Develop a sparse and locally low rank (LLR) regularized reconstruction to accelerate MR fingerprinting (MRF).1/T2 phantom acquisition, and in vivo brain acquisitions in 5 healthy subjects with different undersampling factors. Acceleration was also used in vivo to enable acquisitions with higher in‐plane spatial resolution in comparable scan time.Recent works have introduced low rank reconstructions to MRF, based on temporal compression operators learned from the MRF dictionary. In other MR applications, LLR regularization has been introduced to exploit temporal redundancy in local regions of the image. Here, we propose to include spatial sparsity and LLR regularization terms in the MRF reconstruction. This approach, so called SLLR‐MRF, further reduces aliasing in the time‐point images and enables higher acceleration factors. The proposed approach was evaluated in simulations, TSimulations, phantom, and in vivo results show that low rank MRF reconstructions with high acceleration factors  have residual aliasing artifacts that propagate into the parametric maps. The artifacts are reduced with the proposed SLLR‐MRF resulting in considerable improvements in precision, without changes in accuracy. In vivo results show improved parametric maps for the proposed SLLR‐MRF, potentially enabling MRF acquisitions with 1 radial spoke per time‐point in approximately 2.6 s (~600 time‐point images) for 2 × 2 mm and 9.6 s (1750 time‐point images) for 1 × 1 mm in‐plane resolution.The proposed SLLR‐MRF reconstruction further improves parametric map quality compared with low rank MRF, enabling shorter scan times and/or increased spatial resolution. Non‐Cartesian sampling trajectories are usually used to reduce scan time in MRF, under the premise that residual aliasing artifacts mimic pseudorandom noise in each voxel fingerprint. Nevertheless, if the aliasing is not spatiotemporally incoherent or the aliasing is too severe, these errors may propagate from the time‐point images into the parametric maps.MR fingerprinting (MRF)2 mapping, locally low rank (LLR) constraints have been shown to be powerful regularizers.Recent works have focused on developing MRF tailored reconstructions to further improve parametric map quality and/or reduce scan time. Frameworks incorporating compressed sensing,1/T2 phantom acquisitions, and in vivo brain acquisitions in 5 healthy subjects.In this work, we propose to include sparsity and LLR regularization terms in the low rank MRF framework. Spatial sparsity is enforced in the wavelet domain and LLR is enforced in the temporally compressed domain of the low rank approximation. The proposed sparse and LLR regularized MRF (SLLR‐MRF) approach was evaluated in simulations, standardized T22.1tN (~1000) time‐point MRF images can be temporally compressed to sN (~10) singular images (s < NtN). The MRF reconstruction of sN singular images is faster (less images) and better conditioned (more data per image) than reconstructing individual time‐points. As proposed in McGivney et al,D may be used to determine a global low rank approximation of the MRF signals: D=UΣVH. The temporal compression operator Ur follows from a truncation (to the appropriate rank r) of the matrix U. This global low rank constraint may be enforced directly in the encoding operator E=AFCUr, where C are the coil sensitivities,F is the Fourier transform and A is the sampling operator.MRF is designed to lead the magnetization through a continuous transient state evolution. Different tissues experience distinct signal evolutions; however, the magnetization evolutions are correlated in time, according to the underlying sequence parameters. Thus, the sequence of FUr or UrF. F and Ur have been shown to commuteC and Ur can also be shown to commute. Thus, the encoding operator may be re‐written as E=AUrFC, which is beneficial because only sN Fourier transforms are needed instead of tN.Ur) has been investigated recently in several works.Ur is a valid projection matrix (as long as the dictionary D accurately characterizes the acquisition and the expected tissues). The global low rank MRF reconstruction may be cast as a linear inverse problemIn McGivney et al,x^ are the singular images, and k are the acquired k‐space data. In the formulation above, 𝒙 ∈ CNsNn, C∈CNsNnNc×NsNn, F∈CNsNnNc×NsNnNc, Ur∈CNtNnNc×NsNnNc, 𝑨 ∈ CNtNkNc×NtNnNc,k∈CNtNkNc; Nn is the number of pixels, Nc is the number of coils and Nk is the number of k‐space points (per time‐point). The low rank MRF reconstruction can be solved with the conjugate gradient algorithm.where 2.21‐norm.MR images are known to have sparse representations in certain domains. This information can be leveraged to regularize an otherwise ill‐posed reconstruction by means of minimization of an largminx∑brank(Rbx), where Rb selects an image block around pixel b and reshapes the block into a local Casorati matrix. The solution to this problem is known to be NP‐hard, so the nuclear norm is commonly used as a surrogate functional for rank minimization. Thus, the proposed SLLR‐MRF reconstruction is given by:Locally low rank regularizationλb controls the strength of sparsity in the singular values of Rbx, ‖·‖∗ denotes the nuclear norm, λw is the sparsity strength in the compressed spatial domain, W is the wavelet transform (chosen sparsity domain) and ‖·‖1 denotes the l1‐norm. The above optimization is solved here using the alternating direction method of multipliers (ADMM).where yielding the corresponding Lagrangian form:μi determines regularization strengths and Ub and v are Lagrangian multipliers. Following the ADMM, a solution is found by iteratively optimizing the above functional with respect to x, then with respect to y, then with respect to z and then followed by updating the dual variables Ub and v. This leads to the following set of sub problems:where j is the iteration number. Equation 5 amounts to a Tikhonov regularized problem, where x can be solved for using efficient methods like the conjugate gradient.ybj+1=SVTλb/μ1Rbxj+1+Ubjμ1.b, the SVD of Rbxj+1+Ubjμ1 is computed, truncated to the rank determined by λb/μ1 and stored in the corresponding location in ybj+1. Similarly, the solution to Equation 7 is given by soft thresholding (ST): zj+1=STλw/μ2Wxj+1+Vjμ2. Finally, the updates of Ub and v are performed according to Equations 8 and 9. A diagram with the main operations within each ADMM iteration of the proposed SLLR‐MRF is shown in Figure λb‖Rbx‖∗. The singular images are also sparse in the wavelet domain, which is exploited with the term λw‖Wx‖1.where 2.3The proposed SLLR‐MRF was evaluated in simulations, phantom acquisitions, and in vivo brain data acquired on a 1.5T Ingenia MR system  using a 15‐element head coil. The study was approved by the institutional review board, and written informed consent was obtained from all subjects according to institutional guidelines.2.41, T2, and M0 values. The simulation featured an acquisition similar to the one used in Jiang et al,9) were used. White Gaussian noise was added to the time‐point images with a standard deviation such that the signal‐to‐noise ratio (SNR) in the first time‐point image was approximately 20. The simulated k‐space was uniformly undersampled in time by keeping (1:n:1750) k‐space lines. Different simulated acquisition lengths were tested, with n = , resulting in accelerated series with tN =  time‐points, respectively. Each series was reconstructed with both the low rank MRF approximation and the proposed SLLR‐MRF. To investigate the performance of sparsity and LLR constraints separately, each series was additionally reconstructed using only the sparse regularization (S‐MRF) and LLR regularization (LLR‐MRF). The normalized root mean square error (NRMSE) was measured on the reconstructed parametric maps with a mask excluding the cerebrospinal fluid (CSF), skull, and scalp of the digital phantom.SLLR‐MRF was studied in a digital phantom based on in vivo brain data with realistic T2.51/T2 phantom2, field of view = 320 × 320 mm2, 10 mm slice thickness, total scan time = 7.5 s. For both the phantom and in vivo acquisitions, the acquired k‐space data were retrospectively undersampled in time (as previously described for the simulations) resulting in accelerated series with tN =  time‐points.2D MRF acquisitions were performed on a standardized T2 in‐plane resolution, 1750 time‐points) a second MRF acquisition was performed on the healthy subjects. High in‐plane spatial resolution data were acquired with the same parameters as in the previous in vivo experiment, except for TE/TR = 1.73 / 5.5 ms, in‐plane spatial resolution = 1 × 1 mm2, total scan time = 9.6 s.To investigate the use of SLLR‐MRF to enable higher in‐plane spatial resolution in comparable scan time than current reference . The SLLR‐MRF reconstruction used the following parameters in simulations: rank r = 10, block size = 7, λb = 0.03Sb1, λw= 0.01, μ1 = μ2 = 0.0005, ADMM iterations = 20, conjugate gradient iterations = 5. Phantom data were reconstructed with the same parameters, except λb = 0.05Sb1, μ1 = 0.01, λw=μ2=0 . In vivo data at 2 × 2 mm2 and 1 × 1 mm2 resolutions used the following parameters, respectively: block size = 7 and 17, λb = 0.05Sb1 and 0.04Sb1, λw= 0.02 in both cases, μ1 = μ2 = 0.005 in both cases.The proposed SLLR‐MRF reconstruction was implemented off‐line in MATLAB . Coil sensitivity maps were estimated from the data itself using ESPIRiT.λb=μ1=0 or λw=μ2=0, respectively. A “warm start” strategy was used to improve the starting solution of subsequent ADMM iterations.r = 10 was chosen based on results from McGivney et alλb were chosen in a similar way to Zhang et alO([aN+bNlogN]2rcNcg), where a≈170 is related to gridding and interpolation costs, b≈2 is used for accuracy, N is the number of data points, r is the number of singular values, c is the number of coil channels and Ncg is the number of Conjugate gradient iterations; Equation 6 has an estimated cost of Os2r2N, where s is the block size for the locally low rank; Equation 7 has an estimated cost of O(2rN). The full estimated computational cost of the proposed approach is O[aN+bNlogN]2rcNcg+sr2N+2rNNADMM, where NADMM is the number of ADMM iterations.Reconstructions in simulations using only sparse (S‐LLR) or only LLR‐MRF regularizations were obtained by setting 2 and 1 × 1 mm2, respectively) on a Linux workstation with 12 Intel Xeon X5675 (3.07 GHz) and 200 GB RAM. The 2 × 2 mm2 resolution data were reconstructed with  time‐point series. The 1 × 1 mm2 resolution data were reconstructed using the full 1750 time‐point series. For each case, images were reconstructed using the conventional low rank MRF approximation and the proposed SLLR‐MRF approach.In practice for this work, the bottleneck of operations was solving Equation 5, followed by solving Equation 6 and finally a negligible time to solve Equation 7. The reconstruction with 1750 time‐points took approximately 35 and 80 min  used the following: T1∈  ms, T2∈  ms.MRF dictionaries were simulated using extended phase graphs based on the code available in Weigel.33.1Parameter maps obtained in simulations with low rank MRF, S‐MRF, LLR‐MRF, and the proposed SLLR‐MRF using 875 and 438 time‐points are shown in Figure 1 and residual aliasing in T2 maps; these artifacts are considerably reduced with the proposed SLLR‐MRF. Corresponding error maps are shown in Supporting Information Figure 2. Selected reconstructed time‐point images corresponding to these maps are shown in Supporting Information Figure Parametric maps reconstructed with low rank MRF and SLLR‐MRF are shown in Figure 3.23.2.11 and T2 measurements in the phantom can be seen in Figure 1 and T2 for high values can be observed for SLLR‐MRF; bias of low rank MRF varied with the number of time‐points due to the induced aliasing artifacts. Corresponding parametric maps are shown in Supporting Information Figure Plots for T3.2.22 resolution, using different lengths of the time‐point series (1750 and 584), are shown in Figures 1 and noise amplification in T2 can be seen with low rank MRF, which increase with decreasing number of time‐points. SLLR‐MRF improves the parametric map quality in every case and maintains good map quality even when only a third of time‐points are used. Corresponding reconstructed time‐point images are shown in Supporting Information Figure 1 and T2 encoding power are shown . Low rank MRF has residual artifacts when the number of time‐points is reduced, whereas these are considerably reduced with the proposed SLLR‐MRF.Low rank MRF and SLLR‐MRF parametric maps for 2 representative healthy subjects at 2 × 2 mmseries 170 and 5842 resolution can be seen in Figure 1 for this case, but noise amplification was once again observed with low rank MRF and reduced with SLLR‐MRF. Corresponding time‐point images are shown in Supporting Information Figure Low rank MRF and SLLR‐MRF parametric maps for corresponding subjects at 1 × 1 mm1 and T2 values in selected regions on interest . SLLR‐MRF considerably reduced residual aliasing, improving parametric map quality. Simulation results agreed with a T1/T2 phantom acquisition showing superior accuracy and precision for SLLR‐MRF in comparison to low rank MRF for different lengths of the time‐point series. A slight underestimation of T2 was generally observed in the phantom experiments, more so at high T2 values. A small difference in T2 measurements was also observed in vivo between 2 × 2 mm2 and 1 × 1 mm2 resolution. These errors can be reduced by incorporating B1 correction,1 values was also observed; this bias could also be reduced by accounting for magnetization transfer and inversion efficiency.Aliasing and noise amplification in the reconstructed singular images (and thus in the time‐point series) can propagate into the MRF parametric maps. Low rank MRF results in simulations indicate that residual artifacts from radial sampling generally lead to blurring and noise amplification in the reconstructed T0 and B1 corrections become increasingly necessary with increasing field strength. If B0 is accounted for in the MRF model  bSSFP MRF can be used to achieve superior SNR in similar scan time. Finally, recent studies have revealed optimal MRF sequencesThe large slice thickness (10 mm) used is also a limitation in this study. Thinner slices (in the order of 5 mm) are generally desirable and will have a corresponding reduction in SNR. Sparse and low rank constraints are generally well suited to suppress noise‐like artifacts, although this problem can be complementarily addressed in the acquisition. Increasing the amount of acquired data or reducing the receiver bandwidth will both improve SNR at the expense of scan time. A more data efficient trajectory such as spiral can lead to SNR improvements with no scan time penalty. Improved SNR can be achieved at 3T; however, B2 in‐plane resolution showed that both low rank MRF approximation and SLLR‐MRF achieved good map quality with 1750 time‐point images. However, a reduction of the number of time points resulted in decreased quality for the low rank MRF reconstruction. Conversely, with SLLR‐MRF the number of time‐points could be reduced by a third  while maintaining good parametric map quality. Retrospective uniform undersampling in time by keeping (1:n:1750), with n = 1, 2, 3, 4, was used here to approximate a similar encoding of T1 and T2 values for experiments with different amounts of data. If only the first time‐point images were considered the influence of the initial inversion pulse and the reduced number of FA values would result in different T1 and T2 encodings that those achieved by longer scans, and thus direct comparison between acquisitions would not be adequate.In vivo scans with 2 × 2 mm2 spatial resolution and the same amount of data (1750 time‐points), thus comparable scan time, as the 2 × 2 mm2 maps. T2 noise amplification was considerable with low rank MRF and consequently reduced with SLLR‐MRF. Optimal FA patterns1 and T2 encoding for 2D MRF with highly reduced scan time. Moreover, the advantages of the proposed approach should be more evident in 3D acquisitions where higher undersampling factors are required. The extension of the proposed method to 3D MRFThe better performance of SLLR‐MRF, demonstrated in simulations, phantom, and in vivo scans, was used here to enable in vivo acquisitions with higher in‐plane spatial resolution (and thus higher undersampling factor and lower SNR). Acquisitions were performed with 1 × 1 mmThe proposed SLLR‐MRF is expected to be sensitive to motion, as previously observed in other MRF studies.λb, λw, μi, ADMM iterations, conjugate gradient iterations) that will affect the reconstruction if improperly chosen. The same parameters were used for all the results reported here; however, future studies in larger cohort of subjects need to be performed to investigate the sensitivity of the chosen parameters. The proposed approach was compared against a ground‐truth in simulations and phantom experiments; however, comparison with a fully sampled MRF in vivo was not possible due to scan time constraints. Current reconstruction times were in the order of 1 h for high in‐plane resolution data; this will need to be reduced in the future with implementations in more efficient compiled languages  and/or graphical processing units.Another limitation of the proposed approach is related to parameter selection. Similar to most MRI reconstruction methods, the proposed approach has several tuneable parameters  while maintaining map quality in 2 × 2 mm2 in‐plane resolution data. SLLR‐MRF enabled a considerable improvement in parametric map quality compared with low rank MRF in 1 × 1 mm2 resolution data acquired in 9.6 s.A sparsity and LLR regularization for the low rank approximation reconstruction in MRF has been introduced and validated in simulations, standardized phantom, and in vivo brain acquisitions. The proposed SLLR‐MRF approach removed blurring in TFIGURE S1 T1 and T2 error maps (in milliseconds), for the corresponding parameter maps in Figure 2, reconstructed with the proposed sparse and local low rank constraints (SLLR‐MRF), only local low rank constraint (LLR‐MRF), only sparse constraint (S‐MRF) and unconstrained low rank MRF. Skull and CSF have been masked out when computing errors. Error maps correlate with the parameter maps shown in Figure 2, with higher errors obtained for the low rank MRF and the lowest errors obtained for the proposed SLLR‐MRFFIGURE S2 T1 and T2 error maps (in milliseconds), for the corresponding parameter maps in Figure 3, reconstructed with unconstrained low rank MRF and the proposed SLLR‐MRF. A mask has been used to exclude skull and CSF tissue in the error maps. Errors gradually increase with increasing acceleration factor (decreasing Nt) for both approaches, however, errors are generally milder for the proposed SLLR‐MRF. Corresponding normalized root mean square errors (NRMSE) for these maps can be found in Table FIGURE S3 Reconstructed time points #100 and #1600 reconstructed with low rank MRF and the proposed SLLR‐MRF in simulations. Both methods achieve similar time‐point image quality with 1750 time‐points. Aliasing artifacts appear in low rank MRF when the number of time‐points is reduced; these artifacts are considerably reduced with SLLR‐MRFFIGURE S4 T1 and T2 maps for a standardized phantom reconstructed with low rank MRF and the proposed SLLR‐MRF with 1750 and 584 time‐points. Larger errors are generally present with low rank MRF, more so when less data is used. When using 584 time‐points, the proposed SLLR‐MRF achieves similar quality to the low rank MRF with 1750 time‐pointsFIGURE S5 Time points #100 and #1600 for low rank MRF and the proposed SLLR‐MRF, reconstructed using 1750 and 584 total number of time‐points, for subject 1, 2 × 2 mm2 resolution. Residual aliasing is visible for low rank MRF when the number of time‐points is reduced. Conversely, these artifacts are reduced with the proposed SLLR‐MRFFIGURE S6 Time points #100 and #1600 for low rank MRF and the proposed SLLR‐MRF, reconstructed using 1750 and 584 total number of time‐points, for subject 2, 2 × 2 mm2 resolution. Residual aliasing is visible for low rank MRF when the number of time‐points is reduced. Conversely, these artifacts are reduced with the proposed SLLR‐MRFFIGURE S7 Time points #100 and #1600 for low rank MRF and the proposed SLLR‐MRF, reconstructed using 1750 and 584 total number of time‐points, for subjects 1 and 2, 1 × 1 mm2 resolution. Residual aliasing is present with low rank MRF, whereas SLLR‐MRF reduces aliasing artifactsClick here for additional data file.


Clinacanthus nutans Lindau leaves (family Acanthaceae) demonstrated peripherally and centrally mediated antinociceptive activity via the modulation of opioid/NO-mediated, but cGMP-independent pathway. In the present study, MECN was sequentially partitioned to obtain petroleum ether extract of C. nutans (PECN), which was subjected to antinociceptive study with aims of establishing its antinociceptive potential and determining the role of opioid receptors and l–arginine/nitric oxide/cyclic-guanosine monophosphate (l–arg/NO/cGMP) pathway in the observed antinociceptive activity.Methanol extract (MECN) of n = 6). The effect of PECN on locomotor activity was also evaluated using the rota rod assay. The role of opioid receptors was determined by pre-challenging 500 mg/kg PECN (p.o.) with antagonist of opioid receptor subtypes, namely β–funaltrexamine , naltrindole  or nor–binaltorphimine  followed by subjection to the abdominal constriction test. In addition, the role of l–arg/NO/cGMP pathway was determined by prechallenging 500 mg/kg PECN (p.o.) with l–arg , 1H- oxadiazolo quinoxalin-1-one , or the combinations thereof (l–arg + ODQ) for 5 mins before subjection to the abdominal constriction test. PECN was also subjected to phytoconstituents analyses.The antinociceptive potential of orally administered PECN  was studied using the abdominal constriction-, hot plate- and formalin-induced paw licking-test in mice (p < 0.05) inhibited nociceptive effect in all models in a dose-dependent manner. The highest dose of PECN (500 mg/kg) also did not significantly (p > 0.05) affect the locomotor activity of treated mice. The antinociceptive activity of PECN was significantly (p < 0.05) inhibited by all antagonists of μ-, δ-, and κ-opioid receptors. In addition, the antinociceptive activity of PECN was significantly (p < 0.05) reversed by l–arg, but insignificantly (p > 0.05) affected by ODQ. HPLC analysis revealed the presence of at least cinnamic acid in PECN.PECN significantly (PECN exerted antinocicpetive activity at peripheral and central levels possibly via the activation of non-selective opioid receptors and modulation of the NO-mediated/cGMP-independent pathway partly via the synergistic action of phenolic compounds. Pain is an essential sensation that plays a vital role as a body’s natural defence system by alerting us to possible tissue injury while nociception is described as “the neural processes of encoding and processing noxious stimuli” that usually leads to pain . The proPain can be modulated by various analgesic drugs that suppress pain signals by acting in various mechanisms on the peripheral (PNS) and central nervous system (CNS) . HoweverClinacanthus nutans (C. nutans) Lindau, known to the Malay as “Belalai Gajah”, is one of the medicinal plants that have received considerable attention from many research groups within the past few years. This small shrub belongs to the Acanthaceae family and commonly grows in tropical Southeast Asian countries. Local communities in the Southeast Asian countries including Malaysia have traditionally used C. nutans for the treatment of various disorders , including pain relief  oxadiazole quinoxaline–1–one (ODQ) were purchased from Sigma–Aldrich , while β–funaltrexamine hydrochloride (β–FNA), nor–binaltorphimine dihydrochloride (nor–BNI), and naltrindole hydrochloride (NALT) were purchased from Tocris Bioscience . Acetic acid and dimethyl sulfoxide (DMSO) were purchased from Fisher Scientific . Formaldehyde was obtained from R & M Chemicals . All drugs were dissolved in physiological saline (0.9% [w/v] NaCl) except for PECN, ASA, DZP and MOR, which were dissolved in 10% DMSO (v/v). The vehicle that was used alone had no effects per se on the nociceptive responses in mice. The other solutions  were prepared in 0.9% NaCl. All drugs, chemicals, PECN solutions were administered in 10 mL/kg volumes and were freshly prepared immediately prior to use.The following drugs, namely acetylsalicylic acid (ASA), morphine hydrochloride (MOR), diazepam (DZP), n = 6) were treated with vehicle , negative control), ASA , or PECN  60 min before the administration of phlogistic agent . The number of abdominal constrictions produced was counted from 5 min after acetic acid administration cumulatively for 25 min, as described previously in detail [The animals (n = 6) were treated with vehicle , MOR  or PECN  60 min before the test.In order to evaluate the central antinociceptive effect of PECN, a hot plate test was carried out according to the method previously described in detail by Sani et al. . The anin = 6) received vehicle , ASA , MOR , or PECN  60 min before the intraplantar (i.pl) administration of 5% (v/v) formalin into the right hind paw. The nociceptive response, indicated by the sum of time that the animal spent licking the injected paw, developed between 0-5 min after formalin injection (early phase) and 15–30 min after formalin injection (late phase) were recorded for 30 min.The procedure used was similar to the one used in our previous work . Mice (nn = 6) were treated with the vehicle , DZP , or PECN  60 min before the test. The average time the mice spent to stay on the rota–rod was measured for 120 s at 5, 10, and 15 min after the administration of PECN, respectively.The method used was conducted similarly to the one that was described previously . The appThe possible role of opioid receptor system in the modulation of PECN-induced antinociceptive activity was investigated as previously described . Brieflyl–arg/NO/cGMP pathway to the antinociceptive effect of PECN, the previously described method was adopted from Jiménez–Andrade et al. [n = 6) were pre–treated (i.p.) with 20 mg/kg l–arg (a NO precursor) or 2 mg/kg ODQ (a specific soluble guanylyl cyclase inhibitor) 5 min before the administration of vehicle  or PECN . Sixty minutes after the administration of test solutions, the mice were subjected to acetic acid–induced abdominal constriction test as described above.To investigate the possible contribution of e et al. . The micThe qualitative phytochemical screening of PECN was performed to determine the presence of flavonoids, saponins, triterpenes, tannins, alkaloids and steroids according to the conventional protocols as adopted by Mamat et al. .The HPLC analysis of PECN was conducted at the Laboratory of Phytomedicine, Forest Research Institute of Malaysia, Kepong, Malaysia according to the similar protocols as reported in Zakaria et al. . The HPLp < 0.05.Data are expressed as mean ± standard error of mean (SEM). Except for the hot plate test, the mean differences between the control and treatment groups for the other tests were analysed using the one–way analysis of variance (ANOVA) followed by Dunnet’s post–test . Data for the hot plate test were analysed using the two-way ANOVA followed by the Bonferroni’s post hoc test. In all cases, the differences were considered as significant if p < 0.001) and dose–dependent decrease in the number of abdominal constrictions in comparison to the control group. The percentage of antinociception calculated for the three respective doses of PECN ranged between 63.8 to 77.3%. ASA  also caused significant (p < 0.001) inhibition of abdominal constriction with the percentage of antinociception recorded at approximately 46.8%.The effect of PECN against acetic acid–induced abdominal constriction test in mice is shown in Fig. p < 0.01) changes in response latency to thermal stimulus–induced nociception, which started 60 min after PECN administration and lasted until the end of the experimentation when compared against the control group. Concurrently, MOR given via oral administration at the dose of 5 mg/kg also caused a highly significant (p < 0.001) prolongation of latency response starting at the interval of 60 min and lasted until the end of the experimentation (210 min).The effect of PECN on thermal-induced nociception was assessed using the hot plate test and is shown in Table p < 0.001) reduction in the latency of formalin–induced paw licking in the first phase  of the test as shown in Fig. p < 0.001) reduced the latency of formalin–induced paw licking in the second phase  of the test as shown in Fig. Figure p < 0.001) reduction in the latency spend by the mice to remain on the rota-rod at all interval measured indicating its potential to affect motor coordination.The effect of orally administered PECN on motor coordination of mice was measured using the rota–rod test and is shown in Fig. p < 0.001) reversed after i.p. pretreatment with 10 mg/kg β–FNA, 1 mg/kg NALT or 1 mg/kg nor–BNI, which did not exert any significant (p > 0.05) effect on nociceptive response when tested alone.Effect of PECN on opioid receptors-mediated nociceptive response was determined using the acetic acid-induced abdominal constriction test and is shown in Fig. l–arg/NO/cGMP pathway in the modulation of PECN-induced antinociception is shown in Fig. l–arg or ODQ, alone or in combination with PECN, were assessed using the acetic acid–induced abdominal constriction test. As shown in Fig. l–arg (the NO precursor) alone did not affect the acetic acid-induced nociception but caused significant reversal (p < 0.001) on PECN-induced antinociception when pretreated together. Moreover, ODQ, given alone, caused significant (p < 0.001) attenuation of the acetic acid–induced nociception while pretreatment with PECN caused significant (p < 0.01) reversal of the antinociceptive activity of PECN  = 17.265 min), P2 (retention time (RT) = 18.332 min), P3 (RT = 18.631 min), P4 (RT = 20.136 min) and P5 (RT = 27.494 min). Further analysis demonstrated that the three major peaks showed their λmax values in the region of 222.5–332.6, 192.0–336.2, and 216.6–335.0 nm, respectively, thus, suggesting the presence of phenyl chroman (C6–C3–C6) skeletal structures. As depicted in Fig. The HPLC profiles of PECN were measured at six different wavelengths, namely 210, 254, 280, 300, 330 and 366 nm to obtain the best separation. Based on the respective chromatograms obtained, chromatogram established at the wavelength of 254 nm was found to show the best peaks separation , ethyl acetate and aqueous semi-purified fractions [The current work is a continuation of previous study by Abdul Rahim et al.  on the aractions , which w2 and PGF2), lipoxygenase (LOX) and cyclooxygenase (COX) in the peritoneal cavity that lead to indirect liberation/activation of various endogenous inflammatory mediators. These mediators stimulate the peripheral nociceptive neurons that are sensitive to opioid (i.e. MOR) and non-opioid (i.e. ASA) analgesics [Other than the acetic-acid-induced abdominal constriction test, PECN was found to attenuate nociceptive response when assessed using the hot plate test and formalin-induced paw licking test. The acetic acid–induced abdominal constriction test, which represents inflammatory–mediated peripheral nociceptive response, has been associated with increased production of prostaglandin (PG)  , involveBased on its ability to attenuate both the acetic acid- and thermal-induced nociceptive responses, PECN is suggested to have a potential to inhibit nociceptive response at the peripheral and central levels –22. ThisAlthough the three nociceptive assays used in the present study finally established that PECN possesses antinociceptive potential, it is necessary to determine the extract ability to modulate motor coordination of the mice upon consumption due to its centrally-acting effect since centrally-acting drugs are known to cause possible alterations in the motor coordination, balance and equilibrium ability of the animals . Accordil–arg/NO/cGMP pathway. The opportunity to study and identify any drugs/substances that modulate nociceptive response via mechanisms partly used by standard analgesic (MOR) (viz. opioid receptors and l–arg/NO/cGMP pathway) could be an added advantage in an attempt to find replacement to MOR, which has been associated with side effects such as dependence and tolerance.In an attempt to establish the antinociceptive profile of PECN, the mechanisms of antinociception modulated by PECN were also investigated by focusing on the role of opioid receptor systems  and Role of opioid receptor system in the modulation of antinociceptive action of drugs/substances can be determined via exploitation of certain pharmacological tools such as various antagonists of opioid receptor , 28. Thel–arg/NO/cGMP pathway in the regulation of analgesics action at peripheral and central levels haa been reported [l–arg to l–citrulline and NO by NO synthase, is known to play a complex part in the transmission of nociceptive signals peripherally and centrally [l–arg exerted insignificant increase in the nociceptive intensity when administered alone, it significantly reduced the antinociceptive intensity of PECN when pretreated together indicating the importance of NO presence in the modulation of PECN antinociceptive potential. On the other hand, increased presence of NO at the intracellular level stimulates the soluble guanylate cyclase (sGC), which augments the cGMP synthesis. The important of cGMP in the modulation of hyperalgesic response at peripheral sensory neurons and the involvement of NO/cGMP signaling pathway in the central and peripheral nociceptive processing have been established [l–arg/NO/cGMP pathway plays a pivotal role in the development of tolerance to MOR [C. nutans as an analgesic-based product with lack of unwanted side effects seen with MOR due to the difference in NO-mediated pathway modulated by the former.The involvement of reported . NO, derentrally . In factentrally . Althougablished . In the ablished . One exaablished , 38. Take to MOR , it is rC. nutans leaves demonstrated the presence of flavonoids, phenolic compounds, diterpenes, saponins, chlorophyll and its various derivatives, and steroids (i.e. β–sitosterol and stigmasterol) [Earlier investigation on the phytochemical content of asterol) , 5. Concasterol) , 41, triasterol) , 43, andasterol) , 45 exerGalanthus elwesii. Concurrent with this finding, there are reports on the potential of cinnamic acid derivatives [Further phytoconstituents analysis using HPLC revealed the presence of traces of only a few bioactive compounds , which upon comparison with several pure bioactive compounds revealed the presence of, at least, cinnamic acid. The lack of number of peaks and the presence of small peaks as detected in the chromatogram of PECN might be due to the lack of hydrophilic (water-soluble) bioactive compounds in the hydrophobic-based extract. The presence of cinnamic acid in PECN is parallel to the report of Tüzan and Özdemir  on the pivatives  to exertl–arg/NO-mediated, but cGMP-independent, pathway.In conclusion, PECN, partly through the presence of cinnamic acid, exerted antinociceptive activity at the peripheral and central levels via the non-selective activation of opioid receptors and modulation of the


The aim of this study was to assess the lifetime economic benefits of assisted reproduction in Spain by calculating the return on this investment. We developed a generational accounting model that simulates the flow of taxes paid by the individual, minus direct government transfers received over the individual’s lifetime. The difference between discounted transfers and taxes minus the cost of either IVF or artificial insemination (AI) equals the net fiscal contribution (NFC) of a child conceived through assisted reproduction. We conducted sensitivity analysis to test the robustness of our results under various macroeconomic scenarios. A child conceived through assisted reproduction would contribute €370,482 in net taxes to the Spanish Treasury and would receive €275,972 in transfers over their lifetime. Taking into account that only 75% of assisted reproduction pregnancies are successful, the NFC was estimated at €66,709 for IVF-conceived children and €67,253 for AI-conceived children. The return on investment for each euro invested was €15.98 for IVF and €18.53 for AI. The long-term NFC of a child conceived through assisted reproduction could range from €466,379 to €-9,529 (IVF) and from €466,923 to €-8,985 (AI). The return on investment would vary between €-2.28 and €111.75 (IVF), and €-2.48 and €128.66 (AI) for each euro invested. The break-even point at which the financial position would begin to favour the Spanish Treasury ranges between 29 and 41 years of age. Investment in assisted reproductive techniques may lead to positive discounted future fiscal revenue, notwithstanding its beneficial psychological effect for infertile couples in Spain. Birth and fertility rates in Spain have declined significantly in recent years. In 2011 the birth rate stood at 10.2 births per 1000 inhabitants, its lowest level since 2003, while the fertility rate was 1.36 children per woman , which iPrevious studies have shown that, even under the most optimistic projections, a declining birth rate combined with an ageing population might result in fiscal imbalances that can only be mitigated through spending cuts or tax increases . A higheIn this context, public funding of assisted reproductive treatment could have a positive effect not only on mitigating the excess demand and the current inequity in access to healthcare services, but it could help restore replacement rates and improve fiscal stability . Indeed,The long-term fiscal implications of public funding of assisted reproductive treatment have been estimated previously in countries as diverse as Brazil , DenmarkIn order to investigate whether funding assisted reproduction might be considered an efficient use of public resources in Spain, this analysis models the long-term tax implications that public funding of assisted reproduction might have in the country. Using a generational accounting model, we analyse the fiscal balance of the economic transfers between the government and an individual conceived through assisted reproductive treatment over his/her lifetime. Both IVF and AI treatments are considered.N is the individual’s life expectancy, T is gross revenues received by the government through taxes paid by the individual, X is direct transfers to the individual , K is the cost of assisted reproductive treatment, r is the discount rate and t corresponds to 1 year. Revenues and transfers are apportioned to each year of the individual’s life, from age 0 to the age of life expectancy. We assume that an individual conceived through assisted reproductive treatment is an average individual in terms of education, income, health status, life expectancy, probability of being unemployed and likelihood of being a public servant. Therefore, the model apportions transfers and taxes weighted by the probability of the individual belonging to any category of taxpayers or potential recipients . The model adopts the perspective of the Spanish government and includes the full official list of revenues collected by the State, which comprise not only taxes paid by individuals in the labour force, but also those paid by individuals regardless of age or employment status . Transfers to individuals include education, healthcare and pensions from birth to life expectancy, plus the average cost of IVF or AI cycles needed to achieve a successful pregnancy, which is assumed only once, in year zero of the model. For an overview of all revenues and expenditures, see A generational accounting model was built to estimate the net fiscal value of an individual conceived through assisted reproductive treatment . To analThe base year is the hypothetical year of birth of the individual whose net tax value the model calculates. In the base case, the model assumes that the base year macroeconomic parameters, especially the rate of economic growth and the unemployment rate, are constant over the time horizon. In order to account for possible business cycles contractions and expansions that will occur during the lifetime of the individual, we conducted a linear regression of the annual growth rate of gross domestic product (GDP) in Spain for the period 1970–2012 . In thisThe model’s time horizon is the individual’s life expectancy at birth in Spain in the base year (78 years), which is consistent with previously published empirical models . Table 2To reflect the depreciation of money over time, we applied a discount rate of 3.5% on all transfers to and from the government. This is consistent with discount rates used in previous studies, which range between 2.5%  and 4.0%There are no official data available on the cost of assisted reproduction in the Spanish public health system. IVF and AI costs were based on two published studies that estimate direct healthcare costs of both IVF and AI cycles in two different Spanish hospitals . An averTransfers from the government to the individual were obtained from different sources. In most cases the data are available at the aggregate level, so we estimated what the average individual received on each item. When possible the average by age year is imputed. Otherwise, when data is available by age groups, the average by age group is imputed to each age year within the same age group. In the minority of cases, when age distributions are not available, an average per capita is imputed to all years. All data were obtained for 2006.t can be expressed as:E is education, H is healthcare, W is salaries of governmental employees, and U is unemployment benefits.The sum of transfers from the government to the citizens at time Education expenditure by schooling level  and through grants (non-university and university grants) was obtained from the Ministry of Education databases . EnrolmePublic healthcare expenditure by age group  was obtained from the Ministry of Health  for 2006Pensions received by individuals include orphanhood, widowhood and retirement pensions. The proportion of pensioners and the average amount in euros received in each pension category can be obtained by age (0–78) from the Spanish Labour Force Survey, which is representative at the national level and collects information at the individual level . We assiThis model includes the wages spent by the government on all governmental employees. Total wages were obtained from the . The disAverage unemployment benefits and unemployment rates by age group  are available from the Spanish Treasury databases . We impuTax exceptions due to parenthood are implicitly included in the income tax declared by the individual, which is a transfer from the individuals to the government in the model. As opposed to other countries, child benefit payments do not exist in Spain, and data on paid leave due to parenthood are not available. These two parameters were therefore not included in the model.t is:SS stands for Social Security contributions, I is income tax, C is corporate tax, N is non-resident income tax, A is tax paid on alcohol and beer consumption, H is tax paid on petrol and diesel, Tob is tax paid on tobacco consumption, VAT is value added tax, and O refers to other transfers.The sum of transfers received by the government from the individual at time In Spain all employed persons pay a Social Security contribution. Contributions are age- and employment regime-dependent. We used the Spanish Labour Survey , which cThis category includes the income tax paid by employed individuals in the private sector (including self-employed) and public sector employed individuals. Private sector income tax is available at the individual level from the Spanish Labour Force Survey . Income Corporate tax is paid by business owners, and is available at the aggregate level from the Treasury’s Annual Report . The numThis tax is paid by Spaniards living abroad. It is available at the aggregate level from the Treasury’s Annual Report . The numThe revenue from alcohol and beer, and tobacco consumption are available from the Spanish Treasury Annual Report  at the aThe revenue from the sale of petrol and diesel is available from the Spanish Treasury Annual Report  at the aThe revenue from VAT is available from the Spanish Treasury Annual Report  at the aOther transfers include taxes paid for inheritance, electricity, insurances, sugar consumption, and fiscal sanctions. All are available from the Spanish Treasury Annual Report  at the aDue to the uncertainty of the country’s economic growth, and to test the robustness of the model’s results in a scenario of economic crisis, one-way deterministic sensitivity analysis was performed. The analysis included eight different scenarios where we vary, either alone or combined, those parameters most likely to change in the future and to have an impact on the results: discount rate (1% and 5%), GDP growth rate (± 100%), inflation rate (± 100%), and unemployment rate (± 100%).In the base case, the present value of all taxes paid by a naturally conceived individual equals €370,482, while the transfers made to the individual add up to €275,972. Therefore, the NFC of a naturally conceived individual throughout his/her lifetime is €94,510. In year zero the cost of achieving a live birth through IVF  is €4173 while that of AI is €3629. Therefore, in the base case scenario, an individual conceived through assisted reproduction will have a NFC over his/her life cycle of €66,709 if conceived through IVF and of €67,253 if conceived through AI. These results imply returns on investment of €15.98 and €18.53 for every euro invested in IVF and AI, respectively.If the government were to finance only the first three cycles of either assisted reproductive technique (as it does now) as opposed to financing the necessary cycles to reach a pregnancy, the expected cost of a successful pregnancy would equal €2661 if conceived through IVF and €1424 if conceived through AI, and the net fiscal contributions would be €42,528 for an individual conceived through IVF and €26,387 for an individual conceived through AI, which imply returns on investment of €15.98 and €18.53, respectively. The return on investment does not vary depending on whether the government decides to finance only three cycles or the total number of cycles required for conception, because the expected benefits increase in the same proportion as the expected costs.This is the first empirical study that estimates the NFC of an individual conceived through assisted reproduction in Spain. It is also the first study to compare IVF with AI techniques. Previous studies that have calculated the NFC for the life cycle of an IVF-conceived individual have shown that this can vary, but that, with the exception of The Netherlands , it remaOur model is significantly more accurate than most previous empirical models for several reasons. First, previous empirical models assume that an individual’s economic life cycle can be divided into specific periods depending on his/her age (for example: ‘childhood’ (0–19 years), ‘working years’ (20–64 years), ‘senior years’ (65 + years)) in which the same average transfers and taxes are apportioned for all individuals belonging to the same periods, and regardless of exact age, true schooling level or working status . In our Of course, this model, like all mathematical representations of real-life situations, also has limitations. First, the model estimates the tax benefits that public funding of assisted reproduction would have in women up to 40 years of age. Although performing assisted reproductive techniques in women over 40 years of age has lower associated rates of success, studies in other countries also obtain positive – though less substantial – NFC for individuals born to women over 40. In Spain the public health system finances assisted reproduction only for women up to 40 years of age, a restriction that influences our data. We believe it would be beneficial to carry out a study that would include the costs of financing pregnancies in women over 40 years, to see whether public resources would be well invested in age ranges above 40.Second, it is important to consider that 20% of IVF pregnancies are multiple . Data onThird, since this analysis is performed from the perspective of the Spanish Treasury, our results do not include the estimated individual benefits in terms of quality of life that conceiving provides for couples who suffer from infertility, even extending to the ‘peace of mind’ experienced by those couples who should they fail to conceive, know that they have tried everything. Inclusion of the psychological and social benefits of artificial conception would reveal even greater advantages associated with public funding of assisted reproduction. Finally, our results are only applicable to Spain.In conclusion, an increase in public funding for assisted reproductive techniques in Spain might have positive effects in at least three respects. Notwithstanding the fact that general accounting is only a speculation, our results show that public funding of assisted reproduction might lead to positive net fiscal results for the Spanish Treasury during the life cycles of children conceived through assisted reproduction. Moreover, it would decrease the problem of lack of access to healthcare service, while most likely improving equity in access to the service and quality of life of infertile couples.


ROP of γ-benzyl-l-glutamate N-carboxyanhydride initiated by P(Glx-r-PDLy)-NH2 provided neutral poly(γ-benzyl-l-glutamate)-grafted copolyesters, which were converted by hydrolysis into negatively charged hybrid copolymers. Both water-soluble and nonsoluble copolymers were produced depending on copolymer charge and their grafting degree, and their capacity for self-assembling in nano-objects were comparatively examined. The emulsion solvent-evaporation technique applied to the chloroform-soluble copolymers grafted with benzyl glutamate rendered well-delineated spherical nanoparticles with an average diameter of 200–300 nm. Conversely, micellar solutions in water were produced from copolyesters bearing grafted chains composed of at least 10 units of glutamic acid in the free form. The copolymer micelles were shown to be able to load doxorubicin (DOX) efficiently through electrostatic interactions and also to release the drug at a rate that was markedly pH dependent.The enzymatic ring-opening copolymerization (eROP) of globalide (Gl) and pentadecalactone (PDL) was performed in solution from mixtures of the two macrolactones at ratios covering the whole range of comonomeric compositions. The resulting P(Gl Polypeptides coming from either natural or synthetic sources are regarded as a class of highly refined polymers closely related with nature. Combination of synthetic polymers with polypeptides commonly results in hybrid copolymers in which the properties of each component are profited to surmount their individual limitations . Thus, tMacrolactones (MLs) stand out as ideal monomers for green polymer chemistry . MLs mayThe double bond present in Gl provides a versatile tool for chemical functionalization. Gl has been polymerized on several occasions to render polyglobalide (PGl), an unsaturated polyester  that wasl-glutamate (BLG) from Bachem, and 2,2′-Azobis(2-methylpropionitrile) (AIBN) (98%) and HBr (33% w/w in acetic acid) were acquired from Sigma-Aldrich . Globalide (Gl) was provided by Grupo Indukern (Barcelona), and ω-pentadecalactone (PDL) was purchased from Sigma-Aldrich and distilled under vacuum previous to use. Novozyme 435 (Candida antarctica Lipase B immobilized on cross-linked polyacrylate beads) was a gift of Novozymes , and 2-(Boc-amino)ethanethiol (BAET) (97%) and Sodium trifluoroacetate (98%) were purchased from Sigma-Aldrich and used without further purification. Anhydrous DMF (99.8%), CHCl3 (99.9%), THF (99.9%), ethyl acetate (99.9%), and n-heptane were purchased from Across Organics  and used directly from the bottle under an inert atmosphere. Additionally, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was purchased from Apollo Scientific (UK), and doxorubicin hydrochloride (DOX·HCl) (98%) was purchased from AK Scientific Inc. .Triphosgene and α-pinene were supplied by Sigma-Aldrich and γ-benzyl-1H and 13C NMR spectra were recorded on a Bruker AMX-300 spectrometer  at 25 °C, operating at 300.1 and 75.5 MHz, respectively. Compounds were dissolved in deuterated chloroform (CDCl3) or a mixture of trifluoroacetic acid (TFA) and CDCl3, and spectra were internally referenced to tetramethylsilane (TMS). About 10 mg of sample in 1 mL of solvent were used, and 64 scans were recorded for 1H NMR. FTIR measurements were performed in a Frontier Perkin-Elmer FTIR spectrophotometer . Spectra were obtained from powder samples using a Universal ATR sampling accessory. For spectra recorded at variable temperature, films were prepared by casting an HFIP solution containing 5 mg of polymer in 1 mL of solvent on a NaCl plate and the plate set on a VT FTIR Cell (Specac). Eight scans with a resolution of 4 cm−1 were collected for each sample in the spectral region of 450–4000 cm−1.w/v) sample solution was injected and chromatographed with a flow of 0.4 mL·min−1 using as solvent HFIP with sodium trifluoroacetate added (0.05 M). HR5E and HR2 Waters linear Styragel columns  packed with cross-linked polystyrene and protected with a precolumn were used. Molar mass averages and distributions were calculated against PMMA standards.Molecular weight analysis was performed by gel permeation chromatography (GPC) on a Waters equipment provided with RI and UV detectors. Precisely, 100 µL of 0.1%  using a Perkin-Elmer DSC 8500 apparatus. Thermograms were recorded from 4 to 6 mg samples at heating and cooling rates of 10 °C·min−1 under a nitrogen flow of 20 mL·min−1. Indium and zinc were used as standards for temperature and enthalpy calibration.Thermogravimetric analyses were performed on a Mettler-Toledo TGA/DSC 1 Star System under a nitrogen flow of 20 mL·minDynamic light scattering studies (DLS) were performed at the Parc Científic de Barcelona using a Zetasizer Nano ZS series Malvern instrument equipped with a 4 mW He–Ne laser operating with a wavelength of 633 nm. The noninvasive backscatter optic arrangement was used to collect the light scattered by the particles at an angle of 173°. The samples were analyzed in disposable cuvettes at 25 °C.−1. The energy employed corresponded to a 0.10 nm wavelength, and the spectra were calibrated with silver behenate (AgBh) and Cr2O3.Real-time X-ray diffraction (XRD) studies were carried out using synchrotron radiation at the BL11 beamline for noncrystalline diffraction (NCD) at ALBA . Spectra were recorded from powder samples subjected to heating–cooling cycles at a rate of 10 °C·minγ-Benzyl L-glutamate N-carboxyanhydride (BLG-NCA): γ-benzyl L-glutamate , α-pinene , and ethyl acetate (80 mL) were weighed in a three-neck round-bottom flask and refluxed under nitrogen for 15 min. Then, triphosgene  dissolved in ethyl acetate (20 mL) was added dropwise and refluxing continued until most of the solids disappeared which took about 3 h. The reaction mixture was then cooled down and filtered, and the filtrate was reduced to approximately 30% of its original volume by rotaevaporation. BLG-NCA was precipitated by addition of heptane (60 mL), recovered by filtration under vacuum, recrystallized twice using an ethyl acetate/heptane mixture (90:10 v/v), washed with heptane, and finally dried under vacuum. Yield: 90%.x-r-PDLy) copolyesters by eROP:Synthesis of P was placed in a round-bottom flask and dried over P2O5 for 16 h at 50 °C in a desiccator. Dry toluene (7 mL) and 2 g of the mixture of the two MLs at the selected molar ratio  were then added. The flask was immediately immersed in an oil bath at 70 °C, and the reaction left to proceed for 24 h under stirring in a nitrogen atmosphere. Finally, the reaction mixture was cooled down and toluene was removed by rotaevaporation. The solid residue was dispersed in chloroform, and the enzyme was filtered out. The polymer was precipitated by pouring the filtered chloroform solution into cold methanol, recovered by filtration, and dried before characterization. Yield: 80%–90%. x-r-PDLy) copolyesters via thiol-ene reaction:Functionalization of the P(Gl P(Gl13-r-PDL87) and P(Gl48-r-PDL52) copolyesters were chosen for the synthesis of the grafted copolymers. Briefly, the corresponding copolyester (0.2 g), BAET (1.11 g), and AIBN (50 mg) were weighed in a Schlenk tube purged with nitrogen, and then, 1 mL of THF was added. The reaction was initiated by immersing the tube into an oil bath at 80 °C and left to proceed for 24 h under magnetic stirring. The reaction was terminated by addition of dichloromethane (DCM) and immersion of the tube in an ice bath. The reaction product was precipitated in cold methanol and recovered by centrifugation. This process was performed twice to render the BAET-modified copolymers P[(Gl-BAET)13-r-PDL87] and P[(Gl24-r-(Gl-BAET)24-r-PDL52]. Yield: 90%.Removal of Boc-protecting groups: Solutions of copolyesters, P[(Gl-BAET)13-r-PDL87] and P[Gl24-r-(Gl-BAET)24-r-PDL52], (100 mg in 2 mL of TFA), were stirred at room temperature for 10 min. The solution was then added to an excess of diethyl ether, and the precipitate was then recovered by centrifugation and washed twice with a saturated 0.5 M NaHCO3 aqueous solution. The products, P[(Gl-NH2)13-r-PDL87] and P[Gl24-r-(Gl-NH2)24-r-PDL52], were dried under vacuum at room temperature and stored under such conditions until being used. Yield: 90%.x-r-PDLy)–g–BLGz] graft copolymers:Synthesis of P[(Gl Graft copolymers were prepared by ROP of BLG-NCA using P[(Gl-NH2)13-r-PDL87] and P[Gl24-r-(Gl-NH2)24-r-PDL52] as multiple macroinitiators. To prepare P[(Gl13-r-PDL87)–g–BLG10], the P[(Gl-NH2)13-r-PDL87] copolymer  in 2 mL of dried CHCl3 was injected with a syringe into a Schlenk tube through a rubber septum containing a solution of BLG-NCA  in 6 mL of dry CHCl3. The tube was placed in a NaCl water bath at 0 °C, and the reaction was left to proceed under stirring for 48 h or until the BLG-NCA was completely consumed as monitored by FTIR spectroscopy. The final reaction mixture was poured into an excess of diethyl ether, and the precipitate was recovered by centrifugation and dried under vacuum. The same methodology was used to prepare P[(Gl48-r-PDL52)–g–BLG2] copolymer from P[Gl24-r-(Gl-NH2)24-r-PDL52]  and BLG-NCA  but using DMF as solvent instead of CHCl3. Yield: 80%–90%.Graft copolymer deprotection: A general procedure was used for deprotection of PBLG pendant groups. Briefly, a solution of 170 mg of P[(Gl13-r-PDL87)–g–BLG10] in 2 mL of TFA was first prepared. Then, a solution of HBr in glacial acetic acid in a molar excess of 2.5–5 times respect to the γ-benzyl L-glutamate repeating unit was added slowly to the copolymer solution at 0 °C, and after 2 h, the mixture was poured into an excess of diethyl ether. The precipitate was centrifuged and washed twice with diethyl ether. The obtained polymer was dissolved in 0.5 M NaHCO3 aqueous solution and then dialyzed (MWCO 2000) against distilled water to yield P[(Gl13-r-PDL87)–g–LGA10] in the salt form. P[(Gl48-r-PDL52)–g–BLG2] was treated in the same way to yield P[(Gl48-r-PDL52)–g–LGA2] in 70% yield. l-glutamic acid) (PLGA):Synthesis of poly(γ-benzyl-L-glutamate) (PBLG) and poly was dissolved in 7 mL of anhydrous DMF in a Schlenk tube. The tube was immersed in a 0 °C NaCl water bath, and 80 µL  of a stock solution 0.76 M of hexylamine (HA) in DMF was injected through a rubber septum with a syringe ([NCA]0/[HA]0 = 50). The reaction was left until the BLG-NCA had been completely consumed as monitored by FTIR spectroscopy. After complete monomer conversion, the polypeptide was precipitated into an excess of chilled diethyl ether, filtered, and dried under vacuum. Yield: 84%. Removal of benzyl groups from PBLG was carried out in a similar manner as in the graft copolymer P[(Gl13-r-PDL87)–g–(BLG)10] to produce PLGA in 70% yield. 13-r-PDL87)–g–BLG10] copolymer were prepared by the emulsion-solvent evaporation technique. Precisely, 10 mg of the copolymer was dissolved in 2 mL of chloroform, and the solution was added to 10 mL of 1% (w/w) poly (PVA) (Mn = 2000 g·mol−1) aqueous solution. The mixture was then sonicated thrice for 15 s each time to yield a homogeneous oil-in-water emulsion. This emulsion was immediately poured into 10 mL of 0.3% PVA aqueous solution and magnetically stirred in an open beaker at room temperature for 3 h to evaporate the organic solvent. The NPs were collected by centrifugation at 11,000 rpm and washed three times with distilled water prior to characterization.Spherical nanoparticles (NPs) made of P[(Gl13-r-PDL87)–g–LGA10] to load positively charged drugs by electrostatic conjugation. Briefly, 5 mg of the copolymer was solubilized in 4 mL of deionized water, and the solution (pH 7.0) was stirred for 10 min before passing it through a 0.45 μm filter. Then, DOX·HCl  dissolved in water (1 mL) was added dropwise into the polymer–aqueous mixture under magnetic stirring (300 rpm) and left under stirring for 12 h. Afterward, the mixture was dialyzed  for 24 h against distilled water to remove the free DOX·HCl, and the dialysate was then lyophilized. Drug loading efficiency (DLE) and drug loading content (DLC) were calculated according to the following equations:Doxorubicin hydrochloride (DOX·HCl) was used as a drug model to appraise the capacity of P[(Gl48-r-PDL52)–g–LGA10] conjugate was placed in a dialysis bag  which was then immersed in 25 mL of buffer and kept under constant mild shaking at 37 °C. For measuring the amount of drug released, 1.5 mL aliquots were taken out from the releasing medium at selected time intervals, and the solution was replenished with an equal volume of fresh medium. Quantification of DOX was accomplished by absorption spectrometry at 480 nm using a UV–Vis spectrophotometer.The effect of the pH on drug release was assessed by incubating the DOX-loaded NPs in following buffers: PBS pH 7.4, citrate–phosphate pH 4.2, and hydrochloric acid–potassium chloride pH 2.0. The DOX·P and P[(Glx-r-PDLy)–g–(LGA)z], respectively, are depicted in x-r-PDLy) random copolyesters made of globalide (Gl) and pentadecalactone (PDL) was prepared by enzymatic ring-opening polymerization (eROP) using Candida antarctica Lipase B . The results obtained in these copolymerizations are shown in 1H and 13C NMR spectra of P(Gl13-r-PDL87) are given in 1H NMR spectra for the whole series are compared in x-r-PDLy) was difficult due to their scarce solubility in the solvents commonly used as eluents, their chain sizes were estimated by end-group NMR analysis. The area of signals due to CH2OH end groups appearing at 3.6 ppm (peak “d” in 2OOC appearing at 4.2 ppm (peaks d and d’), and assuming that chains were ended by both hydroxyl and carboxyl end groups, the degree of polymerization was estimated. Number-average molecular weights (Mn) oscillating in the 9000–12,000 g·mol−1 range without showing apparent correlation with composition were measured. Determination of comonomers distribution along the copolymer chain was unfeasible because NMR spectra were scarcely sensitive to sequence distribution effects given the long distance between ester groups and also extremely complex due to the existence of both constitutional and geometric isomerism. In fact, the Gl sample used in this work consisted of a 60/40 mixture of two monounsaturated isomers corresponding to the double bond placed at either 11- or 12-position with an overall diastereomeric E/Z configuration ratio of 78/22. 13C NMR spectra of Gl and PGl are compared in The set of reactions leading to the synthesis of the x-r-PDLy) copolyesters in the absence of oxygen was evaluated by TGA along the 30–600 °C interval under a circulating nitrogen flow. Their TGA traces along with those recorded for the two homopolyesters, PGl and PPDL, as well as their respective derivative curves are shown in maxTd values closely around those of PGl and PPDL. As it is characteristic of most of aliphatic polyesters and according to what should be expected from the high resistance to heat displayed by PGl and PPDL, the TGA data collected in this study ascertain the great thermal stability of the P(Glx-r-PDLy) copolyesters and reveal their ability to decompose cleanly without hardly leaving residual product.The thermal stability of P(Glx-r-PDLy) copolyesters was performed by recording heating–cooling–reheating cycles over the −30 to 200 °C interval. The first heating and cooling traces are shown in Tm at 42 and 95 °C, respectively, according to what is recurrently reported for these poly(macrolactone)s  copolyesters were then grafted by ROP of the BLG-NCA. Amino groups initiated the grafting reaction with an amino conversion close to 100%. The GPC analysis of the grafted copolymers provided chromatograms consisting essentially in a single peak –g–(BLG)z] with a TFA/HBr mixture, the COOH functionality of glutamic acid was readily regenerated to render P[(Glx-r-PDLy)–g–(LGlu)z] copolymers which were then duly characterized by NMR. For illustrative purposes, the 1H NMR spectra of P[(Gl13-r-PDL87)–g–(BLG)10] and P[(Gl13-r-PDL87)–g–(LGA)10] are shown in 48-r-PDL52)–g–(BLG)2] and P[(Gl48-r-PDL52)–g–(LGA)2] are included in the SI file as 2– with any of the signals characteristic of the copolyester –g–(LGlu)z] copolymers were measured by TGA and DSC, respectively. They are collected in x-r-PDLy) copolyesters –g–(LGlu)z] copolymers together with those of the parent polypeptides are shown in 13-r-PDL87)–g–(BLG)10] over the 115–120 °C range is attributed to the helical transition undergone by the (BLG)10 side chains. The inobservance of this transition in the other copolymers is according to expectations given the short number or/and charged state of the glutamic acid units in such cases.The heating, cooling, and reheating DSC traces recorded from the P[(Glx-r-PDLy)–g–(LGlu)z] copolymers was examined in detail by FTIR using homopolypeptides poly(γ-benzyl L-glutamate) (PBLG) and poly(L-glutamic acid) (PLGA) as reference. The 1800–1500 cm−1 region of the infrared spectra recorded from samples in the powder form is shown in −1 on the spectra of both P[(Gl13-r-PDL87)–g–(BLG)10] and PBLG50, respectively, as well as the absence of absorption around 1630 cm−1, are solid indications of the arrangement of the (BLG)10 side chain in α-helix conformation [48-r-PDL52)–g–(BLG)2] show a conspicuous peak at 1630 cm−1 consistent with the presence of a considerable amount of the (BLG)2 in β-form. The spectra of the unprotected copolymers showed broad amide bands more according with the polypeptide in a disordered state although the band at 1620 cm−1 observed in the spectrum of P[(Gl48-r-PDL52)–g–(LGA)2] suggests the presence of some β-form in this copolymer. These FTIR results are in good agreement with that is commonly accepted for the conformational properties of polypeptides, i.e., the α-helical conformation is favored by longer amino acid sequences but becomes incompatible with the ionically charged form [13-r-PDL87)–g–(BLG)10] and P[(Gl48-r-PDL52)–g–(BLG)2] copolymers within the 20–200 °C range –g–(BLG)10] copolymer recorded at real time at temperatures varying over the 0–200 °C range are shown in x-r-PDLy) copolyesters. According to DSC results, these peaks disappeared at temperatures above melting, i.e., ~75 °C to be replaced by a broad peak at 0.46 nm arising from the disordered state. Additionally, a set of peaks corresponding to lattice spacings roughly related by the 1:√3:2 ratio,  was observed. As it has been previously reported on several occasions [48-r-PDL52)–g–(BLG)2] are provided in X-ray diffraction (XRD) of the hybrid copolymers in the solid state afforded complementary information in support of the results obtained by both DSC and FTIR. XRD profiles of the P[–g–(LGlu)z], i.e., with the carboxyl group free or in the ester form, determined their solubility and consequently, the procedure suitable for promoting their self-assembly into nanometric entities. Thus, the emulsion-solvent evaporation method was applied to the nonwater-soluble P[(Gl13-r-PDL87)–g–(BLG)10] copolymer to obtain spherical nanoparticles of average diameter around 250 nm displaying an acceptable polydispersity and a zeta potential of −3.75 mV. The SEM analysis of these nanoparticles revealed that they have a nearly round shape and are well delineated without showing apparent aggregation –g–(BLG)10] led to the strongly amphiphilic and water-soluble P[(Gl13-r-PDL87)–g–(LGA)10] copolymer. The emulsion-solvent evaporation method successfully used with the protected copolymer was not applicable after deprotection because the carboxylic copolymer is not soluble in the usual volatile solvents required for preparing the organic solution. Conversely, when P[(Gl13-r-PDL87)–g–(LGA)10] was dissolved in water at concentrations above 0.5 mg·mL−1, it became spontaneously self-organized to form micelle-like objects as it was revealed by the DLS analysis. The critical micelle concentration (cmc) of P[(Gl13-r-PDL87)–g–(LGA)10] measured by DLS was 0.15 mg·mL−1 (−1 (Deprotection of the benzyl carboxylate groups of P[(Gl mg·mL−1 . The micmL−1 (−1 . The Z-p3+ group provided that they are located at the particle surface [13-r-PDL87)–g–(LGA)10] as nanocarrier, this copolymer was mixed with DOX·HCl in water at different LGA:drug molar ratios , and the resulting DOX-loaded micelles were examined by DLS. The results found for 1.25 and 3 mg·mL−1 copolymer concentrations with an LGA:drug ratio of 1:0.4 are shown in DOX is a well-known amphiphilic drug that is commonly used in cancer therapy . The ami surface ,45,46,4713-r-PDL87)–g–(LGA)10] for DOX loading was assessed by estimating the drug-loading efficiency (DLE) and drug-loading content (DLC) for the three LGA:drug molar ratios tested in this study. The bar plot in 13-r-PDL87)–g–(LGA)10]·DOX to deliver the drug as well as to assess the response of the system to pH changes. The DOX-releasing profiles obtained upon incubation of this conjugate at pH 2.0, 4.2, and 7.4 are compared in The suitability of P[(Glx-r-PDLy) made of two macrolactones, i.e., globalide (Gl) and pentadecalactone (PDL), and covering the whole range of compositions as well as the homopolyesters PGl and PPDL were successfully prepared by enzymatic ROP. The DSC study demonstrated that the copolyesters were crystalline and able to recrystallize from the melt. Crystallinity and density of double bonds in these copolyesters were tuned by composition. Amino acid grafting of P(Glx-r-PDLy) was satisfactorily performed by ROP of BLG-NCA initiated by amino functions previously inserted in the Gl units of the copolyester. The benzyl-protecting group could be then readily removed to produce strongly amphiphilic copolyesters bearing free carboxylate groups in the grafting side chains. Both the amount of grafted Gl units and the average length of the grafting polyglutamate side chains could be accurately controlled so that copolymers displaying different water solubility were prepared. Neutral nonwater-soluble copolymers were able to self-assemble in spherical nanoparticles with an average diameter of 200–300 nm. These nanoparticles based on graft copolyester are unique in containing a crystalline highly hydrophobic core covered by a shell of polypeptide in α-helical conformation. On the other hand, the water-soluble graft copolyesters bearing ionized glutamic acid side chains produced micelles that were able to load fair amounts of DOX with a high capturing efficiency. Electrostatic ammonium–carboxylate interactions were responsible for the good loading capacity exhibited by the graft copolymer and also for the remarkable changes in the drug delivery profile displayed by the DOX-loaded micelles when incubated in aqueous medium at different pHs.Random copolyesters P(Gl


Cycled under 6 C (6.6 mA cm−2), a 1.0 mAh cm−2 LiNi0.6Co0.2Mn0.2O2 electrode maintains a substantial 74% of its capacity by pairing with such anode.To achieve good rate capability of lithium metal anodes for high-energy-density batteries, one fundamental challenge is the slow lithium diffusion at the interface. Here we report an interpenetrated, three-dimensional lithium metal/lithium tin alloy nanocomposite foil realized by a simple calendering and folding process of lithium and tin foils, and spontaneous alloying reactions. The strong affinity between the metallic lithium and lithium tin alloy as mixed electronic and ionic conducting networks, and their abundant interfaces enable ultrafast charger diffusion across the entire electrode. We demonstrate that a lithium/lithium tin alloy foil electrode sustains stable lithium stripping/plating under 30 mA cm 22Sn5 alloy design to address this issue. The composite anode sustains stable Li stripping/plating cycling with a low overpotential of 20 mV under 30 mA cm−2 in a commercial carbonate electrolyte.Sluggish lithium diffusion on the surface of Li metal anodes poses a fundamental challenge. Here the authors report a Li/Li However, these conventional LIBs are reaching the limits regarding energy and power density5. The development of rechargeable lithium-based batteries with much higher energy and power density is of vital importance for fast expanding their applications, which certainly relies on breakthroughs in materials and electrode design7. An effective approach is to search for high-capacity anode materials with low potential against cathode materials and high lithium-ion diffusion rate to replace the most widely used graphite material, which delivers a relatively low theoretical capacity of 372 mAh g−1 and slow lithium-ion diffusion rate (10−12 and 10−6 cm2 s−1)8. Lithium metal is a holy grail anode due to its high theoretical specific capacity (3860 mAh g−1) and low potential (−3.040 V vs. standard hydrogen electrode). However, the practical application of lithium metal anode suffers from unsatisfactory cyclability, inferior rate capability and safety issues12. The high chemical reactivity makes lithium metal react with the liquid electrolyte to form an unstable solid-electrolyte interphase (SEI) layer. Such SEI layer breaks under considerable volume variation and repairs after the exposure of fresh lithium surface to the liquid electrolyte during cycling, leading to the continual consumption of active lithium and liquid electrolyte, and finally failure of the cell14. The slow lithium diffusion at the electrode/electrolyte interface may cause large overpotential under high current densities and therefore confine the rate capability of lithium metal anode. The infinite relative volume change of lithium metal electrode without a host material leads to the absence of the spatial control of lithium deposition and thereby the growth of lithium dendrites, and eventually causes safety concerns10.Lithium-ion batteries (LIBs) based on intercalation chemistry with the combination of a lithium transition metal oxide (or phosphate) cathode and a graphite anode have been widely used in consumer electronics and are making their way to electric vehicles and grids16, self-healing electrostatic shield17, fluorinated electrolyte18, and high salt concentration20) and interface engineering  for stabilizing the interface between the electrode and electrolyte, use of solid electrolytes for preventing dendrite growth28, and design of stable scaffolds/hosts for minimizing volume change33. These efforts effectively alleviated certain problems of lithium metal anode mainly under moderate/low current densities . However, achieving high rate capability of lithium metal anode still remains challenging34. The issues of lithium metal anode are aggravated under high current densities and high areal capacities, resulting in more severe battery failures. Recently, lithium metal structural design with high electrolyte-accessible surface area showed improved rate capability by reducing the local currents32. However, the increased contact area with electrolytes may lead to severe side reactions and reduce the lifespan of batteries. To date, there have been few significant breakthroughs that enable long-term stable cycling of lithium metal anodes at high current densities  and moderately high areal capacities  with acceptable overpotentials in commercial carbonate electrolytes.Considerable effort has been devoted to tackling the challenges of lithium metal anodes, including electrolyte  and Li3PO4 phases have high lithium-ion diffusion coefficients (10 × 10−8 to 10 × 10−6 cm2 s−1)38 and a surface layer of such phases on lithium metal has proved to be effective in improving lithium diffusion at the electrode/electrolyte interface25. However, high rate capability requires fast lithium-ion diffusion kinetics over the entire electrode, including both the surface and interior, which relies rational electrode design.High rate capability of electrodes requires fast lithium-ion diffusion kinetics22Sn5) integrated networks. The 3D nanostructured metallic lithium network acts as active lithium source of the electrode. The 3D nanostructured Li22Sn5 network keeps composition and structure invariant and acts as a “pathway” for lithium diffusion and electron conduction during the stripping and plating of metallic lithium. The strong affinity between the 3D metallic Li and Li22Sn5 networks, and their abundant interfaces enable small interface impedance and therefore ultrafast lithium diffusion at these Li/Li22Sn5 interfaces. A moderate potential difference (~0.3 V) between the Li22Sn5 and metallic lithium functions as the driving force for lithium diffusion within the entire electrode. As a result, the as-achieved Li/Li22Sn5 nanocomposite delivered ultrahigh-rate capability and good stability for long-term lithium stripping/deposition cycling. Under an ultrahigh current density of 30 mA cm−2 and high areal capacity of 5 mAh cm−2, the Li/Li22Sn5 nanocomposite sustained stable electrodeposition/dissolution over 200 cycles with a very low overpotential of 20 mV in a commercial carbonate electrolyte. Furthermore, by pairing with a Li/Li22Sn5 anode, a substantial 74% of the capacity was maintained for a 1.0 mAh cm−2 LiNi0.6Co0.2Mn0.2O2 electrode cycled at 6 C (6.6 mA cm−2). A Li/Li22Sn5|LiFePO4 cell delivered a high specific capacity of 132 mAh g−1 at 5 C (4 mA cm−2) and showed stable and flat potential profiles with high-capacity retention of 91% for 500 cycles.Here, we report a nanostructured lithium metal foil electrode with in situ formed three-dimensional (3D) interconnected metallic lithium and mixed electron and lithium-ion conductive lithium tin alloy Li + 5Sn → Li22Sn5 + xLi(excess)], featuring 3D interconnected metallic lithium and Li22Sn5 integrated networks with strong affinity and abundant interfaces between metallic Li and Li22Sn5. Since the Li/Li22Sn5 nanocomposite foils with Li/Sn atomic ratios of 44/5 and 88/5 showed same structure and very similar electrochemical performance (discussed in the next section), we performed the detailed materials and battery characterizations using the foil with Li/Sn atomic ratio of 44/5 as an example unless otherwise stated. The Li/Li22Sn5 nanocomposite exhibits a foil structure  analyses were performed after Ar sputtering to reveal the surface electronic state of the elemental composition. Different from a single characteristic peak at 55.0 eV in the high-resolution Li 1s spectrum for the pure lithium metal foil39, two distinct peaks at 55.2 eV and 56.3 eV were observed for the Li/Li22Sn5 nanocomposite, the latter of which was ascribed to the lithium element in Li22Sn5  in the conventional Li metal anode. Thus, the local current density for the metallic Li in the Li/Li22Sn5 composite electrode can be greatly reduced in comparison to that of the conventional Li metal anode when same overall current density is applied.The Li/Libox Fig. . During oil Fig. . The sigSn5 Fig. . In the Sn5 Fig. . Scanninoil Fig. . After eces Fig. . Therefo22Sn5 network forms an lithium diffusion “pathway” over the entire Li/Li22Sn5 electrode. Metallic lithium can easily transport through such “pathway” back and forth. Meanwhile, the 3D nanostructured metallic lithium and Li22Sn5 networks both provide an electron “pathway” over the entire Li/Li22Sn5 electrode. Second, the potential difference (~0.3 V) between Li22Sn5 and metallic lithium can act as the driving force for lithium diffusion through such a “pathway”. These advantages enable fast lithium diffusion over the entire the Li/Li22Sn5 electrode, leading to good rate capability. Furthermore, fast lithium diffusion helps to alleviate the formation of lithium metal dendrites during cycling41 and thus improves the safety of rechargeable lithium metal batteries. Third, the Li22Sn5 is less reactive with the liquid electrolyte than the metallic lithium due to its higher chemical potential. Thus, less electrolyte consumption and longer cycle life can be expected. Fourth, the 3D interconnected Li22Sn5 network remains invariant in the composition and structure on cycling and is capable of working as a stable host for stripping/plating of lithium metal and thus addressing the challenge of significant volume change.Such unique nanostructure allows fast lithium diffusion over the entire electrode and enables stable lithium stripping/plating cycling under high current densities without lithium dendrite growth due to its multiple advantages: First, due to the high lithium-ion diffusion coefficient, strong lithium affinity and abundant interfaces to metallic lithium, the 3D nanostructured Li22Sn5 electrode for high-power-density lithium metal batteries, stripping/plating measurements were performed with a practical high areal capacity of lithium (5 mAh cm−2) at various high current densities  in symmetric cells using commercial carbonate-based electrolytes. Figure 22Sn5|Li/Li22Sn5 symmetric cells and the Li|Li counterparts for different cycles at 5 mA cm−2 with fixed areal capacity of 5 mAh cm−2. Supplementary Fig. 22Sn5|Li/Li22Sn5 symmetric cells. For Li|Li symmetric cells cycled at 5 mA cm−2, a high overpotential of 0.65 V was observed at the beginning of the first cycle , indicating much better charge carrier transport through the entire Li/Li22Sn5 electrode. The overpotential of the Li/Li22Sn5 electrode further decreased and remained under 5 mV after five cycles after the surface activation  and stable cycling for 200 cycles  and LiFePO4 (LFP) cathodes. The electrochemical measurement of NCM|Li/Li22Sn5 and NCM|Li cells was performed at increasing current rates based on a theoretical specific capacity of 170 mAh g−1 for NCM and ~6.5 mg cm−2 active mass loading , such a NCM|Li/Li22Sn5 cell can fill up 74% of its capacity within 10 mins, suggesting the good rate capability of the Li/Li22Sn5 electrode. Similar rate capacities were achieved on five NCM|Li/Li22Sn5 cells, showing the repeatability |Li/Li22Sn5 cells exhibited a stable discharge capacity of 1 mAh cm−2 at 33.1 mA cm−2 (15 C), suggesting the good stability of the Li/Li22Sn5 electrode at ultrahigh current density  and low areal capacity ratio of negative to positive electrodes  were further built and their electrochemical performance was investigated. A NCM|Li/Li22Sn5 full cell delivered an initial capacity of 3.33 mAh cm−2 for the 1st cycle and 2.80 mAh cm−2 for the 100th cycle at 4 mA cm−2, with a capacity retention of 84 %  for the 1st cycle and 120 mAh g−1 for the 500th cycle, delivering high-capacity retention of 91%. Also, the capacity vs. cycle number profile of the LFP|Li/Li22Sn5 cell showed little fluctuation during cycling  can be an ideal Li reservoir to evaluate the Coulombic efficiency of a Li metal anode since it has near 100% Coulombic efficiency and does not provide Li during cycling. 10 mAh cm−2 Li/Li22Sn5 electrode and pristine Li metal electrode were paired with ~2.8 mAh cm−2 of LTO at 1.4 mA cm−2 (0.5 C) in a commercial carbonate electrolyte. The capacity of the LTO|Li cell started to quickly decay at the 30th cycle, showing a Coulombic efficiency of 91.2%, and the LTO|Li cell lost all its capacity after 60 cycles  for 75 cycles, giving a higher Coulombic efficiency of 96.5%  elemental mapping images exhibit strong signals of C, F, and P elements on the surface layer and weak signals on the bottom layer  extend within the structure as cycling takes place. The formation of this loose interphase consumes active lithium and electrolyte, suggesting the serious corrosion of the bulk Li metal electrode. In contrast, the Li/Li22Sn5 electrode preserves its dense structure and the signals of C, F, and P elements are very weak over the entire cross section . Although the volume change at the electrode level would be reduced by using these mechanical supports, side reactions between the electrolyte and electrode would be enhanced due to the movement of electrode/electrolyte interface  by pairing such a Li/Li22Sn5 anode. High capacity retention of 91% and stable potential profiles were achieved for an LFP|Li/Li22Sn5 cell for 500 cycles at 5 C (4 mA cm−2). These results suggest the potential application of Li/Li22Sn5 nanostructured electrode in lithium metal batteries with high power and long lifespan.In this work, we demonstrated that, a unique nanostructured lithium metal electrode with 3D interconnected metallic lithium and Li22Sn5 foil was realized using a repeated folding and calendaring method, and a spontaneous reaction between metallic lithium and tin. A tin foil and two lithium foils with same size and designed ratio of Li/Sn were first stacked to form a Li–Sn–Li “sandwich” and pressed together by mechanical rolling using a roll squeezer in an Ar-filled glove box. The overall thickness of the produced Li–Sn–Li foil was 0.5 mm, which could be changed by tuning the spacing between the two rollers of the roll squeezer. The Li–Sn–Li “sandwich” was folded and rolled repeatedly, which led to the gradual increase in the number and reduction in the thickness of each metal layer. Such process produced rich amount of fresh Li/Sn interfaces, where the metallic lithium and tin reacted spontaneously, and formed a 3D Li22Sn5 framework with excess lithium evenly embedded in [(22 + x)Li + 5Sn → Li22Sn5 + xLi (excess)]. The as-achieved Li/Li22Sn5 foil was cut into 12-mm-diameter electrodes for electrochemical measurements.The fabrication of the Li/Li22Sn5 foil were investigated using XRD , field-emission scanning electrode microscopy , X-ray photoelectron spectroscopy  and transmission electron microscopy . Before the XRD measurement, samples were loaded on a glass slide and covered with Kapton tape in the Ar-filled glove box to avoid the reactions between the samples and ambient air. Samples for SEM, XPS, and TEM measurements were sealed in the Ar-filled glove box before being transferred into the chamber of the equipment. To observe the Li22Sn5 framework of the Li/Li22Sn5 foil, metallic Li was electrochemically stripped away using a Li/Li22Sn5|Li cell configuration. The sample for characterization was rinsed by dimethyl carbonate. In situ optical microscopy  observations of lithium metal electrodeposition on the Li/Li22Sn5 and the pristine Li foil substrates were carried out using a side-by-side-type cell . The Li metal counter and reference electrodes and GFF separator were assembled in an argon-filled glove box with less than 1 ppm of oxygen and moisture. The monitoring of the Li metal was performed by a BioLogic SP-300.The morphology, microstructure, and component of the Li/Li6) in 1:1:1 ethylene carbonate (EC)/propylene carbonate (PC)/diethyl carbonate (DEC) with 10% fluoroethylene carbonate (FEC) and 1% vinylene carbonate (VC). Celgard 2300  was used as the separator. Battery performance was investigated in a galvanostatic mode at various current densities using a LAND battery tester. The electrochemical impedance spectroscopy (EIS) measurement was performed on a Biologic VMP3 system. The NCM and LFP electrodes were fabricated with 80% active materials, 10% polyvinylidene fluoride (PVDF) and 10% carbon black. The active mass loadings of NCM and LFP electrodes were ~6.5 and ~5.0 mg cm−2, respectively. The current rates for NCM and LFP are based on their practical specific capacities of 170 mAh g−1 and 160 mAh g−1, respectively. For full cell measurement with high mass loading, the active mass loading of NCM electrode was ~23.7 mg cm−2.2032 coin-type cells were assembled in an Ar-filled glove box for electrochemical measurements. The electrolyte was 1 M lithium hexafluorophosphate (LiPFSupplementary InformationDescription of Additional Supplementary FilesSupplementary Movie 1Supplementary Movie 2


Uniform migration of lithium (Li) ions between the separator and the lithium anode is critical for achieving good quality Li deposition, which is of much significance for lithium metal battery operation, especially for Li–sulfur (Li–S) batteries. Commercial separators such as polypropylene or polyethylene can be prepared by wet or dry processes, but they can indeed cause plentiful porosities, resulting in the uneven Li ion stripping/plating and finally the formation of Li dendrites. Thence, we constructed an atomic interlamellar ion channel by introducing the layered montmorillonite on the surface of the separator to guide Li ion flux and achieved stable Li deposition. The atomic interlamellar ion channel with a spacing of 1.4 nm showed strong absorption capacity for electrolytes and reserved capacity for Li ions, thus promoting rapid transfer of Li ions and resulting in even Li ion deposition at the anode. When assembled with the proposed separator, the Coulombic efficiency of Li||Cu batteries was 98.2% after 200 cycles and stable plating/stripping even after 800 h was achieved for the Li||Li symmetric batteries. Importantly, the proposed separator allows 140% specific capacity increase after 190 cycles as employing the Li–S batteries.The online version contains supplementary material available at 10.1186/s11671-021-03508-z. Nevertheless, the existence of irregular pores in commercial separators can lead to poor quality of deposited lithium, which can result in dendritic formation and consuming more lithium metals and electrolytes during the repeated plating/stripping processes [With ever-increasing demand for high-performance electronic applications such as electric vehicles and portable systems, the research focused on energy storage devices with high energy density and long cycle life has received extensive attention –3. Specirocesses , 8.Consequently, Li dendrites could form the “dead” Li metal when they are easily broken away from the conductive collector, resulting in low Coulomb efficiency (CE) and irreversible capacity loss , 10. Add−2. To improve the critical current density of LMBs, the addition of inorganic particles within the separator to improve the porous structure and increase critical current density can be another effective method. However, uneven pore distribution in the separator can generally lead to disordered diffusion of Li ions during the plating/strip process, leading to the uneven deposition of Li ions and the formation of Li dendrites [Among the components of LMBs, the separator not only plays a key role to segment anode and cathode electrodes for avoiding short circuit, but also directly affects the performance of batteries via authorizing Li ion migration , 20, 21.endrites . Therefo−2 with a capacity of 1 mAh cm−2. Moreover, the batteries with Li-MMT@PP separators also deliver good cycle stability with 140% specific capacity increased as compared to PP separators after 190 cycles at 0.5 mA cm−2 with sulfur loading of 1.5 mg cm−2.In this work, aiming to guide the migration of Li ions evenly through the separator, a Li-based montmorillonite (Li-MMT) modified composite separator is fabricated via constructing atomic interlamellar ion channels on the PP separator. The as-prepared separator embedded with interlamellar spacing (~ 1.4 nm) provides abundant active sites for Li ion diffusion and electrolyte wetting . Thus, t2SO3) were obtained from Sinopharm Chemical Reagent Co., Ltd. Sulfur powder (S) and acetylene black (denoted as C powder) were purchased from Alfa Aesar. Celgard 2500 was used as separator. The Li-MMT powder was prepared via cation exchange. Typically, 0.2 M H2SO3 solution was used to covert the cations within the interlayer of MMT to ions and then LiOH solution was used to make the solution at PH = 7 as well as covert the hydrogen ions to the Li ions. Freeze-drying technology was used to collect the Li-MMT powder. For the preparation of Li-MMT@PP separator, only one side of the separator was coated the Li-MMT slurry that Li-MMT and PVDF powder with mass ratio 9:1 were uniform dispersed in the NMP solution and the average mass loading of Li-MMT is only ~ 0.15 mg cm−2.Montmorillonite (MMT), polyvinylidene fluoride (PVDF), and lithium hydroxide (LiOH) were purchased from Aladdin. The N-methyl pyrrolidone (NMP) and sulfuric acid (HX-ray diffraction (XRD) spectrum using a UltimaIV diffractometer with CuKα1 radiation (λ = 1.4506 Å) was employed to investigate the crystal structure of Li-MMT powder. High-resolution transmission electron microscope (HRTEM) was used to observe the interlayer of Li-MMT and the scanning electron microscope  was used to analyze the surface morphologies.−2 to use as the Li sources. The electrolyte was 1 M bistrifluoromethanesulfonimide lithium salt (LiTFSI) in a mixture of 1,3-dioxacyclopentane (DOL) and 1,2-dimethoxyethane (DME) (1:1 v/v) with 2 wt% lithium nitrate (LiNO3) as additive. For the Li–S battery tests, the S cathode was prepared via our previous method that The C and S powder were mixed and heated at 155 ℃ for 24 h with a mass ratio of 8:2 [−2 which was coated on the carbon coated aluminum foil. The batteries were assembled via stainless steel coin battery (CR2025) in an argon-filled glove box. Li foil was used as anode. 20 uL electrolyte was used to wet the lithium anode and additional 20 µL was used to wet the separator and cathode. Before testing, the assembled Li–S batteries was rest 12 h and then 0.2 mA cm−2 with 5 cycles was used to active the battery performance. The electrochemical test system was CT2001A battery test system . The cut-off voltage was 1.7–2.7 V. Electrochemical impedance spectroscopy (EIS) was tested by Electrochemical workstation .For the Li||Cu and Li||Li battery tests, typically, the Cu foils were firstly washed with deionized water and ethanol three times to remove the possible impurities. Then, the lithium foil was cut into circles with area of 1 cmo of 8:2 . And the+, Na+, Mg2+, Ca2+, etc. Therefore, cation exchange method is necessary to covert the host cations to Li ions [To illustrate the lithium ion flux across the commercial PP separator, the schematics are shown in Fig.  Li ions . The bas Li ions . With th Li ions , 25. TheThe precise measurement of interlayer space of Li-MMT is shown in Fig. −2 with a capacity of 1 mAh cm−2. During the tests, it can be observed that all of the CE present an upward trend in the first 5 cycles, caused by the surface passivation of Li deposition. However, higher average CE in the first 5 cycles of Li-MMT@PP separator highlights the advantages that the deposited Li metal suffers lower side reaction with the liquid electrolyte as coupled with Li-MMT@PP separator. With the reduplicative plating/stripping, the shortcoming of PP separator is gradually exposed that the assembled Li||Cu battery only endures ~ 50 cycles and its CE decreases sharply to 60% and almost to zero after 150 cycles. On the contrary, the CE of Li||Cu battery assembled with Li-MMT@PP separator still delivers stable cycles with lower over-potential  measurements show the pore size distribution of Li-MMT powder within the scope of 1–3 nm   measurement. As shown in Fig. +). The cyclic voltammetry (CV) tests were conducted and presented in Additional file −1 with negligible voltage hysteresis. However, for the PP separator, only ~ 210 mAh g−1 capacity is observed, indicating that partially released long-chain polysulfides  are not involved in the subsequent redox reaction to contribute the capacity. The higher discharge capacity during the first plateau implies the Li-MMT layer can effective avoid the shuttle of soluble long-chain polysulfides to the Li anode surface. At the second conversion steps, obviously, for the PP separator, small amounts of short-chain polysulfides are formed due to the existence of shuttle effect within the ether-based electrolyte, which has been confirmed by our previously work [−1. Long-term cycles with good stability are the primary goals for the commercial batteries. The long-term cyclability of Li-MMT@PP separators is shown in Fig. To demonstrate the potential of Li-MMT@PP separator in the practical application of Li metal batteries, the S cathode with S loading of 1.5 mg cmsly work . In contsly work . The exc−1  with a 100% CE after 190 cycles at the current density of 0.5 mA cm−2 with the sulfur loading of 1.5 mg cm−2.In summary, the interatomic ion channel (Li-MMT) was constructed on the porous PP separator to modulate the Li ion flux and then guide the even deposition of Li ion on the Li anode during the electroplating/stripping. Due to the wide interlayer space (~ 1.4 nm) of Li-MMT, the Li-MMT@PP separator greatly ensures the cyclability of Li metal anode by unifying the flow direction of lithium ions, resulting in the uniform deposition of Li ions on the anode surface, thus forming a dendritic free lithium anode. As assembled with the Li-MMT@PP separator, the Li–S battery exhibits a remarkable reversible capacity of 776 mAh gAdditional file 1: Table S1. The comparison of Li-MMT@PP separator with previously reported functional separator. Fig. S1. BET results of Li-MMT powder. Fig. S2. Cyclic voltammograms of PP and Li-MMT@PP separator, recorded at 0.1 mV/s.