Expanding Cyclic Topology-Based Biomedical Polymer Panel: Universal Synthesis of Hetero-"8"-Shaped Copolymers and Topological Modulation of Polymer Degradation.

8-Shaped copolymers with two macrocycles connected together represent an interesting cyclic topology-derived polymer species due to the simultaneous incorporation of two cyclic moieties and the reported unique physical and chemical properties. To provide a proof-of-concept for a broad readership on biomedical polymers, a well-defined hetero-8-shaped amphiphilic copolymer, cyclic-poly(oligo(ethylene glycol)monomethyl ether methacrylate)-b-cyclic PCL (cPOEGMA-b-cPCL) is synthesized by an elegant integration of intrachain click cyclization and interchain click coupling. The potential of the self-assembled micelles of cPOEGMA-b-cPCL for controlled drug release is evaluated by in vitro drug loading and drug release, cellular uptake, cytotoxicity, and degradation studies. Most importantly, the micelles based on cPOEGMA-b-cPCL show much slower degradation profiles than the previously reported linear counterpart, POEGMA-b-PCL and tadpole-shaped analog, PEG-b-cPCL because of the presence of cyclic hydrophilic POEGMA segment. Therefore, this study not only develops a robust strategy for a universal precise synthesis of well-defined hetero-8-shaped copolymers based on diverse vinyl and ring-structured monomers, but also reveals the first modulation of polymer degradation property by topological control of the nondegradable moiety in the polymer construct through advanced macromolecular engineering.

Continuous hemodiafiltration as a rescue therapy for patients with cardiopulmonary failure caused by enterovirus-71: a retrospective observational study in a PICU.

BACKGROUND: Hand, foot and mouth disease (HFMD) remains a burdensome health issue in mainland China. Enterovirus71 (EV-A71) is the main pathogen of severe HFMD. Continuous hemofiltration improves fluid overload, restores kidney function and alleviates inflammatory reactions. The aim of the present study was to evaluate the effects of continuous veno-venous hemodiafiltration (CVVHDF) on severe HFMD caused by EV-A71(EV-A71-HFMD) in a pediatric intensive care unit (PICU). METHODS: A retrospective observational study was performed in a tertiary university PICU from January 2012 to December 2016. Children with severe EV-A71-HFMD complicated by cardiopulmonary failure were included. The patients were divided into a CVVHDF group and a conventional therapy (control) group (non-CVVHDF). The demographics, characteristics, and outcomes between the groups were collected and analyzed. RESULTS: Twenty-nine patients with severe EV-A71-HFMD were enrolled. The 28-day mortality was 17.6% (3/17) in the CVVHDF group and 33.3% (4/12) in the non-CVVHDF group, with no statistical significance between the two groups (P = 0.403). The median interval between CVVHDF initiation and PICU admission was 6 (4,8.5) hrs, and the median duration of CVVHDF was 48 (36, 64) hrs. The left ventricular ejection fraction (LVEF) and cardiac index (CI) in the CVVHDF group were improved after treatment. The plasma levels of catecholamines and renin-angiotensin-aldosterone system (RAAS) substances in the CVVHDF group were significantly decreased after treatment. The decreased catecholamines and RAAS substances included adrenalin (169.8 [145.5, 244.6] vs. 148.0 [109.0, 208.1] ng/L, P = 0.033), dopamine (152.7 [97.0, 191.1] vs. 96.0 [68.0, 160.9] ng/L, P = 0.026), angiotensin II (185.9 [125.2, 800.0] vs. 106.0 [90.8, 232.5] ng/L, P = 0.047), aldosterone (165.7 [94.0, 353.3] vs. 103.3 [84.3, 144.3] ng/L, P = 0.033), and renin (1.12 [0.74, 3.45] vs. 0.79 [0.52, 1.25] µg/L/h, P = 0.029), CONCLUSIONS: CVVHDF reduced the levels of catecholamines and RAAS substances and improved cardiovascular function. Continuous hemodiafiltration may represent a potential therapy in patients with severe EV-A71-HFMD complicated with cardiopulmonary failure.

Liposome-based nanomedicine for immune checkpoint blocking therapy and combinatory cancer therapy.

The discovery of immune checkpoint (IC) has led to a wave of leap forward in cancer immunotherapy that represents probably the most promising strategy for cancer therapy. However, the clinical use of immune checkpoint block (ICB) therapy is limited by response rates and side effects. A strategy that addresses the limitations of ICB therapies through combination therapies, using nanocarriers as mediators, has been mentioned in numerous research papers. Liposomes have been probably one of the most extensively used nanocarriers for clinical applications, with broad drug delivery and high safety. A timely review on this hot subject of research, i.e., the application of liposomes for ICB, is thus highly desirable for both fundamental and clinical translatable studies, but remains, to our knowledge, unexplored so far. For this purpose, this review is composed to address the dilemma of ICB therapy and the reasons for this dilemma. We later describe how other cancer treatments have broken this dilemma. Finally, we focus on the role of liposomes in various combinatory cancer therapy. This review is believed to serve as a guidance for the rational design and development of liposome for immunotherapy with enhanced therapeutic efficiency.

Enhancing myocardial infarction treatment through bionic hydrogel-mediated spatial combination therapy via mtDNA-STING crosstalk modulation.

Myocardial infarction (MI)-induced impaired cardiomyocyte (CM) mitochondrial function and microenvironmental inflammatory cascades severely accelerate the progression of heart failure for compromised myocardial repair. Modulation of the crosstalk between CM mitochondrial DNA (mtDNA) and STING has been recently identified as a robust strategy in enhancing MI treatment, but remains seldom explored. To develop a novel approach that can address persistent myocardial injury using this crosstalk, we report herein construction of a biomimetic hydrogel system, Rb1/PDA-hydrogel comprised of ginsenoside Rb1/polydopamine nanoparticles (Rb1/PDA NPs)-loaded carboxylated chitosan, 4-arm-PEG-phenylboronic acid (4-arm-PEG-PBA), and 4-arm-PEG-dopamine (4-arm-PEG-DA) crosslinked networks. An optimized hydrogel formulation presents not only desired adhesion properties to the surface of the myocardium, but also adaptability for deep myocardial injection, resulting in ROS scavenging, CM mitochondrial function protection, M1 macrophage polarization inhibition through the STING pathway, and angiogenesis promotion via an internal-external spatial combination. The enhanced therapeutic efficiency is supported by the histological analysis of the infarcted area, which shows that the fibrotic area of the MI rats decreases from 58.4% to 5.5%, the thickness of the left ventricular wall increases by 1-fold, and almost complete recovery of cardiac function after 28 days of treatment. Overall, this study reported the first use of a strong adhesive and injectable hydrogel with mtDNA and STING signaling characteristics for enhanced MI treatment via an internal-external spatial combination strategy.

Dual functionalization of poly(ε-caprolactone) film surface through supramolecular assembly with the aim of promoting in situ endothelial progenitor cell attachment on vascular grafts.

In this study, we developed a method for the dual functionalization of a poly(ε-caprolactone) (PCL) surface by means of the supramolecular assembly technology. Polyethylene glycol (PEG), with resistance to protein adsorption, and TPSLEQRTVYAK (TPS) peptide, which can specifically bind endothelial progenitor cells (EPCs), were immobilized on the PCL surface through host-guest inclusion complexation. The chemical composition as well as the hydrophilic/hydrophobic property of the functionalized surface was characterized by X-ray photoelectron spectroscopy and water contact angle measurements. The relative composition of two functional molecules on the dually functionalized surface was further analyzed by fluorescence quantification. Finally, the fibrinogen adsorption, platelet adhesion and activation, and selective attachment of cells were systematically evaluated on the functionalized surface. The results show that the presence of PEG evidently inhibited the adsorption of plasma protein and platelet adhesion, thus reducing the possibility of thrombus formation on the functionalized surface. At the same time, the TPS-functionalized surface demonstrated enhanced attachment toward EPC compared with the surfaces in the absence of TPS functionalization. For the surface functionalized by both PEG and TPS, the functions provided by each component have been well demonstrated. The relative composition of the PEG and TPS could be further fine-tuned by adjusting the feeding ratio. All these results indicate that the dually functionalized surface developed in this study is a suitable candidate for vascular graft to induce and promote in situ endothelialization.

[Adsorption and isolation of macroporous resin for three isoflavonoids from puerariae lobatae radix].

OBJECTIVE: To study the adsorption function of macroporous resins for the separation and purification of three isoflavonoids (3'-hydroxypuerarin, puerarin, daidzin) in Puerariae Lobatae Radix. METHODS: The contents of 3'-hydroxypuerarin, puerarin, daidzin were determined by HPLC. D101, AB-8, XDA-5, HP-20 and other five resins were systematically investigated for their adsorption capability, adsorption isothermal curve, adsorption and elution properties with static and dynamic experiments. RESULTS: Experimental results showed that macroporous resin XDA-5 owned optimum adsorption and elution parameters. Optimal conditions for adsorption and elution the three components were: per 1 mL solution contained Puerariae Lobatae Radix 0.5 - 0.8 g, flow rate 2BV/h, adsorbed 3'-hydroxypuerarin, puerarin and daidzin could be desorbed by alcohol at flow rate 1BV/h. CONCLUSION: The purity of 3'-hydroxypuerarin, puerarin and daidzin of the product obtained from Puerariae Lobatae Radix with optimum technology is 23.39%, 52.09% and 19.21%, respectively.

Engineered cyclodextrin-based supramolecular hydrogels for biomedical applications.

Cyclodextrin (CD)-based supramolecular hydrogels are polymer network systems with the ability to rapidly form reversible three-dimensional porous structures through multiple cross-linking methods, offering potential applications in drug delivery. Although CD-based supramolecular hydrogels have been increasingly used in a wide range of applications in recent years, a comprehensive description of their structure, mechanical property modulation, drug loading, delivery, and applications in biomedical fields from a cross-linking perspective is lacking. To provide a comprehensive overview of CD-based supramolecular hydrogels, this review systematically describes their design, regulation of mechanical properties, modes of drug loading and release, and their roles in various biomedical fields, particularly oncology, wound dressing, bone repair, and myocardial tissue engineering. Additionally, this review provides a rational discussion on the current challenges and prospects of CD-based supramolecular hydrogels, which can provide ideas for the rapid development of CD-based hydrogels and foster their translation from the laboratory to clinical medicine.

Hyaluronic acid-based injectable nanocomposite hydrogels with photo-thermal antibacterial properties for infected chronic diabetic wound healing.

A hydrogel wound dressing with a single functionality fails to meet the requirements for successful clinical treatment of chronic diabetic wounds that generally possess complicated microenvironments. A multifunctional hydrogel is thus highly desirable for improved clinical treatment. For this purpose, we reported herein construction of an injectable nanocomposite hydrogel with self-healing and photo-thermal properties as an antibacterial adhesive via dynamic Michael addition reaction and electrostatic interactions among three building moieties, i.e., catechol and thiol-modified hyaluronic acid (HA-CA and HA-SH), poly(hexamethylene guanidine) (PHMG), and black phosphorus nanosheets (BPs). An optimized hydrogel formulation eliminated over 99.99 % of bacteria (E. coli and S. aureus) and exhibited a free radical scavenging capability >70 % as well as photo-thermal properties in addition to viscoelastic characteristics, degradation properties in vitro, good adhesion and self-adaptation capacity. Wound healing experiments in vivo further confirmed the better performance of the developed hydrogels than that of a commercially available dressing (Tegaderm™) in promoting the healing of infected chronic wounds by preventing wound infection, decreasing inflammation, supporting collagen deposition, facilitating angiogenesis, and improving granulation tissues formation in the wound sites. Overall, the HA-based injectable composite hydrogels developed herein represent promising multifunctional wound dressings for infected diabetic wound repair.

UV Irradiation-Induced Cyclic-to-Linear Topological Changes of a Light/pH Dual-Sensitive Cyclic Copolymer for Enhanced Drug Delivery.

Cyclic polymers with cleavable backbones triggered by either external or internal stimuli can realize simultaneous extracellular stability and intracellular destabilization of cyclic polymer-based nanocarriers but remain seldom reported. To this end, we prepared herein cyclic-ONB-P(OEGMA-st-DMAEMA) (c-ONB-P(OEGMA-st-DMAEMA)) with a light-cleavable junction in the polymer backbone based on oligo (ethylene glycol) monomethyl ether methacrylate (OEGMA) and N,N-dimethylaminoethyl methacrylate (DMAEMA) using a light-cleavable atom transfer radical polymerization (ATRP) initiator containing an o-nitrobenzyl (ONB) ester group. Together with the pH-sensitivity of DMAEMA, c-ONB-P(OEGMA-st-DMAEMA) shows a light-cleavable mainchain and pH-sensitive side chains. Notably, doxorubicin (DOX)-loaded c-ONB-P(OEGMA4-st-DMAEMA38) (C2) micelles mediated an IC50 value of 2.28 µg/mL in Bel-7402 cells, which is 1.7-fold lower than that acquired without UV irradiation. This study thus reported the synthesis of a cyclic copolymer with a UV-cleavable backbone and uncovered the effects of topological modulation on the in vitro controlled release properties of cyclic polymers.

Pd(II)-based coordination polymer nanosheets for ratiometric colorimetric and photothermal dual-mode assay of serum alkaline phosphatase.

Fabrication of a multi-signal readout assay with high sensitivity and selectivity is highly desirable for clinical and biochemical analysis, but remains a challenge due to laborious procedures, large-scale instruments, and inadequate accuracy. Herein, a straightforward, rapid, and portable detection platform based on palladium(II) methylene blue (MB) coordination polymer nanosheets (PdMBCP NSs) was unveiled for the ratiometric dual-mode detection of alkaline phosphatase (ALP) with temperature and colorimetric signal readout properties. The sensing mechanism is the ALP-catalyzed generation of ascorbic acid for competitive binding and etching PdMBCP NSs to release free MB in a quantitive means for detection. Specifically, ALP addition led to the decrease of temperature signal readout from the decomposed PdMBCP NSs under 808 nm laser excitation, and simultaneous increase of the temperature from the generated MB with a 660 nm laser, together with the corresponding absorbance changes at both wavelengths. Notably, this ratiometric nanosensor exhibited a detection limit of 0.013 U/L (colorimetric) and 0.095 U/L (photothermal) within 10 min, respectively. The reliability and satisfactory sensing performance of the developed method were further confirmed by clinic serum samples. Therefore, this study provides a new insight for the development of dual-signal sensing platforms for convenient, universal, and accurate detection of ALP.

Synthesis of enzyme-responsive theranostic amphiphilic conjugated bottlebrush copolymers for enhanced anticancer drug delivery.

Synthesis of polyfluorene (PF) based theranostic amphiphilic copolymers with simultaneously high drug loading efficiency and tumor microenvironment-specific responsiveness for promoted intracellular drug release and enhanced cancer therapy has been rarely reported likely due to the lack of efficient synthetic approaches to integrate these desirable properties. In this work, we recorded the successful preparation of well-defined theranostic amphiliphilic bottlebrush copolymers composing of fluorescent backbone of PF and tunable enzyme-degradable side chains of polytyrosine (PTyr) and POEGMA by integrating Suzuki coupling, NCA ROP and ATRP techniques. Notably, the resulting copolymer, PF25-g-(PTyr26-b-(POEGMA28)2 (P4) with two branched POEGMA brushes tethered to one PTyr termini for each unit could form steady unimolecular micelles with higher fluorescence quantum yield of 18.3% in aqueous and greater entrapment efficiency (EE) of 91.0% for DOX ascribed to the efficient π-π stacking interactions between PTyr blocks and drug molecules and the unique structure of branched hydrophilic brushes with a moderate chain length. DOX@P4 micelles revealed visualization of intracellular trafficking and accelerated drug release due to the enzyme-triggered degradation of PTyr blocks with proteinase K and subsequent deshielding of POEGMA corona for micelle destruction. In vitro and In vivo animal study further verified the intensive therapeutic efficiency with attenuated systematic toxicity. Taken together, we provided a universal strategy toward multifunctional polymeric delivery vehicles based on conjugated PF and biocompatible and degradable polypeptide by integratied Suzuki coupling and NCA ROP, and identified the branched structure of hydrophilic brushes for better performance of bottlebrush copolymers-based micelles for drug delivery applications. STATEMENT OF SIGNIFICANCE: Synthesis of polyfluorene (PF)-based theranostic amphiphilic copolymers with simultaneously high drug loading efficiency and tumor microenvironment-specific responsiveness for promoted intracellular drug release and enhanced cancer therapy has been rarely reported likely due to the lack of efficient synthetic approaches to integrate these desirable properties. We reported herein successful preparation of enzyme-responsive theranostic amphiliphilic bottlebrush copolymers with simultaneously high drug loading efficiency and tumor microenvironment-specific responsiveness for enhanced chemotherapy in vivo. This study therefore not only developed a universal strategy for the construction of multifunction polymeric vehicles based on the conjugated polymer of PF and degradable polypeptide by integrated Suzuki coupling and NCA ROP, but also emphasized the better stability of micelles endowed by the branched hydrophilic brushes than linear ones.

A ROS-Responsive Liposomal Composite Hydrogel Integrating Improved Mitochondrial Function and Pro-Angiogenesis for Efficient Treatment of Myocardial Infarction.

Mitochondrial dysfunction of cardiomyocytes (CMs) has been identified as a significant pathogenesis of early myocardial infarction (MI). However, only a few agents or strategies have been developed to improve mitochondrial dysfunction for the effective MI treatment. Herein, a reactive oxygen species (ROS)-responsive PAMB-G-TK/4-arm-PEG-SG hydrogel is developed for localized drug-loaded liposome delivery. Notably, the liposomes contain both elamipretide (SS-31) and sphingosine-1-phosphate (S1P), where SS-31 acts as an inhibitor of mitochondrial oxidative damage and S1P as a signaling molecule for activating angiogenesis. Liposome-encapsulated PAMB-G-TK/4-arm-PEG-SG hydrogels demonstrate myocardium-like mechanical strength and electrical conductivity, and ROS-sensitive release of SS-31 and S1P-loaded liposomes. Further liposomal release of SS-31, which can target cytochrome c in the mitochondrial inner membrane of damaged CMs, inhibits pathological ROS production, improving mitochondrial dysfunction. Meanwhile, S1P released from the liposome induces endothelial cell angiogenesis by activating the S1PR1/PI3K/Akt pathway. In a rat MI model, the resulting liposomal composite hydrogel improves cardiac function by scavenging excess ROS, improving mitochondrial dysfunction, and promoting angiogenesis. This study reports for the first time a liposomal composite hydrogel that can directly target mitochondria of damaged CMs for a feedback-regulated release of encapsulated liposomes to consume the overproduced pathological ROS for improved CM activity and enhanced MI treatment.

Optimized aptamer functionalization for enhanced anticancer efficiency in vivo.

Nucleic acid aptamers (Apt) are RNA or DNA fragments that can bind specifically to a target molecule or to a target substrate with great affinity, thus has attracted great attention for diagnosis and treatment of various malignant diseases. Two primary strategies reported for efficient incorporation of Apt into a nanocarrier include physical encapsulation via electrostatic interactions and chemical conjugation via covalent bonds. Generally, physical encapsulation offers an easier approach for Apt functionalization than covalent bonding that involves sophisticated chemical design as well as synthesis and purification procedures. However, the effect of Apt's incorporation strategies on the property and performance of Apt-functionalized nanocarriers, to our knowledge, remains unclear, which clearly hampers the biomedical applications and potential clinical translations of Apt-decorated delivery systems. To clarify this critical issue toward better performance of Apt for biomedical applications, an Apt moiety with a specific targeting property to liver cancer cells was introduced to a previously fabricated polymeric prodrug, chitosan-5-fluorouracil-1-acetic acid (CS-FU) via either an amide link or electrostatic interactions to afford two types of Apt-functionalized polymeric prodrugs, i.e., Apt/CS-FU and Apt-CS-FU with an equivalent amount of incorporated Apt, respectively. The in vivo and in vitro anti-tumor efficacy and targeting properties of these two Apt-functionalized polymeric prodrugs were investigated and further compared in detail. Interestingly, the two self-assembled micelles showed almost identical in vitro targeting and antitumor efficiency, but Apt-CS-FU mediated 1.5-fold greater tumor inhibition rate (TIR) than Apt/CS-FU in murine tumor models. The better performance of Apt-CS-FU than that of Apt/CS-FU was substantially attributed to the smaller size of Apt-CS-FU than that of Apt/CS-FU in the presence of serum for prolonged in vivo circulation. The first disclosed Apt incorporation strategy effects on the performance and property of Apt-decorated nanocarriers is believed to promote rational design and future clinical translations of Apt-functionalized nanoplatforms with greater therapeutic efficiency.

Multicyclic topology-enhanced anticancer drug delivery.

Inspired by the biological use of a combination of precision and self-assembly to achieve exquisite control and diversity from 20 natural amino acids, there is considerable scope for the development of synthetic precision materials with complex architecture that can access advanced function for biomedical applications. Single cyclic polymers (SCPs) have been shown to offer different and often better performance compared to their linear analogues. Because multicyclic topology in nature offers enhanced effects relative to single cyclization, we hypothesize that multicyclic polymers (MCPs) would access unique features compared to SCPs. However, there are currently quite limited ways to efficiently synthesize MCPs and to precisely modulate the valency of cyclic units. In this work, we report for the first time a straightforward and robust strategy to synthesize MCPs with controllable valency via facile one-pot statistical reversible addition-fragmentation chain transfer (RAFT) copolymerization. We use this strategy to synthesize biocompatible MCPs based on the most classic and important biocompatible polymers of oligo (ethylene glycol) (OEG) and cyclic poly(ε-caprolactone) (cPCL), which can further self-assemble into well-defined nanostructures. We then apply these MCP-based formulations as drug delivery vehicles and demonstrate greater colloidal stability with a low critical micelle concentration (CMC) of 80.3 nM, larger drug loading capacity, higher cellular uptake efficiency, more tumor accumulation, and increased anti-tumor efficacy in murine tumor models compared to SCP-based analogues. We believe this cumulative work demonstrating facile synthesis of MCPs and demonstration of multicyclic topology-enhanced anti-cancer efficiency in vivo provides key technologies and concepts to the burgeoning field of cyclic topology-derived biomaterials.

Review of lipoic acid: From a clinical therapeutic agent to various emerging biomaterials.

Lipoic acid (LA), an endogenous small molecule in organisms, has been extensively used for the highly efficient clinical treatment of malignant diseases, which include diabetes, Alzheimer's disease, and cancer over the past seven decades. Tremendous progresses have been made on the use of LA in nanomedicine for the development of various biomaterials because of its unique biological properties and highly adaptable structure since the first discovery. However, there are few reviews thus far, to our knowledge, summarizing this hot subject of research of LA and its derived biomaterials. For this purpose, we present herein the first comprehensive summary on the design and development of LA and its derived materials for biomedical applications. This review first discusses the therapeutic use of LA followed by the description of synthesis and preclinical study of LA-derived-small molecules. The applications of various LA and poly (lipoic acid) (PLA)-derived-biomaterials are next summarized in detail with an emphasis on the use of LA for the design of biomaterials and the diverse properties. This review describes the development of LA from a clinical therapeutic agent to a building unit of various biomaterials field, which will promote the further discovery of new therapeutic uses of LA as therapeutic agents and facile development of LA-based derivates with greater performance for biomedical applications.

[Cockayne syndrome].

Cockayne syndrome is a rare autosomal recessive disease. This paper reports a case of Cockayne syndrome confirmed by gene analysis. The baby (male, 7 years old) was referred to Peking University Third Hospital with recurrent desquamation, pigmentation and growth and development failure for 6 years, and recurrent dental caries and tooth loss for 2 years. Physical examination showed very low body weight, body length and head circumference, yellow hair, a lot of fawn spots on the face, skin dry and less elastic, and subcutaneous lipopenia. He had an unusual appearance with sunken eyes, sharp nose, sharp mandible, big auricle and dental caries and tooth loss. Crura spasticity and ataxia with excessive tendon reflexion, and ankle movement limitation while bending back were observed. He had slured speech. The level of serum insulin like growth factor I was low, and the results of blood and urinary amino acid analysis suggested malnutrition. The results of blood growth hormone, thyroxin, parathyroxin, liver function, renal function, lipoprotein profile and blood glucose and electrolytes were all within normal limit. An electronic hearing examination showed moderate neural hearing loss. The sonogram of eyes revealed small eye axis and vitreous body opacity of right side. MRI of brain revealed bilateral calcification of basal ganglia and generalized cerebral and cerebellar atrophy, and brainstem and callus were also atrophic. Genetic analysis confirmed with CSA gene mutation. So the boy was definitely diagnosed with Cockayne syndrome. He was discharged because of no effective treatment.

Titanium Alloy Gamma Nail versus Biodegradable Magnesium Alloy Bionic Gamma Nail for Treating Intertrochanteric Fractures: A Finite Element Analysis.

OBJECTIVE: To using finite element analysis to investigate the effects of the traditional titanium alloy Gamma nail and a biodegradable magnesium alloy bionic Gamma nail for treating intertrochanteric fractures. METHODS: Computed tomography images of an adult male volunteer of appropriate age and in good physical condition were used to establish a three-dimensional model of the proximal femur. Then, a model of a type 31A1 intertrochanteric fracture of the proximal femur was established, and the traditional titanium alloy Gamma nails and biodegradable magnesium alloy bionic Gamma nails were used for fixation, respectively. The von Mises stress, the maximum principal stress, and the minimum principal stress were calculated to evaluate the effect of bone ingrowth on stress distribution of the proximal femur after fixation. RESULTS: In the intact model, the maximum stress was 5.8 MPa, the minimum stress was -11.7 MPa, and the von Mises stress was 11.4 MPa. The maximum principal stress distribution of the cancellous bone in the intact model appears in a position consistent with the growth direction of the principal and secondary tensile zones. After traditional Gamma nail healing, the maximum stress was 32 MPa, the minimum stress was -23.5 MPa, and the von Mises stress was 31.3 MPa. The stress concentration was quite obvious compared with the intact model. It was assumed that the nail would biodegrade completely within 12 months postoperatively. The maximum stress was 18.7 MPa, the minimum stress was -12.6 MPa, and the von Mises stress was 14.0 MPa. For the minimum principal stress, the region of minimum stress value less than -10 MPa was significantly improved compared with the traditional titanium alloy Gamma nail models. Meanwhile, the stress distribution of the bionic Gamma nail model in the proximal femur was closer to that of the intact bone, which significantly reduced the stress concentration of the implant. CONCLUSION: The biodegradable magnesium alloy bionic Gamma nail implant can improve the stress distribution of fractured bone close to that of intact bone while reducing the risk of postoperative complications associated with traditional internal fixation techniques, and it has promising clinical value in the future.

Delivery of Liver-Specific miRNA-122 Using a Targeted Macromolecular Prodrug toward Synergistic Therapy for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) poses a great threat to human health. The elegant combination of gene therapy and chemotherapy by nanocarriers has been repeatedly highlighted to realize enhanced therapeutic efficacy relative to monotreatment. However, the leading strategy to achieve the efficient codelivery of the gene and drug remains the electrostatic condensation with the nucleic acid and the hydrophobic encapsulation of drug molecules by the nanocarriers, which suffers substantially from premature drug leakage during circulation and severe off-target-associated side effects. To address these issues, we reported in this study the codelivery of liver-specific miRNA-122 and anti-cancer drug 5-fluorouracil (5-Fu) using a macromolecular prodrug approach, that is, electrostatic condensation with miRNA-122 using galactosylated-chitosan-5-fluorouracil (GC-FU). The delivery efficacy was evaluated comprehensively in vitro and in vivo. Specifically, the biocompatibility of GC-FU/miR-122 nanoparticles (NPs) was assessed by hemolysis activity analysis, BSA adsorption test, and cell viability assay in both normal liver cells (L02 cells) and endothelial cells. The resulting codelivery systems showed enhanced blood and salt stability, efficient proliferation inhibition of HCC cells, and further induction apoptosis of HCC cells, as well as downregulated expression of ADAM17 and Bcl-2. The strategy developed herein is thus a highly promising platform for an effective codelivery of miRNA-122 and 5-Fu with facile fabrication and great potential for the clinical translation toward HCC synergistic therapy.

Direct observation of time and temperature dependent transition from spherical micelles to vesicles.

An interesting transition from spherical micelles to vesicles, which was time and temperature dependent, was observed for the first time; it is tentatively attributed to the thermal hysteresis of temperature-responsive poly(N-isopropylacrylamide).

Ratcheting behavior of UHMWPE reinforced by carbon nanofibers (CNF) and hydroxyapatite (HA): Experiment and simulation.

Uniaxial tensile tests were performed to investigate the mechanical properties of the ultra-high molecular weight polyethylene (UHMWPE) with different modification conditions. It was found that the different modification conditions have great influence on the mechanical properties of the UHMWPE. Subsequently, the uniaxial ratcheting behaviors of the UHMWPE/CNF and UHMWPE/HA composite materials were observed under the stress-controlled cyclic tensile condition at room temperature. The dependence of uniaxial ratcheting of composite materials on the mean stress, stress amplitude, stress rate and nano-material content was investigated. The results show that the ratcheting strain and its rate of the two composite materials increase as the mean stress and stress amplitude increase, however, the ratcheting strain and its rate decrease with the increase of the stress rate and nano-material content. Furthermore, it is found that the ratcheting strain of the UHMWPE/HA composite material is more remarkable than that of the UHMWPE/CNF composite material. A new viscoplastic constitutive model is proposed to describe the ratcheting behavior of the UHMWPE composite materials. In this model, a new viscosity function and modified kinematic hardening law were employed. Comparison of simulation and experimental results shows that the simulations are in good agreement with the experimental results.