BIODEGRADABLE POLYMERS WITH A PHOSPHORYL-CONTAINING BACKBONE:TISSUE ENGINEERING AND CONTROLLED DRUG DELIVERY APPLICATIONS

This review provides a glimpse of the potential of the biodegradable phos-phoryl-containing polymers in medical applications. Undoubtedly these polymerspossess unique properties that are yet to be fully understood. Many areas warrantfurther investigation and much optimization remains to be done. The fascinatingchemistry of phosphorus poses interesting hurdles but at the same time leavesample room for polymer scientists to exercise their creativity in designinginteresting biomaterials. As the mutual understanding between basic and clinicalscientists on the need of medical devices and the capabilities of these newbiomaterials expands, imaginative application of new biomaterials to other medi-cal applications can be expected.

Synthesis and Properties of Biodegradable Copolymers of 9-Phenyl-2, 4, 8, 10-tetraoxaspiro-[5, 5]undcane-3-one and Ethylene Ethyl Phosphate

Novel biodegradable copolymer poly（CC-co-EEP） was synthesized by ring-opening copolymerization of cyclic carbonate 9-phenyl-2, 4, 8, 10-tetraoxaspiro-[5, 5]undcane-3-one （CC） and ethylene ethyl phosphate （EEP）. The obtained poly （CC-co-EEP）s were characterized by FTIR, ^1H NMR, ^13C NMR and gel permeation chromatography （GPC）. In vitro hydrolytic degradation of the copolymers were investigated in phosphate buffer solution （pH=7.4）. Hydrophilic phosphate units apparently improved the degradability of poly（carbonate-phosphate）.

Simultaneous Removal of Perchlorate and Nitrate Using Biodegradable Polymers Bioreactor Concept

Simultaneous perchlorate and nitrate removal from contaminated groundwater in one reactor has been realized with different methods in the past. The usage of biodegradable polymers as biofilm carriers and carbon source is new. Polymer in this paper was designed out of the copolymer of starch and polyvinyl alcohol. Under polluted water with 2 mg/L of perchlorate and 20 mg/L of NO3-N, it was possible to produce completely denitrification only for 5 h and below the detection limit to perchlorate within 9 h. Results indicating a significant impact of liquor pH on the biodegradation of but slight effect on nitrate reduction. Packed-bed reactor filled with polymer granules could remove 2 mg/L perchlorate and 25 mg/L NO3-N completely with influent flow rate?of 1.17 mL/min. Morphological observation indicated the developed biofilm coverage on the outer surfaces of the carriers was dense and primarily composed of bacillus and coccus. The microbes in biofilm decomposed polymer, the chink and filament structure on the carrier surface developed, through metabolism and provided carbon source for them by releasing small organic molecules.

WAXD and FTIR Studies of Electron Beam Irradiated Biodegradable Polymers

Poly（L-lactic acid） （PLLA） and poly（e-caprolactone） （PCL） have been receiving much attention lately due to their biodegradability in human body as well as in the soil, also due to their biocompatibility, environmentally friendly characteristics and non-toxicity. Morphology of biodegradable polymers affects the rate of their biodegradation. A polymer that has high degree of crystallinity will degrade at a slower rate due to the inherent increased stability. PCL homopolymer crosslinking degree increases with increasing doses of high energy radiation. On the other hand, the irradiation ofPLLA homopolymer promotes mainly chain-scissions at doses below 250 kGy. In the present work, twin screw extruded films of PLLA and PCL biodegradable homopolymers and 50：50 （w：w） blend were electron beam irradiated using electron beam accelerator Dynamitron （E = 1.5 MeV） from Radiation Dynamics, Inc. at doses in the range of 50 kGy to 103 kGy in order to evaluate the effect of electron beam radiation. Wide-angle X-ray diffraction （WAXD） patterns of non irradiated and irradiated samples were obtained using a diffractometer Rigaku Denki Co. Ltd., Multiflex model; and Fourier transform infrared spectroscopy （FTIR） spectra was obtained using a NICOLET 4700, attenuated total reflectance （ATR） technique. By WAXD patterns of as extruded non irradiated and irradiated PLLA it was verified broad diffusion peaks corresponding to amorphous polymer. There was a slight increase of the mean crystallite size of PCL homopolymer with increasing radiation dose. PCL crystalline index （CI） decreased with radiation dose above 500 kGy. But then, PLLA CI increased with radiation dose above 750 kGy. From another point of view, PLLA presence on the 50：50 blend did not interfere on the observed mean crystallite size increase up to 250 kGy. From 500 kGy to 103 kGy the crystallite size of PCL was a little bigger in the blend than the homopolymer. In contrast, FTIR results have shown that this technique was not sensitive enough to observe the degradation promoted by ionizing radiation of the studied homopolymers and blends, and neither on the miscibility of the blends.

Effect of nonionic surfactants in release media on accelerated in-vitro release profile of sirolimus eluting stents with biodegradable polymeric coating

It is a well-known fact that sirolimus(SRL) undergoes degradation process via hydrolysis in aqueous media, leading to incorrect assessment of drug amount and thus release characteristics of formulations.The main objective of the present study was to evaluate the effect of nonionic surfactants in media on invitro release profiles for sirolimus eluting stents(SES) coated with biodegradable polymeric matrix.Phosphate buffer and acetate buffer incorporating nonionic surfactants with varying concentrations were examined for adequate solubility and stability(by RP-HPLC). Good sink condition was achieved in phosphate buffer(at pH 4.0) with 1.0% Tween 20, 1.0% Brij 35% and 0.5% Brij 58. Hydrodynamic size(by DLS) and the micelle-water partition coefficient(P) with standard free energy of solubilization(ΔGs°) of drug were evaluated to get some understanding about the solubilization phenomena. About 80% of drug release during the period of 48 h was achieved in optimized drug release media which was 1.0% Tween20 in phosphate buffer pH 4.0. The obtained accelerated SRL release profile in optimized medium correlated well with the real time in-vitro release in phosphate buffer(pH 7.4). Surface morphology changes(by SEM), changes in gravimetric weights and molecular weight change(by GPC) were examined before and after drug release to understand the drug release mechanism which explains that the polymer did not undergo degradation during the drug release.

Six-month results of a biodegradable polymer and rapamycin-coating stent for coronary artery disease

Objective To assess the safety and efficacy of a novel biodegradable polymer and rapamycin-coating stent, the EXCEL stent, in the treatment of coronary artery disease (CAD), as compared with the CypherTM stent. Methods In this prospective, non-randomized study, 60 consecutive patients with symptomatic CAD received either an EXCEL stent (n=32), or a CypherTM stent(n=28),according to their respective treatment intention. Follow-up angiography was performed at a mean of 180±40 days. The primary endpoint of the study was the occurrence of a major adverse cardiac event (MACE), including death, myocardial infarction, or target-vessel revascularization during the 6 months after stenting. The secondary end points included the in-stent late luminal loss (LLL), percentage of in-stent stenosis of the luminal diameter, and the rate of restenosis (luminal narrowing of 50 percent or more) at 6 months. Results There were no significant differences between the two groups in baseline characteristics, including the distribution of target vessel and lesion types. During the follow up period of 6 months, there were no occurrences of MACE in either group. Twenty-seven patients(84%) in the EXCEL group and 10 (36 %) in the CypherTM group underwent quantitative coronary angiography at 6 months. For these patients, no restenosis occurred, and there were no differences in the in-stent stenosis of the luminal diameter (5.98±5.52% vs 5.21 ±6.3%,P＞0.05) and the LLL (-0.02±0.09 mm vs -0.01±0.07 mm, P＞0.05). Conclusions Compared with the CypherTM stent, the EXCEL Stent with biodegradable polymer and rapamycin-coating showed similar efficacy in the prevention of neointimal proliferation, restenosis, and associated clinical events in CAD patients.

Femtosecond laser-mediated anchoring of polymer layers on the surface of a biodegradable metal

Mg has received much attention as a next-generation implantable material owing to its biocompatibility,bone-like mechanical properties,and biodegradability in physiological environments.The application of various polymer coatings has been conducted in the past to reduce the rapid formation of hydrogen gas and the local change in pH during the initial phase of the chemical reaction with the body fluids.Here,we propose femtosecond(fs)laser-mediated Mg surface patterning for significant enhancement of the binding strength of the coating material,which eventually reduces the corrosion rate.Analyses of the structural,physical,crystallographic,and chemical properties of the Mg surface have been conducted in order to understand the mechanism by which the surface adhesion increases between Mg and the polymer coating layer.Depending on the fs laser conditions,the surface structure becomes rough owing to the presence of several microscaled pits and grooves of nanoporous MgO,resulting in a tightly bonded poly(lactic-co-glycolic acid)(PLGA)layer.The corrosion rate of the PLGA-coated,fs laser-treated Mg is considerably slow compared with the non-treated Mg;the treated Mg is also more biocompatible compared with the non-treated Mg.The fs laser-based surface modification technique offers a simple and quick method for introducing a rough coating on Mg;further,it does not require any chemical treatment,thereby overcoming a potential obstacle for its clinical use.

Composition Dependence of the Thermal Behavior,Morphology and Properties of Biodegradable PBS/PTMO Segment Block Copolymer

A series of aliphatic biodegradable poly（ether-ester）s based on poly（butylene succinate）（PBS）as hard segment and poly（tetramethylene oxide）（PTMO,M_n=1 000 g/mol） as soft segment were synthesized.The composition dependence of thermal behavior,morphology and mechanical properties was investigated by differential scanning calorimetry（DSC）,atomic force microscopy（AFM）,and tensile testing.The crystallization temperature（T_c） and melting temperature（T_m） of the PBS block within poly（ether-ester）s decrease steadily at first,but decrease sharply with PTMO content above 50 wt%.Two crystallization peaks were detected for PTMO in PBSPTMO60 sample,suggesting the occurrence of fractionated crystallization.The crystallization enthalpies（△H_c） and melting enthalpies（△H_m） of PBS block decrease at first,then increase as PTMO content increases further.AFM has demonstrated that phase-separated morphology transforms from a phase of continuous hard matrix to one of continuous soft matrix containing isolated hard domain as PTMO content is increased.Finally,the results of tensile testing show that the poly（ether-ester）s present the behavior of plastics when PTMO content is below 40 wt%,and of thermoplastic elastomers with PTMO content above 50 wt%.By varying the composition of copolymer,the aliphatic poly（ether-ester）s plastics,or especially biodegradable aliphatic poly（ether-ester）s thermoplastic elastomers can be obtained.

Safety and Performance of Sirolimus-Eluting Coronary Stent System with Biodegradable Polymer: A Retrospective Analysis in Real-World Patient Population

Background and Aim: Newer generation coronary stent systems with low profile metallic frame, biodegradable polymer coating and potent but safe anti-restenosis drug from “limus family” are emerging as safe and effective stents. To evaluate the safety and performance of Metafor SES (Meril life Sciences Pvt. Ltd., Vapi, India) in consecutive patients in a real-world population. Methods: The study was a retrospective, non-randomized, single-center study which evaluated the data of 127 patients who underwent percutaneous coronary intervention (PCI) treated with Metafor SES from February 2012 to February 2015 and mean follow-up period of those patients was 3.6 ± 0.6 years. The primary endpoint was a major adverse cardiac event (MACE) including cardiac death, myocardial infarction (MI), and target lesion revascularization (TLR). In addition, Stent thrombosis (ST) was analyzed at respective follow-up period. Results: A total of 127 patients (mean age: 53.70 ± 8.41 years and 99 males) were included. Among those 80 (63%) patients had hypertension and 58 (45.7%) patients with diabetes mellitus.At follow-up, MACE in form of TLR was observed in 2 (1.6%) patients only. No cardiac death or stent thrombosis was reported in any patient. A total of 169 lesions were treated with the Metafor SES (1.3 stents per lesion). The 38.4% of patients treated with the Metafor SES with lesion length ≥24 mm, and the procedural success was 100%. Conclusions: The lower incidence of MACE in uncontrolled and real world population at long term follow-up clearly depicts the prolonged safety and performance of the Metafor SES.

Highly Elastic,Bioresorbable Polymeric Materials for Stretchable,Transient Electronic Systems

Substrates or encapsulants in soft and stretchable formats are key components for transient,bioresorbable electronic systems;however,elastomeric polymers with desired mechanical and biochemical properties are very limited compared to nontransient counterparts.Here,we introduce a bioresorbable elastomer,poly(glycolide-co-ε-caprolactone)(PGCL),that contains excellent material properties including high elongation-at-break(<1300%),resilience and toughness,and tunable dissolution behaviors.Exploitation of PGCLs as polymer matrices,in combination with conducing polymers,yields stretchable,conductive composites for degradable interconnects,sensors,and actuators,which can reliably function under external strains.Integration of device components with wireless modules demonstrates elastic,transient electronic suture system with on-demand drug delivery for rapid recovery of postsurgical wounds in soft,time-dynamic tissues.

7-Oxa-2,3-Diazanorbornene:A One-Step Accessible Monomer for Living Ring-Opening Metathesis Polymerization to Produce Backbone-Biodegradable Polymers

Traditional ring-opening metathesis polymerization(ROMP)reactions exhibit broad functional group compatibility and precise control over polymer architectures,albeit with non-biodegradable backbones.Recent progress has resulted in a series of biodegradable ROMP products with diverse cleavable functional groups,yet the majority of the monomers display moderate to low ring strain,which restricts their living polymerization reactivity.In this study,a novel category of readily available 7-oxa-2,3-diazanorbornenes(ODAN)is presented,which exhibits the highest ring strain(22.8 kcal/mol)compared to existing degradable ROMP monomers.This trait endows ODAN with the ability to perform living polymerization reactions,generating narrowly dispersed homopolymers,block copolymers,and statistical copolymers with various cyclic olefin comonomers,thereby enabling precise control over distribution of the biodegradable functional groups.Additionally,the resultant polymers comprise directly connected allyl hemiaminal ether and urethane units,which are hydrolyzable at controllable rates.Thus,these well-defined,structure-tunable,and backbone-biodegradable ROMP polymers are applied as nanoetching materials and biodegradable delivery carriers.

Safety evaluation of the biodegradable polymer-based sirolimus-eluting stent with faster drug eluting rate and polymer absorption kinetics in complex patient and lesion subgroup

Background and Objective Previous reports from PANDA III trial had proven that BuMA biodegradable polymer(BP)sirolimus-elutingstents(SES),with faster drug eluting rate and polymer absorption kinetics,was non-inferior to the Excel SES in an all-comers population for 1-year target lesion failure(TLF),with a lower incidence of stent thrombosis(ST).The aim of the present study was to perform a safety evaluation of BuMA SES in the complex patient and lesion subgroup.

Clinical Performance of the Cobalt-Chromium Biodegradable Polymer Coated Sirolimus-Eluting Stent in an Unselected Real-World Population

OBJECTIVE: The primary objective of the S-CORE registry was to assess the safety and efficacy of the Supralimus-Core? sirolimus-eluting stent deployment for the treatment of coronary artery disease and event-free survival of patients treated with this coronary stent. METHODS: S-CORE Registry is an observational, single-arm, non-randomized, post-marketing surveillance multicenter registry in which 562 patients undergoing single or multi-vessel percutaneous coronary intervention were enrolled. The pre-specified primary outcome was the rate of major adverse cardiac events (MACE), defined as the composite of cardiac death, myocardial infarction (MI), target lesion revascularisation (TLR) and target vessel revascularisation (TVR) at 12-month post-procedure. Stent thrombosis (ST) served as the safety endpoint. RESULTS: A total of 640 lesions were treated in 562 enrolled patients (mean age 57.4 ± 10.7 years) with average stent length of 25.0 ± 9.0 mm. Stent delivery was successful in 99% cases. A total of 554 (98.6%) patients have been followed up to 12 months. The incidence of MACE at 30 days and 6 months was 7 (1.2%) and 12 (2.1%) respectively. The composite rate of MACE at a 12-month clinical follow-up was 19 (3.4%), consisting of 12 (2.1%) cardiac deaths, 0 (0%) MI, 6 (1.1%) TLR and 1 (0.2%) TVR. The long-term follow-up of this registry is going on to confirm safety and efficacy profiles. CONCLUSIONS: This multicenter registry demonstrated satisfactory safety and efficacy profiles, as evidenced by low rates of major adverse cardiac events up to 12 months, for the cobalt-chromium biodegradable polymer-based sirolimus-eluting Supralimus-Core? stent in a “real-world” setting.

Biodegradable polymer drug-eluting stents versus second-generation drug-eluting stents in patients with and without diabetes mellitus:a single center study

Objective It remains undetermined whether biodegradable polymer drug-eluting stents(BP-DES)are superior to second generation drugeluting stents(G2-DES)in patients with and without diabetes mellitus(DM).The study aims to evaluate the efficacy and safety of G2-DES and BP-DES in patients with and without DM in a high-volume cardiovascular center in China.

Safety and Efficacy of Ultra-Thin, Biodegradable Polymer Coated Sirolimus-Eluting Supralimus-Core Stents in Real-World Patients: Outcomes at 24-Month Follow-Up

Aim: The purpose of this registry was to establish long-term safety and efficacy through implantation of Supralimus-Core sirolimus-eluting stents (SES) in real-world patients with coronary artery disease (CAD). Methods:The present registry was a retrospective, singe-arm, single-centre, investigator-initiated registry. A total of 372 consecutive patients were implanted with Supralimus-Core SES between January 2015 and November 2016. The primary endpoints were major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction (MI), target lesion revascularization (TLR) and target vessel revascularization (TVR) at 24 months. The secondary endpoints were all-cause death and all separate components of the primary endpoint. Additional endpoints included events of stent thrombosis classified as definite, probable, and possible stent thrombosis. Follow-ups were conducted at 30-days, 6-months, 12-months and 24-months after the index procedure. Results: The mean age of the registry population was 56.3 ± 11.1 years. Males constituted 276 (74.2%) patients. Hypertensives, diabetics, alcoholics, tobacco chewers and smokers comprised 198 (53.2%), 160 (43.0%), 93 (25.0%), 91 (24.5%) and 88 (23.7%) of the registry population, respectively. The mean length and diameter of stents implanted was 19.3 ± 8.8 mm and 2.9 ± 0.3 mm, respectively. At the 24-month follow-up, MACE was reported in 14 (3.8%) patients. Cardiac death, MI, TLR and TVR was reported in 7 (1.9%), 4 (1.1%), 3 (0.8%) and 4 (1.1%) patients, respectively. Overall stent thrombosis occurred in 4 (1.1%) patients. Conclusions: The low MACE rate of 3.8% at the 24-month follow-up indicates favorable long-term results after implantation of the ultra-thin strut Supralimus-Core SES in all-comer, real-world patients.

A Novel Biodegradable Poly (Hydroxybutanedioic Acid-co-2-hydroxypropane-1,2,3-tricarboxylic Acid) Copolymer for Water Treatment Applications

Minimizing the formation of inorganic scale deposits in industrial water continues to be a challenge for water treatment systems. In order to meet this challenge a novel biodegradable poly (DL-malic acid-co-citric acid) copolymer, effective in providing calcium carbonate scale inhibition was developed. Synthesis and characterization of the biodegradable, water-soluble and polyester copolymer was performed. Synthesis was done by direct bulk melt condensation in the absence of a catalyst above 150°C. Characterization of the copolymer was carried out using infrared absorption spectra (FTIR), differential scanning calorimetry (DSC) and thermo gravimetric analysis (TGA) equipment. In the present work the precipitation of calcium carbonate from relative supersaturated solutions at different weight ratios of comonomer inhibition rates have been studied. The results indicate that the copolymer is an effective calcium carbonate descaling inhibitor that suppresses the growth process against calcium mineral scale deposits.

Preliminary Clinical Outcomes after Implantation of Newer-Generation Biodegradable Polymer-Coated Everolimus-Eluting Stent in “Real-World” Patients with Coronary Artery Disease

Background and Objective: In the contemporary practice, the use of drug-eluting stents is still associated with low mortality benefits, restenosis and stent thrombosis. To address these issues, newer generation, thin-strut, biodegradable polymer coated stents has been designed. Thus, the aim of the study is to assess the safety and clinical performance of the Everoflex (Sahajanand Medical Technologies Pvt. Ltd., Surat, India), a newer generation biodegradable polymer coated everolimus-eluting stent, in unselected “real-world” patients with coronary artery disease. Methods: It is a multicentre, retrospective, non-randomized, single-arm study enrolling all the consecutive patients who underwent implantation with the Everoflex for coronary artery disease from April 2014 to March 2016. The primary end-point of the study is 30-day major adverse cardiovascular events (MACE) rate, which consists of cardiac death, myocardial infarction, target lesion revascularization and target vessel revascularization. Stent thrombosis was also analyzed and reported. Results: A total of 340 patients were intervened successfully with 395 everolimus eluting stents (1.3 ± 0.6 stents per patient). Out of total patients (58.7 ± 10.5 years), 77.9% were male and comorbidities like diabetes and hypertension were observed in 31.2% and 35.3% patients, respectively. According to ACC/AHA classification, there were 34.4% type B lesions and 53.2% type C lesions, indicating a higher proportion of complexity involved. Moreover, 57.9% patients had multivessel disease and there were 15.4% total occlusions. At 30 days, follow-up was completed in 100% patients. The MACE was found to be 1.5%, which is a composite of 1.2% cardiac death and 0.3% target lesion revascularization. Stent thrombosis at 30 days was found to be 0.3%. Conclusion: The low incidence of MACE and stent thrombosis clearly depicts excellent safety and clinical performance of the Everoflex in unselected real world patients with coronary artery disease.

All-Comers Study of Percutaneous Coronary Interventions with Ultrathin Strut Biodegradable-Polymer Sirolimus-Eluting Stents—ORSHINE Registry

Current new generation stent technology has made remarkable progress in stent design, structure, and component material to improve its performance in reducing stent thrombosis, and restenosis compared to earlier DES and BMS. Orsiro-Sirolimus eluting stent is new generation ultra-thin strut stent with biodegradable abluminal coating that leaves a polymer free stent after drug release enhances coverage of stent struts and prevents excess neo intimal proliferation. A retrospective data analysis was done to see safety and efficacy of Orsiro in patients treated with ultra-thin DES with Orsiro stents at Sunshine Hospitals, Hyderabad. A total of 331 patients with 525 lesions were treated with 506 Orsiro stents and the major adverse cardiac events (MACE) rate and stent thrombosis (ST) at 2 years’ follow-up were analysed. MACE rate was 1.6% for an average follow-up at 2 years. Out of 2 patients who developed ST, one presented with definite acute stent thrombosis and one with possible, late stent thrombosis and 1.8% non-cardiac death reported during the follow-up. Despite many patients with complex PCI in the ACS subset, Orsiro reduced significant reduction in MACE rate in all spectrum of coronary artery disease patients with excellent acute and long-term results similar to other established FDA-approved current generations stents.

Local immunotherapy with interleukin - 2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma.

OBJECTIVE:Local delivery of carmustine(BCNU)from biodegradablepolymers prolongs survival against experi-mental brain tumors.Moreover,paracrine administration of interleukin-2(IL-2)has been shown to elicit apotent antitumor immune response and to improve survival in animal brain tumor models.We report the use of anovel polymeric microsphere delivery vehicle to release IL-2.We demonstrate both in vitro release of cytokinefrom the microspheres and histological evidence of the inflammatory response elicited by IL-2 released from themicrospheres in the rat brain.Thees microspheres are used to deliver IL-2,and biodegradable polymer wafers

2种BDPs固相反硝化的脱氮效果对比

利用批量和连续流填充床试验对比了2种BDPs(可生物降解聚合物)——PBS(聚丁二酸丁二醇酯)和PCL(聚ε-己内酯)的反硝化效果.批量试验结果表明,在脱氮稳定阶段,B1(PCL)和B2(PBS)对TN的平均去除率和反硝化速率分别为97.4%、67.0%和7.5、1.8 mg(L·h),B2均明显优于B1.连续流试验中,在进水ρ(NO3--N)为16.8～18.8 mgL、HRT(水力停留时间)为4.0 h的条件下,L1(PCL填充床)的反硝化速率大于L2(PBS填充床).但是随着HRT的减小,L1呈现出比L2更快的反硝化速率.L2和L1分别在HRT为2.0和1.5 h时获得最大反硝化速率,分别为7.7和9.3 mg(L·h).ESEM(环境扫描电子显微镜)观察结果表明,生物膜剥离后,PCL和PBS颗粒表面均出现大量的坑洞,并且PCL颗粒表面坑洞的密集程度远大于PBS.三维荧光光谱(3D-EEM)分析结果表明,L2和L1出水中的溶解性有机物主要为类色氨酸这类简单的蛋白质和SMP(溶解性微生物代谢产物),并且L1水中SMP的荧光峰强度明显高于L2.