Hydrogel as Delivery System in Spinal Cord Injury: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Rong Ji
,
Zhizhong Hao
,
Hao Wang
,
Xingfan Li
,
Linyan Duan
,
Fangxia Guan
,
Shanshan Ma

Spinal cord injury (SCI) is a severe neurological injury caused by traffic accidents, trauma, or falls, which leads to significant loss of sensory, motor, and autonomous functions and seriously affects the patient’s life quality. Although considerable progress has been made in mitigating secondary injury and promoting the regeneration/repair of SCI, the therapeutic effects need to be improved due to drug availability. Given their good biocompatibility, biodegradability, and low immunogenicity, injectable hydrogels can be used as delivery systems to achieve controlled release of drugs and other substances (cells and proteins, etc.), offering new hope for SCI repair. 

  • injectable hydrogel
  • spinal cord injury
  • delivery systems

1. Introduction

Spinal cord injury (SCI), one of the most serious public health problems, often results in irreversible neurological damage and dysfunction, which has huge emotional, economic, and social impacts on patients and their families [1]. The leading causes of SCI include collisions, sports-related accidents, falls, and violence-related injuries [2][3]. SCI can be divided into primary injuries and secondary injuries. Primary injuries occur at the initial stage of injuries and disrupt the structural integrity of the tissue within seconds, and they are characterized by tears in bone fragments and spinal ligaments. Secondary injuries are divided into three stages: acute, subacute, and chronic stage [4]. Acute secondary injuries are direct results of the primary mechanical trauma and are accompanied by features such as vascular damage, free radical production, lipid peroxidation, inflammation, and ischemia [5]. In the subacute phase, the events include cell apoptosis, axonal demyelinating, and glial scarring. Subacute secondary injury can lead to a chronic phase of SCI, characterized by cystic cavity formation and glial scarring maturation [4][6].
At present, the treatment methods for SCI mainly include surgical decompression, pharmacological intervention, and non-drug treatment (such as cell-based transplantation), etc. (Figure 1) [7][8][9][10][11]. Surgical decompression is to mitigate further secondary injury by reducing the mechanical stress on the spinal cord exerted by bleeding and edema [12]. However, surgical decompression is an invasive method with no uniform standard for surgical timing, and the timing of surgery remains controversial for patients. Methylprednisolone, riluzole, phenylpropylpyridine, erythropoietin (EPO), and minocycline are common clinical drugs for SCI therapy to reduce the inflammatory response at the injury area and inhibit excitotoxicity, but there are some limitations, such as side effects and other complications [13][14]. Cell therapies, represented by stem cells, may be promising strategies for the treatment of SCI [9]. Due to their multidirectional differentiation potential and immunomodulatory and active factor secretion functions, stem cells have become the seed cells and have been widely used in SCI therapy with many breakthroughs [15]. The cell types commonly used for SCI treatment include embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and others [16]. However, the harsh microenvironment in the lesion is not conducive to the survival, proliferation, and differentiation of the implanted stem cells [17]. Thus, although considerable progress has been made in the treatment and care of SCI, clinical outcomes are less than satisfactory, and there is an urgent need to develop new strategies for the treatment of SCI.
Gels 09 00907 g001
Figure 1. The role and limitations of existing treatments for SCI.
Flourishing advances of biomaterials and tissue engineering technologies have provided novel therapeutic strategies for SCI treatment [1][18]. Hydrogels are a kind of highly hydrated polymeric materials with three-dimensional network structures that can maintain their structural integrity through physical and chemical interactions [19]. As a multifunctional platform, the physical and chemical properties of hydrogels (e.g., hardness, pore size, viscoelasticity, degradability, and stimulus-responsive properties) can be tuned through rational structural and functional design [20]. Thus, hydrogels are widely used in the treatment of refractory diseases, such as SCI, due to their injectability, good biocompatibility, biodegradability, and ability to match irregular injuries [21][22]. In addition, hydrogels can be used as delivery systems for cells, drugs, or other substances to achieve the long-term controlled release of drugs or cellular molecules [23][24][25], making them highly valuable for the treatment of SCI [26].

2. Types of Hydrogels

2.1. Natural Hydrogel

Natural hydrogels are formed by the polymerization of natural biomaterials or their derived derivatives, such as hyaluronic acid (HA), collagen, chitosan, agarose, alginate, etc. [27]. Natural polymers have inherent advantages, including abundant natural availability, specific molecules for cell adhesion, biodegradable, and biocompatibility [28], which can also reduce chronic inflammation or stimulation of the immune response due to their similarity to extracellular matrix (ECM) [29]. The various advantages of natural hydrogels make them widely used in the treatment of SCI. Kushchayev et al. found that HA hydrogel could protect the spinal cord from inflammation and reduce secondary injury in a SCI model of Sprague–Dawley (SD) rats [30], and injectable hyaluronate hydrogels with rapid self-healing ability served as a bridge and promoted angiogenesis, remyelination, and neural regeneration in SCI mice [31]. In addition, implantation of HA hydrogel in a rat model of dorsal hemisection injury of the spinal cord limited astrocyte activation and scar formation [32]. Collagen is highly abundant in the ECM and is an auspicious scaffold for promoting the repair, recovery, and regeneration of SCI [33]. Collagen hydrogel combined with small molecules, stem cells, or exosomes could promote neurogenesis, inhibit cell apoptosis and reduce glial scar production in SCI sites [34][35][36].
Chitosan has excellent biological properties, such as nontoxicity, biodegradation, and antibacterial activity [37]. Recently, chitosan-based hydrogel has attracted significant attention for SCI repair in nerve tissue engineering applications, which could inhibit neuroinflammation, promote the recovery of motor function, and prevent scar tissue formation in SCI animals [38][39][40]. In addition, Han et al. indicated that agarose scaffold containing Matrigel could support and enhance the regeneration of damaged spinal axons, and successfully reestablish the descending motor projection between motor cortical neurons and outside the lesion site [41]. 

2.2. Synthetic Hydrogel

Synthetic hydrogels are formed through the physical or chemical cross-linking of synthetic polymers. Synthetic polymers are easier to mass-produce and have highly adjustable properties that can be customized to the needs of specific applications [42]. Polyethylene glycol (PEG), polyacrylamide (PAM), polyhydroxyethyl methacrylate (PHEMA), and poly-ε-caprolactone (PCL) are the common synthetic polymers [43]. PEG is a versatile polymer with no apparent toxicity or irritation [44], and hydrophilic PEG hydrogels can be fabricated through multiple crosslinking to produce scaffolds with different degradation rates and drug release rates [45][46]. Accumulating evidence has shown that PEG hydrogel could inhibit neuroinflammation in the early stages of SCI, repair membrane damage, promote axonal regeneration, and improve motor function after severe SCI [47][48][49].
Additionally, PAM hydrogels are widely used in the field of peripheral nerve regeneration because of their good biocompatibility, [50] but pure PAM hydrogels usually have poor mechanical properties and high brittleness [51]. Jiang et al. prepared PAM gels using DNA as a crosslinker, and when rat spinal cord cells were cultured in the hydrogel for a period of time, spinal cord neurons were observed to extend primary dendrites and shorter axons on the gel [52]. PHEMA has high mechanical strength and good biostability, which can be used as a basic ingredient in the treatment of SCI as a hydrogel. 

2.3. Composite Hydrogel

Composite hydrogels combine the biocompatibility of natural hydrogels with the tunable mechanical and physical properties of synthetic hydrogels, thus holding promise for a wide range of applications in SCI [43]. Zhao et al. developed a double crosslinked biomimetic composite hydrogel comprised of acellularized spinal cord matrix, gelatin-acrylated-β-cyclodextrin-polyethene glycol diacrylate, and WAY-316606, which could recruit endogenous neural stem cells, improve neuronal differentiation, and induce neural tissue regeneration and functional recovery after SCI with no obvious cytotoxicity [53]. In addition, a novel multifunctional composite hydrogel consisting of fibrin hydrogels and functionalized self-assembling peptides promoted spinal cord regeneration by guiding regenerative tissue, accelerating axonal regeneration and remyelination, and promoting angiogenesis [54].

3. Application of Hydrogel as a Delivery System in SCI

Injectable hydrogels as delivery systems can encapsulate different substances, such as cells, drugs, and biomolecules (Figure 2) and release them slowly and controllably at the site of injury to improve drug utilization and efficacy (Table 1). Thus, hydrogels have received accumulating attention and made many breakthroughs in the treatment of SCI as a drug delivery system.
Gels 09 00907 g002
Figure 2. Hydrogel loaded with stem cells, drugs, and growth factors.
Table 1. Application of hydrogels as delivery systems in SCI.
Encapsulated Substances Hydrogel Composition Specific Substances Function Ref
Stem cells PLGA; TA; oxidized dextran (Dex) and hyaluronic acid-hydrazide NSCs Promote the differentiation of NSCs into neurons while inhibiting the differentiation of astrocytes [55]
  HA; collagen NSCs Promote NSCs to differentiate into neuron-like cells and play neuroprotective roles [56]
  Gelatin; peroxidase (HRP) and galactose oxidase (GalOx) MSCs Enhance the neural differentiation and functional recovery of SCI; [57]
  ECM Human iPSCs Reduces inflammation, enhance nerve regeneration, and significantly improve movement [58]
  Gelatin; methacrylic ADSCs Promote axon growth, reduce neuroinflammation, and ultimately improve motor function in SCI rats [59]
Drugs Alginate; chitosan Erythropoietin (EPO) Improve tissue repair and histopathological appearance of the spinal cord at the site of injury [60]
  Chitosan; collagen Serpins Improve the neurological and motor function and reduce tissue damage caused by in-flammation in SCI rats [61]
  Chitosan Cannabidiol (CBD) Reduce apoptosis, improve neurogenesis by enhancing mitochondrial biogenesis [62]
  PLGA; PEG Baricitinib Reduce neuronal apoptosis and promote functional recovery in SCI rats [63]
  Chitosan Curcumin Favor functional recovery of SCI rats [64]
Growth factors Heparin-poloxamer bFGF and NGF Improve neuronal survival, inhibit reactive astrogliosis, and promote recovery of motor performance [65]
  Alginate GDNF Stimulate neurite growth and functional recovery [66]
  Naphthalene acetic acid-phenylalanine-phenylalanine-glycine Platelet-derived growth factor (PDGF) Inhibit M1 macrophage infiltration and extrinsic or intrinsic cells apoptosis [67]
  Heparin-Laponite FGF4 Inhibit inflammatory response, increase myelination regeneration, and reduce glial/fibrotic scarring [68]

3.1. Stem Cells

Stem cells are a kind of cells with the potential of self-renewal and multi-differentiation, which can repair damaged tissues, improve microenvironment, and promote tissue regeneration through substitution and paracrine and immune regulation [69]. Stem cell therapy has great application prospects in neurological diseases such as SCI. The cell types commonly used for SCI treatment include embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and others [16]. However, the efficacy of single stem cell transplantation cannot meet people’s expectations, mainly because the inflammatory and oxidative stress microenvironment at the injured site is not conducive to the survival and differentiation of stem cells [70][71]. Additionally, the implanted stem cells are easy lose with the blood, which makes it difficult for free stem cells to form functional networks, thus seriously affecting the efficacy of stem cells [9].
In recent years, researchers have used tissue engineering techniques to prepare a variety of hydrogel scaffolds loaded with stem cell grafts to achieve better results in neural repair due to the good biocompatibility and biodegradability of hydrogels [22]. In terms of SCI repair, hydrogel combined with stem cell therapy has three advantages: (1) The hydrogel can be used as a carrier to load stem cells to the lesion, reducing the loss of cells to surrounding tissues; (2) hydrogels provide 3D support, which is conducive to cell migration, proliferation, and differentiation; (3) functional hydrogels can regulate the microenvironment of the damaged site and protect the activity and biological function of stem cells [15][72].

3.2. Drugs

Though many drugs have been tested in experimental models of SCI, the clinical translation of established therapeutic agents for the treatment of SCI remains challenging. First, most systemic drugs cannot reach the site of injury due to the impermeability of the blood–spinal cord barrier [73]. In addition, most drugs usually have short half-lives and require high doses and/or frequent administration to reach therapeutic concentrations at the site of injury, which can lead to harmful side effects and may lead to sustained inflammatory activation [74]. Injectable hydrogels with sustained drug delivery properties, degradability, and tunable physical properties can overcome and optimize these shortcomings either as a model of transport for the drug itself or as a carrier for drug-loaded particles/carriers [22][75]. Erythropoietin (EPO) is a growth factor that exhibits neuroprotective effects in the treatment of SCI [76]. Studies have shown that EPO-chitosan/alginate (EPO-CH/AL) hydrogels have controlled release characteristics for EPO, and EPO-CH/AL hydrogels significantly improve tissue repair and the histopathological appearance of the spinal cord at the site of injury [60]. Serine protease inhibitors (serpins) are “suicide” inhibitors with a highly conserved structure, which prevents excessive bleeding or clotting.

3.3. Growth Factors

Growth factors (GFs) could stimulate the growth of specific tissues, direct specific cellular responses in the microenvironment, and promote axonal regeneration [77]. Commonly used GFs include fibroblast growth factor (bFGF), nerve growth factor (NGF), BDNF, and glial neurotrophic factor (GDNF), etc., all of which are associated with neurodevelopment and neurogenesis [78]. The use of GFs for SCI has been shown to promote axonal regeneration and functional recovery [79]. However, direct administration of GFs is limited by their rapid degradation and dilution at the site of injury [65]. As a biocompatible biological scaffold, hydrogels have a high affinity for GFs and can stably control the release of GFs, avoiding the side effects of high GFs concentrations at the injection site and protecting them from enzymatic hydrolysis [80].
Thus, controlled delivery of multiple GFs to the lesion is becoming an attractive strategy for repairing SCI. For instance, Hu et al. developed a heparin-poloxamer (HP)-based hydrogel for the delivery of bFGF and NGF, which significantly improved neuronal survival, inhibited reactive astrogliosis, and promoted recovery of motor performance in SCI rats [65]. Ansorena et al. found that GDNF-loaded injectable alginate hydrogels stimulated neurite growth and functional recovery after SCI with more growing neuritis at the lesion site [66].

4. Therapeutic Mechanism of Injectable Hydrogels in SCI

4.1. Anti-Inflammation

The inflammatory response following SCI is a complex process coordinated by many cell types and inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interferon-γ (IFN-γ), etc. [81]. TNF-α and IL-6 are significantly upregulated around the area of SCI from 3 to 24 h [5]. Although inflammation is a universal consequence of systemic trauma and an essential defense mechanism for the host, ref. [82] inflammation in SCI is a double-edged sword [83]. For one thing, the inflammatory response is necessary to effectively remove tissue debris and promote wound healing and tissue repair. For another, various factors harmful to neurons, glial cells, axons, and myelin are also released during the inflammatory response. With the increase of inflammatory cytokines, the toxic microenvironment leads to the formation of cavities and glial scars, thus inhibiting the recovery of nerve function [84]. Microglia/macrophage-mediated neuroinflammation persists for a long period of time and affects SCI repair. Therefore, suppression of chronic inflammation is favorable for the recovery of SCI, but the timing of inflammatory interventions should be kept in mind [85]. Hydrogel can control the release of stem cells, anti-inflammatory drugs, GFs, etc., and improving the local microenvironment in the lesion, which has broad application prospects in SCI treatment [86].

4.2. Antioxidant

SCI is accompanied by the loss of ionic homeostasis, glutamate excitotoxicity, mitochondrial dysfunction, and oxidative stress [71]. The accumulation of large amounts of reactive oxygen species (ROS) leads to massive neuronal death, which further leads to secondary damage in SCI. Inhibition of post-injury peroxidation of biomolecules through effective antioxidant interventions will be a strategy for the treatment of SCI [87]. Therefore, functionalized hydrogels with free radical scavenging capacity or loaded with antioxidants will be beneficial for SCI recovery and functional reconstitution [88].
For example, the manganese-dioxide-nanoparticle-dotted (MnO2NPs) HA hydrogel prepared by Li et al. regulated the ROS microenvironment of SCI, thereby effectively improving the viability of MSCs and synergistic promotion of spinal cord repair [89]. Liu et al. prepared a N-acryloylglycinamide/methacrylic gelatin/laponite/tannic acid (TA) hydrogel combined with MSC-derived small extracellular vesicles (MSC-sEVs), which can realize local, sustainable, and stable delivery of MSC-sEVs at the SCI site, effectively scavenge free radicals, and reduce the expression of 4-hydroxynonenal and 8-hydroxydeoxyguanosine caused by oxidative stress [90].

4.3. Anti-Apoptosis

Apoptosis is a physiological process that occurs in cell development, but damaged cells die during apoptosis [91]. There are two pathways of cell death in the injured spinal cord: immediate necrosis and delayed apoptosis of cells. The latter lasts for approximately 14 days after trauma and involves neurons and glial cells that are far from the traumatic area [92]. Apoptosis may lead to neuronal cell death and play an important role in the pathogenesis of neurological disorders [93]. The main genes involved in apoptosis are Bcl-2 (apoptosis inhibitor) and Bax (apoptosis promoter). A growing number of studies have shown that injectable hydrogels can reduce neuronal apoptosis and promote neuronal cell survival, which has great potential in SCI treatment [94].
For example, Yuan et al. developed a CaNeu hydrogel as a delivery vehicle for ADSCs, and studies have shown that this hydrogel significantly inhibited neuroinflammation and cell apoptosis by reducing the expression of the pro-apoptotic protein Bax at the lesion site, while increasing the expression level of anti-apoptotic protein Bcl-6 [59]. Li et al. co-immobilized umbilical cord MSCs and bFGF in ECM and HP to form a bioactive, heat-sensitive hydrogel, which exerted promising utility for the functional recovery of SCI by reducing cell apoptosis and improving mitochondrial function [95].

4.4. Pro-Neurogenesis

Severe and chronic SCI are often associated with the permanent loss of neurological function, mainly due to the failure of injured axons to regenerate and rebuild functional connections and the loss of neurons. Therefore, promoting neural regeneration is a feasible idea for improving sensorimotor recovery of SCI [2].
Neural regeneration is the regeneration and repair of damaged neural tissue (neurons, axons, synapses, and glial cells) after injury [96], which includes the elongation of axons, the germination and growth of new axons, or the regeneration of neuronal cells [97]. Thus, regeneration, including both neuronal and axonal regeneration, is a complex biological process that requires joint coordination [98]. Current drug- or cell-based SCI therapies fail to provide topographic guidance for regenerating neurons and result in random growth and poor therapeutic efficacy [96]. Injectable hydrogels as biological scaffolds can not only load drugs or cells but can also create structures that allow neuronal growth and guide axon regeneration throughout the injury site [99].
Axons are the tiny nerve fibers that connect neurons and allow them to communicate [100]. Zhang et al. found that GelMA hydrogel lengthened the axons of mouse neurons, increased the expression of growth-related protein GAP43, and promoted the recovery of neurological function of SCI mice [101]. Fan et al. demonstrated that gelatin methacrylate (GM)-modified hydrogels immobilized BMSC exosomes and promoted axon outgrowth and neural synaptic network formation in vitro.

5. Combination Therapy

Currently, low-frequency pulsed electromagnetic field (LFPEMF) is a clinically used non-invasive therapeutic measure for neural repair that has been shown to prevent inflammation and oxidative stress, and it exhibits powerful neuroprotective effects in the nervous system [102]. Conductive hydrogels are attractive candidates for accelerating SCI repair because they match the electrical and mechanical properties of the neural tissues [103]. Therefore, hydrogels combined with electromagnetic stimulation (ES) to treat SCI have become an interesting strategy. For example, Liu et al. demonstrated that combined with ES by electrode needles, thermosensitive-electroactive-hydrogel-loaded NGF significantly inhibited astrocyte differentiation and restored spinal circuitry and locomotor function by stimulating endogenous neurogenesis in a rat SCI model [104]. Moreover, implantation of an IONP-embedded gelatin–genipin hydrogel system along with MF (17.96 μT, 50 Hz uniform EMF) exposure modulated the microenvironment, making it conducive to neural repair and regeneration after SCI in rats [105].

6. Conclusions

In summary, natural, synthetic, and composite injectable hydrogels can all be used as delivery systems to encapsulate stem cells, drugs, or GFs for a wide range of applications in SCI therapy. The mechanisms by which hydrogels promote SCI repair include anti-inflammation, anti-oxidation, anti-apoptosis, and pro-neurogenesis (Figure 3), etc. In addition, hydrogel combined with electromagnetic stimulation or phototherapy can also improve the repair of SCI. Although much progress has been made in the study of injectable hydrogels for SCI, there are still certain limitations. 

Gels 09 00907 g003
Figure 3. Mechanisms of action of injectable hydrogel in the treatment of spinal cord injury. Green arrow: up; blue arrow: down; yellow arrow: facilitation; red arrow: inhibition.

This entry is adapted from the peer-reviewed paper 10.3390/gels9110907

References

  1. Courtine, G.; Sofroniew, M.V. Spinal cord repair: Advances in biology and technology. Nat. Med. 2019, 25, 898–908.
  2. Hutson, T.H.; Di Giovanni, S. The translational landscape in spinal cord injury: Focus on neuroplasticity and regeneration. Nat. Rev. Neurol. 2019, 15, 732–745.
  3. Anjum, A.; Yazid, M.D.; Fauzi Daud, M.; Idris, J.; Ng, A.M.H.; Selvi Naicker, A.; Ismail, O.H.R.; Athi Kumar, R.K.; Lokanathan, Y. Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms. Int. J. Mol. Sci. 2020, 21, 7533.
  4. Quadri, S.A.; Farooqui, M.; Ikram, A.; Zafar, A.; Khan, M.A.; Suriya, S.S.; Claus, C.F.; Fiani, B.; Rahman, M.; Ramachandran, A.; et al. Recent update on basic mechanisms of spinal cord injury. Neurosurg. Rev. 2020, 43, 425–441.
  5. Freyermuth-Trujillo, X.; Segura-Uribe, J.J.; Salgado-Ceballos, H.; Orozco-Barrios, C.E.; Coyoy-Salgado, A. Inflammation: A Target for Treatment in Spinal Cord Injury. Cells 2022, 11, 2692.
  6. Sterner, R.C.; Sterner, R.M. Immune response following traumatic spinal cord injury: Pathophysiology and therapies. Front. Immunol. 2022, 13, 1084101.
  7. Karsy, M.; Hawryluk, G. Modern Medical Management of Spinal Cord Injury. Curr. Neurol. Neurosci. Rep. 2019, 19, 65.
  8. De Almeida, F.M.; Marques, S.A.; Dos Santos, A.C.R.; Prins, C.A.; Dos Santos Cardoso, F.S.; Dos Santos Heringer, L.; Mendonça, H.R.; Martinez, A.M.B. Molecular approaches for spinal cord injury treatment. Neural Regen. Res. 2023, 18, 23–30.
  9. Zipser, C.M.; Cragg, J.J.; Guest, J.D.; Fehlings, M.G.; Jutzeler, C.R.; Anderson, A.J.; Curt, A. Cell-based and stem-cell-based treatments for spinal cord injury: Evidence from clinical trials. Lancet. Neurol. 2022, 21, 659–670.
  10. Kim, H.N.; McCrea, M.R.; Li, S. Advances in molecular therapies for targeting pathophysiology in spinal cord injury. Expert Opin. Ther. Targets 2023, 27, 171–187.
  11. Venkatesh, K.; Ghosh, S.K.; Mullick, M.; Manivasagam, G.; Sen, D. Spinal cord injury: Pathophysiology, treatment strategies, associated challenges, and future implications. Cell Tissue Res. 2019, 377, 125–151.
  12. Russo, G.S.; Mangan, J.J.; Galetta, M.S.; Boody, B.; Bronson, W.; Segar, A.; Kepler, C.K.; Kurd, M.F.; Hilibrand, A.S.; Vaccaro, A.R.; et al. Update on Spinal Cord Injury Management. Clin. Spine Surg. 2020, 33, 258–264.
  13. Rabchevsky, A.G.; Patel, S.P.; Springer, J.E. Pharmacological interventions for spinal cord injury: Where do we stand? How might we step forward? Pharmacol. Ther. 2011, 132, 15–29.
  14. Cox, A.; Varma, A.; Banik, N. Recent advances in the pharmacologic treatment of spinal cord injury. Metab. Brain Dis. 2015, 30, 473–482.
  15. Shao, A.; Tu, S.; Lu, J.; Zhang, J. Crosstalk between stem cell and spinal cord injury: Pathophysiology and treatment strategies. Stem Cell Res. Ther. 2019, 10, 238.
  16. Gao, L.; Peng, Y.; Xu, W.; He, P.; Li, T.; Lu, X.; Chen, G. Progress in Stem Cell Therapy for Spinal Cord Injury. Stem Cells Int. 2020, 2020, 2853650.
  17. Kiyotake, E.A.; Martin, M.D.; Detamore, M.S. Regenerative rehabilitation with conductive biomaterials for spinal cord injury. Acta Biomater. 2022, 139, 43–64.
  18. Cofano, F.; Boido, M.; Monticelli, M.; Zenga, F.; Ducati, A.; Vercelli, A.; Garbossa, D. Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy. Int. J. Mol. Sci. 2019, 20, 2698.
  19. Wang, X.; Wang, Q. Enzyme-Laden Bioactive Hydrogel for Biocatalytic Monitoring and Regulation. Acc. Chem. Res. 2021, 54, 1274–1287.
  20. Cao, H.; Duan, L.; Zhang, Y.; Cao, J.; Zhang, K. Current hydrogel advances in physicochemical and biological response-driven biomedical application diversity. Signal Transduct. Target. Ther. 2021, 6, 426.
  21. Lv, Z.; Dong, C.; Zhang, T.; Zhang, S. Hydrogels in Spinal Cord Injury Repair: A Review. Front. Bioeng. Biotechnol. 2022, 10, 931800.
  22. Walsh, C.M.; Wychowaniec, J.K.; Brougham, D.F.; Dooley, D. Functional hydrogels as therapeutic tools for spinal cord injury: New perspectives on immunopharmacological interventions. Pharmacol. Ther. 2022, 234, 108043.
  23. Liu, W.; Xu, B.; Zhao, S.; Han, S.; Quan, R.; Liu, W.; Ji, C.; Chen, B.; Xiao, Z.; Yin, M.; et al. Spinal cord tissue engineering via covalent interaction between biomaterials and cells. Sci. Adv. 2023, 9, eade8829.
  24. Ma, T.; Wu, J.; Mu, J.; Gao, J. Biomaterials reinforced MSCs transplantation for spinal cord injury repair. Asian J. Pharm. Sci. 2022, 17, 4–19.
  25. Assunção-Silva, R.C.; Gomes, E.D.; Sousa, N.; Silva, N.A.; Salgado, A.J. Hydrogels and Cell Based Therapies in Spinal Cord Injury Regeneration. Stem Cells Int. 2015, 2015, 948040.
  26. Wang, Y.; Lv, H.Q.; Chao, X.; Xu, W.X.; Liu, Y.; Ling, G.X.; Zhang, P. Multimodal therapy strategies based on hydrogels for the repair of spinal cord injury. Mil. Med. Res. 2022, 9, 16.
  27. Wang, Y.; Tan, H.; Hui, X. Biomaterial Scaffolds in Regenerative Therapy of the Central Nervous System. BioMed Res. Int. 2018, 2018, 7848901.
  28. Seliktar, D. Designing cell-compatible hydrogels for biomedical applications. Science 2012, 336, 1124–1128.
  29. Taghipour, Y.D.; Hokmabad, V.R.; Del Bakhshayesh, A.R.; Asadi, N.; Salehi, R.; Nasrabadi, H.T. The Application of Hydrogels Based on Natural Polymers for Tissue Engineering. Curr. Med. Chem. 2020, 27, 2658–2680.
  30. Kushchayev, S.V.; Giers, M.B.; Hom Eng, D.; Martirosyan, N.L.; Eschbacher, J.M.; Mortazavi, M.M.; Theodore, N.; Panitch, A.; Preul, M.C. Hyaluronic acid scaffold has a neuroprotective effect in hemisection spinal cord injury. J. Neurosurg. Spine 2016, 25, 114–124.
  31. Li, S.; Ke, Z.; Peng, X.; Fan, P.; Chao, J.; Wu, P.; Xiao, P.; Zhou, Y. Injectable and fast gelling hyaluronate hydrogels with rapid self-healing ability for spinal cord injury repair. Carbohydr. Polym. 2022, 298, 120081.
  32. Khaing, Z.Z.; Milman, B.D.; Vanscoy, J.E.; Seidlits, S.K.; Grill, R.J.; Schmidt, C.E. High molecular weight hyaluronic acid limits astrocyte activation and scar formation after spinal cord injury. J. Neural Eng. 2011, 8, 046033.
  33. Mneimneh, A.T.; Mehanna, M.M. Collagen-based scaffolds: An auspicious tool to support repair, recovery, and regeneration post spinal cord injury. Int. J. Pharm. 2021, 601, 120559.
  34. Yang, Y.; Fan, Y.; Zhang, H.; Zhang, Q.; Zhao, Y.; Xiao, Z.; Liu, W.; Chen, B.; Gao, L.; Sun, Z.; et al. Small molecules combined with collagen hydrogel direct neurogenesis and migration of neural stem cells after spinal cord injury. Biomaterials 2021, 269, 120479.
  35. Liu, X.; Zhang, L.; Xu, Z.; Xiong, X.; Yu, Y.; Wu, H.; Qiao, H.; Zhong, J.; Zhao, Z.; Dai, J.; et al. A functionalized collagen-I scaffold delivers microRNA 21-loaded exosomes for spinal cord injury repair. Acta Biomater. 2022, 154, 385–400.
  36. Liu, S.; Xie, Y.Y.; Wang, L.D.; Tai, C.X.; Chen, D.; Mu, D.; Cui, Y.Y.; Wang, B. A multi-channel collagen scaffold loaded with neural stem cells for the repair of spinal cord injury. Neural Regen. Res. 2021, 16, 2284–2292.
  37. Cheung, R.C.; Ng, T.B.; Wong, J.H.; Chan, W.Y. Chitosan: An Update on Potential Biomedical and Pharmaceutical Applications. Mar. Drugs 2015, 13, 5156–5186.
  38. Liu, K.; Dong, X.; Wang, Y.; Wu, X.; Dai, H. Dopamine-modified chitosan hydrogel for spinal cord injury. Carbohydr. Polym. 2022, 298, 120047.
  39. Zhao, C.; Rao, J.S.; Duan, H.; Hao, P.; Shang, J.; Fan, Y.; Zhao, W.; Gao, Y.; Yang, Z.; Sun, Y.E.; et al. Chronic spinal cord injury repair by NT3-chitosan only occurs after clearance of the lesion scar. Signal Transduct. Target. Ther. 2022, 7, 184.
  40. Xiang, W.; Cao, H.; Tao, H.; Jin, L.; Luo, Y.; Tao, F.; Jiang, T. Applications of chitosan-based biomaterials: From preparation to spinal cord injury neuroprosthetic treatment. Int. J. Biol. Macromol. 2023, 230, 123447.
  41. Han, S.; Lee, J.Y.; Heo, E.Y.; Kwon, I.K.; Yune, T.Y.; Youn, I. Implantation of a Matrigel-loaded agarose scaffold promotes functional regeneration of axons after spinal cord injury in rat. Biochem. Biophys. Res. Commun. 2018, 496, 785–791.
  42. Jung, K.; Corrigan, N.; Wong, E.H.H.; Boyer, C. Bioactive Synthetic Polymers. Adv. Mater. 2022, 34, e2105063.
  43. Peng, H.; Liu, Y.; Xiao, F.; Zhang, L.; Li, W.; Wang, B.; Weng, Z.; Liu, Y.; Chen, G. Research progress of hydrogels as delivery systems and scaffolds in the treatment of secondary spinal cord injury. Front. Bioeng. Biotechnol. 2023, 11, 1111882.
  44. Ibrahim, M.; Ramadan, E.; Elsadek, N.E.; Emam, S.E.; Shimizu, T.; Ando, H.; Ishima, Y.; Elgarhy, O.H.; Sarhan, H.A.; Hussein, A.K.; et al. Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products. J. Control. Release Off. J. Control. Release Soc. 2022, 351, 215–230.
  45. Peppas, N.A.; Keys, K.B.; Torres-Lugo, M.; Lowman, A.M. Poly(ethylene glycol)-containing hydrogels in drug delivery. J. Control. Release Off. J. Control. Release Soc. 1999, 62, 81–87.
  46. Aghaie, T.; Jazayeri, M.H.; Manian, M.; Khani, L.; Erfani, M.; Rezayi, M.; Ferns, G.A.; Avan, A. Gold nanoparticle and polyethylene glycol in neural regeneration in the treatment of neurodegenerative diseases. J. Cell. Biochem. 2019, 120, 2749–2755.
  47. Estrada, V.; Brazda, N.; Schmitz, C.; Heller, S.; Blazyca, H.; Martini, R.; Müller, H.W. Long-lasting significant functional improvement in chronic severe spinal cord injury following scar resection and polyethylene glycol implantation. Neurobiol. Dis. 2014, 67, 165–179.
  48. Kong, X.B.; Tang, Q.Y.; Chen, X.Y.; Tu, Y.; Sun, S.Z.; Sun, Z.L. Polyethylene glycol as a promising synthetic material for repair of spinal cord injury. Neural Regen. Res. 2017, 12, 1003–1008.
  49. Shi, R. Polyethylene glycol repairs membrane damage and enhances functional recovery: A tissue engineering approach to spinal cord injury. Neurosci. Bull. 2013, 29, 460–466.
  50. Zhang, L.; Han, Q.; Chen, S.; Suo, D.; Zhang, L.; Li, G.; Zhao, X.; Yang, Y. Soft hydrogel promotes dorsal root ganglion by upregulating gene expression of Ntn4 and Unc5B. Colloids Surf. B Biointerfaces 2021, 199, 111503.
  51. Walters, B.D.; Stegemann, J.P. Strategies for directing the structure and function of three-dimensional collagen biomaterials across length scales. Acta Biomater. 2014, 10, 1488–1501.
  52. Jiang, F.X.; Yurke, B.; Firestein, B.L.; Langrana, N.A. Neurite outgrowth on a DNA crosslinked hydrogel with tunable stiffnesses. Ann. Biomed. Eng. 2008, 36, 1565–1579.
  53. Zhao, X.; Lu, X.; Li, K.; Song, S.; Luo, Z.; Zheng, C.; Yang, C.; Wang, X.; Wang, L.; Tang, Y.; et al. Double crosslinked biomimetic composite hydrogels containing topographical cues and WAY-316606 induce neural tissue regeneration and functional recovery after spinal cord injury. Bioact. Mater. 2023, 24, 331–345.
  54. Man, W.; Yang, S.; Cao, Z.; Lu, J.; Kong, X.; Sun, X.; Zhao, L.; Guo, Y.; Yao, S.; Wang, G.; et al. A multi-modal delivery strategy for spinal cord regeneration using a composite hydrogel presenting biophysical and biochemical cues synergistically. Biomaterials 2021, 276, 120971.
  55. Huang, F.; Chen, T.; Chang, J.; Zhang, C.; Liao, F.; Wu, L.; Wang, W.; Yin, Z. A conductive dual-network hydrogel composed of oxidized dextran and hyaluronic-hydrazide as BDNF delivery systems for potential spinal cord injury repair. Int. J. Biol. Macromol. 2021, 167, 434–445.
  56. Duan, H.; Li, X.; Wang, C.; Hao, P.; Song, W.; Li, M.; Zhao, W.; Gao, Y.; Yang, Z. Functional hyaluronate collagen scaffolds induce NSCs differentiation into functional neurons in repairing the traumatic brain injury. Acta Biomater. 2016, 45, 182–195.
  57. Yao, M.; Li, J.; Zhang, J.; Ma, S.; Wang, L.; Gao, F.; Guan, F. Dual-enzymatically cross-linked gelatin hydrogel enhances neural differentiation of human umbilical cord mesenchymal stem cells and functional recovery in experimental murine spinal cord injury. J. Mater. Chem. B 2021, 9, 440–452.
  58. Wertheim, L.; Edri, R.; Goldshmit, Y.; Kagan, T.; Noor, N.; Ruban, A.; Shapira, A.; Gat-Viks, I.; Assaf, Y.; Dvir, T. Regenerating the Injured Spinal Cord at the Chronic Phase by Engineered iPSCs-Derived 3D Neuronal Networks. Adv. Sci. 2022, 9, e2105694.
  59. Yuan, X.; Yuan, W.; Ding, L.; Shi, M.; Luo, L.; Wan, Y.; Oh, J.; Zhou, Y.; Bian, L.; Deng, D.Y.B. Cell-adaptable dynamic hydrogel reinforced with stem cells improves the functional repair of spinal cord injury by alleviating neuroinflammation. Biomaterials 2021, 279, 121190.
  60. Gholami, M.; Gilanpour, H.; Sadeghinezhad, J.; Asghari, A. Facile fabrication of an erythropoietin-alginate/chitosan hydrogel and evaluation of its local therapeutic effects on spinal cord injury in rats. DARU J. Fac. Pharm. Tehran Univ. Med. Sci. 2021, 29, 255–265.
  61. Kwiecien, J.M.; Zhang, L.; Yaron, J.R.; Schutz, L.N.; Kwiecien-Delaney, C.J.; Awo, E.A.; Burgin, M.; Dabrowski, W.; Lucas, A.R. Local Serpin Treatment via Chitosan-Collagen Hydrogel after Spinal Cord Injury Reduces Tissue Damage and Improves Neurologic Function. J. Clin. Med. 2020, 9, 1221.
  62. Zhang, H.; Hu, T.; Xiong, M.; Li, S.; Li, W.X.; Liu, J.; Zhou, X.; Qi, J.; Jiang, G.B. Cannabidiol-loaded injectable chitosan-based hydrogels promote spinal cord injury repair by enhancing mitochondrial biogenesis. Int. J. Biol. Macromol. 2022, 221, 1259–1270.
  63. Zheng, X.Q.; Huang, J.F.; Lin, J.L.; Zhu, Y.X.; Wang, M.Q.; Guo, M.L.; Zan, X.J.; Wu, A.M. Controlled release of baricitinib from a thermos-responsive hydrogel system inhibits inflammation by suppressing JAK2/STAT3 pathway in acute spinal cord injury. Colloids Surf. B Biointerfaces 2021, 199, 111532.
  64. Luo, J.; Shi, X.; Li, L.; Tan, Z.; Feng, F.; Li, J.; Pang, M.; Wang, X.; He, L. An injectable and self-healing hydrogel with controlled release of curcumin to repair spinal cord injury. Bioact. Mater. 2021, 6, 4816–4829.
  65. Hu, X.; Li, R.; Wu, Y.; Li, Y.; Zhong, X.; Zhang, G.; Kang, Y.; Liu, S.; Xie, L.; Ye, J.; et al. Thermosensitive heparin-poloxamer hydrogel encapsulated bFGF and NGF to treat spinal cord injury. J. Cell. Mol. Med. 2020, 24, 8166–8178.
  66. Ansorena, E.; De Berdt, P.; Ucakar, B.; Simón-Yarza, T.; Jacobs, D.; Schakman, O.; Jankovski, A.; Deumens, R.; Blanco-Prieto, M.J.; Préat, V.; et al. Injectable alginate hydrogel loaded with GDNF promotes functional recovery in a hemisection model of spinal cord injury. Int. J. Pharm. 2013, 455, 148–158.
  67. Wu, W.; Jia, S.; Xu, H.; Gao, Z.; Wang, Z.; Lu, B.; Ai, Y.; Liu, Y.; Liu, R.; Yang, T.; et al. Supramolecular Hydrogel Microspheres of Platelet-Derived Growth Factor Mimetic Peptide Promote Recovery from Spinal Cord Injury. ACS Nano 2023, 17, 3818–3837.
  68. Wang, C.; Gong, Z.; Huang, X.; Wang, J.; Xia, K.; Ying, L.; Shu, J.; Yu, C.; Zhou, X.; Li, F.; et al. An injectable heparin-Laponite hydrogel bridge FGF4 for spinal cord injury by stabilizing microtubule and improving mitochondrial function. Theranostics 2019, 9, 7016–7032.
  69. Zakrzewski, W.; Dobrzyński, M.; Szymonowicz, M.; Rybak, Z. Stem cells: Past, present, and future. Stem Cell Res. Ther. 2019, 10, 68.
  70. Hashimoto, S.; Nagoshi, N.; Shinozaki, M.; Nakanishi, K.; Suematsu, Y.; Shibata, T.; Kawai, M.; Kitagawa, T.; Ago, K.; Kamata, Y.; et al. Microenvironmental modulation in tandem with human stem cell transplantation enhances functional recovery after chronic complete spinal cord injury. Biomaterials 2023, 295, 122002.
  71. Fan, B.; Wei, Z.; Yao, X.; Shi, G.; Cheng, X.; Zhou, X.; Zhou, H.; Ning, G.; Kong, X.; Feng, S. Microenvironment Imbalance of Spinal Cord Injury. Cell Transplant. 2018, 27, 853–866.
  72. Khayambashi, P.; Iyer, J.; Pillai, S.; Upadhyay, A.; Zhang, Y.; Tran, S.D. Hydrogel Encapsulation of Mesenchymal Stem Cells and Their Derived Exosomes for Tissue Engineering. Int. J. Mol. Sci. 2021, 22, 684.
  73. Jin, L.Y.; Li, J.; Wang, K.F.; Xia, W.W.; Zhu, Z.Q.; Wang, C.R.; Li, X.F.; Liu, H.Y. Blood-Spinal Cord Barrier in Spinal Cord Injury: A Review. J. Neurotrauma 2021, 38, 1203–1224.
  74. Gerndt, S.J.; Rodriguez, J.L.; Pawlik, J.W.; Taheri, P.A.; Wahl, W.L.; Micheals, A.J.; Papadopoulos, S.M. Consequences of high-dose steroid therapy for acute spinal cord injury. J. Trauma 1997, 42, 279–284.
  75. Almawash, S.; Osman, S.K.; Mustafa, G.; El Hamd, M.A. Current and Future Prospective of Injectable Hydrogels-Design Challenges and Limitations. Pharmaceuticals 2022, 15, 371.
  76. Singh, P.L.; Agarwal, N.; Barrese, J.C.; Heary, R.F. Current therapeutic strategies for inflammation following traumatic spinal cord injury. Neural Regen. Res. 2012, 7, 1812–1821.
  77. Wang, Z. Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling. Cells 2021, 10, 3327.
  78. Lauzon, M.A.; Daviau, A.; Marcos, B.; Faucheux, N. Growth factor treatment to overcome Alzheimer’s dysfunctional signaling. Cell. Signal. 2015, 27, 1025–1038.
  79. Liu, S.M.; Xiao, Z.F.; Li, X.; Zhao, Y.N.; Wu, X.M.; Han, J.; Chen, B.; Li, J.Y.; Fan, C.X.; Xu, B.; et al. Vascular endothelial growth factor activates neural stem cells through epidermal growth factor receptor signal after spinal cord injury. CNS Neurosci. Ther. 2019, 25, 375–385.
  80. Shan, B.H.; Wu, F.G. Hydrogel-Based Growth Factor Delivery Platforms: Strategies and Recent Advances. Adv. Mater. 2023, e2210707.
  81. Van Opdenbosch, N.; Lamkanfi, M. Caspases in Cell Death, Inflammation, and Disease. Immunity 2019, 50, 1352–1364.
  82. Hellenbrand, D.J.; Quinn, C.M.; Piper, Z.J.; Morehouse, C.N.; Fixel, J.A.; Hanna, A.S. Inflammation after spinal cord injury: A review of the critical timeline of signaling cues and cellular infiltration. J. Neuroinflam. 2021, 18, 284.
  83. David, S.; López-Vales, R.; Wee Yong, V. Harmful and beneficial effects of inflammation after spinal cord injury: Potential therapeutic implications. Handb. Clin. Neurol. 2012, 109, 485–502.
  84. Liu, X.; Zhang, Y.; Wang, Y.; Qian, T. Inflammatory Response to Spinal Cord Injury and Its Treatment. World Neurosurg. 2021, 155, 19–31.
  85. Orr, M.B.; Gensel, J.C. Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses. Neurother. J. Am. Soc. Exp. Neuro Ther. 2018, 15, 541–553.
  86. Bellotti, E.; Schilling, A.L.; Little, S.R.; Decuzzi, P. Injectable thermoresponsive hydrogels as drug delivery system for the treatment of central nervous system disorders: A review. J. Control. Release Off. J. Control. Release Soc. 2021, 329, 16–35.
  87. Chio, J.C.T.; Punjani, N.; Hejrati, N.; Zavvarian, M.M.; Hong, J.; Fehlings, M.G. Extracellular Matrix and Oxidative Stress Following Traumatic Spinal Cord Injury: Physiological and Pathophysiological Roles and Opportunities for Therapeutic Intervention. Antioxid. Redox Signal. 2022, 37, 184–207.
  88. Fan, B.; Wei, Z.; Feng, S. Progression in translational research on spinal cord injury based on microenvironment imbalance. Bone Res. 2022, 10, 35.
  89. Li, L.; Xiao, B.; Mu, J.; Zhang, Y.; Zhang, C.; Cao, H.; Chen, R.; Patra, H.K.; Yang, B.; Feng, S.; et al. A MnO(2) Nanoparticle-Dotted Hydrogel Promotes Spinal Cord Repair via Regulating Reactive Oxygen Species Microenvironment and Synergizing with Mesenchymal Stem Cells. ACS Nano 2019, 13, 14283–14293.
  90. Liu, Z.; Guo, S.; Dong, L.; Wu, P.; Li, K.; Li, X.; Li, X.; Qian, H.; Fu, Q. A tannic acid doped hydrogel with small extracellular vesicles derived from mesenchymal stem cells promotes spinal cord repair by regulating reactive oxygen species microenvironment. Mater. Today. Bio 2022, 16, 100425.
  91. Bertheloot, D.; Latz, E.; Franklin, B.S. Necroptosis, pyroptosis and apoptosis: An intricate game of cell death. Cell. Mol. Immunol. 2021, 18, 1106–1121.
  92. Basnak’ian, A.G.; Baskov, A.V.; Sokolov, N.N.; Borshchenko, I.A. Apoptosis during spinal cord trauma: Prospects for pharmacological correction. Vopr. Meditsinskoi Khimii 2000, 46, 431–443.
  93. Robertson, G.S.; Crocker, S.J.; Nicholson, D.W.; Schulz, J.B. Neuroprotection by the inhibition of apoptosis. Brain Pathol. 2000, 10, 283–292.
  94. Li, X.; Duan, L.; Kong, M.; Wen, X.; Guan, F.; Ma, S. Applications and Mechanisms of Stimuli-Responsive Hydrogels in Traumatic Brain Injury. Gels 2022, 8, 482.
  95. Li, Y.; Yang, L.; Hu, F.; Xu, J.; Ye, J.; Liu, S.; Wang, L.; Zhuo, M.; Ran, B.; Zhang, H.; et al. Novel Thermosensitive Hydrogel Promotes Spinal Cord Repair by Regulating Mitochondrial Function. ACS Appl. Mater. Interfaces 2022, 14, 25155–25172.
  96. Kim, M.S.; Lee, H.B. Perspectives on tissue-engineered nerve regeneration for the treatment of spinal cord injury. Tissue Eng. Part A 2014, 20, 1781–1783.
  97. Zheng, B.; Tuszynski, M.H. Regulation of axonal regeneration after mammalian spinal cord injury. Nat. Rev. Mol. Cell Biol. 2023, 24, 396–413.
  98. Han, Q.; Xie, Y.; Ordaz, J.D.; Huh, A.J.; Huang, N.; Wu, W.; Liu, N.; Chamberlain, K.A.; Sheng, Z.H.; Xu, X.M. Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury. Cell Metab. 2020, 31, 623–641.e628.
  99. Morgado, P.I.; Palacios, M.; Larrain, J. In situ injectable hydrogels for spinal cord regeneration: Advances from the last 10 years. Biomed. Phys. Eng. Express 2019, 6, 012002.
  100. Curcio, M.; Bradke, F. Axon Regeneration in the Central Nervous System: Facing the Challenges from the Inside. Annu. Rev. Cell Dev. Biol. 2018, 34, 495–521.
  101. Zhang, H.; Xu, J.; Saijilafu. The effects of GelMA hydrogel on nerve repair and regeneration in mice with spinal cord injury. Ann. Transl. Med. 2021, 9, 1147.
  102. Wang, C.; Liu, Y.; Wang, Y.; Wei, Z.; Suo, D.; Ning, G.; Wu, Q.; Feng, S.; Wan, C. Low-frequency pulsed electromagnetic field promotes functional recovery, reduces inflammation and oxidative stress, and enhances HSP70 expression following spinal cord injury. Mol. Med. Rep. 2019, 19, 1687–1693.
  103. Yang, B.; Liang, C.; Chen, D.; Cheng, F.; Zhang, Y.; Wang, S.; Shu, J.; Huang, X.; Wang, J.; Xia, K.; et al. A conductive supramolecular hydrogel creates ideal endogenous niches to promote spinal cord injury repair. Bioact. Mater. 2022, 15, 103–119.
  104. Liu, W.; Luo, Y.; Ning, C.; Zhang, W.; Zhang, Q.; Zou, H.; Fu, C. Thermo-sensitive electroactive hydrogel combined with electrical stimulation for repair of spinal cord injury. J. Nanobiotechnol. 2021, 19, 286.
  105. Bhattacharyya, S.; Dinda, A.; Vishnubhatla, S.; Anwar, M.F.; Jain, S. A combinatorial approach to modulate microenvironment toward regeneration and repair after spinal cord injury in rats. Neurosci. Lett. 2021, 741, 135500.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback