Effectiveness and safety of umbilical cord milking in premature infants: A randomized controlled trial.

INTRODUCTION: Both UCM and DCC are used to treat preterm infants, but there is no uniform standard for the length of UCM. The aim of this work was to explore the effectiveness and safety of different umbilical cord milking (UCM) lengths versus delayed cord clamping (DCC). METHODS: We enrolled premature infants from the Affiliated Hospital of Zunyi Medical University between September 2019 and October 2020 with random allocation (1:1:1:1) to the UCM 10 cm, UCM 20 cm, UCM 30 cm, and DCC groups. The primary outcome was hemoglobin at birth. RESULTS: Ultimately, 143 participants completed the trial (UCM 10 cm, n = 35; UCM 20 cm, n = 35; UCM 30 cm, n = 38; DCC, n = 35). The hemoglobin levels were significantly lower at birth in the UCM 10 cm group than in the UCM 20 and 30 cm and DCC groups (182.29 ±â€…22.15 vs 202.83 ±â€…21.46, 208.82 ±â€…20.72, and 198.46 ±â€…24.92, P = .001, .001, and .003, respectively). The systolic blood pressure and diastolic pressures in the UCM 30 cm group were higher than those in the UCM 10 and 20 cm and DCC groups at birth, postnatal day 3 and postnatal day 7 (P < .05). The occurrence rates of anemia were significantly higher in the UCM 10 cm group than in the UCM 20 and 30 cm and DCC groups (42.9% vs 14.3%, 10.5%, and 14.3%, all P < .0083). There were no significant differences in heart rate or complications among the 4 groups. CONCLUSIONS: A UCM of 20 or 30 cm is a safe, effective operation for preterm infants and could improve blood pressure and hemoglobin levels and reduce anemia.

Evidence-based biomaterials research.

The fast development of biomaterials science and engineering has generated significant number of studies and publications as well as tremendous amount of research data. A methodology is needed to translate such research data and results to validated scientific evidence. This article for the first time proposes the concept and methodology of evidence-based biomaterials research, which is to use evidence-based research approach represented by systematic reviews to generate evidence for answering scientific questions related to biomaterials. After briefly introducing the advancement of biomaterials since 1950s, the scientific and engineering nature of biomaterials are discussed along with the roadmap of biomaterials translation from basic research to commercialized medical products, and the needs of scientific evidence. Key information of the evidence-based approach such as its origination from evidence-based medicine, levels of evidence, systematic review and meta-analysis, differences between systematic and narrative reviews is then highlighted. Applications with a step-by-step procedure of conducting evidence-based biomaterials research, three examples of biomaterials research using evidence-based approach to generate scientific evidence, and opportunities and challenges of evidence-based biomaterials research are presented. With its notable impact on the practice of medicine, the evidence-based approach is also expected to make influential contributions to the biomaterials field.

Preparation and characterization of photopolymerized poly(l-lactide-co-ε-caprolactone-co-N-vinyl-2-pyrrolidone) network as anti-biofouling materials.

The anti-biofouling properties have important applications in the medical field. In this study, cross-linked networks were prepared by photopolymerizing two synthetic macromonomers, including fumaric acid monoethyl ester (FAME) functionalized, three-armed poly(l-lactide) prepolymers (3-PLLA-F) and poly(ε-caprolactone) prepolymers (2-PCL-F), with N-vinyl-2-pyrrolidone (NVP) as the diluent. The prepared networks were characterized by their thermal properties, mechanical properties, cytotoxicity experiments and anti-biofouling properties. The Young's modulus and tensile strength of networks decreased by increasing PCL content. In contrast, the elongation of networks significantly increased. Moreover, no obvious cytotoxicity was observed, and the adhesion of L929 fibroblasts and platelets was resisted. Combined with Digital Light Processing technology (DLP) in the future, the designed polymer network could potentially be commercial in the field of biological anti-fouling materials.

Regulatory perspectives of combination products.

Combination products with a wide range of clinical applications represent a unique class of medical products that are composed of more than a singular medical device or drug/biological product. The product research and development, clinical translation as well as regulatory evaluation of combination products are complex and challenging. This review firstly introduced the origin, definition and designation of combination products. Key areas of systematic regulatory review on the safety and efficacy of device-led/supervised combination products were then presented. Preclinical and clinical evaluation of combination products was discussed. Lastly, the research prospect of regulatory science for combination products was described. New tools of computational modeling and simulation, novel technologies such as artificial intelligence, needs of developing new standards, evidence-based research methods, new approaches including the designation of innovative or breakthrough medical products have been developed and could be used to assess the safety, efficacy, quality and performance of combination products. Taken together, the fast development of combination products with great potentials in healthcare provides new opportunities for the advancement of regulatory review as well as regulatory science.

A transparent hydrophilic anti-biofouling coating for intraocular lens materials prepared by "bridging" of the intermediate adhesive layer.

The attachment of bio-foulants, including unwanted cells, proteins, and bacteria, to a medical device such as an intraocular lens can lead to implantation failure. Hydrophilic polymers are often used as surface modifiers in the fabrication of anti-biofouling coatings, but a hydrophilic coating can easily become swollen and peel off the substrate. In this study, we chose polymethyl methacrylate (PMMA) as the representative material of intraocular lenses because PMMA has better biocompatibility, a higher refractive index, better optical clarity, lighter weight, more stable performance, and lower cost than other intraocular lens materials. We fabricated polyvinyl alcohol (PVA) coatings with or without a "bridge", that is, an intermediate adhesive layer (AL), to increase the adhesion bonding effect between the anti-biofouling coating and the substrate. The results indicated that the prepared coatings were transparent and noncytotoxic. Moreover, the anti-adhesion properties of the cells and the resistance properties to nonspecific protein adsorption of PMMA modified by both AL and PVA coatings were better and more durable compared with the sample only modified with a physically dipped PVA coating. The coating prepared by AL "bridging" provides a new strategy for the preparation of a transparent hydrophilic anti-biofouling coating suitable for PMMA intraocular lens materials.

Photopolymerized poly(l-lactide-b-N-vinyl-2-pyrrolidone) network resists cell adhesion in situ.

A three-armed star-shaped poly(l-lactide) (PLLA) oligomer was synthesized using glycerol to ring-opening and polymerize l-lactide. The resultant oligomer introduced photoreactive groups at the terminal of PLLA chains by a coupling reaction with monoethyl fumarate (FAME). Photopolymerizable resin has been prepared by mixing PLLA 3-FAME, N-vinyl-2-pyrrolidone (NVP) as a reactive diluent and Irgacure 2959 as a photoinitiator. The PLLA 3-FAME/NVP cross-linked network could be formed by UV curing and was characterized through mechanical property tests, cytotoxicity experiments and cell adhesion experiments. In the dry state, Young's modulus and tensile strength of the network were significantly higher than those of pure PLLA formed by fused deposition modeling (FDM) printing, due to the formation of the cross-linked net. In the wet state, however, Young's modulus and tensile strength of the network were reduced by less than those of PLLA since the water-absorbed NVP content was easy to stretch. Moreover, the resultant network not only exhibited no obvious cytotoxicity but also resisted the adhesion of L929 fibroblasts. Combined with Digital Light Processing (DLP) technology, the poly(l-lactide-b-N-vinyl-2-pyrrolidone) network may be widely used in the field of anti-adhesion barrier materials and/or biological anti-fouling materials with customization requirements.

A Novel Long-circulating DOX Liposome: Formulation and Pharmacokinetics Studies.

BACKGROUND: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDA-approved PEG-liposomes of DOX for the treatment of over 600,000 cancer patients, and it can overcome doxorubicin-induced cardiomyopathy and other side effects and prolong life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. OBJECTIVE: We intended to prepare a novel DOX liposome that was prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical application. METHODS: DOX liposomes were prepared using the combination of thin-film dispersion ultrasonic method and ammonium sulfate gradient method and the factors that influenced formulation quality were optimized. After formulation, particle size, entrapment efficiency, drug loading, stability, and pharmacokinetics were determined. RESULTS: DOX liposomes were near-spherical morphology with the average size of 90 nm and polydispersity index (PDI) of less than 0.30. The drug loading was up to 7.5%, and the entrapment efficiency was over 80%. The pharmacokinetic studies showed that free DOX could be easily removed and the blood concentration of free DOX group was significantly lower than that of DOX liposomes, which indicated that the novel DOX liposome had a certain sustainedrelease effect. CONCLUSION: In summary, DOX liposome is economical and easy-prepared with prolonged circulation time. Lay Summary: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDAapproved PEG-liposomes of DOX to treat over 600.000 cancer patients, overcoming doxorubicin- induced cardiomyopathy and other side effects and prolonging life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. We intend to prepare a novel DOX liposome prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical use. The novel DOX liposome is economical and easy-prepared with prolonged circulation time.

Performance of PEGylated chitosan and poly (L-lactic acid-co-ε-caprolactone) bilayer vascular grafts in a canine femoral artery model.

The fabrication of a functional small-diameter vascular graft with good biocompatibility, in particular hemocompatibility, has become an urgent clinical necessity. We fabricated a native bilayer, small-diameter vascular graft using PEGylated chitosan (PEG-CS) and poly (L-lactic acid-co-ε-caprolactone; PLCL). To stabilize the inner layer, a PEG-CS blend with PLCL at ratio of 1:6 was casted on a round metal bar by a drip feed, and the outer layer, a PLCL blend with water-soluble PEG that acted as a sacrificial part to enhance pore size, was fabricated by electrospinning. The results showed excellent hemocompatibility and strong mechanical properties. In vitro, the degradation of the graft was evaluated by measuring the graft structure, mass loss rate, and changes in molecular weight. The results indicated that the graft had adequate support for the regeneration of blood vessels before collapse. An in vivo study was performed in a canine femoral artery model for up to 24 weeks, which demonstrated that the PEGylated bilayer grafts possessed excellent structural integrity, high compatibility with blood, good endothelial cell (EC) and smooth muscle cell (SMC) growth, and high expression levels of angiogenesis-related proteins, features that are highly similar to autologous blood vessels. Moreover, the results showed almost negligible calcification within 24 weeks. These findings confirm that the bilayer graft mimics native cells, thereby effectively improving vascular remodeling.

Non-Cross-Linking Aggregation of DNA-Carrying Polymer Micelles Triggered by Duplex Formation.

Colloidal behaviors of particles functionalized with biomolecules are generally complicated. This study describes that colloidal behaviors of double-stranded (ds) DNA-carrying polymer micelles are well controlled by altering the molar ratio of single-stranded (ss) DNA moiety in the dsDNA shell. ssDNA-carrying micelles composed of a poly( N-isopropylacrylamide) (PNIPAAm) core surrounded by a dense shell of ssDNAs were prepared through self-assembly of PNIPAAm grafted with ssDNA by incubating its solution above the lower critical solution temperature. Spontaneous, non-cross-linking aggregation of the micelles was triggered by DNA duplex formation on the surface. Comparison of the critical coagulation concentration of NaCl among a series of the DNA-carrying micelles revealed the relationship between the helical structure of the surface-bound DNA and the colloidal stability of the micelles. The electrophoretic mobility analysis of the micelles indicated that the duplex formation reduced the structural flexibility of the surface-bound DNA, thereby decreasing the interparticle entropic repulsion. It is also suggested that the augmented rigidity of the surface-bound DNA increases the number of terminal base pairs facing the solvent, which could lead to multiple blunt-end stacking interaction among the micelles. Therefore, small DNA molecules could be considered unique surface-modifiers capable of controlling interactions between the surfaces of materials.

Recent development of temperature-responsive surfaces and their application for cell sheet engineering.

Cell sheet engineering, which fabricates sheet-like tissues without biodegradable scaffolds, has been proposed as a novel approach for tissue engineering. Cells have been cultured and proliferate to confluence on a temperature-responsive cell culture surface at 37°C. By decreasing temperature to 20°C, an intact cell sheet can be harvested from the culture surface without enzymatic treatment. This new approach enables cells to keep their cell-cell junction, cell surface proteins and extracellular matrix. Therefore, recovered cell sheet can be easily not only transplanted to host tissue, but also constructed a three-dimensional (3D) tissue by layering cell sheets. Moreover, cell sheet manipulation technology and bioreactor have been combined with the cell sheet technology to fabricate a complex and functional 3D tissue in vitro. So far, cell sheet technology has been applied in regenerative medicine for several tissues, and a number of clinical studies have been performed. In this review, recent advances in the preparation of temperature-responsive cell culture surface, the fabrication of organ-like tissue and the clinical application of cell sheet engineering are summarized and discussed.

Shear stress-dependent cell detachment from temperature-responsive cell culture surfaces in a microfluidic device.

A new approach to quantitatively estimate the interaction between cells and material has been proposed by using a microfluidic system, which was made of poly(dimethylsiloxane) (PDMS) chip bonding on a temperature-responsive cell culture surface consisted of poly(N-isopropylacrylamide) (PIPAAm) grafted tissue culture polystyrene (TCPS) (PIPAAm-TCPS) having five parallel test channels for cell culture. This construction allows concurrently generating five different shear forces to apply to cells in individual microchannels having various resistance of each channel and simultaneously gives an identical cell incubation condition to all test channels. NIH/3T3 mouse fibroblast cells (MFCs) and bovine aortic endothelial cells (BAECs) were well adhered and spread on all channels of PIPAAm-TCPS at 37 °C. In our previous study, reducing culture temperature below the lower critical solution temperature (LCST) of PIPAAm (32 °C), cells detach themselves from hydrated PIPAAm grafted surfaces spontaneously. In this study, cell detachment process from hydrated PIPAAm-TCPS was promoted by shear forces applied to cells in microchannels. Shear stress-dependent cell detachment process from PIPAAm-TCPS was evaluated at various shear stresses. Either MFCs or BAECs in the microchannel with the strongest shear stress were found to be detached from the substrate more quickly than those in other microchannels. A cell transformation rate constant C(t) and an intrinsic cell detachment rate constant k(0) were obtained through studying the effect of shear stress on cell detachment with a peeling model. The proposed device and quantitative analysis could be used to assess the possible interaction between cells and PIPAAm layer with a potential application to design a cell sheet culture surface for tissue engineering.

Comb-type grafted poly(N-isopropylacrylamide) gel modified surfaces for rapid detachment of cell sheet.

A comb-type grafted poly(N-isopropylacrylamide) (PIPAAm) gel modified surface was newly developed for providing a rapid cell sheet recovery for tissue engineering. PIPAAm macromonomer was prepared by the etherification reaction of the hydroxyl terminal moieties of PIPAAm with acryloyl chloride, followed by the radical telomerization reaction of N-isopropylacrylamide (IPAAm) monomer using 2-mercaptoethanol as a chain transfer agent. Solution containing IPAAm monomer and PIPAAm macromonomer was spread on the surface of tissue culture polystyrene (TCPS), and then the surface was subjected to electron beam irradiation for grafting the monomer and macromonomer on the surfaces, resulting in comb-type grafted PIPAAm gel modified TCPS (GG-TCPS). Besides the difference of the amount of the modified PIPAAm, no distinct difference was found between the properties of GG-TCPSs and normal-type PIPAAm gel modified TCPS (NG-TCPS) through XPS, AFM and a contact angle measurement. At 37 degrees C, bovine aortic endothelial cells (BAECs) were well adhered and spread on GG-TCPS as well as NG-TCPS regardless of the macromonomer concentration. By lowering temperature to 20 degrees C, BAECs detached themselves more rapidly from GG-TCPS compared with NG-TCPS. Upon lowering temperature, the grafted polymer was speculated to accelerate the hydration of modified PIPAAm gel, resulting in a rapid cell sheet detachment.

Turbidimetric detection of ATP using polymeric micelles and DNA aptamers.

Two types of turbidimetric detection of adenosine 5'-triphosphate (ATP) by the naked eye were achieved through a combination of non-cross-linking aggregation of DNA-linked polymeric micelles and molecular recognition of ATP by a DNA aptamer.

Affinity precipitation separation of DNA binding protein using block conjugate composed of poly(N-isopropylacrylamide) grafted double-stranded DNA and double-stranded DNA containing a target sequence.

In this research, we synthesized a novel DNA-polymer conjugate and evaluated its application to an affinity precipitation separation of TATA-box binding protein (TBP), which is a representative general transcription factor. The conjugate was composed of two fractions. One was a double-stranded DNA modified by the grafting of poly(N-isopropylacrylamide) (PNIPAAm), which is known as a thermosensitive vinyl polymer. The other fraction is a native double-stranded DNA containing a specific base sequence (5'-TATAAA-3') called a TATA-box. These two fractions, which have EcoRI termini, were treated with T4 DNA ligase, and the block conjugate was obtained as a precipitate after two wash processes. When the resultant block conjugate was introduced into a sample solution containing TBP (0.26 microM) and bovine serum albumin (BSA) (0.39 microM), a rapid and selective precipitation separation of TBP under homogeneous conditions was achieved by controlling temperature. The purity of TBP in the precipitation fraction was estimated to be above 90%.