prospect for the future development direction of combining electrospun nanofiber scaffolds with other tools, aiming to improve the treatment efficacy for treating brain injury.
2. Pathologies of Different Types of Brain Injuries
Brain injuries can be caused by different reasons, such as external shocks, near-drowning, cerebrovascular diseases, and brain surgery [36], leading to TBI, IS, hemorrhagic stroke, and so on. Current clinical treatment strategies mainly include clinical surgery (e.g., blood drainage), pharmacological treatment (e.g., recombinant tissue plasminogen activator (rtPA)), and physical therapy (e.g., electrotherapy and ultrasound), all of which are very limited to prevent the onset of sequelae [37]. Understanding the pathologies after brain injury is important to explore new treatment strategies for providing brain injury patients with a better quality of life.
2.1. Traumatic brain injury
TBI involves brain tissue damage and dysfunction, which is caused by a series of sharp or blunt mechanical external forces, usually resulting from traffic accidents, falls, sports injuries, and criminal violence. TBI includes primary injury caused by the direct action of mechanical external forces and secondary injury triggered minutes or hours later [38]. Depending on the degree of the injury, primary injury can manifest as increased intracranial pressure, nerve damage, vascular damage, tissue swelling, and hypoxic damage [39]. Then, secondary brain injury can be immediately triggered through the four main mechanisms of cellular excitotoxicity, neuroinflammatory cytokines, oxidative stress, and apoptosis [40,41].
Cellular excitotoxicity, primarily caused by the massive release of glutamate, is a form of secondary damage [42]. The damage caused to axons by mechanical forces leads to extravasation of glutamate into the ECM, resulting in the swelling of neurons and astrocytes through the inward flow of sodium and calcium ions [38]. In addition, the high intracellular calcium levels can activate a range of catabolic enzymes capable of disrupting both cellular and mitochondrial membranes as well as the cytoskeleton and can also cause DNA fragmentation, ultimately leading to cell death [43]. At the same time, intracellular calcium overload leads to the opening of mitochondrial permeability transition pores, significantly affecting the function of the mitochondria and preventing them from producing adenosine triphosphate to meet metabolic demands [44]. Glutamate also contributes to the production of reactive oxygen species (ROS), which can cause damage to critical cellular components like DNA and lipid membranes [38,40].
Cytokines are biologically active proteins that are secreted by immune and certain non-immune cells. These regulate cell growth and differentiation as well as affect and regulate immune response by binding to corresponding receptors. Cytokines secreted by immune cells include interleukins, interferons, and chemokines, which can be involved in the neuroinflammatory response [40,45]. After TBI occurs, inflammatory cells such as activated microglia, neutrophils, and macrophages produce a variety of pro-inflammatory mediators to promote neuroinflammation [46], thereby accelerating brain edema, disruption of the BBB, and cell death, while resulting in secondary post-traumatic injury.
Oxidative stress is the imbalance between oxidation and anti-oxidation in the body, and a tendency toward oxidation results in an excess of free ROS, which damages the molecules that makeup DNA, proteins, and lipids, ultimately leading to apoptosis and tissue necrosis [47]. As the inflammatory response of microglia gradually increases, the upregulation of NADPH oxidase 2 (NOX2) in phagocytes occurs for several days, catalyzing the production of large amounts of ROS that significantly contribute to oxidative stress injury and neuronal death. Furthermore, other major sources of ROS include oxidation products from hemoglobin and products from the activation of NOX2 by bradykinin, etc [48].
Apoptosis of neurons is initiated by a variety of pathways, among which the main one being the initiation of mitochondrial dysfunction through the cysteine-aspartate protease (caspase)-dependent pathway [49]. A series of different caspases are activated by proteolytic cleavage to form a complex that causes the release of cytochrome C, a molecule that can induce apoptosis. Beyond that, some caspase-independent pathways may also regulate cell death. For example, mitochondria can cause chromatin condensation at peripheral nucleus and the fragmentation of DNA through the release of apoptosis-inducing factor (AIF) [40].
2.2. Ischemic stroke
Stroke is the second leading reason of death worldwide and can cause long-term disability [50]. Resulting in brain damage due to clogged or ruptured vessels in the brain, stroke is characterized as a group of diseases that include IS and hemorrhagic stroke (intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH)), with IS dominating the morbidity of strokes overall [50]. The development of IS involves a variety of factors, such as genetic factors, type of diet, and lifestyle. The pathogenesis of IS is complex and is usually caused by cerebral thrombosis and cerebral embolism, accompanied by atherosclerotic plaque destruction, with thrombosis being the main clinical pathogenesis [51]. Atherosclerosis, caused by damage to the endothelium [52], leads to the occlusion of the arteries in the brain, eventually resulting in reduced cerebral blood flow and consequent cerebral ischemia [53]. The release of damage-associated molecular patterns (DAMPs) from neurons in the central ischemic area activates the immune response, followed by the release of TNF-α, IL-1β, and other inflammatory factors from astrocytes and microglia, as well as the upregulation of ICAM-1 expression in vascular endothelial cells, which can then trigger an inflammatory response and irreversible neuronal death, as shown in Fig. 2.
The area surrounding the infarct core, known as the penumbra, is a potentially salvageable area of the brain that remains metabolically active and returns to normal function after continuing to receive an adequate blood supply [54]. Thus, the penumbra, which typically accounts for half of the brain volume damaged after a stroke, provides an opportunity for treatment. Neuronal death in the penumbra is much slower than in the infarct core and may take several days to occur, so at least some neurons of the penumbra may be salvageable if there is a timely therapeutic intervention to restore blood [55]. However, if treatment is not timely, neurons in the penumbra will suffer from apoptosis through mitochondrial dysfunction, oxidative stress, and autophagy [56,57]. On one hand, the dysregulated sodium-potassium pumps of neurons in the penumbra result in the release of large amounts of glutamate into the synaptic gap, causing excitatory amino acid toxicity in the cells. Simultaneously, one part of the glutamates binds to α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors to facilitate
inward flow [58], ultimately inducing apoptosis through membrane potential imbalance, DNA damage, and mitochondrial dysfunction. The dysfunctional mitochondria release apoptosis proteins, from the caspase-dependent and independent apoptosis pathways to exert apoptosis [59]. Another part of glutamates binds to N-methyl-d-aspartic acid (NMDA) receptors and then releases ROS and RNS to trigger an oxidative stress response leading to apoptosis. While, on the other hand, the expression of LC-3, beclin 1, and other related autophagy proteins are up-regulated in the neurons of the penumbra, which causes the over-activation of the cellular autophagic response, leading to cell death through degradation of the nucleus. The relevant signaling pathways are also described in Fig. 2. In addition, oxidative stress in cells can also induce cellular autophagy [60].
2.3. Hemorrhagic stroke
Hemorrhagic strokes account for 15% of all strokes, and can cause the most damage and mortality [61]. There are two types of hemorrhagic strokes, ICH and SAH, of which ICH is twice as common. In addition, most survivors of ICH exhibit various sequelae symptoms, causing significant inconvenience in daily life [62]. A variety of factors can contribute to the development of ICH, involving the angiorrhexis at different locations in the brain due to chronic hypertension, cerebral amyloid angiopathy (CAA), arteriovenous malformations, or systemic diseases [63].
Brain injury after ICH is similar to TBI, mainly consisting of primary injury and secondary injury [64]. Primary injury is caused by hemorrhage, and involves mechanical damage triggered by the effect of the hematoma mass on the surrounding tissues during the hyperacute phase of ICH, where blood rapidly accumulates at the brain parenchyma within minutes, causing damage to normal tissue structures and increasing pressure to the cranial cavity [65]. High intracranial pressure decreases cerebral blood flow and can even cause displacement of brain tissue, resulting in brain herniation. In addition, mechanical compression from the hematoma as well as blood clots including some toxic substances can cause the death of neurons and damage of the BBB, ultimately inducing cerebral edema [65]. Secondary injury is caused by the pathological response to the hematoma, and it occurs as the body responds to the hematoma and high intracranial pressure in a series of ways, the mechanisms of which involve inflammation, oxidative stress, cellular excitotoxicity, and cytotoxicity [63]. The main signaling pathways are shown in Fig. 3. After the occurrence of ICH, the blood released by a ruptured blood vessel enters the brain tissue and triggers an immune response in the brain. The activated immune system accelerates the infiltration of surrounding inflammatory cells into the lesion site in brain, triggering inflammation by releasing inflammatory factors. Meanwhile, excess glutamate released by damaged neurons can lead to the inward flow of
and eventually resulting in cellular edema. Meanwhile, stimuli such as high mobility group protein 1(HMGB1) generated by dead neurons can bind to TLR4 receptors, thereby activating microglia [63]. In addition, hemoglobin (Hb) produced by the breakdown of released red blood cells from the blood can be degraded to heme, which in turn is broken down by heme oxygenase-1 and heme oxygenase-2 to iron [66,67], carbon monoxide, and biliverdin. The excess iron is then removed from the cells via efflux transporters (FPNs) and deposited in brain tissue, where it releases numerous ROS through the Fenton reaction, inducing oxidative stress and inflammation [64]. At the same time, fibrinogen released from the blood can cause inflammation by activating microglia, leading to neuronal death. After hematoma production, the coagulation system can limit the expansion of the hematoma by activating and releasing thrombin, which likewise causes microglial activation and increases the release of inflammatory cytokines [68].
Ruptured intracranial aneurysms are the main cause of most non-traumatic cases of SAH [69]. Other causative factors include cerebral venous thrombosis, cerebrovascular malformations, pituitary apoplexy, and so on [70]. The pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH) can be divided into two phases: early-type brain injury within the first 72 hours and delayed cerebral ischemia (DCI) within 3-14 days after initial bleeding [71]. The blood released by a ruptured blood vessel enters into the subarachnoid space, causing intracranial macro-physiological changes, such as increased intracranial pressure (ICP) [72], decreased cerebral perfusion pressure (CPP), and cerebral blood flow (CBF), thus triggering whole-brain ischemia. Eventually, whole-brain ischemic and released blood in the subarachnoid space can induce neuroinflammation, oxidative stress, BBB disruption, brain edema, and the death of neurons through different mechanisms [71]. DCI is the main complication of aSAH [73]. Among the listed various etiological factors, vasospasm is the main pathogenesis and is caused by luminal narrowing due to the strong contraction of smooth muscle in the vessel wall that results in reduced blood flow within the brain tissue. At present, there is an abundance of showing that oxygen-containing hemoglobin (OxyHb) plays a vital role in causing vasospasm [74], with contributing related mechanisms that include oxidative stress, inflammation, decreased nitric oxide (NO) levels, and increased endothelin (ET) levels, among others [71].
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