Advanced strategies in the application of gelatin-based bioink for extrusion bioprinting

The significance of bioink suitability for the extrusion bioprinting of tissue-like constructs cannot be overemphasized.Gelatin,derived from the hydrolysis of collagen,not only can mimic the extracellular matrix to immensely support cell function,but also is suitable for extrusion under certain conditions.Thus,gelatin has been recognized as a promising bioink for extrusion bioprinting.However,the development of a gelatin-based bioink with satisfactory printability and bioactivity to fabricate complex tissue-like constructs with the desired physicochemical properties and biofunctions for a specific biomedical application is still in its infancy.Therefore,in this review,we aim to comprehensively summarize the state-of-the-art methods of gelatin-based bioink application for extrusion bioprinting.Wefirstly outline the properties and requirements of gelatin-based bioinks for extrusion bioprinting,highlighting the strategies to overcome their main limitations in terms of printability,structural stability and cell viability.Then,the challenges and prospects are further discussed regarding the development of ideal gelatin-based bioinks for extrusion bioprinting to create complex tissue-like constructs with preferable physicochemical properties and biofunctions.

The impact of post-operative atrial fibrillation on outcomes in coronary artery bypass graft and combined procedures

BACKGROUND Postoperative atrial fibrillation(POAF)is a common yet understudied clinical issue after coronary artery bypass graft(CABG)leading to higher mortality rates and stroke.This systematic review and metaanalysis evaluated the rates of adverse outcomes between patients with and without POAF in patients treated with CABG or combined procedures.METHODS The search period was from the beginning of PubMed and Embase to May 18th,2020 with no language restrictions.The inclusion criteria were:(1)studies comparing new onset atrial fibrillation before or after revascularization vs.no new onset AF before or after revascularization.The outcomes assessed included allcause mortality,cardiac death,cerebral vascular accident(CVA),myocardial infarction(MI),repeated revascularization,major adverse cardiac event(MACE),and major adverse cardiac and cerebrovascular events(MACCEs).RESULTS Of the 7,279 entries screened,11 studies comprising of 57,384 patients were included.Compared to nonPOAF,POAF was significantly associated with higher risk of allcause mortality(Risk Ratio(RR)=1.58;95%Confidence Interval(CI):1.42−1.76,P<0.00001)with accompanying high level of heterogeneity(I^(2)=62%).Conclusions Patients with POAF after CABG or combined procedures are at an increased risk of allcause mortality or CVAs.Therefore,POAF after such procedures should be closely monitored and treated judiciously to minimize risk of further complications.While there are studies on POAF versus no POAF on outcomes,the heterogeneity suggests that further studies are needed.

Small-molecule amines:a big role in the regulation of bone homeostasis

Numerous small-molecule amines(SMAs)play critical roles in maintaining bone homeostasis and promoting bone regeneration regardless of whether they are applied as drugs or biomaterials.On the one hand,SMAs promote bone formation or inhibit bone resorption through the regulation of key molecular signaling pathways in osteoblasts/osteoclasts;on the other hand,owing to their alkaline properties as well as their antioxidant and anti-inflammatory features,most SMAs create a favorable microenvironment for bone homeostasis.However,due to a lack of information on their structure/bioactivity and underlying mechanisms of action,certain SMAs cannot be developed into drugs or biomaterials for bone disease treatment.In this review,we thoroughly summarize the current understanding of SMA effects on bone homeostasis,including descriptions of their classifications,biochemical features,recent research advances in bone biology and related regulatory mechanisms in bone regeneration.In addition,we discuss the challenges and prospects of SMA translational research.

Immunostimulant nanomodulator boosts antitumor immune response in triple negative breast cancer by synergism of vessel normalization and photothermal therapy

Tumor vascular dysfunction and immune suppression predict poor outcomes of tumor therapy.Combination of photothermal therapy(PTT)and vessel normalization with tumor immunotherapy is promising to augment antitumor benefit.Herein,we develop a potential immunostimulatory nanomodulator for treatment of triple-negative breast cancer(TNBC)treatment via synergism of PTT,vessel normalization,and priming of tumoral suppressive immune microenvironment by blocking transforming growth factor-β(TGF-β)pathway.The nanomodulator,namely Vac@Apt@BPs,is developed by conjugation of TGF-βinhibitor Vactosertib(Vac)and nucleolin-recognizing aptamer(Apt)on the surface of black phosphorus nanoparticles(BPs).Vac@Apt@BPs show good accumulation in TNBC via aptamer-induced active targeting of TNBC.Via the blockade of TGF-βsignaling,Vac@Apt@BPs effectively inhibit the formation of tumor neovascular,and normalize the vessels to recover vascular integrity and alleviate the hypoxia stress.Together with the tumor eradication and immunogenic cell death via PTT,robust immune response was boosted by promoted maturation of dendritic cells,suppression of regulatory T cells,and stimulation of effective T cells.This synergistic therapeutic strategy potentially suppresses the growth of TNBC in mice.

From surface to bulk modification: Plasma polymerization of amine-bearing coating by synergic strategy of biomolecule grafting and nitric oxide loading

Integration of two or more biomolecules with synergetic and complementary effects on a material surface can help to obtain multi-functions for various biomedical applications.However,the amounts of biomolecules integrated and their physiological functions are compromised due to the limited surface anchoring sites.Herein,we propose a novel concept of film engineering strategy“from surface to bulk synergetic modification”.This new concept is realized by employing the surface amine groups of plasma polymerized allylamine(PPAm)film for grafting a molecule e.g.,thrombin inhibitor,bivalirudin(BVLD),meanwhile its bulk amine groups is used as a universal depot for storing and releasing therapeutic nitric oxide(NO)gas as supplement to the functions of BVLD.It is demonstrated that such a“from surface to bulk synergetic modification”film engineering can impart the modified-substrates with anti-platelet and anti-coagulant dual functions,giving rise to a highly endotheliummimetic thromboresistant property.We believe that our research provides a very promising strategy to deliver multifunctional surface versatilely that require NO release in combination with other properties,which will find broad biomedical applications in blood-contacting devices,and et al.Moreover,it also provides a brand-new film engineering strategy for tailoring surface multi-functionalities of a wide range of materials.

Synthesis of gold/rare-earth-vanadate core/shell nanorods for integrating plasmon resonance and fluorescence

nanoscale 核心 / 壳 heterostructure 是一个特别地有效的主题联合 plasmonic 材料和稀土元素的混合物的有希望的性质；然而，在那里由于在这二内在地无敌的材料之间的大界面的精力在合成控制仍然是重要挑战。此处，我们报导种 rare-earth-vanadate 的一条合成线路在金 nanorod (AuNR ) 上轰炸核心。在通过表面活化剂交换与油酸盐修改 AuNR 表面以后，包装得好的稀土元素的氧化物(例如， Gd 2 O 3:Eu) 壳由于油酸盐的多重角色在 AuNRs 上被种。而且，壳的作文从氧化物被改变了到 vanadate (用一个阴离子交换方法的 GdVO 4:Eu) 。由于小心地设计的策略， AuNR 核心在合成过程期间维持形态学；因此，最后的 Au/GdVO 4:Eu 核心 / 壳 NR 展出强壮的吸收乐队和高 photothermal 效率。另外， Au/GdVO 4:Eu NR 象 ~ 一样高与量产量展出明亮的 Eu 3+ 荧光 17% ；明亮的 Sm 3+ 和 Dy 3+ 荧光能被改变在氧化物形成做的 lanthanide 也获得。由于 plasmonic 和荧光性质的吸引人的集成，如此的核心 / 壳 heterostructures 将在区域的一个宽数组发现特别应用，从 biomedicine 到精力。

Coaxial-printed small-diameter polyelectrolyte-based tubes with an electrostatic self-assembly of heparin and YIGSR peptide for antithrombogenicity and endothelialization

Low patency ratio of small-diameter vascular grafts remains a major challenge due to the occurrence of thrombosis formation and intimal hyperplasia after transplantation.Although developing the functional coating with release of bioactive molecules on the surface of small-diameter vascular grafts are reported as an effective strategy to improve their patency ratios,it is still difficult for current functional coatings cooperating with spatiotemporal control of bioactive molecules release to mimic the sequential requirements for antithrombogenicity and endothelialization.Herein,on basis of 3D-printed polyelectrolyte-based vascular grafts,a biologically inspired release system with sequential release in spatiotemporal coordination of dual molecules through an electrostatic self-assembly was first described.A series of tubes with tunable diameters were initially fabricated by a coaxial extrusion printing method with customized nozzles,in which a polyelectrolyte ink containing of ε-polylysine and sodium alginate was used.Further,dual bioactive molecules,heparin with negative charges and Tyr-Ile-Gly-Ser-Arg(YIGSR)peptide with positive charges were layer-by-layer assembled onto the surface of these 3D-printed tubes.Due to the electrostatic interaction,the sequential release of heparin and YIGSR was demonstrated and could construct a dynamic microenvironment that was thus conducive to the antithrombogenicity and endothelialization.This study opens a new avenue to fabricate a small-diameter vascular graft with a biologically inspired release system based on electrostatic interaction,revealing a huge potential for development of small-diameter artificial vascular grafts with good patency.

Synthesis of different-sized gold nanostars for Raman bioimaging and photothermal therapy in cancer nanotheranostics

Gold nanoparticles(AuNPs) have been attractive for nanomedicine because of their pronounced optical properties.Here,we customerized the methods to synthesize two types of gold nanostars,Au nanostars-1 and Au nanostars-2,which have different spire lengths and optical properties,and also spherical AuNPs.Compared to nanospheres,gold nanostars were less toxic to a variety of cells,including macrophages.Au nanostars-1 and Au nanostars-2 also manifested a similar pattern of tissue distribution upon in vivo administration in mice to that of nanospheres,and but reveled less liver retention than nanospheres.Due to their strong absorption in the near-infrared(NIR),Au nanostars-2 induced a strong hyperthermia effect in vitro upon excitation at 808 nm,and elicited a robust photothermal therapy(PTT) efficacy in ablating tumors in a mouse model of orthotopic breast cancer using 4T1 breast cancer cells.Meanwhile,Au nanostars-1 showed a great capability to enhance the Raman signal through surface-enhanced Raman spectroscopy(SERS) in 4T1 cells.Our combined results opened a new avenue to develop Au nanostars for cancer imaging and therapy.

Vital role of hydroxyapatite particle shape in regulating the porosity and mechanical properties of the sintered scaffolds

The effect of particle shape on the porosity and compressive strength of porous hydroxyapatite(HA)scaffolds was investigated by sintering the mixture of rod-shaped HA(r-HA) and spherical HA(s-HA)with polyacrylamide used as the sacrificial template. It was found, for the first time, that addition of r-HA into s-HA could exponentially decrease the porosity of sintered HA scaffolds and enhance their compressive strength with the increase of r-HA content. The mechanism, according to the results from scanning electron microscopy and X-ray diffraction, lies in the restriction of s-HA to the grain formation and growth of r-HA during sintering and results in the fusion of r-HA with s-HA. These findings suggest that mixture of r-HA and s-HA might provide a new and facile way to improve the compressive strength of porous HA scaffolds.

Mapping the elastic properties of two-dimensional MoS_(2) via bimodal atomic force microscopy and finite element simulation

Elasticity is a fundamental mechanical property of two-dimensional(2D)materials,and is critical for their application as well as for strain engineering.However,accurate measurement of the elastic modulus of 2D materials remains a challenge,and the conventional suspension method suffers from a number of drawbacks.In this work,we demonstrate a method to map the in-plane Young’s modulus of mono-and bi-layer MoS_(2) on a substrate with high spatial resolution.Bimodal atomic force microscopy is used to accurately map the effective spring constant between the microscope tip and sample,and a finite element method is developed to quantitatively account for the effect of substrate stiffness on deformation.Using these methods,the in-plane Young’s modulus of monolayer MoS_(2) can be decoupled from the substrate and determined as 265±13 GPa,broadly consistent with previous reports though with substantially smaller uncertainty.It is also found that the elasticity of mono-and bi-layer MoS_(2) cannot be differentiated,which is confirmed by the first principles calculations.This method provides a convenient,robust and accurate means to map the in-plane Young’s modulus of 2D materials on a substrate.

Advances in cancer nanomedicine

Cancer has become the leading cause of death.The progress in diagnosis and treatment is still limited.Over the past three decades,emergence and rapid development of nanotechnology have brought new hopes for cancer therapy.A repertoire of nanomaterials with controllable size-,shape-,and composition-dependent physiochemical proper

Degradable Photothermal Conversion Materials Based on Two-Dimensional Black Phosphorus

Nanomaterials with strong near-infrared absorption and high photothermal conversion ability have shown great application potential in many areas including cancer treatment.However,the current photothermal conversion nanomaterials generally have poor biodegradability and would stay in

Collagen-based bioinks for regenerative medicine: Fabrication, application and prospective

In the field of regenerative medicine,the importance of 3D bioprinting is self-evident and nonnegligible.However,3D bioprinting technology also requires bioink with excellent performance as support material to fabricate a multi-functional bioinspired scaffold.Collagen-based bioink is regarded as an ideal 3D bioprinting ink for its excellent biocompatibility,controllable printability and cell loading property.It is an important breakthrough in regenerative medicine with the progress of collagen-based bioink,which fabricates bioinspired scaffolds with different functions and is applied in different repair scenarios.This review summarizes the different applications of collagen-based bioink and classifies them as soft tissue and hard tissue according to the target region.The applications of target region in soft tissues include skin,cartilage,heart and blood vessels,while in hard tissues include femur,skull,teeth and spine.When the collagen-based bioink is applied in repairing soft tissue,the requirements of function are higher,while the mechanical properties must be further improved in repairing hard tissue.We further summarize the characteristics of collagen-based bioink and point out the most important properties that should be considered in different repair scenarios,which can provide reference for the preparation of bioinks with different functions.Finally,we point out the main challenges faced by collagen-based bioink and prospect the future research directions.

Theranostic gold cluster nanoassembly for simultaneous enhanced cancer imaging and photodynamic therapy

As one of near-infrared(NIR) fluorescent(FL) nanoprobes, gold nanoclusters(Au NCs) are delicated to passive-targeting tumors for NIR FL imaging, but which easily cleared by the kidneys for the small size(<1.5 nm). Herein, the well-defined gold clusters nanoassembly(Au CNA) was synthesized by the selfassembly of Au NCs based on protein cross-linking approach. The as-prepared Au CNA demonstrated highly effective cellular uptake and precise tumor targeting compared to that of Au NCs. Moreover, with the irradiation of 660 nm laser, Au CNA generated largely reactive oxygen species(ROS) for photodynamic therapy(PDT). In vitro and [39_TD$IF]in vivo PDT revealed that Au CNA exhibited largely cell death and significantly tumor removal at a low power density of 0.2 W/cm^2. It could be speculated that the laser-excited Au CNA produced photon energy, which further obtained electron from oxygen to generate radical species.Therefore, Au CNA as a photosensitizer could realize NIR FL imaging and NIR laser induced PDT.

Spectrin:Structure, function and disease

Spectrin is a large,cytoskeletal,and heterodimeric protein composed of modular structure of and subunits,it typically contains 106 contiguous amino acid sequence motifs called"spectrin repeats".Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell.Moreover,it contributes to diverse cell functions such as cell adhesion,cell spreading,and the cell cycle.Mutations of spectrin lead to various human diseases such as hereditary hemolytic anemia,type 5 spinocerebellar ataxia,cancer,as well as others.This review focuses on recent advances in determining the structure and function of spectrin as well as its role in disease.

Pluripotent Stem Cell-derived Strategies to Treat Acute Liver Failure: Current Status and Future Directions

Liver disease has long been a heavy health and economic burden worldwide.Once the disease is out of control and progresses to end-stage or acute organ failure,orthotopic liver transplantation(OLT)is the only therapeutic alternative,and it requires appropriate donors and aggressive administration of immunosuppressive drugs.Therefore,hepatocyte transplantation(HT)and bioartificial livers(BALs)have been proposed as effective treatments for acute liver failure(ALF)in clinics.Although human primary hepatocytes(PHs)are an ideal cell source to support these methods,the large demand and superior viability of PH is needed,which restrains its wide usage.Thus,a finding alternative to meet the quantity and quality of hepatocytes is urgent.In this context,human pluripotent stem cells(PSC),which have unlimited proliferative and differential potential,derived hepatocytes are a promising renewable cell source.Recent studies of the differentiation of PSC into hepatocytes has provided evidence that supports their clinical application.In this review,we discuss the recent status and future directions of the potential use of PSC-derived hepatocytes in treating ALF.We also discuss opportunities and challenges of how to promote such strategies in the common applications in clinical treatments.

COVID-19:immunopathogenesis and Immunotherapeutics

The recent novel coronavirus disease(COVID-19)outbreak,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is seeing a rapid increase in infected patients worldwide.The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations.SARS-CoV-2 not only activates antiviral immune responses,but can also cause uncontrolled inflammatory responses characterized by marked pro-inflammatory cytokine release in patients with severe COVID-19,leading to lymphopenia,lymphocyte dysfunction,and granulocyte and monocyte abnormalities.These SARS-CoV-2-induced immune abnormalities may lead to infections by microorganisms,septic shock,and severe multiple organ dysfunction.Therefore,mechanisms underlying immune abnormalities in patients with COVID-19 must be elucidated to guide clinical management of the disease.Moreover,rational management of the immune responses to SARSCoV-2,which includes enhancing anti-viral immunity while inhibiting systemic inflammation,may be key to successful treatment.In this review,we discuss the immunopathology of COVID-19,its potential mechanisms,and clinical implications to aid the development of new therapeutic strategies against COVID-19.

Akermanite used as an alkaline biodegradable implants for the treatment of osteoporotic bone defect

In osteoporosis scenario, tissue response to implants is greatly impaired by the deteriorated boneregeneration microenvironment. In the present study, a Mg-containing akermanite (Ak) ceramic wasemployed for the treatment of osteoporotic bone defect, based on the hypothesis that both beneficialions (e.g. Mg^2+ ect.) released by the implants and the weak alkaline microenvironment pH (μe-pH) itcreated may play distinct roles in recovering the abnormal bone regeneration by stimulating osteoblasticanabolic effects. The performance of Ak, b-tricalcium phosphate (β-TCP) and Hardystone (Har) in healinga 3 mm bone defect on the ovariectomized (OVX) osteoporotic rat model was evaluated. Our resultsindicated that, there's more new bone formed in Ak group than in β-TCP or Har group at week 9. Theinitial me-pHs of Ak were significantly higher than that of the β-TCP and Blank group, and this weakalkaline condition was maintained till at least 9 weeks post-surgery. Increased osteoblastic activity whichwas indicated by higher osteoid secretion was observed in Ak group at week 4 to week 9. An intermediatelayer which was rich in phosphorus minerals and bound directly to the new forming bone wasdeveloped on the surface of Ak. In a summary, our study demonstrates that Ak exhibits a superior boneregenerative performance under osteoporosis condition, and might be a promising candidate for thetreatment of osteoporotic bone defect and fracture.

Fractal Design Boosts Extrusion-Based 3D Printing of Bone-Mimicking Radial-Gradient Scaffolds

Although extrusion-based three-dimensional(EB-3D)printing technique has been widely used in the complex fabrication of bone tissue-engineered scaffolds,a natural bone-like radial-gradient scaffold by this processing method is of huge challenge and still unmet.Inspired by a typical fractal structure of Koch snowflake,for the first time,a fractal-like porous scaffold with a controllable hierarchical gradient in the radial direction is presented via fractal design and then implemented by EB-3D printing.This radial-gradient structure successfully mimics the radially gradual decrease in porosity of natural bone from cancellous bone to cortical bone.First,we create a design-to-fabrication workflow with embedding the graded data on basis of fractal design into digital processing to instruct the extrusion process of fractal-like scaffolds.Further,by a combination of suitable extruded inks,a series of bone-mimicking scaffolds with a 3-iteration fractal-like structure are fabricated to demonstrate their superiority,including radial porosity,mechanical property,and permeability.This study showcases a robust strategy to overcome the limitations of conventional EB-3D printers for the design and fabrication of functionally graded scaffolds,showing great potential in bone tissue engineering.

Rapid identification of two-dimensional materials via machine learning assisted optic microscopy

A combination of Fresnel law and machine learning method is proposed to identify the layer counts of 2D materials.Three indexes,which are optical contrast,red-green-blue,total color difference,are presented to illustrate and simulate the visibility of 2D materials on Si/SiO_(2) substrate,and the machine learning algorithms,which are k-mean clustering and k-nearest neighbors,are employed to obtain thickness database of 2D material and test the optical images of 2D materials via red-green-blue index.The results show that this method can provide fast,accurate and large-area property of 2D material.With the combination of artificial intelligence and nanoscience,this machine learning assisted method eases the workload and promotes fundamental research of 2D materials.