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.

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.

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.

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

Stereoselective synthesis of biodegradable polymers by salen-type metal catalysts

Biodegradable polymers are a promising sustainable alternative to conventional petroleum-based polymers and have attracted recent extensive research interest due to their potential environmental friendliness and sustainability. Among them, aliphatic polyesters and polycarbonates are the most extensively studied ones. The metal-catalyzed ring-opening polymerization(ROP) of cyclic esters and ring-opening copolymerization(ROCOP) of epoxides with anhydrides or CO_(2) are often considered to be the classic and efficient methods to synthesize stereoregular polymers. Moreover, the versatile salen-type metal complexes have been used to prepare almost all types of biodegradable polymers with excellent stereoselectivity control. Hence, this review focuses on stereoselective synthesis of biodegradable polymers by salen-type metal catalysts developed in the last decade.Aliphatic polyesters from ROP of cyclic esters, ROCOP of epoxides with cyclic anhydrides, and carbonylative polymerization of epoxides, as well as aliphatic poly(thio)carbonate from ROCOP of epoxides with CO_(2) or COS are discussed in detail. This review highlights the polymerization mechanisms, catalyst characteristics, and factors controlling the stereoselectivity of each polymerization reaction, aiming to provide general rules for the future design of stereoselective catalysts.

Biodegradable polymeric nanoparticles based on amphiphilic principle:construction and application in drug delivery

The use of nanotechnology in drug-delivery systems(DDS) is attractive for advanced diagnosis and treatment of cancer diseases. Biodegradable polymeric nanoparticles, for example, have promising applications as advanced drug carriers in cancer treatment. In this review, we discuss the development of drug-delivery systems based on an amphiphilic principle mainly conducted by our group for anti-cancer drug delivery. We first briefly address the synthetic chemistry for amphiphilic biodegradable polymers. In the second part, we summarize progress in the application of self-assembled polymer micelles using amphiphilic biodegradable copolymers as anti-tumor drug carriers.

In vivo inducing collagen regeneration of biodegradable polymer microspheres

Biodegradable polymer particles have been used as dermal fillers for pre-clinical and clinical trials.The impact of material properties of polymers is very important to develop products for aesthetic medicine such as dermal fillers.Herein,eight biodegradable polymers with different molecular weights,chemical compositions or hydrophilic-hydrophobic properties were prepared and characterized for systematical study for aesthetic medicine applications.Polymer microspheres with 20-100 lmwere prepared.The in vitro degradation study showed that poly(L-lactic-co-glycolic acid)75/25 microspheres degraded the fastest,whereas poly(L-lactic acid)(PLLA)microspheres with intrinsic viscosity of 6.89([g]¼6.89)with the highest molecular weight showed the slowest degradation rate.After these microspheres were fabricated dermal fillers according to the formula of SculptraVR,they were injected subcutaneously into the back skin of rabbits.In vivo results demonstrated that the degradation rate of microspheres strongly correlated with the foreign body reaction and collagen regeneration was induced by microspheres.The microspheres with faster degradation rate induced inflammatory response and the collagen regeneration maintained in shorter time.PLLA([g]¼3.80)microsphere with a moderate molecular weight and degradation rate could strongly regenerate Type I and III collagen to maintain a long-term aesthetic medicine effect.These properties of size,morphology and degradation behavior would influence the foreign body reaction and collagen regeneration.

Current research on electrospinning of silk fibroin and its blends with natural and synthetic biodegradable polymers

Silk fibroin （SF） is a kind of natural polymers with a great potential in biomedical application. Due to its good biocompatibility, biodegradability and minimal inflammatory reaction, SF is an excellent candidate for generating tissue engineering scaffolds. Electrospinning is a simple and effective method to fabricate nanofibers, which has several amazing characteristics such as very large surface area to volume ratio, flexibility in surface functionalities, and superior mechanical performance. The electro- spun nanofibers from SF and its blends have been used for varied tissue engineering. This paper will give a brief review about the structure, properties and applications of SF and blend nanofibers via electrospinning.

Novel completed biodegradable polymer sirolimus-eluting stent versus durable polymer sirolimus-eluting stent in de novo lesions： nine-month angiographic and three-year clinical outcomes of HOPE trial

Background Drug-eluting stents（DES） with durable polymer have significantly reduced restenosis and target vessel revascularization compared with bare metal stents. Durable polymer has been linked with persistent inflammation of vessel wall and delayed endothelial healing that may increase the risk of late and very late stent thrombosis. This study sought to evaluate the efficacy and safety of HELLOS completed biodegradable polymer sirolimus-eluting stent （SES） in de novo coronary lesions.Methods Totally, 287 patients with one or two de novo coronary lesions （lesion length ≤38 mm and reference vessel diameter 2.5-4.0 mm） were enrolled in the HOPE study, a prospective, multicenter, randomized, non-inferiority trial. Patients were randomized to treatment either with HELIOS completed biodegradable polymer SES （n=142） or PARTNER durable polymer SES （n=145）. The primary endpoint was angiographic in-stent late lumen loss （LLL） at 9-month follow-up. The secondary endpoint included stent thrombosis and major adverse cardiac events including cardiac death, myocardial infarction （MI） and target lesion revascularization （TLR）.Results The 9-month in-stent LLL in the HELIOS group was similar to the PARTNER group, （0.16±0.22） mm vs. （0.19±0.30） mm （P=0.28）. The difference and 95% confidence interval were -0.03 （-0.09, 0.04）, and the P value for non-inferiority 〈0.01. Major adverse cardiovascular event （MACE） occurred in 7.9% vs. 8.2%, MI in 2.4% vs. 3.0%, TLR in 5.5% vs. 3.0%, and stent thrombosis in 0 vs. 1.5%; and events were comparable between the HELIOS group and PARTNER aroup at three-year follow-up （all P 〉0.05）. The three-year cardiac death was lower in the HELIOS group, butwith no significant difference, 0 vs. 3.0% （P=0.12）. Conclusions In the HOPE trial, the novel completed biodegradable polymer SES HELIOS was non-inferior to the durable polymer SES PARTNER with respect to nine-month in-stent LLL in de novo coronary lesions. The incidence of other clinical endpoints was low for both of the stents in three-year follow-up.

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.

3D Printing of Biodegradable Polymer Vascular Stents:A Review

Biodegradable polymer vascular stents(BPVSs)have been widely used in percutaneous coronary interventions for the treatment of coronary artery diseases.The development of BPVSs is an integrated process that combines material design/selection,manufacturing,and performance characterization.Three-dimensional(3D)printing technology is a powerful tool for polymer stent fabrication.Current review studies have focused primarily on the material and structural design of polymer stents but have failed to comprehensively discuss different 3D printing approaches and stent characterization techniques.In this paper,we address these shortcomings by discussing 3D printing methods and their application in BPVSs.First,some commonly used 3D printing methods(including material extrusion,vat polymerization,and powder bed fusion)and potential 3D printing strategies(including material jetting and binder jetting)for fabricating BPVSs are discussed;furthermore,the main post-treatments are summarized.Then,techniques to characterize the morphology,mechanical properties,and biological prop-erties of the printed BPVSs are introduced.Subsequently,representative commercial BPVSs and lab-grade BPVSs are compared.Finally,based on the limitations of stent printing and characterization processes,future perspec-tives are proposed,which may help develop new techniques to fabricate more customized stents and accurately evaluate their performance.

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）.

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.

Special Topic on Bio-based and Biodegradable Polymers

In the past decades,bio-based and biodegradable polymers have attracted wide and increasing interests because of the shortage of fossil resource,concerns on environmental pollution,demands for some medical fields as well as support of government policies.Depending on the sustainable source of organic carbon,biodegradability and biocompatibility,these polymers have shown promising applications in industry,agriculture,biomedicine and daily life.To impart excellent physical properties and functions to them,scientists and engineers have exploited versatile methods to tune

RING OPENING COPOLYMERIZATION OF SUCCINIC ANHYDRIDE-ETHYLENE OXIDE BY Al(Ⅲ) ORGANOMETALLIC CATALYSTS

Ring opening copolymerization of succinic anhydride (SA) with ethylene oxide (EO)was successfully carried out by using a series of aluminum-based catalyst in 1,4-dioxane at62±2℃. The results showed that in-situ AlR_3-H_2O (R=ethyl, iso-butyl) catalysts gavehigher molecular weight (M_w～10~4), while Al(OR)_3 catalysts gave the higher alternatingcopolymer structure with slightly lower molecular weight. The in-situ AlR_3-H_2O systemshave been evaluated in more detail for the reaction which showed the optimum H_2O/Almolar ratio to be 0.5. The copolymers with different composition (F_(SA)/F_(EO)= 36/64to 45/55 mol/mol) were synthesized by using different monomer feed ratio. The melt-ing point (T_m), glass transition temperature (T_g) and enthalpy of fusion (ΔH_f) of thesecopolymers are depended on the copolymer composition and in the range of 87～102℃,-12～-18℃, and 37～66J/g, respectively. The second heating scan of DSC also in-dicated that the higher alternating copolymer was more easily recrystallized. The onsetdecomposition temperature was more than 300℃ under nitrogen and influenced by thecopolymer composition.

Vessel healings after stenting with different polymers in STEMI patients

Background Different stems implantation in ST-segmem elevation myocardial infarction （STEMI） patients may influence the long term prognosis by affecting vessel healings after stenting. The aim of this study was to evaluate the vessel healings after implantation of drug elming stems （DES） with biodegradable or durable polymer or of bare-metal stems （BMS） in patients with ache STEMI. Methods This study included 50 patients, who underwem follow up angiogram and optical coherence tomography （OCT） assessment about one year after percutaneous coronary intervemion （PCI） for STEMI. According to the initial stems types, these patients were classified to durable （n = 19） or biodegradable polymer sirolimus-eluting stems （n = 15）, or BMS （n = 16） groups. The conditions of stem struts coverage and malapposi- tion were analyzed with OCT technique. Results A total of 9003 struts were analyzed： 3299, 3202 and 2502 from durable or biodegradable polymer DES, or BMS, respectively. Strut coverage rate （89.0%, 94.9% and 99.3%, respectively）, malapposition presence （1.7%, 0.03% and 0 of struts, respectively） and average intimal thickness over struts （76 ± 12 μm, 161 ± 30 μm and 292 ± 29 μm, respectively） were significantly differem among different stent groups （all P 〈 0.001）. Conclusions Vessel healing status in STEMI patients is superior after implantation of biodegradable polymer DES than durable polymer DES, while both are inferior to BMS.

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.

Syntheses and Drug Delivery Property of Biodegradable Polyether-Anhydrides

Both polyanhydrides and polyethers are new types of biodegradble polymers, They are of particular interest as materials for controlled drug release system duo to their excellent surface erosion properties of polyanhydrides and excellent biocompatibility of polyethers. They hate been widly used in biomaterials. A series of polyether anhydrides elastomer were firstly synthesed through introducing PEG into the polyanhydrides chains. Their degradation and drug release property were also studied. These materials may be used in applications where materials are needed with properties more close to those of natural skin.

Study on the Properties of Esterified Corn Starch/Polylactide Biodegradable Blends

Fully bio-based and biodegradable starch/polylactic acid blends have received increasing attentions for their biodegradability and potential to offset the use of unsustainable fossil resources,specifically,their application in packaging.Herein,corn starch was first esterified with maleic anhydride and then compounded with polylactide(PLA)to prepare esterified corn starch/polylactic acid blends with starch content up to 35 wt%.The structures,morphologies,thermal and mechanical properties of starch or blends were investigated.The results showed that corn starch was successfully grafted with maleic anhydride,which showed increased crystallinity and particle size than native starch.Esterified corn starch/polylactic acid blends showed good surficial compatibility and good thermal stability with main decomposition temperature in the range of 300℃to 400℃.Additionally,incorporation of corn starch increased the hydrophilicity and water uptake of composites.However,the tensile and flexural strengths of blends decreased with increasing esterified starch amount.

SYNTHESIS OF POLY(ETHYLENE TEREPHTHALATE)-POLYCAPROLACTONE BLOCK COPOLYMER BY DIRECT COPOLYMERIZATION

Po ly(ethylene terephthalate)-polycaprolactone block copolymer (PCL-b-PET) is a polyester with improved biodegradability. In the present paper, a new direct copolymerization method of epsilon-caprolactone (epsilon-CL) and bishydroxyethylene terephthalate (BHET) in the presence of Ti(OBu)(4) was proposed for the synthesis of PCL-b-PET. The PCL-b-PET copolymer was characterized by IR, GPC and H-1-NMR techniques, and the effects of synthesis conditions, such as temperature, reaction time and concentration of catalyst on the copolymerization were discussed.