IPN Hydrogels Research Articles

Facile fabrication of a thermal/pH responsive IPN hydrogel drug carrier based on cellulose and chitosan through simultaneous dual-click strategy

Herein, an interpenetrating network hydrogel (IPN-Gel) based on cellulose and chitosan was synthesized via simultaneous amino-anhydride and azide–alkyne click reaction in water in one pot. The samples were characterized by various analytical methods including FTIR, SEM, XRD, XPS, 1H NMR and so forth. The fabrication conditions were optimized by single factor experiments with water uptake (WU) and gel mass fraction (GMF) as two indexes. The WU and GMF of the IPN-Gel prepared under optimized conditions were 1192.37 % and 74.00 %, respectively. Its WU descended with the ascension in temperature, and first descended and then gradually ascended with the ascension in pH, confirming that the IPN-Gel had thermal/pH dual responsiveness. Using 5-Fu as a model drug, the release behavior of 5-Fu in IPN-Gel was explored. Its release behavior could be regulated by changing temperature and pH values, and it followed the Korsmeyer Peppas model. The viability of 4 T1 cells and HUVEC cells exceeded 80 % after 48 h of incubation at a high concentration of 200 μg/mL IPN-Gel, and hemolytic percentage was below the allowed limit of 5 %. The study provides a new strategy for the preparation of the IPN-Gel with biocompatibility, swelling reversibility and controllable drug release.

BC-g-PAA: Characterization and Establishment of the IPN Hydrogel

A study on the manufacture of bacterial cellulose IPN hydrogel crosslinked poly acrylic acid using the MBA crosslinker. This study aims to characterize and observe the reaction to form bacterial cellulose-based hydrogel IPN. The BC-g-PAA was characterized by the degree of cross-linking, swelling ratio, and FTIR analysis. The results of this study found predictions of the reaction process for the formation of IPN Hydrogel in several process stages, namely 1) The polymerization process of bacterial cellulose chains that form cross-linked networks independently, 2) The process of cross-linking Acrylate monomers with MBA crosslinkers in three steps, i.e. initiation, propagation and termination, 3) Reaction process Formation of IPN network. The results of the characterization test for the degree of crosslinking were 54.55%; Swelling ratio of 1631.25%. FTIR analysis shows that there is a peak that identifies the occurrence of crosslinking

An Injectable Nanocomposite IPN Hydrogel Based on Gelatin Methacrylate/Alginate/COF for Tissue Engineering Applications

AbstractThe primary request nowadays is for innovative and superior scaffold designs that mimic the characteristics of native tissue in cartilage tissue engineering. GelMA/Alginate (G/A) interpenetrating polymer network (IPN) has become a popular hydrogel material for tissue engineering because of its superior mechanical and biological properties. Here, to balance the properties, a hydrogel composed of G/A and covalent organic frameworks (COF) nanoparticles is specially designed. In this study, a hydrogel of GelMA/Alginate/COF (G/A/C) with improved properties such as pore size, swelling, mechanical strength, shear‐thinning behavior, and biocompatibility is produced. Furthermore, the G/A/C hydrogel facilitate the printing of complex three dimensional (3D) scaffolds. The test result demonstrates that the addition of COF up to 1% (w/w) enhances the porosity and decreases pore size (0.2 times), improves the compression strength (six times), and decreases the degradation ratio (0.05 times) and the swelling (0.3 times) compared to the G/A hydrogel sample. Besides, the cell viability test confirms the cell growth during the incubation and great biological behavior (more than 98%). The suitable performance of the G/A hydrogel containing 1% COF and its shape fidelity during the injection by 3D printer is confirmed. Nanocomposite IPN hydrogel based on G/A/C could be useful in tissue engineering applications.

Engineering sulfated polysaccharides and silk fibroin based injectable IPN hydrogels with stiffening and growth factor presentation abilities for cartilage tissue engineering.

The extracellular matrix (ECM) presents a framework for various biological cues and regulates homeostasis during both developing and mature stages of tissues. During development of cartilage, the ECM plays a critical role in endowing both biophysical and biochemical cues to the progenitor cells. Hence, designing microenvironments that recapitulate these biological cues as provided by the ECM during development may facilitate the engineering of cartilage tissue. In the present study, we fabricated an injectable interpenetrating hydrogel (IPN) system which serves as an artificial ECM and provides chondro-inductive niches for the differentiation of stem cells to chondrocytes. The hydrogel was designed to replicate the gradual stiffening (as a biophysical cue) and the presentation of growth factors (as a biochemical cue) as provided by the natural ECM of the tissue, thus exemplifying a biomimetic approach. This dynamic stiffening was achieved by incorporating silk fibroin, while the growth factor presentation was accomplished using sulfated-carboxymethyl cellulose. Silk fibroin and sulfated-carboxymethyl cellulose (s-CMC) were combined with tyraminated-carboxymethyl cellulose (t-CMC) and crosslinked using HRP/H2O2 to fabricate s-CMC/t-CMC/silk IPN hydrogels. Initially, the fabricated hydrogel imparted a soft microenvironment to promote chondrogenic differentiation, and with time it gradually stiffened to offer mechanical support to the joint. Additionally, the presence of s-CMC conferred the hydrogel with the property of sequestering cationic growth factors such as TGF-β and allowing their prolonged presentation to the cells. More importantly, TGF-β loaded in the developed hydrogel system remained active and induced chondrogenic differentiation of stem cells, resulting in the deposition of cartilage ECM components which was comparable to the hydrogels that were treated with TGF-β provided through media. Overall, the developed hydrogel system acts as a reservoir of the necessary biological cues for cartilage regeneration and simultaneously provides mechanical support for load-bearing tissues such as cartilage.

Multifunctional and self-healable conductive IPN hydrogels functionalized with reduced magnetite graphene oxide for an advanced flexible all in one solid-state supercapacitor

The all in one solid-state (AIOS) stretchable and flexible hydrogel electronic devices play a pivotal role in the development of elastic supercapacitors for energy storage and fast charging–discharging rates.

Polyoxometalate nanocluster-infused triple IPN hydrogels for excellent microplastic removal from contaminated water: detection, photodegradation, and upcycling.

Microplastic (MP) pollution pervades global ecosystems, originating from improper plastic disposal and fragmentation due to factors like hydrolysis and biodegradation. These minute particles, less than 5 mm in size, have become omnipresent, impacting terrestrial, freshwater, and marine environments worldwide. Their ubiquity poses severe threats to marine life by causing physical harm and potentially transferring toxins through the food chain. Addressing this environmental crisis necessitates a sustainable strategy. Our proposed solution involves a highly efficient copper substitute polyoxometalate (Cu-POM) nanocluster infused triple interpenetrating polymer network (IPN) hydrogel, comprising chitosan (CS), polyvinyl alcohol (PVA), and polyaniline (PANI) (referred to as pGel@IPN) for mitigating MP contamination from water. This 3D IPN architecture, incorporating nanoclusters, also enhances the hydrogel's photodegradation capabilities. Our scalable approach offers a sustainable strategy to combat MPs in water bodies, as demostrated by the adsorption behaviors on the hydrogel matrix under varying conditions, simulating real-world scenarios. Evaluations of physicochemical properties, mechanical strength, and thermal behavior underscore the hydrogel's robustness and stability. Detecting minute MP particles remains challenging, prompting us to label MPs with Nile red for fluorescence microscopic analysis of their concentration and adsorption on the hydrogel. The catalytic properties of POM within the hydrogel facilitate UV-induced MP degradation, highlighting a sustainable solution. Our detailed kinetics and isotherm studies revealed pseudo-first-order and Langmuir models as fitting descriptors for MP adsorption, exhibiting a high maximum adsorption capacity (Qm). Notably, pGel@IPN achieved ∼95% and ∼93% removal efficiencies for polyvinyl chloride (PVC) and polypropylene (PP) MPs at pH ∼ 6.5, respectively, also demonstrating reusability for up to 5 cycles. Post-end-of-life, the spent adsorbent was efficiently upcycled into carbon nanomaterials, effectively removing the heavy metal Cr(VI), exemplifying circular economy principles. Our prepared hydrogel emerges as a potent solution for MP removal from water, promising effective mitigation of the emerging pollutants of MPs while ensuring sustainable environmental practices.

Effect of Linear Polyacrylamide on the Properties of semi–IPN Hydrogels Based on N, N’–Dimethylacrylamide, and Maleic Acid

In this work, the semi–interpenetrating polymer network hydrogels based on Polyacrylamide; N, N’–Dimethylacrylamide, and Maleic acid were synthesized and investigated by changing the content of linear polyacrylamide in the obtained materials. The chemical properties, morphology, swelling behaviors in distilled water, and mechanical properties of the hydrogels were investigated. Fourier transform infrared spectra confirmed the polymerization ability of monomers, scanning electronic microscopy images showed that the pore size could be controlled by the added volume of linear polyacrylamide was in the range of 252.8 ± 5.0 ~ 888.5 ± 3.5 µm. The swelling ratio and the mechanical properties of the hydrogels increased with increasing linear polyacrylamide content. All of the results in this work showed that semi–interpenetrating polymer network hydrogels based on Polyacrylamide; N, N’–Dimethylacrylamide, and Maleic acid had a high swelling ratio, good water retention, thermal properties, and mechanical properties. Potential applications of the obtained hydrogels are in progress.

The Deswelling of IPN Hydrogel Tablets by Lattice Boltzmann Method

The Deswelling of IPN Hydrogel Tablets by Lattice Boltzmann Method

Injectable neural hydrogel as in vivo therapeutic delivery vehicle.

This study demonstrated in vivo delivery of a decellularized, injectable peripheral nerve (iPN) hydrogel and explored options for using iPN in combination with regenerative biomolecular therapies like stem cell secretome. Rat-derived iPN hydrogel solutions were combined with a dextran-dye before subcutaneous injection into adult Sprague Dawley rats. After injection, an in vivo imaging system (IVIS) was used to visualize hydrogels and quantify dextran-dye release over time. Poly(lactic-co-glycolic) acid (PLGA) was used to encapsulate the dextran-dye to prolong molecular release from the hydrogel scaffolds. Lastly, we investigated use of adipose-derived stem cell (ASC) secretome as a potential future combination strategy with iPN. ASC secretome was assessed for growth factor levels in response to media stimulation and was encapsulated in PLGA to determine loading efficiency. Gelation of iPN hydrogels was successful upon subcutaneous injection. When combined with iPN, a 10 kDa dextran-dye was reduced to 54% its initial signal at 24 hours, while PLGA-encapsulated dextran-dye in iPN was only reduced to 78% by 24 hours. Modified media stimulation resulted in changes in ASC phenotype and dramatic upregulation of VEGF secretion. The PLGA encapsulation protocol was adapted for use with temperature sensitive biomolecules, however, considerations must be made with loading efficiency for cell secretome as the maximum efficiency was 28%. The results of this study demonstrated successful injection and subsequent gelation of our iPN hydrogel formulation in vivo. Biomolecular payloads can be encapsulated in PLGA to help prolong their release from the soft iPN hydrogels in future combination therapies. We developed an injectable decellularized tissue scaffold from rat peripheral nerve tissue (called iPN), a potential minimally invasive therapeutic meant to fill lesion spaces after injury. This study was the first demonstration of iPN delivery to a living animal. The iPN solution was injected subcutaneously in a rat and properly formed a gelled material upon entering the body. Our results showed that encapsulating biomolecules in an FDA-approved polymer (PLGA) slowed the release of biomolecules from the iPN, which could allow therapeutics more time around the scaffold to help repair native tissue. Lastly, we investigated one potential avenue for combining iPN with other regenerative cues obtained from adipose-derived stem cells. Future work must focus on optimal loading conditions and release profiles from the iPN hydrogels. Next steps will be applying iPN in various combination therapies for spinal cord injury. We will focus efforts on developing a pro-regenerative secretome that directly promotes neurite extension and neural cell infiltration into iPN scaffolds upon transplantation in spinal cord.

Synthesis and characterization of new interpenetrated hydrogels from N-isopropylacrylamide, 2-oxazoline macromonomer and acrylamide

New interpenetrated hydrogels (IPN), sensitive to pH and temperature, were synthesized by sequential free radical polymerizations in aqueous medium. In the first stage, a thermosensitive hydrogel of poly(N-isopropylacrylamide) (HG-PNiPAAm) was prepared, and in the second stage a hydrogel of acrylamide and 2-oxazoline macromonomer (MM) containing carboxylic acid ester groups was synthesized in the presence of the PNiPAAm hydrogel. In both stages, bisacrylamide was used as a crosslinker. The 2-oxazoline macromonomer was a random copolymer of methyl-3-(oxazol-2-yl)-propionate (EsterOxa) (23 % mol) and 2-methyl-2-oxazoline (MeOxa) (77 % mol) with a polymerization degree of 21 and contained a vinylbenzene end group for radical polymerization. Five different IPN-hydrogels were synthesized, the amount of the oxazoline was varied systematically, and the EsterOxa units were finally hydrolyzed to carboxylic acid groups. The structure of the IPNs was characterized by 1H HR-MAS NMR spectroscopy. All IPN hydrogels showed a conformational transition when varying the temperature or the pH value and these transitions were a function of the composition of the IPN hydrogel. While pure HG-PNiPAAm resulted in a transition temperature of 31 °C, this value rose to 50 °C and higher for MM-H containing IPNs. This property was shown macroscopically as a contraction or expansion of the hydrogel but also in the 1H HR-MAS NMR measurements. The sensitivity to pH in the IPN hydrogels was manifested as a contraction of the volume of the hydrogel at low pH. While introducing poly(acryl amide) PAAm increased the degree of water absorption, increasing the amount of hydrolyzed EsterOxa macromonomer within the hydrogel decreased this absorption at high pH values. These features were attributed to the formation of hydrogen bonds between the acid and amide or protonated amino groups. A lower initial swelling at elevated temperatures but constant switching pH value (pH = 6) supported this reasoning. Importantly, at 20 °C and pH = 5.7 all IPN had a similar degree of swelling Q of 34 to 39, strongly reduced due to the IPN structure compared to a PAAmMM hydrogel (Q > 200). The reported IPNs result from a straight forward synthesis and are thus an interesting material for future applications as potent actuator and sensor materials.

Facile fabrication of high performance zwitterionic P(NVP‐co‐SPE)/polyvinyl alcohol hydrogel polyelectrolyte for capacitor

AbstractPolyelectrolyte hydrogel used for supercapacitors have the roles of both electrolyte and separator, the morphology and the strength of gel polyelectrolyte (GPE) are the keys for ionic transport properties therein. Here, the P(NVP‐co‐SPE)/polyvinyl alcohol (PVA) IPN hydrogel was prepared by photopolymerization and thermal polymerization, respectively. The influences of preparation method on morphology, mechanical strength and electrochemical performances were studied. Photopolymerized IPN GPE (UV‐GPE) exhibits a special regular microphase separation structure, and therefore has outstanding strength‐toughness and better electrochemical performance. The tensile strength and the toughness increased intensively from the 6.2 MPa and 3.4 MJ m−3 of thermal polymerized IPN GPE (TH‐GPE) to 28.5 MPa and 24.9 MJ m−3, respectively. The maximum swelling ratio of UV‐GPE is increased from 327% of TH‐GPE to 630%. The ionic conductivity of UV‐GPE increased from 4.29 × 10−2 S/cm of TH‐GPE to 5.82 × 10−2 S/cm. UV‐GPE has higher response current and specific capacitance. It also has the obviously better charge–discharge symmetry and cycling stability, and the capacity retention rate is still 92.3% after 1000 cycles. Thus, it brings out the fast, eco‐economic photopolymerization method is an effective way to prepare high‐performance polyelectrolyte hydrogel.

Synthesis of magnetic responsive poly(NIPAAm-co-VSA)/Fe3O4 IPN ferrogels and modeling their deswelling and heating behaviors under AMF by using artificial neural networks

Synthesis of stimuli-responsive hydrogels and modeling their behaviors under stimulus are very important for the use of smart materials in biomedical applications. In the present study, magnetic field responsive and novel poly(N-Isopropylacrylamide-co-Vinylsulfonic acid)/Fe3O4 interpenetrating polymer network (poly(NIPAAm-co-VSA)/Fe3O4 IPN) hydrogel composite (ferrogel) series were successfully synthesized. Firstly, temperature- responsive poly(NIPAAm-co-VSA) IPN hydrogels containing various amount of vinylsulfonic acid (VSA) were synthesized by two polymerization method: emulsion and solution polymerization. Then, Fe3O4 nanoparticles were loaded to hydrogel systems through in situ reduction of Fe2+/Fe3+ ions. Their chemical structures, magnetic properties and surface morphologies were characterized by FT-IR, VSM and SEM analysis techniques. The effects of the VSA content in ferrogel composition on deswelling and heating behavior of ferrogels under various of alternating magnetic fields (AMFs) were experimentally investigated. In order to characterize their heating and deswelling behaviors by magnetic induction heating, heating and deswelling kinetics under 1.37, 1.64 and 1.91 mT magnetic fields were investigated. Their fully swollen states showed complex deswelling and heating behaviors. Artificial neural networks (ANNs) in MATLAB were used to model these behaviors. The ANN models which associated input variables, were able to accurately predict complex deswelling and heating behaviors of magnetic field-responsive poly(NIPAAm-co-VSA)/Fe3O4 IPN hydrogel composites.

Modeling the Effect of Physical Crosslinking Degree of pH and Temperature Responsive Poly(NIPAAm-Co-VSA)/Alginate IPN Hydrogels on Drug Release Behavior

Modeling the Effect of Physical Crosslinking Degree of pH and Temperature Responsive Poly(NIPAAm-Co-VSA)/Alginate IPN Hydrogels on Drug Release Behavior

Strong and tough, pH sensible, interpenetrating network hydrogels based on gelatin and poly(methacrylic acid)

AbstractHydrogels are promising materials for biomedical applications due to highly hydrated, porous, permeable structure with possibility to accommodate living cells, drugs, or bioactive factors. In this paper, we reported poly(methacrylic acid) (PMAA)/gelatin IPN hydrogels, synthesized by free‐radical polymerization, with adjustable mechanical, structural, physicochemical, and biological characteristics. The influence of methacrylic acid (MAA), gelatin, and cross‐linker in the precursor solution on hydrogels properties was investigated. The increasing concentration of MAA, gelatin, and cross‐linker led to better mechanical properties, lower porosity, and water content. The compressive mechanical properties of hydrogels were significantly better in comparison to a single‐network PMAA hydrogel, while the obtained compressive strength values up to 16 MPa were comparable with tough hydrogels. The increasing concentration of MAA and cross‐linker reduced fatigue resistance and degradability, while the increase in gelatin content acted in the opposite way. Swelling tests in different pH conditions demonstrated strong pH‐sensibility of the hydrogels, which was more pronounced as MAA concentration was higher, and gelatin and cross‐linker concentrations were lower. In addition, the hydrogels strongly promoted the proliferation of human periodontal ligament stem cells and MRC‐5 cells as assayed by MTT assay.

Fabrication Parameter-Dependent Physico-Chemical Properties of Thiolated Gelatin/PEGDA Interpenetrating Network Hydrogels.

The development of three-dimensional hydrogels using polymeric biomaterials is a key technology for tissue engineering and regenerative medicine. Successful tissue engineering requires the control and identification of the physicochemical properties of hydrogels. Interpenetrating network (IPN) hydrogel was developed using thiolated gelatin (GSH) and poly(ethylene glycol) diacrylate (PEGDA), with the aid of ammonium persulfate (APS) and N,N,N,N'-tetramethylethylenediamine (TEMED) as radical initiators. Each component was prepared in the following concentrations, respectively: 2.5 and 5% GSH (LG and HG), 12.5 and 25% PEGDA (LP and HP), 3% APS/1.5% TEMED (LI), and 4% APS/2% TEMED (HI). IPN hydrogel was fabricated by the mixing of GSH, PEGDA, and initiators in 5:4:1 volume ratios, and incubated at 37°C for 30min in the following 6 experimental formulations: (1) HG-LP-LI, (2) HG-LP-HI, (3) LG-HP-LI, (4) LG-HP-HI, (5) HG-HP-HI, and (6) HG-HP-LI. Herein, the physico-chemical characteristics of IPN hydrogels, including their morphological structures, hydrolytic degradation properties, mechanical properties, embedded protein release kinetics, and biocompatibility, were investigated. The characteristics of the hydrogel were significantly manipulated by the concentration of the polymer, especially the conversion between HP and LP, rather than the concentration of the initiator, and no hydrogel formulation exhibited any toxicity to fibroblast and HaCaTcells. We provide structural-physical relationships of the hydrogels by which means their physical properties could be conveniently controlled through component control, which could be versatilely utilized for various organizational engineering strategies.

Preparation and characterization of dual-network interpenetrating structure hydrogels with shape memory and self-healing properties

Smart hydrogels that connect shape memory and self-healing properties through the same interaction are popular research projects. Based on supramolecular action and dynamic covalent bonds, a L-cysteine-Polyvinyl alcohol/hydroxyethyl cellulose(Cys-PVA/HEC) IPN hydrogel with shape memory and self-repair properties was prepared. Cys was grafted onto PVA by esterification reaction to form the copolymer Cys-PVA. Cys-PVA/HEC composite hydrogel was prepared by introduction of HEC into Cys-PVA, introduce the second network structure improved the mechanical properties of the hydrogel. The mechanical properties of Cys-PVA/HEC hydrogel were tested by dynamic mechanics (DMA), and the tensile strength is 65% higher than Cys-PVA. Cys-PVA/HEC hydrogel has been tested by thermal stimulation and redox stimulation experiments, showing significant shape memory performance. It is confirmed that Cys-PVA/HEC hydrogel has multi-response triple shape memory. Cys-PVA/HEC hydrogel showed good self-healing performance. The breaking tensile strength of the Cys-PVA/HEC hydrogel repaired after cutting can be restored to 87% by the DMA breaking tensile test. In addition, the morphology, pore size distribution, hygroscopic swelling performance and thermal stability of Cys-PVA/HEC hydrogel were investigated. The results show that Cys-PVA/HEC hydrogel is expected to become a potential candidate material in the field of intelligence.

Investigation of the viscoelastic behavior of PVA-P(AAm/AMPS) IPN hydrogel with enhanced mechanical strength and excellent recoverability

Investigation of the viscoelastic behavior of PVA-P(AAm/AMPS) IPN hydrogel with enhanced mechanical strength and excellent recoverability

Ionic conductive and stretchable interpenetrating hydrogels prepared with homogenously synthesized acrylamide-modified agar and polyacrylamide for strain sensing

In this article, the IPN hydrogels were prepared with acrylamide-modified agar (AMA), oxidized alginate (ADA) and polyacrylamide (PAM). The agar was firstly homogenously modified with acrylamide to facilitate the formation of hydrogen bonds and enhancement of the ionic conductivity of the hydrogel. The prepared IPN hydrogels showed high flexibility and conductivity. The composite hydrogel prepared with 20 wt% acrylamide, 0.25 wt% AMA and 5% ADA (hydrogel-5) possessed high toughness and can be stretched 20 times of its origin length. The hydrogel-5 also showed highest elastic modulus of 110 kPa compared with other hydrogels. The free potassium and sodium ions in acrylamide-modified agar and oxidized alginate chains endowed the hydrogel with conductive properties. The IPN hydrogels showed strain sensitive properties and can be used to detect various motion of human beings. The hydrogel still possessed high flexibility and conductivity after storing for six months. The IPN hydrogels with conductivity and high mechanical properties can be applied in various engineering fields.

Lattice Boltzmann method simulations of swelling of cuboid-shaped IPN hydrogel tablets with experimental validation

Lattice Boltzmann method simulations of swelling of cuboid-shaped IPN hydrogel tablets with experimental validation

Decellularized peripheral nerve as an injectable delivery vehicle for neural applications.

Damage to the nervous system can result in loss of sensory and motor function, paralysis, or even death. To facilitate neural regeneration and functional recovery, researchers have employed biomaterials strategies to address both peripheral and central nervous system injuries. Injectable hydrogels that recapitulate native nerve extracellular matrix are especially promising for neural tissue engineering because they offer more flexibility for minimally invasive applications and provide a growth-permissive substrate for neural cell types. Here, we explore the development of injectable hydrogels derived from decellularized rat peripheral nerves (referred to as "injectable peripheral nerve [iPN] hydrogels"), which are processed using a newly developed sodium deoxycholate and DNase (SDD) decellularization method. We assess the gelation kinetics, mechanical properties, cell bioactivity, and drug release kinetics of the iPN hydrogels. The iPN hydrogels thermally gel when exposed to 37°C in under 20 min and have mechanical properties similar to neural tissue. The hydrogels demonstrate in vitro biocompatibility through support of Schwann cell viability and metabolic activity. Additionally, iPN hydrogels promote greater astrocyte spreading compared to collagen I hydrogels. Finally, the iPN is a promising delivery vehicle of drug-loaded microparticles for a combinatorial approach to neural injury therapies.