• Users Online: 403
  • Home
  • Print this page
  • Email this page

 Table of Contents  
Year : 2017  |  Volume : 12  |  Issue : 6  |  Page : 1003-1008

Polyethylene glycol as a promising synthetic material for repair of spinal cord injury

1 Department of Brain, Affiliated Hospital of China Logistics College of People’s Armed Police Forces, Tianjin; Tianjin University of Traditional Chinese Medicine, Tianjin, China
2 Tianjin Key Laboratory of Neurological Trauma Repair, Tianjin, China
3 Jinzhou Medical University, Jinzhou, Liaoning Province, China

Date of Acceptance05-Apr-2017
Date of Web Publication4-Jul-2017

Correspondence Address:
Shi-zhong Sun
Tianjin Key Laboratory of Neurological Trauma Repair, Tianjin
Xu-yi Chen
Tianjin Key Laboratory of Neurological Trauma Repair, Tianjin
Yue Tu
Tianjin Key Laboratory of Neurological Trauma Repair, Tianjin
Login to access the Email id

Source of Support: This study was supported by a grant from National Key Science and Technology Research & Development Plan in China, No. 2016YFC1101500; the National Natural Science Foundation of China, No. 11672332., Conflict of Interest: None

DOI: 10.4103/1673-5374.208597

Rights and Permissions

Polyethylene glycol is a synthetic, biodegradable, and water-soluble polyether. Owing to its good biological and material properties, polyethylene glycol shows promise in spinal cord tissue engineering applications. Although studies have examined repairing spinal cord injury with polyethylene glycol, these compelling findings have not been recently reviewed or evaluated as a whole. Thus, we herein review and summarize the findings of studies conducted both within and beyond China that have examined the repair of spinal cord injury using polyethylene glycol. The following summarizes the results of studies using polyethylene glycol alone as well as coupled with polymers or hydrogels: (1) polyethylene glycol as an adjustable biomolecule carrier resists nerve fiber degeneration, reduces the inflammatory response, inhibits vacuole and scar formation, and protects nerve membranes in the acute stage of spinal cord injury. (2) Polyethylene glycol-coupled polymers not only promote angiogenesis but also carry drugs or bioactive molecules to the injury site. Because such polymers cross both the blood-spinal cord and blood-brain barriers, they have been widely used as drug carriers. (3) Polyethylene glycol hydrogels have been used as supporting substrates for the growth of stem cells after injury, inducing cell migration, proliferation, and differentiation. Simultaneously, polyethylene glycol hydrogels isolate or reduce local glial scar invasion, promote and guide axonal regeneration, cross the transplanted area, and re-establish synaptic connections with target tissue, thereby promoting spinal cord repair. On the basis of the reviewed studies, we conclude that polyethylene glycol is a promising synthetic material for use in the repair of spinal cord injury

Keywords: nerve regeneration; spinal cord injury; polyethylene glycol; nerve tissue engineering; biomaterials; spinal nerve repair; biological drug; blood-spinal cord barrier; neural stem cells; carrier; cell culture; neural regeneration

How to cite this article:
Kong Xb, Tang Qy, Chen Xy, Tu Y, Sun Sz, Sun Zl. Polyethylene glycol as a promising synthetic material for repair of spinal cord injury. Neural Regen Res 2017;12:1003-8

How to cite this URL:
Kong Xb, Tang Qy, Chen Xy, Tu Y, Sun Sz, Sun Zl. Polyethylene glycol as a promising synthetic material for repair of spinal cord injury. Neural Regen Res [serial online] 2017 [cited 2022 Jan 21];12:1003-8. Available from: http://www.nrronline.org/text.asp?2017/12/6/1003/208597

Xian-bin Kong, Zhong-lei Sun
These authors contributed equally to this work.

  Introduction Top

After spinal cord injury (SCI), the cavity formed by the necrosis of neurons and glial cells and the glial scar formed by reactive astrocyte hyperplasia are important factors that affect nerve regeneration (Flynnj et al., 2011). Therefore, improving the microenvironment after SCI and filling tissue defects are important strategies for repair of the injured spinal cord (Zhao et al., 2015). Scaffold materials for repairing SCI contain both natural and synthetic materials. Natural materials have good biocompatibility, and the degradation products are easily absorbed without causing inflammatory responses. However, their mechanical properties differ from normal spinal cord tissue, and their quality is difficult to control. Synthetic materials also provide good biocompatibility and tissue degradation, but they offer the additional advantages of high purity, good repeatability, and controllable mechanical and physical properties.

Polyethylene glycol (PEG) is a synthetic material with a wide range of clinical applications, as its functions can be modified by regulating the physical and chemical properties of it or its graft-related materials (Luo, 2004; Cui et al., 2015; Yang et al., 2015). For example, PEG has been approved by the U.S. Food and Drug Administration for use as a preservative additive prior to organ transplantation to limit cold ischemia/reperfusion injury (Pasut et al., 2016). PEG is also used to modify nanoparticles so that they cannot be recognized by the immune system. PEGylated copper oxide nanoparticles selectively reduce the activity of tumor cells and mitigate the inflammatory response (Giannousi et al., 2016). Another clinical use for PEG is to slow the removal of the nanoparticle pharmaceutical drug carrier. For example, the amount of time gold nanoparticles circulate throughout the blood and body is extended when they have been modified with PEG, promoting the accumulation of the nanoparticles at the tumor site (Huo et al., 2017). The application of PEG in SCI has been studied extensively. PEG has been shown to inhibit the inflammatory response, provide neuroprotection, suppress microenvironment changes in SCI, traverse the blood-brain barrier or blood-spinal cord barrier (Liu et al., 2008), and play important roles in cell therapy and tissue regeneration.

This review summarizes previous research findings examining the use of PEG in SCI ([Figure 1]) and provides new ideas and solutions for the particularly difficult problems associated with SCI repair. Although PEG is a potentially important material for the repair of SCI, we found some limitations in the use of PEG; thus, we also suggest future research directions for the development of improved PEG materials.
Figure 1: Overview of the topics discussed herein.
This review summarizes current research on polyethylene glycol (PEG) and PEG-coupled polymers and their uses in the field of spinal nerve tissue engineering and their development for use as synthetic scaffolds in the repair of spinal cord injury. These materials have the advantages of good biocompatibility and degradation as well as controllable mechanical and physical properties

Click here to view

  Characteristics of PEG and Repair of Spinal Nerves Top

PEG, as a biodegradable synthetic scaffold, shows good biocompatibility and low immunogenicity and it is nontoxic. PEG is soluble in both water and many organic solvents. PEG inhibits vacuole and scar formation and will not accumulate in the body (Potter et al., 2008; Krsko et al., 2009). PEG resists nerve fiber degeneration, reduces the inflammatory response, protects the nerve membrane, reduces cell death, protects mitochondria, accelerates improvement of electroneurographic signals, and can be used as a sealant for injured axon membranes (Luo et al., 2002, 2004; Laverty et al. 2004; Phillips et al., 2005; Burdick et al., 2006).

As soft polymers, PEG hydrogels can be used as drug carriers whose size, structure, and property can be controlled to differentially affect biological properties in vivo. Electron beam lithography and ultraviolet optical lithography have been used to tightly control the size and shape of hydrogels, successfully generating PEG hydrogels with controllable size and nanostructure (Bae et al., 2010). Fourier transform infrared spectroscopy has been used to verify the formation of a cross-linking network between the polymer chains. A mesoporous silica templating method has also been used to adjust the molecular weight, particle size, and template of PEG hydrogel particles in biomolecular carriers (Cui et al., 2015), thereby reducing its phagocytosis in vivo.

PEG has been shown to lessen the inflammatory response and effectively inhibit nerve fiber degeneration in the early stage of SCI. Luo et al. (2004) suggested that PEG applied in the acute phase of SCI inhibits the formation of vacuoles and scars, effectively inhibits nerve fiber degeneration, and creates a good microenvironment for the regeneration of nerve fibers. The role of PEG in blocking nerve fiber degeneration may be related to its ability to protect cell integrity, reduce antigen release, and mitigate the inflammatory response.

PEG hydrogels can rapidly repair nerve conduction after severe SCI, promote the myelination of axons, and improve sensory and motor functions. The implantation of PEG hydrogels into the cavity can provide an attachment or a new pathway for the continuous migration of astrocytes, which will migrate to the empty area, eliminate cell aggregation, and inhibit scar formation (Phillips et al., 2005; Burdick et al., 2006; Potter et al., 2008; Krsko et al., 2009). Estrada et al. (2014) implanted an immunologically inert PEG600 material into the scar area after resection of a chronic SCI scar; their results showed that long-distance axonal regeneration at the scar area was conducive to the migration of beneficial cells (Schwann cells, endothelial cells, and astrocytes) and elongation (astrocytes), promoting neurological repair.

PEG reduces cell apoptosis by protecting cell membranes and mitochondria and inhibits free radicals and prevents lipid peroxidation. PEG implanted at the injury site markedly reverses the injury-induced changes in cell membrane permeability (Luo et al., 2002, 2004). Shi et al. (1999) showed that PEG implantation at the site of the completely transected spinal cord in pigs promotes reconstruction of the spinal cord and is conducive to the recovery of spinal cord function. Luo et al. (2007) reported that after SCI, PEG significantly reduces caspase-3 activity by repairing damaged cell membranes and decreases programmed cell death. The interaction of PEG with mitochondria enhances mitochondrial function, decreases the release of cytochrome c, and then inhibits cell apoptosis. Laverty et al. (2004) showed that the application of an aqueous solution of PEG in the subarachnoid space reduces the cavity and promotes the recovery of function in dogs, and its local application protects nerve membranes and accelerates improvement of electroneurographic signals.

  PEG Loaded with Biological Drugs Top

The key to successful SCI treatment is to minimize secondary injury, such as the immune inflammatory response, syringomyelia and scar formation, deficiency of neurotrophic factors, and increased neurite growth inhibitors (e.g., Nogo) (Adams, 2007; Walmsley, 2007; Xu et al., 2008). Drugs and biotherapy, such as cyclosporine A and glutathione, are important means of preventing and reducing secondary neuronal apoptosis and improving the local microenvironment. PEG hydrogels have good biocompatibility and certain advantageous compressive properties. In vitro and in vivo nerve cell co-cultures show that PEG hydrogels are not toxic to nerve cells (Liu et al., 2008; Jiang et al., 2014). PEG-coupled polymers not only promote angiogenesis but also carry drugs or bioactive molecules directly to the SCI site. PEG-coupled polymers can cross both the blood-spinal cord and blood-brain barriers and are thus widely used as drug carriers (Rip et al., 2014).

The polyvinyl alcohol (PVA)/PEG scaffold containing ciprofloxacin inhibits microbial growth, and its application in tissue engineering is promising. The PVA/PEG scaffold is not cytotoxic, promotes cell growth, is strong, and shows good drug release. Zhou et al. (2016) suggested that PEG increases the release efficiency of ciprofloxacin. PEG expands the microchannel and weakens the interaction between PVA chains and ciprofloxacin so that the crystal size of the ciprofloxacin is miniaturized. The introduction of PEG can affect the diffusion and dissolution of the scaffold and increase its release capacity. The layer-by-layer assembly of multilayers of drug or proteins and scaffolding can be customized according to the desired drug or protein release rate. For example, Mehrotra et al. (2010) reduced the speed of protein released from a PEG plus protein plus polyacrylic acid multilayer film to provide sustained, long-term release of brain-derived neurotrophic factor and promote axonal growth. Moreover, Lee et al. (2016) suggested that PEG cross-linking and bridging mechanisms affect protein release efficiency and diffusion coefficients.

PEG-grafted-chitosan (PEG-g-CS) hydrogel is a potential thermal system that is not obviously cytotoxic in the body. An implanted PEG-g-CS hydrogel was maintained in vivo for 2 weeks, gradually dissolving at 3 weeks, and resulting in only a mild inflammatory response. Effective drug concentrations were still detected in the blood 5 weeks after implantation (Jiang et al., 2014). Experiments conducted in vitro have shown that hydrogels sustain stable release of cyclosporin A for 3 weeks, with no significant burst release. Blood concentration fluctuations have been decreased by regulating PEG-g-CS hydrogel degradation (Jiang et al., 2014; Hou et al., 2016).

  Modified PEG Traverses Blood-Brain and Blood-Spinal Cord Barriers Top

Transactivating-transduction protein (TAT) promotes absorption by human microvascular endothelial cells. TAT-modified PEG material can effectively traverse both the blood-brain barrier and the blood-spinal cord barrier (Liu et al., 2008). Liu et al. (2008) prepared the bioactive polymer TAT-PEG-b-cholesterol as a nanocarrier. Ciprofloxacin was successfully adsorbed on the nanocarrier. Scanning electron microscopy showed that the average diameter of the nanocarrier was less than 200 nm. These TAT-modified nanoparticles are able to traverse the blood-brain barrier and enter the neuronal cytoplasm.

Glutathione PEGylated liposomes were developed to safely enhance drug delivery to the brain. The results of Rip et al. (2014) support the versatility of glutathione-PEG liposomes for enhanced drug delivery to the brain. Wang et al. (2010) suggested that TAT-conjugated PEGylated magnetic polymeric liposomes (TAT-PEG-MPLs) could traverse the blood-spinal cord barrier in rats. They observed low magnetic resonance imaging signals in T2-weighted images and found that TAT-PEG-MPL nanoparticles had significantly accumulated around the injury site as well as inside neurons as determined by their histological analysis as well as by cryo-electron microscopy and flame atomic absorption spectrophotometry (Wang et al., 2010).

Although fibroblast growth factor 2 (FGF2) has excellent potential for treatment of SCI because of its angiogenic and trophic effects, it is unable to penetrate spinal cord tissue when delivered locally (Reuss et al., 2003). However, conjugation to PEG is known to improve penetration of proteins into tissue by reducing clearance and providing immunogenic shielding. Kang et al. (2010) conjugated PEG to FGF2 to nearly double the concentration of FGF2 in the injured spinal cord, indicating that PEGylation of FGF2 enhances tissue penetration

  PEG Polymer Hydrogels as Carriers for Stem Cells Top

The mechanical properties of the PEG hydrogel scaffold are very similar to those of the spinal cord. There is less immune rejection after implantation with a PEG hydrogel scaffold in the injured spinal cord than with other hydrogel scaffolds in the injured spinal cord (Kumar et al., 2016; Lawrence et al., 2016), thereby promoting the growth of regenerated axons into the scaffold. PEG hydrogels are also used as supporting substrates for the growth of stem cells after injury, inducing cell migration, proliferation, and differentiation (Bakshi et al., 2004; Hardy et al., 2015). Simultaneously, PEG hydrogels isolate or reduce local glial scar invasion, promote and guide axonal regeneration, cross the transplanted area, and re-establish synaptic connections with the target tissue, thereby promoting spinal cord repair (Estrada et al., 2014). At present, the commonly used seed cells include mainly bone marrow mesenchymal stem cells and neural stem cells.

Hardy et al. (2015) showed that oxime cross-linked hydrogels formed by PEG and hyaluronic acid derivatives are conducive to bone marrow mesenchymal stem cell adhesion. Bhutani et al. (2010) chemically fused mouse embryonic stem cells with human fibroblasts under the induction of PEG, and successfully induced human fibroblasts into pluripotent stem cells. Mulyasasmita et al. (2014) developed protein-PEG hybrid hydrogels, called MITCH-PEG, which slowly release encapsulated vascular endothelial growth factor, and provide significant protection from cell damage. MITCH-PEG co-delivery of induced pluripotent stem cells and vascular endothelial growth factor was found to reduce inflammation and promote angiogenesis.

  Adjusting PEG for Cell Culture Top

Gelatin- and PEG-based hydrogels provide a powerful cell culture platform for tissue engineering applications (Li et al., 2016; Truong et al., 2016). Truong et al. (2016) used a rapid cross-linking process to form hydrogels within minutes of mixing the polymer solutions under physiological conditions, showing that hydrogels can be used as injectable materials. Murine embryonic fibroblastic cells cultured in soft gels demonstrate high cell viability.

The addition of silica nanoparticles has been shown not only to improve the mechanical strength and cell adhesion properties of PEG hydrogels but also to control the degree of cell adhesion for use in biomedicine. Gaharwar et al. (2013) found that the addition of silica nanospheres noticeably inhibited the degree of hydration of the PEG hydrogels, which indicated surface interactions between the polymer chains and the silica nanospheres. No obvious change in hydrogel microstructure or average pore size was detected after the addition of the silica nanospheres. Nevertheless, addition of silica nanospheres markedly increased both the mechanical strength and toughness of the hydrogel networks. The biological properties of these nanocomposite hydrogels were assessed by seeding fibroblasts on the hydrogel surface. The addition of silica nanospheres enhanced cell adhesion, promoted cell spreading, and increased the metabolic activity of the cells (Gaharwar et al., 2013).

Kim et al. (2016) believed that the concentration and molecular weight of the PEG cross-linkers could be varied to control the swelling/shrinking behavior and drug release properties as well as lower the critical solution temperature of poly(N-isopropylacrylamide)-PEG hydrogels. This strategy could be applied to various hydrogel systems to control their physical properties for biomedical applications. Akimoto et al. (2016) prepared a poly(N-isopropylacrylamide) hydrogel cross-linked by PEG for three-dimensional cell culture. By altering the temperature, the volume and the storage elastic modulus of the gel were changed. C2C12 cell adhesion was confirmed using RGDS pendants. Such PEG-cross-linked hydrogels are expected to be useful as new material for three-dimensional cell culture to control cell fate and to improve the biocompatibility of cells.

  PEG Limitations and Proposed Applications Top

Rao et al. (2011) suggested that the efficacy of PEG alone is not ideal but that polylysine-modified PEG hydrogel promotes nerve cell adhesion, elevates biocompatibility and stability of neural tissue integration, and contributes to axon regeneration and remyelination. The use of PEG alone cannot completely mimic the three-dimensional porous structure of the spinal cord, and the biocompatibility is relatively insufficient. In addition, its position after transplantation in vivo is randomly relative to the structure of the spinal cord, allowing the upper and lower fiber bundles to grow in mismatched or even misplaced channels or pores.

PEG-poly (-L-lactic acid) (PLLA) hydrogels provide biodegradable, porous structures with pore sizes that do not change during degradation. Chiu et al. (2013) found that the pore size was controlled by the particulate size, and they adjusted the polymer concentration, optimized the degradation time, and provided additional guidance for the optimization of material properties to generate three-dimensional, degradable, porous PEG hydrogels. Such coupled hydrogels mitigate the disadvantages of PEG alone. The optimized design of the three-dimensional, porous PEG polymer scaffold along with the biomimetic spinal cord scaffold created by three-dimensional printing technology provided a structural basis for the extension of nerve cell growth across the diseased spinal cord (Namba et al., 2009; Soman et al., 2012). However, because of the limitations imposed by mechanical properties and changes in the microenvironment after SCI, three-dimensional bioprinting of biomimetic porous PEG scaffolds remains a tough challenge and a hot topic in tissue engineering.

PEG has shown good safety and is approved by the U.S. Food and Drug Administration as a preservative additive and in modified nanoparticles for use before organ transplantation to reduce the inflammatory response and slow the in vivo clearance rate of nanoparticle drug carriers (Giannousi et al., 2016; Pasut et al., 2016; Huo et al., 2017). However, Romano et al. (2014) found that pegylated liposomal doxorubicin used for treating multiple myeloma was associated with some adverse events, including thrombocytopenia (9%), peripheral neuropathy (8%), and infections (8%). In addition, low-molecular-weight PEG accelerated the accumulation of platelet derived growth factor and reduced its activity, thereby reducing the differentiation of neural stem/progenitor cells into oligodendrocytes (Elliott Donaghue et al., 2015). Because of the wide use of PEG, the safety of PEG and PEG polymers in vivo needs to be further improved.

The drug loading capacity of PEG alone is relatively low, but PEG polymers can improve this. For example, an in vivo study demonstrated that PEG-PLA copolymers increase the hydrophobic drug loading capacity as well as enhance slow release, avoid phagocytosis by phagocytes, increase the time drugs spend circulating in the blood, and improve bioavailability (Xiao et al., 2010). PEG-poly(lactic-co-glycolic acid) copolymers have been shown to increase the loading efficiency of poorly soluble drugs (Zhang et al., 2014). The development of new PEG polymers may help optimize the low drug-loading efficiency of PEG alone. The research and development of such PEG polymers and new materials remains a hot research topic.

Although PEG has several shortcomings, it has been used as a component of new materials. Many of its properties may be transferred to these conjugates, giving the material new properties, such as hydrophilicity and flexibility. The end groups of PEG play decisive roles, as the various end groups offer different advantages. Functional groups, such as toluenesulfonate, amino, carboxyl and aldehyde, can be introduced into both ends of the PEG chain to further expand the useful applications of PEG. Thus, PEG has broad application prospects in organic synthesis, peptide synthesis, the slow or controlled release of drugs, targeted drug delivery, and stem cell transplantation.

  Conclusions Top

Multiple disciplines are involved in the repair of SCI. Engineered materials, such as PEG, are important components of research in spinal cord tissue engineering. Research has shown that in addition to being stable, nontoxic, and biocompatible, PEG does not accumulate in the body, can be used as a sealant for injured axon membranes, inhibits the formation of vacuoles and scars, protects against nerve fiber degeneration, reduces inflammation, protects nerve membranes, decreases cell death, protects mitochondria, suppresses cell apoptosis, and improves electroneurographic signals. Such advantages of PEG offer promise for its use coupled with bioactive molecules and drugs as tissue-engineered scaffolds in the repair of the injured spinal cord.[51]

  References Top

Adams M, Carlstedt T, Cavanagh J, Lemon RN, McKernan R, Priestley JV, Raisman G, Verhaagen J (2007) International spinal research trust research strategy. III: a discussion document. Spinal Cord 45:2-14  Back to cited text no. 1
Akimoto AM, Hasuike E, Tada H, Nagase K, Okano T, Kanazawa H, Yoshida R (2016) Design of Tetra-arm PEG-crosslinked thermoresponsive hydrogel for 3d cell culture. Anal Sci 32:1203-1205  Back to cited text no. 2
Bae M, Divan R, Suthar KJ, Mancini DC, Gemeinhart RA (2010) Fabrication of poly(ethylene glycol) hydrogel structures for pharmaceutical applications using electron beam and optical lithography. J Vac Sci Technol B Microelectron Nanometer Struct Process Meas Phenom 28:C6P24-6P29  Back to cited text no. 3
Bakshi A, Fisher O, Dagci T, Himes BT, Fischer I, Lowman A (2004) Mechanically engineered hydrogel scaffolds for axonal growth and angiogenesis after transplantation in spinal cord injury. J Neurosurg Spine 1:322-329  Back to cited text no. 4
Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM (2010) Reprogramming towards pluripotency requires AID–dependent DNA demethylation. Nature 463:1042-1047  Back to cited text no. 5
Burdick JA, Ward M, Liang E, Young MJ, Langer R (2006) Stimulation of neurite outgrowth by neurotrophins delivered from degradable hydrogels. Biomaterials 27:452-459.  Back to cited text no. 6
Chiu YC, Kocagöz S, Larson JC, Brey EM (2013) Evaluation of physical and mechanical properties of porous poly (ethylene glycol)-co-(L-lactic acid) hydrogels during degradation. PLoS One 8:e60728  Back to cited text no. 7
Cui J, De Rose R, Alt K, Alcantara S, Paterson BM, Liang K, Hu M, Richardson JJ, Yan Y, Jeffery CM, Price RI, Peter K, Hagemeyer CE, Donnelly PS, Kent SJ, Caruso F (2015) Engineering poly (ethylene glycol) particles for improved biodistribution. ACS Nano 9:1571-1580  Back to cited text no. 8
Elliott Donaghue I, Shoichet MS (2015) Controlled release of bioactive PDGF-AA from a hydrogel/nanoparticle composite. Acta Biomater 25:35-42  Back to cited text no. 9
Estrada V, Brazda N, Schmitz C, Heller S, Blazyca H, Martini R, Müller HW (2014) Long-lasting significant functional improvement in chronic severe spinal cord injury following scar resection and polyethylene glycol implantation. Neurobiol Dis 67:165-179  Back to cited text no. 10
Flynnj R, Graham BA, Galea MP, Callister RJ (2011) The role of propriospinal interneurons in recovery from spinal cord injury. Neuropharmacology 60:809-822  Back to cited text no. 11
Gaharwar AK, Rivera C, Wu CJ, Chan BK, Schmidt G (2013) Photocrosslinked nanocomposite hydrogels from PEG and silica nanospheres: structural, mechanical and cell adhesion characteristics. Mater Sci Eng C Mater Biol Appl 33:1800-1807  Back to cited text no. 12
Giannousi K, Hatzivassiliou E, Mourdikoudis S (2016) Synthesis and biological evaluation of PEGylated CuO nanoparticles. J Inorg Biochem 164:82-90  Back to cited text no. 13
Hardy JG, Lin P, Schmidt CE (2015) Biodegradable hydrogels composed of oxime crosslinkedpoly(ethylene glycol), hyaluronic acid and collagen: a tunable platform for soft tissue engineering. J Biomater Sci Polym Ed 26:143-161  Back to cited text no. 14
Huo S, Chen S, Gong N (2017) Ultrasmall gold nanoparticles behavior in vivo modulated by surface polyethylene glycol (PEG) grafting. Bioconjug Chem doi: 10.1021/acs.bioconjchem.6b00488  Back to cited text no. 15
Huo S, Chen S, Gong N, Liu J, Li X, Zhao Y, Liang XJ (2016) Synthesis, characterization, and application of reversible PDLLA-PEG-PDLLA copolymer thermogels in vitro and in vivo. Sci Rep 6:19077  Back to cited text no. 16
Jiang G, Sun J, Ding F (2014) PEG-g-chitosan thermosensitive hydrogel for implant drug delivery: cytotoxicity, in vivo degradation and drug release. J Biomater Sci Polym Ed 25:241-256  Back to cited text no. 17
Kang CE, Tator CH, Shoichet MS (2010) Poly (ethylene glycol) modification enhances penetration of fibroblast growth factor 2 to injured spinal cord tissue from an intrathecal delivery system. J Control Release 144:25-31  Back to cited text no. 18
Kim S, Lee K, Cha C (2016) Refined control of thermoresponsive swelling/deswellin and drug release properties of poly(N-isopropylacrylamide) hydrogels using hydrophilic polymer crosslinkers. J Biomater Sci Polym Ed 27:1698-1711  Back to cited text no. 19
Krsko P, McCann TE, Thach TT, Laabs TL, Geller HM, Libera MR (2009) Length-scale mediated adhesion and directed growth of neural cells by surface-patterned poly (ethylene glycol) hydrogels. Biomaterials 30:721-729.  Back to cited text no. 20
Kumar M, Coburn J, Kaplan DL, Mandal BB (2016) Immuno-informed 3d silk biomaterials for tailoring biological responses. ACS Appl Mater Interfaces 43:29310-29322  Back to cited text no. 21
Laverty PH, Leskovar A, Breur GJ, Coates JR, Bergman RL, Widmer WR, Toombs JP, Shapiro S, Borgens RB (2004) A preliminary study of intravenous surfactants in paraplegic dogs: polymer therapy in canine clinical SCI. J Neurotrauma 21:1767-1777  Back to cited text no. 22
Lee S, Tong XM, Yang F (2016) Effects of the poly(ethylene glycol) hydrogelcrosslinking mechanism on protein release. Biomater Sci 4:405-411  Back to cited text no. 23
Liu L, Guo K, Lu J, Venkatraman SS, Luo D, Ng KC, Ling EA, Moochhala S, Yang YY (2008) Biologically active core/shell nanoparticles self-assembled from cholesterol-terminated PEG-TAT for drug delivery across the blood-brain barrier. Biomaterials 29:1509-1517.  Back to cited text no. 24
Liu L, Venkatraman SS, Yang YY, Guo K, Lu J, He B, Moochhala S, Kan L (2008) Polymeric micelles anchored with TAT for delivery of antibiotics across the blood-brain barrier. Biopolymers 90:617-623  Back to cited text no. 25
Luo J, Borgens R, Shi R (2002) Polyethylene glycol immediately repairs neuronal membranes and inhibits free radical production after acute spinal cord injury. J Neuroehem 83:471-480  Back to cited text no. 26
Luo J, BorgensR, Shi R (2004) Polyethylene glycol improves function and reduces oxidative stress in synaptosomal preparations following spinal cord injury. J Neurotrauma 21:994-1007  Back to cited text no. 27
Luo J, Shi R (2004) Diffusire oxidative stress following acute spinal cord injury in guinea pigs and its inhibition by polyethylene glycol. Neurosci Lett 359:167-170  Back to cited text no. 28
Luo J, Shi R (2007) Polyethylene glycol inhibits apoptotic cell death following traumatic spinal cord injury. Brain Res 1155:10-16  Back to cited text no. 29
Li Y, Meng H, Liu Y, Narkar A, Lee BP (2016) Gelatin microgel incorporated poly (ethylene glycol)-based bioadhesive with enhanced adhesive property and bioactivity. ACS Appl Mater Interfaces 8:11980-11989  Back to cited text no. 30
Lawrence PB, Price JL (2016) How PEGylation influences protein conformational stability. Curr Opin Chem Biol 34:88-94  Back to cited text no. 31
Mehrotra S, Lynam D, Maloney R, Pawelec KM, Tuszynski MH, Lee I, Chan C, Sakamoto J (2010) Time controlled protein release from layer-by-layer assembled multilayer functionalized agarose hydrogels. Adv Funct Mater 20:247-258  Back to cited text no. 32
Mulyasasmita W, Cai L, Dewi RE, Jha A, Ullmann SD, Luong RH, Huang NF, Heilshorn SC (2014) Avidity-controlled hydrogels for injectable co-delivery of induced pluripotent stem cell-derived endothelial cells and growth factors. J Control Release 191:71-81  Back to cited text no. 33
Namba RM, Cole AA, Bjugstad KB, Mahoney MJ (2009) Development of porous PEG hydrogels that enable efficient, uniform cell-seeding and permit early neural process extension. Acta Biomater 5:1884-1897  Back to cited text no. 34
Pasut G, Panisello A, Folch-Puy E, Lopez A, Castro-Benítez C, Calvo M, Carbonell T, García-Gil A, Adam R, Roselló-Catafau J (2016) Polyethylene glycols: an effective strategy for limiting liver ischemia reperfusion injury. World J Gastroenterol 22:6501-6508  Back to cited text no. 35
Phillips JB, Bunting SC, Hall SM, Brown RA (2005) Neural tissue engineering: a self-organizing collagen guidance conduit. Tissue Eng 11:1611-1617  Back to cited text no. 36
Potter W, Kalil RE, Kao WJ (2008) Biomimetic material systems for neural progenitor cell-based therapy. Front Biosci 13:806-821  Back to cited text no. 37
Rao SS, Han N, Winter JO (2011) Polylysine-modified PEG-based hydrogels to enhance the neuro-electrode interface. J Biomater Sci Polym Ed 22:611-625  Back to cited text no. 38
Rip J, Chen L, Hartman R, van den Heuvel A, Reijerkerk A, van Kregten J, van der Boom B, Appeldoorn C, de Boer M, Maussang D, de Lange EC, Gaillard PJ (2014) Glutathione PEGylated liposomes: pharmacokinetics and delivery of cargo across the blood-brain barrier in rats. J Drug Target 22:460-467  Back to cited text no. 39
Reuss B, Dono R, Unsicker K (2003) Functions of fibroblast growth factor (FGF)-2 and FGF-5 in astroglial differentiation and blood-brain barrier permeability: evidence from mouse mutants. J Neurosci 23:6404-6412  Back to cited text no. 40
Romano A, Chiarenza A, Conticello C, Cavalli M, Vetro C, Di Raimondo C, Cunsolo R, Palumbo GA, Di Raimondo F (2014) Salvage therapy with pegylated liposomal doxorubicin, bortezomib, cyclophosphamide, and dexamethasone in relapsed/refractory myeloma patients. Eur J Haematol 93:207-213  Back to cited text no. 41
Shi R, Borgens RB, Blight AR (1999) Functional reconnection of severed mammalian spinalcord axons with polyethylene glycol. J Neurotrauma 16:727-738  Back to cited text no. 42
Soman P, Tobe BT, Lee JW, Winquist AA, Singec I, Vecchio KS, Snyder EY, Chen S (2012) Three-dimensional scaffolding to investigate neuronal derivatives of human embryonic stem cells. Biomed Microdevices 14:829-838  Back to cited text no. 43
Truong VX, Hun ML, Li F, Chidgey AP, Forsythe JS (2016) In situ-forming click-crosslinked gelatin based hydrogels for 3D culture of thymic epithelial cells. Biomater Sci 4:1123-1131  Back to cited text no. 44
Walmsley AR, Mir AK (2007) Targeting the Nogo-A euritis pathway to promote recovery following acute CNS injury. Curr Pharm Des 13:2470-2484  Back to cited text no. 45
Wang H, Zhang S, Liao Z, Wang C, Liu Y, Feng S, Jiang X, Chang J (2010) PEGlated magnetic polymeric liposome anchored with TAT for delivery of drugs across the blood-spinal cord barrier. Biomaterials 31:6589-6596  Back to cited text no. 46
Xiao RZ, Zeng ZW, Zhou GL, Wang JJ, Li FZ, Wang AM (2010) Recent advances in PEG-PLA block copolymer nanoparticles. Int J Nanomedicine 5:1057-1065  Back to cited text no. 47
Xu P, Gong WM, Li Y, Zhang T, Zhang K, Yin DZ, Jia TH (2008) Destructive pathological changes in the rat spinal cord due to chronic mechanical compression. Neurosurg Spine 8:279-285  Back to cited text no. 48
Yang ZQ, He Y, Shi JD (2015) Polyethylene glycol effects on the performance of rifampicin-polylactic acid-glycolic acid polymer microspheres. Zhongguo Zuzhi Gongcheng Yanjiu 19:421-426.  Back to cited text no. 49
Zhang K, Tang X, Zhang J, Lu W, Lin X, Zhang Y, Tian B, Yang H, He H (2014) PEG-PLGA copolymers: their structure and structure-influenced drug delivery applications. J Control Release 183:77-86  Back to cited text no. 50
Zhou XH, Wei DX, Ye HM, Zhang X, Meng X, Zhou Q (2016) Development of poly(vinyl alcohol) porous scaffold with high strength and well ciprofloxacin release efficiency. Mater Sci Eng C Mater Biol Appl 67:326-335.  Back to cited text no. 51

Author contributions: XBK conceived and prepared the paper. XBK and ZLS collected the data. XYC, YT and SZS provided critical revision of the paper. All authors approved the final version of the paper.
Conflicts of interest: None declared.
Contributor agreement: A statement of “Publishing Agreement” has been signed by an authorized author on behalf of all authors prior to publication.
Plagiarism check: This paper has been checked twice with duplication-checking software iThenticate.
Peer review: A double-blind and stringent peer review process has been performed to ensure the integrity, quality and significance of this paper. Open peer reviewer: Idiris Altun, KSÜ University Medical faculty of Turkey, Turkey.


  [Figure 1]

This article has been cited by
1 Advances in Biomaterial-Based Spinal Cord Injury Repair
He Shen, Caixia Fan, Zhifeng You, Zhifeng Xiao, Yannan Zhao, Jianwu Dai
Advanced Functional Materials. 2021; : 2110628
[Pubmed] | [DOI]
2 A rechargeable drug delivery system based on pNIPAM hydrogel for the local release of curcumin
Zahra Ayar,Mehdi Shafieian,Narges Mahmoodi,Omid Sabzevari,Zahra Hassannejad
Journal of Applied Polymer Science. 2021; : 51167
[Pubmed] | [DOI]
3 Microparticle-tagged image-based cell counting (ImmunoSpin) for CD4?+?T cells
Sang-Hyun Hwang, John Jeongseok Yang, Yoon-Hee Oh, Dae-Hyun Ko, Heungsup Sung, Young-Uk Cho, Seongsoo Jang, Chan-Jeoung Park, Heung-Bum Oh
Microchimica Acta. 2021; 188(12)
[Pubmed] | [DOI]
4 Degradation mechanisms and acceleration strategies of Poly (lactic acid) scaffold for bone regeneration
Pei Feng,Jiye Jia,Mingyang Liu,Shuping Peng,Zhenyu Zhao,Cijun Shuai
Materials & Design. 2021; : 110066
[Pubmed] | [DOI]
5 Densities, Viscosities, and Self-Diffusion Coefficients of Ethylene Glycol Oligomers
Markus M. Hoffmann,Rachel H. Horowitz,Torsten Gutmann,Gerd Buntkowsky
Journal of Chemical & Engineering Data. 2021;
[Pubmed] | [DOI]
6 Densities, Viscosities, and Self-Diffusion Coefficients of Several Polyethylene Glycols
Markus M. Hoffmann, Joseph D. Kealy, Torsten Gutmann, Gerd Buntkowsky
Journal of Chemical & Engineering Data. 2021;
[Pubmed] | [DOI]
7 Engineering bioactive synthetic polymers for biomedical applications: a review with emphasis on tissue engineering and controlled release
Edna Johana Bolívar-Monsalve,Mario Moisés Alvarez,Samira Hosseini,Michelle Alejandra Espinosa-Hernandez,Carlos Fernando Ceballos-González,Margarita Sanchez-Dominguez,Su Ryon Shin,Berivan Cecen,Shabir Hassan,Ernesto Di Maio,Grissel Trujillo-de Santiago
Materials Advances. 2021;
[Pubmed] | [DOI]
8 Design of graphenic nanocomposites containing chitosan and polyethylene glycol for spinal cord injury improvement
Ayda Yari-Ilkhchi,Abbas Ebrahimi-Kalan,Mehdi Farhoudi,Mehrdad Mahkam
RSC Advances. 2021; 11(33): 19992
[Pubmed] | [DOI]
9 Diamond Concept as Principle for the Development of Spinal Cord Scaffold: A Literature Review
Yudha M. Sakti, Rusdy Ghazali Malueka, Ery Kus Dwianingsih, Ahmad Kusumaatmaja, Akbar Mafaza, Deas Makalingga Emiri
Open Access Macedonian Journal of Medical Sciences. 2021; 9(F): 754
[Pubmed] | [DOI]
10 Mechanically strengthened hybrid peptide-polyester hydrogel and potential applications in spinal cord injury repair
Hong Zhai,Jing Zhou,Jinghui Xu,Xiumin Sun,Yiwei Xu,Xibo Qiu,Chi Zhang,Zejia Wu,Houqing Long,Ying Bai,Daping Quan
Biomedical Materials. 2020; 15(5): 055031
[Pubmed] | [DOI]
11 Enhanced regeneration of osteochondral defects by using an aggrecanase-1 responsively degradable and N-cadherin mimetic peptide-conjugated hydrogel loaded with BMSCs
Xue Feng,Tong Zhou,Peifang Xu,Juan Ye,Zhongru Gou,Changyou Gao
Biomaterials Science. 2020;
[Pubmed] | [DOI]
12 X-ray scattering study on the crystalline and semi-crystalline structure of water/PEG mixtures in their eutectic phase diagram
Björn Kuttich,Alexander Matt,Christian Appel,Bernd Stühn
Soft Matter. 2020;
[Pubmed] | [DOI]
13 Design of hydrogel-based scaffolds for the treatment of spinal cord injuries
Nazanin Ghane,Mohammad-Hossein Beigi,Sheyda Labbaf,Mohammad-Hossein Nasr-Esfahani,Amirkianoosh Kiani
Journal of Materials Chemistry B. 2020;
[Pubmed] | [DOI]
14 Extracellular vesicles in diabetes mellitus induce alterations in endothelial cell morphology and migration
Sharon F. Wu,Nicole Noren Hooten,David W. Freeman,Nicolle A. Mode,Alan B. Zonderman,Michele K. Evans
Journal of Translational Medicine. 2020; 18(1)
[Pubmed] | [DOI]
15 Nanofibers as a Delivery System for Arbuscular Mycorrhizal Fungi
José M. Campaña,Melvin Arias
ACS Applied Polymer Materials. 2020;
[Pubmed] | [DOI]
16 Polyethylene glycol: A promising approach for sustainable organic synthesis
Jay Soni,Nusrat Sahiba,Ayushi Sethiya,Shikha Agarwal
Journal of Molecular Liquids. 2020; : 113766
[Pubmed] | [DOI]
17 Enhanced proliferation and differentiation of neural stem cells by peptide-containing temperature-sensitive hydrogel scaffold
Yanpiao Long,Lesan Yan,Honglian Dai,Dong Yang,Xiaopei Wu,Xianzhen Dong,Kun Liu,Wenying Wei,Yuzhe Chen
Materials Science and Engineering: C. 2020; 116: 111258
[Pubmed] | [DOI]
18 Promising Role of Nano-Encapsulated Drugs for Spinal Cord Injury
Tasneem Ismail Khan,S. Hemalatha,Mohammad Waseem
Molecular Neurobiology. 2020;
[Pubmed] | [DOI]
19 Commercial hydrogels for biomedical applications
S.H. Aswathy,U. Narendrakumar,I. Manjubala
Heliyon. 2020; 6(4): e03719
[Pubmed] | [DOI]
20 Recreating Physiological Environments In Vitro: Design Rules for Microfluidic-Based Vascularized Tissue Constructs
Sin Yen Tan,Ziuwin Leung,Angela Ruohao Wu
Small. 2020; : 1905055
[Pubmed] | [DOI]
21 Minimally Invasive and Regenerative Therapeutics
Nureddin Ashammakhi,Samad Ahadian,Mohammad Ali Darabi,Mario El Tahchi,Junmin Lee,Kasinan Suthiwanich,Amir Sheikhi,Mehmet R. Dokmeci,Rahmi Oklu,Ali Khademhosseini
Advanced Materials. 2019; 31(1): 1804041
[Pubmed] | [DOI]
22 Motor and sensitive recovery after injection of a physically cross-linked PNIPAAm-g-PEG hydrogel in rat hemisectioned spinal cord
Maxime Bonnet,Thomas Trimaille,Brezun Jean-Michel,François Feron,Didier Gigmes,Tanguy Marqueste,Patrick Decherchi
Materials Science and Engineering: C. 2019; : 110354
[Pubmed] | [DOI]
23 Bridging the gap: Spinal cord fusion as a treatment of chronic spinal cord injury
Xiaoping Ren,C-Yoon Kim,Sergio Canavero
Surgical Neurology International. 2019; 10: 51
[Pubmed] | [DOI]
24 Regenerative Therapies for Spinal Cord Injury
Nureddin Ashammakhi,Han-Jun Kim,Arshia Ehsanipour,Rebecca D. Bierman,Outi Kaarela,Chengbin Xue,Ali Khademhosseini,Stephanie K. Seidlits
Tissue Engineering Part B: Reviews. 2019;
[Pubmed] | [DOI]
25 Looking into the Future: Toward Advanced 3D Biomaterials for Stem-Cell-Based Regenerative Medicine
Zhongmin Liu,Mingliang Tang,Jinping Zhao,Renjie Chai,Jiuhong Kang
Advanced Materials. 2018; : 1705388
[Pubmed] | [DOI]
26 Isoniazid-loaded orodispersible strips: Methodical design, optimization and in vitro-in silico characterization
Oluwatoyin A. Adeleke,Pei-Chin Tsai,Krizia M. Karry,Nkwe O. Monama,Bozena B. Michniak-Kohn
International Journal of Pharmaceutics. 2018; 547(1-2): 347
[Pubmed] | [DOI]
27 Displacement and hybridization reactions in aptamer-functionalized hydrogels for biomimetic protein release and signal transduction
Jinping Lai,Shihui Li,Xuechen Shi,James Coyne,Nan Zhao,Fengping Dong,Yingwei Mao,Yong Wang
Chem. Sci.. 2017;
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Characteristics ...
PEG Loaded with ...
Modified PEG Tra...
PEG Polymer Hydr...
Adjusting PEG fo...
PEG Limitations ...
Article Figures

 Article Access Statistics
    PDF Downloaded763    
    Comments [Add]    
    Cited by others 27    

Recommend this journal