At present, a large number of economic resources are invested in different institutions around the world to carry out hundreds of investigations to study the pathophysiology and degenerative evolution of SCI and to learn more about the pathological mechanisms in order to develop new and more effective alternative therapies. This is a consequence of the worrying and increasing morbidity and mortality that this destructive neurological and pathological state entails (2).

In general terms, the pathophysiology of SCI is divided into an acute phase and a chronic phase. During its progression, a cascade of destructive events occurs from inflammatory processes, oxidative stress, cell apoptosis, and ischemia, which give place to the loss of locomotor and sensory functions (3). SCI triggers a series of biochemical and cellular events that eventually lead to the death of neurons, oligodendrocytes, astrocytes, and cell precursors. The main determinants of the severity of SCI are the extent of initial destruction (2, 3, 5).

Acute SCI commonly occurs from severe trauma to the spine where vertebral fractures or dislocations also occur. The primary injury appears immediately after the initial injury and is divided into two stages: Initially, it involves neural tissue damage, axonal connection interruption, glial membrane detachment, and hemorrhage. While clinical evidence suggests this causes a complete loss of functions, it has been observed that certain axonal connections remain during the primary SCI phase, demonstrating the existence of a state when there is only a partial lesion (2, 3, 6).

The secondary injury is triggered by the primary injury, causing other chemical and mechanical damages to the rachidial tissue. This produces neuronal excitotoxicity due to the high accumulation of calcium inside the cells increases the concentrations of reactive oxygen species and the release of glutamate. These events cause oxidative damage in proteins, phospholipids, and nucleic acids which can cause neurological dysfunction. Neuronal and glial damage include augmented cell permeability, edema, ion dysregulation, vascular damage, lipid peroxidation, apoptotic signaling, excitotoxicity, inflammation, demyelination, Wallerian degeneration, fibroglial scarring, and cyst formation (2, 3). Neuroinflammatory mechanisms could be induced by the events of secondary injury or on the other side the inflammatory response exacerbates it. For this reason, it is known that neuroinflammation after SCI can induce both beneficial and detrimental effects on locomotor function recovery; hence, it is necessary to characterize all the implications caused by inflammation to approach therapy research correctly (7).

The inflammatory response starts from the disruption of the blood–brain barrier (BBB), and the rupture of blood vessels causes hemorrhage into the spinal tissues, thus increasing the permeability of immune cells from the circulatory system to the lesion microenvironment, followed by monocyte, neutrophil, lymphocyte, and macrophage infiltration to the spine. The inflammatory cytokine output such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor (TNF-α), 6 to 12 h after injury, as a result of immune cells and anti-inflammatory cytokines presence, a neurological inflammatory process is given (3, 6, 8). During the acute phase (48 h after the lesion), vast inflammatory cells migrate into the exposed tissue and secrete cytokines (5). At this early phase, neutrophils reach their peak 24 h post-lesion. Afterward, the chronological arrival of inflammatory cells is characterized, in the subacute phase, by microglia peaking on day 7 and T cells peaking on day 9 after the lesion. Furthermore, at the late phase, a secondary injury cascade, starting 14 days after the injury, the peak of cellular inflammation takes place on day 60 post-lesion (characterized by the high prevalence of microglia) and it is still detectable for all three cell types over 180 days (9). Inflammation progresses through the action of pro-inflammatory cytokines, which include TNFα, gamma-interferon (IFNγ), CXC motif chemokine ligand 1 (CXCL1), IL-1, IL-12, IL-18, and the granulocyte–macrophage colony-stimulating factor (GMCSF), and it is solved with anti-inflammatory cytokines such as IL-4, IL-10, and IL-13 (10).

The presence of T helper cells (Th) in CNS is regulated by three specific points: subarachnoid vessels, choroid plexus and parenchyma, and post-capillary venules. CD4+ T cells might also become tissue-resident after inflammatory episodes (11). These cells modulate how innate and adaptive immune cells function and are recruited through the secretion of anti-inflammatory cytokines and growth factors. One crucial feature of T cells is the immunological synapse, which is the connection that allows an adaptive immune response to mediate injury repair and then differentiates to variable phenotypes of T cells according to the cytokines that are released, except for Th1 and Th2 subsets (12). The acute lesion is usually distinguished by the presence of Th1 subsets that control the discharge of pro-inflammatory cytokines, such as IL-2, IL-12, and IFNγ, therefore resulting in demyelination and parenchyma destruction, although their possible beneficial effects are still under debate. Prior to that, at the subacute phase, Th2, Treg, and Th17 prevalence can be identified due to the release of IL-4, IL-10, IL-17, and IL-23 cytokines, protecting the spine from autoimmune effects. If the microenvironment characteristics are optimal and the susceptibility of the individual is appropriate, recovery could be enhanced during this phase by reducing neuroinflammation (11). However, several articles show that different Th phenotypes can mediate immune-mediated damage, Exacerbated inflammatory response or even generate autoimmune CNS inflammation (9, 13). In addition, inflammatory conditions allow the predominance of T-cell phenotypes, such as Th1 and Th17 (14). Even though they mainly secrete a profile of pro-inflammatory cytokines, they also contribute to lesion repair by different pathways: Reactive astrocytes help to the restoration of BBB by inducing endothelial tight junction repair, cleaning cellular debris, and reducing excitotoxicity (15). Reactive astrocytes form a dense glial scar at the edge of the lesion surrounding a central lesion composed of proteoglycans and activated phagocytic microglia/macrophages. These cells have a constant cross-talk interaction with phagocytic cells by the release of different profiles of cytokines and chemokines (16). The formation of this scar limits the spread of necrotic, apoptotic, and infiltrating inflammatory cells, inhibiting neuroinflammation (7). Furthermore, negatively, the formation of glial scar interrupts axonal regeneration (15). To counteract all these harmful effects, strategies have been designed for therapeutic biomaterials to control neuroinflammation.

Now, different drugs regulate or inhibit different mechanisms involved in the inflammatory response; however, the direct effect is not possible and that limited the recovery after SCI and has a secondary consequence that depends on the type of drug administered. A viable strategy for solving it is nanomedicine, which has increased its importance and presence in different investigations in recent years. This has a fundamental role in the design of new therapeutic strategies in pharmacology, such as the controlled kinetic release and bioavailability of active ingredients, managing to increase the effectiveness of already established treatments, and reducing adverse effects. In the technological branch, nanomaterials such as NPs and nanofibers are being developed to serve as a replacement for the neural tissue affected or lost in SCI, as well as nanopharmaceuticals that manages to integrate the tissue to its normal state (17–19).

Mesenchymal stem cells are an attractive approach for cellular therapy due to their self-renewal ability and differentiation to multiple variable mesenchymal lineages. As multipotent cells, MSCs are able to differentiate into other mesodermal tissues such as bone, cartilage, and cardiac muscle. Immunomodulatory properties and paracrine mechanisms of MSC benefits have been described in multiple studies (65, 66). MSCs have favorable effects by stem cell therapy after SCI, as a result of the advantages listed: (1) simple isolation and cryopreservation, (2) preserve regenerative ability and self-renew ability even at −80°C, (3) elevated proliferation rate and potential of multilineage differentiation, and 4) decreased the immunoreactivity and graft-vs.-host reaction of transplanted allogeneic MSCs (66, 67).

The principal sources of MSCs are bone marrow, umbilical cord blood, adipose tissue, and peripheral blood, even though they can be obtained from a variable range of tissues. MSCs are a viable option for lessening the negative pathophysiological effects of SCI (65). In regard to recovery after SCI, therapeutic methods mainly focus on achieving axon re-growth, inhibition of apoptosis, and substitution of damaged cells with oligodendrocytes in favor of axon remyelination (68). When MSCs are administered to the injury site following SCI, they produce and release different growth factors, including brain-derived neurotrophic factor (BDNF), glial derivate neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF-2), and transforming growth factor (TGFβ), the molecules that promote axonal regeneration. In addition, MSCs downregulate apoptosis by reducing levels of apoptotic molecules and increasing the survival molecules in SCI animal models. Another important effect of these cells on cytokines is an increase in serum IL-10 and a decrease in tumor TNFα, which plays a relevant role in T-cell transitions from pro-inflammatory Th1 to anti-inflammatory Th2 phenotype, as well as macrophage phenotype transition from M1 (immune surveillance) to M2 (downregulating immune response). Through these mechanisms, MSCs enhance the survival and development of neurons and axonal regeneration (69, 70).

Stem cell transplantation is receiving increased attention as a therapeutic approach for the treatment of neurological diseases (71, 72). At the time of writing this article, there were 52,055 clinical trials involving neurological diseases and 743 involving stem cell-based therapy for neurological diseases. After SCI, only 60 studies included stem cell-based therapy and only six studies used NPs and stem cells on other pathologies (www.clinicaltrials.gov, accessed on 8 December 2022). Although a limited research area exists for stem cells' potentiated effect with NPs, MSCs have an immunomodulatory effect; however, none of these cells have produced more than a partial recovery of function, being an active area of research.

The therapeutic strategies that combination with NPs could potentially exacerbate the neurorestorative effect of MSCs, based on these foundations in 2015, Tukmachev et al. exposed that superparamagnetic IONPs can promote the taking in of MSCs at the injury site in a rat model of SCI (45). In the same context, Vishwakarma et al. developed a novel gadolinium-SPIO (Gd-SPIO) that acts like magnetic NPs with an elevated level of biocompatibility and potentially acquires a better contrast in MRI. As a result, it was proposed that the transplantation of neuronal cells labeled with Gd-SPIONPs could be an excellent approach for achieving high-contrast imaging and non-intrusive cell trapping at specific sites while remaining unaffected by inhibitory molecules. In a different study, magnetically labeled MSCs were introduced into the subarachnoid space in both the magnet and non-magnet groups. MSCs agglomerations were detected superficial to the SCI in the magnet group; on the contrary, few MSCs were observed in the non-magnet group. The hindlimb motor function of the magnet group displayed a significant improvement in comparison with the non-magnet groups (73). Furthermore, this combined therapeutic approach for regeneration after SCI is capable of potentiating the use of tissue engineering strategies to effectively bridge the injury (74). As regards, anti-inflammatory, anti-oxidative, and anti-excitotoxicity effects of ferulic acid (FA) and glycol chitosan (GC), both can be contemplated as natural neuroprotective compounds (75, 76). FA is capable of absorbing a hydrogen atom to form a phenoxy radical by the phenolic hydroxyl group; as a result, it protects cells from oxidative stress (76). Apart from that, the primary amines of GC might have a relevant role in neuroprotection. Wu et al. produced hydrophobic self-assembled FA-GCNPs by chemical conjugation, which displayed neuroprotective effects of FA–GCNPs following SCI. Systemic administration of these NPs promoted neuron cells and axons survival at the injury site and reduced the number of macrophages and activated astrocytes. Hence, these neuroprotective effects led to significant recovery after SCI (77).

The regenerative efficacy of IONPs-treated human MSCs was evaluated using exosome-mimetic nanovesicles (NV-IOPs) in a SCI model, with the results showing an increased amount of therapeutic growth factors associated with IONPs, which were slowly ionized to iron ions for the activation of JNK and c-Jun signaling cascades in human NSCs. In vivo systemic administration of these with magnetic guidance upregulated their number at the injury site. In addition, NV-IONP agglomeration promoted angiogenesis, generated anti-inflammatory and anti-apoptotic effects in SCI, and therefore had beneficial effects on SC function (78).

The principal focus of experimental models of SCI is stem cell transplantation into injured SC for motor recovery; however, bladder dysfunction investigation is almost none. However, Lee et al. investigated the effect of B10 human MSCs grafts into the bladder wall of SCI rats to prove their capability of collagen deposit inhibition and cystometric parameter improvement. Consequently, the SCI rats decreased their weights and collagen deposition, and furthermore, these cells differentiated into smooth muscle cells. The transplanted B10 cells helped to prevent bladder fibrosis and bladder dysfunction in the rat SCI model. Therefore, MSCs-based cell transplantation is a potential therapeutic approach for bladder dysfunction in patients with SCI (79).

Human NSCs are derived from induced pluripotent stem cells (iPSC-NSC), human MSCs, and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C), which promote the sustained secretion of curcumin delivered into the intrathecal space in SCI contusion model in rats with stem cell transplantation. As a consequence, the locomotor function was improved (BBB scale), scars had reduced in size, and β-III tubulin-positive axons, motoneurons, and myelinated tracts were preserved. PA-C therapy promoted microglia into an anti-inflammatory phenotype (80). These studies advocate that MSC combination with other therapies is possible in favor of boosting their therapeutic potential. For example, another cell therapy is NSCs.

These cells are multipotent cells with a high capacity for self-renewal and multidirectional differentiation potential to separate themselves into mature neurons and glial cell phenotypes. This provides a promising strategy, which could restore neuron loss after injury or in disease states. However, treatments with NSCs present challenges in terms of their regulation and evaluation of outcomes, including survival, distribution, differentiation, and integration. Long-term therapies generally focus on secondary damage alterations such as neuroinflammation and maladaptive plasticity, aiming at preserving the tissue and multiplying the production of exogenous NSCs to increase regeneration (26, 81). The combination of nanotechnology with stem cells is continuously developing and has shown that it can favor clinical and therapeutic diagnosis in various CNS diseases. NPs are innovative components for regenerative medicine due to their physicochemical characteristics (26, 82); they can be made of organic, inorganic, or composite-based materials and can be combined with different polymers to improve their hydrophilicity, biocompatibility, bioavailability, targeting capacity, and approach efficacy that can reduce dose-related and drug release at the site of injury (29).

GNPs provide a very effective method for introducing substances into cells and are characterized as being non-toxic, non-immunogenic, and biocompatible, which makes them ideal resources to be applied in biomedicine (83). The GNPs are distributed as negatively charged or positively charged. After SCI, GNPs positively increase neuronal growth when incorporated into embryonic cells or NSCs when applied on rats with SCI, promoting neuroregeneration and motor recovery function, thus suggesting that transplantation may be an effective therapy for injury repair (84).

Chitosan NPs (ChNPs) and valproic acid (VANPs) have shown efficacy as protective agents in SCI treatment. A study in 2021 found that ChNPs treatment with VANPs benefited tissue regeneration and locomotor function after SCI, significantly improved NSC proliferation and secretion levels of neurotrophic factors, promoted the outgrowth of neurite since it stimulated overexpression of microtubule-associated protein, and decreased IL-1β, IL-6, and TNF-α expression (85).

Chitosan NPs have chemical characteristics that are determined by two variables: molecular weight and the degree of acetylation (DA). Previous research has shown that DA plays a key role in the incorporation of artificial membranes, the sealing of mammalian membranes, and, finally, the restoration of neurophysiological function ex vivo (56).

Poly[lactic-co-glycolic acid] is a biodegradable polymer approved by the US FDA and the EMA. It has drawn attention due to its excellent biocompatibility and biodegradability, as well as its predictable biodegradation kinetics. Due to these characteristics, it has been used as a nanocarrier, has low toxicity and immunogenicity, and allows prolonged drug release. PLGA-encapsulated methylprednisolone has been used in SCI, and it has demonstrated a decrease in secondary injuries related to inflammation as well as a significant regenerative outcome 7 days post-injury (30). Another study has used electrospun nanofibers of PLGA and PEG, which enhanced the adhesion and proliferation of NSC derived from induced pluripotent stem cells (iPS). iPS derived from NSCs proved greater differentiation potential on the exterior of PLGA/PEG biomaterials. Furthermore, scaffold strategies combined with iPSC-NPC therapy have been demonstrated to improve functional SC rehabilitation after transection (86).

Neuroregeneration through NSCs in combination with NPs could provide promising therapies to repair and/or regenerate the damage caused by neurodegenerative diseases; likewise, these therapies may emerge as alternatives in the diagnosis of some CNS disorders.

In SCI, the use of NPs can increase the survival rate, decrease the diffusion of stem cells after transplantation, elevate the rate of differentiation into functional neurons, and direct the growth of stem cells. NPs and stem cells can be complementary therapeutic options.

Olfactory ensheathing cells are a resident of glial cells which are found in the peripheral nervous system (PNS) and CNS and are mostly observed in the central olfactory bulb (OB) and the nasal olfactory mucosa (87). They come with the surface of olfactory nerve fibroblasts, in order to hold the bundles of olfactory nerve fibers from the nasal mucosa for permitting synapsis in the OB (88). A study has shown that OB transplants can be differentiated for generating connections between the periphery and brain (87).

Brain-derived neurotrophic factor, GDNF, and NGF are expressed for OECs, and these are important for the propagation and guidance of axons, displaying similar features with astrocytes and Schwann cells (89, 90). The neurotrophic factors are able to protect neurons as a result of their capacity to inhibit the formation of scars and promote axonal re-establishment (91). They also are crucial for neural regeneration in reason of their capacity to proliferate and migrate from PNS and CNS. Recent studies have shown that extracellular vehicles (EVs) with OECs regulate cell–cell communication, viability, and toxicity (92).

Additional studies are needed to know more about the effect of the combining OECs and NPS ChABC-loaded PLGA at the injured site 1 week following the contusion, demonstrating myelin in the group with NPs ChABC-loaded PLGA and a significant therapeutic effect on functional recovery (93). Other outcomes demonstrate a function for human OEC-derived EVs in NSC proliferation and oxidative stress-induced neuronal toxicity model (94).

Fan et al. showed that isolated exosomes by the PEG-based method are a critical role in immunomodulation and could be engulfed by microglia and polarized anti-inflammatory response after SCI. The disadvantage is that the categorized EVs may perhaps trespass on other cell membranes, causing the results to be misinterpreted. Further studies are needed with regard to giving greater evidence about the effectiveness of this combinatory therapy with OECs and NPs (34).