Peptide-dendrimer-reinforced bioinks for 3D bioprinting of heterogeneous and biomimetic in vitro models.

Despite 3D bioprinting having emerged as an advanced method for fabricating complex in vitro models, developing suitable bioinks that fulfill the opposing requirements for the biofabrication window still remains challenging. Although naturally derived hydrogels can better mimic the extracellular matrix (ECM) of numerous tissues, their weak mechanical properties usually result in architecturally simple shapes and patchy functions of in vitro models. Here, this limitation is addressed by a peptide-dendrimer-reinforced bioink (HC-PDN) which contained the peptide-dendrimer branched PEG with end-grafted norbornene (PDN) and the cysteamine-modified HA (HC). The extensive introduction of ethylene end-groups facilitates the grafting of sufficient moieties and enhances thiol-ene-induced crosslinking, making HC-PDN exhibits improved mechanical and rheological properties, as well as a significant reduction in reactive oxygen species (ROS) accumulation than that of methacrylated hyaluronic acid (HAMA). In addition, HC-PDN can be applied for the bioprinting of numerous complex structures with superior shape fidelity and soft matrix microenvironment. A heterogeneous and biomimetic hepatic tissue is concretely constructed in this work. The HepG2-C3As, LX-2s, and EA.hy.926s utilized with HC-PDN and assisted GelMA bioinks closely resemble the parenchymal and non-parenchymal counterparts of the native liver. The bioprinted models show the endothelium barrier function, hepatic functions, as well as increased activity of drug-metabolizing enzymes, which are essential functions of liver tissue in vivo. All these properties make HC-PDN a promising bioink to open numerous opportunities for in vitro model biofabrication. STATEMENT OF SIGNIFICANCE: In this manuscript, we introduced a peptide dendrimer system, which belongs to the family of hyperbranched 3D nanosized macromolecules that exhibit high molecular structure regularity and various biological advantages. Specifically, norbornene-modified peptide dendrimer was grafted onto PEG, and hyaluronic acid (HA) was selected as a base material for bioink formulation because it is a component of the ECM. Peptide dendrimers confer the following advantages to bioinks: (a) Geometric symmetry can facilitate construction of bioinks with homogeneous networks; (b) abundant surface functional groups allow for abundant crosslinking points; (c) the biological origin can promote biocompatibility. This study shows conceptualization to application of a peptide-dendrimer bioink to extend the Biofabrication Window of natural bioinks and will expand use of 3D bioprinting of in vitro models.

Functionalized gelatin-alginate based bioink with enhanced manufacturability and biomimicry for accelerating wound healing.

Three-dimensional (3D) bioprinting is a promising technique to construct heterogeneous architectures that mimic cell microenvironment. However, the current bioinks for 3D bioprinting usually show some limitations, such as low printing accuracy, unsatisfactory mechanical properties and compromised cytocompatibility. Herein, a novel bioink comprising hydroxyphenyl propionic acid-conjugated gelatin and tyramine-modified alginate is developed for printing 3D constructs. The bioink takes advantage of an ionic/covalent intertwined network that combines covalent bonds formed by photo-mediated redox reaction and ionic bonds formed by chelate effect. Benefiting from the thermosensitivity of gelatin and the double-crosslinking mechanism, the developed bioink shows controllable rheological behaviors, enhanced mechanical behavior, improved printing accuracy and structure stability. Moreover, the printed cell-laden hydrogels exhibit a homogeneous cell distribution and considerable cell survival because the pre-crosslinking of the bioink prevents cellular sedimentation and the visible light crosslinking mechanism preserves cell viability. Further in vivo studies demonstrate that resulting cell-laden hydrogels are beneficial for the reduction of inflammation response and the promotion of collagen deposition and angiogenesis, thereby improving the quality of skin wound healing. This convenient and effective strategy is of great significance for accelerating the development of multifunctional bioinks and broadening the biomedical applications of 3D bioprinting.

Electroactive shape memory polyurethane composites reinforced with octadecyl isocyanate-functionalized multi-walled carbon nanotubes.

Shape memory polymers (SMPs) have a wide range of potential applications in many fields. In particular, electrically driven SMPs have attracted increasing attention due to their unique electrical deformation behaviors. Carbon nanotubes (CNTs) are often used as SMP conductive fillers because of their excellent electrical conductivities. However, raw CNTs do not disperse into the polymer matrix well. This strictly limits their use. In this study, to improve their dispersion performance characteristics in the polymer matrix, hydroxylated multi-walled carbon nanotubes (MWCNT-OHs) were functionalized with octadecyl isocyanate (i-MWCNTs). Polyurethane with shape memory properties (SMPU) was synthesized using polycaprolactone diol (PCL-diol), hexamethylene diisocyanate (HDI), and 1,4-butanediol (BDO) at a 1:5:4 ratio. Then, electroactive shape memory composites were developed by blending SMPU with i-MWCNTs to produce SMPU/i-MWCNTs. The functionalized i-MWCNTs exhibited better dispersibility characteristics in organic solvents and SMPU composites than the MWCNT-OHs. The addition of i-MWCNTs reduced the crystallinity of SMPU without affecting the original chemical structure. In addition, the hydrogen bond index and melting temperature of the SMPU soft segment decreased significantly, and the thermal decomposition temperatures of the composites increased. The SMPU/i-MWCNT composites exhibited conductivity when the i-MWCNT content was 0.5 wt%. This conductivity increased with the i-MWCNT content. In addition, when the i-MWCNT content exceeded 1 wt%, the composite temperature could increase beyond 60°C within 140 s and the temporary structure could be restored to its initial state within 120 s using a voltage of 30 eV. Therefore, the functionalized CNTs exhibit excellent potential for use in the development of electroactive shape memory composites, which may be used in flexible electronics and other fields.

Hydrogels for 3D embedded bioprinting: a focused review on bioinks and support baths.

Three-dimensional (3D) bioprinting has played an increasingly crucial role in the manufacturing of organized complex tissues and organs, which has shown tremendous potential in the field of tissue engineering. Extrusion-based bioprinting takes advantage of its competitive pricing and flexibility to print various biomaterials, and it has now developed into one of the most used printing techniques. However, extruding soft hydrogels, also known as bioinks, often leads to poor fidelity when printed in air. As an emerging printing approach, 3D embedded bioprinting deposits bioinks not on a platform but into a support bath, preventing constructs from settling and collapsing. This review discusses the challenges faced in the traditional 3D bioprinting of soft or low-viscosity bioinks and the changes brought by embedded bioprinting as an emerging solution. Particular focus is given to the progress of hydrogels used as bioinks and support baths. Finally, we highlight the challenges involved in this process and look forward to the prospects of this technology.

A review of flexible force sensors for human health monitoring.

BACKGROUND: In recent years, health monitoring systems (HMS) have aroused great interest due to their broad prospects in preventive medicine. As an important component of HMS, flexible force sensors (FFS) with high flexibility and stretch-ability can monitor vital health parameters and detect physical movements. AIM OF REVIEW: In this review, the novel materials, the advanced additive manufacturing technologies, the selective sensing mechanisms and typical applications in both wearable and implantable HMS are discussed. KEY SCIENTIFIC CONCEPTS AND IMPORTANT FINDINGS OF REVIEW: We recognized that the next generation of the FFS will have higher sensitivity, wider linear range as well as better durability, self-power supplied and multifunctional integrated. In conclusion, the FFS will provide powerful socioeconomic benefits and improve people's quality of life in the future.

Channel innovations for inertial microfluidics.

Inertial microfluidics has gained significant attention since first being proposed in 2007 owing to the advantages of simplicity, high throughput, precise manipulation, and freedom from an external field. Superior performance in particle focusing, filtering, concentrating, and separating has been demonstrated. As a passive technology, inertial microfluidics technology relies on the unconventional use of fluid inertia in an intermediate Reynolds number range to induce inertial migration and secondary flow, which depend directly on the channel structure, leading to particle migration to the lateral equilibrium position or trapping in a specific cavity. With the advances in micromachining technology, many channel structures have been designed and fabricated in the past decade to explore the fundamentals and applications of inertial microfluidics. However, the channel innovations for inertial microfluidics have not been discussed comprehensively. In this review, the inertial particle manipulations and underlying physics in conventional channels, including straight, spiral, sinusoidal, and expansion-contraction channels, are briefly described. Then, recent innovations in channel structure for inertial microfluidics, especially channel pattern modification and unconventional cross-sectional shape, are reviewed. Finally, the prospects for future channel innovations in inertial microfluidic chips are also discussed. The purpose of this review is to provide guidance for the continued study of innovative channel designs to improve further the accuracy and throughput of inertial microfluidics.

Fluid-Structure Interaction Analysis of Perfusion Process of Vascularized Channels within Hydrogel Matrix Based on Three-Dimensional Printing.

The rise of three-dimensional bioprinting technology provides a new way to fabricate in tissue engineering in vitro, but how to provide sufficient nutrition for the internal region of the engineered printed tissue has become the main obstacle. In vitro perfusion culture can not only provide nutrients for the growth of internal cells but also take away the metabolic wastes in time, which is an effective method to solve the problem of tissue engineering culture in vitro. Aiming at user-defined tissue engineering with internal vascularized channels obtained by three-dimensional printing experiment in the early stage, a simulation model was established and the in vitro fluid-structure interaction finite element analysis of tissue engineering perfusion process was carried out. Through fluid-structure interaction simulation, the hydrodynamic behavior and mechanical properties of vascularized channels in the perfusion process was discussed when the perfusion pressure, hydrogel concentration, and crosslinking density changed. The effects of perfusion pressure, hydrogel concentration, and crosslinking density on the flow velocity, pressure on the vascularized channels, and deformation of vascularized channels were analyzed. The simulation results provide a method to optimize the perfusion parameters of tissue engineering, avoiding the perfusion failure caused by unreasonable perfusion pressure and hydrogel concentration and promoting the development of tissue engineering culture in vitro.

Fabrication of Microfluidic Chips Based on an EHD-Assisted Direct Printing Method.

Microfluidic chips have been widely used in many areas such as biology, environmental monitoring, and micromixing. With the increasing popularity and complexity of microfluidic systems, rapid and convenient approaches for fabricating microfluidic chips are necessary. In this study, a method based on EHD (electrohydrodynamic)-assisted direct printing is proposed. Firstly, the principle of EHD-assisted direct printing was analyzed. The influence of the operating voltage and moving speed of the work table on the width of a paraffin wax model was studied. Then, two kinds of paraffin wax molds for micromixing with channel widths of 120 µm were prepared. A polydimethylsiloxane (PDMS) micromixer was fabricated by replicating the paraffin wax mold, and the micromixing of blue and yellow dye was realized. The results show that EHD-assisted direct printing can be used to make complex microscale structures, which has the potential to greatly simplify the manufacturing process.

The Research on Multi-material 3D Vascularized Network Integrated Printing Technology.

Three-dimensional bioprinting has emerged as one of the manufacturing approaches that could potentially fabricate vascularized channels, which is helpful to culture tissues in vitro. In this paper, we report a novel approach to fabricate 3D perfusable channels by using the combination of extrusion and inkjet techniques in an integrated manufacture process. To achieve this, firstly we investigate the theoretical model to analyze influencing factors of structural dimensions of the printed parts like the printing speed, pressure, dispensing time, and voltage. In the experiment, photocurable hydrogel was printed to form a self-supporting structure with internal channel grooves. When the desired height of hydrogel was reached, the dual print-head was switched to the piezoelectric nozzle immediately, and the sacrificial material was printed by the changed nozzle on the printed hydrogel layer. Then, the extrusion nozzle was switched to print the next hydrogel layer. Once the printing of the internal construct was finished, hydrogel was extruded to wrap the entire structure, and the construct was immersed in a CaCl2 solution to crosslink. After that, the channel was formed by removing the sacrificial material. This approach can potentially provide a strategy for fabricating 3D vascularized channels and advance the development of culturing thick tissues in vitro.

Synthesis of Samarium-Based Metal Organic Compound Nanoparticles with Polychromatic-Photoluminescence for Bio-Tissue Fluorescence Imaging.

The development of nanomaterials with special optical window is critical for clinical applications and the optoelectronic industry. In this work, eight kinds of samarium-based metal organic compound nanoparticles (Sm-Fe, Sm-Ga, Sm-Mn, Sm-Na, Sm-Nb, Sm-W, Sm-Cu, and Sm-Al) were synthesized through a solution method. They show polychromatic-photoluminescence spectra extended from the UV to near-infrared (NIR) region when excited by 280 nm, 380 nm, 480 nm, 580 nm, and 785 nm light. They emit direct white light with respect to UV excitation. Tunable white-to-green fluorescence can be achieved by variation of excitation light around 300-400 nm. When they are excited by a 785 nm light source, they show intense fluorescence around 800-1100 nm, which is promising for NIR bio-imaging. Their application in multicolor ultra-wide-range bio-tissue fluorescence imaging is demonstrated by UV (359-371 nm), blue (450-490 nm), green (540-552 nm), and NIR light (central wavelength = 785 nm) excitation with pig kidney tissue samples.

Fabrication of Different Microchannels by Adjusting the Extrusion Parameters for Sacrificial Molds.

Using the 3D printed mold-removal method to fabricate microchannel has become a promising alternative to the conventional soft lithography technique, due to the convenience in printing channel mold and the compatibility with PDMS material. Although having great potential, the use of single filament extruded by fused deposition modeling (FDM) as the sacrificial channel mold has not been elaborately studied. In this paper, we demonstrate the fabrication of microchannels with different structure and size by controllably extruding the sacrificial channel molds. The influences of the main processing parameters including working distance, extrusion amount and printing speed on the printed microchannels are systematically investigated. The results show that, the circular and low-aspect-ratio straight microchannels with different sizes can be fabricated by adjusting the extrusion amounts. The sinusoidal, 3D curved and cross-linked curved microchannels along straight path can be fabricated, either independently or in combination, by the combined control of the working distance, extrusion amount and printing speed. The complex microchannels with different structural features can also be printed along curved serpentine, rectangular serpentine, and spiral paths. This paper presents a simple and powerful method to fabricate the complex microchannels with different structure and size by just controlling the processing parameters for extruding channel molds.

Design and biomechanical characteristics of porous meniscal implant structures using triply periodic minimal surfaces.

BACKGROUND: Artificial meniscal implants can be used to replace a severely injured meniscus after meniscectomy and restore the normal functionality of a knee joint. The aim of this paper was to design porous meniscal implants and assess their biomechanical properties. METHODS: Finite element simulations were conducted on eight different cases including intact healthy knees, knee joints with solid meniscal implants, and knee joints with meniscal implants with two types of triply periodic minimal surfaces. Compression stresses, shear stresses, and characteristics of stress concentrated areas were evaluated using an axial compressive load of 1150 N and an anterior load of 350 N. RESULTS: Compared to the solid meniscal implant, the proposed porous meniscal implant produced lower levels of compression and shear stresses on the cartilage, which facilitated the cartilage to retain a semilunar characteristic similar to the natural meniscus. Moreover, both compression and shear stresses on the artificial cartilage were found to be sensitive to the pore properties of the meniscal implant. The meniscal implants with primitive surfaces (porosity: 41%) showed a better performance in disseminating stresses within the knee joint. CONCLUSION: The present commercial meniscal implant has the problem of equivalent biomechanical properties compared to natural menisci. The main advantage of the proposed porous structure is that it can be used to prevent excessive compression and shear stresses on the articular cartilages. This structure has advantages both in terms of mechanics and printability, which can be beneficial for future clinical applications.

Recent advances in microfluidic cell sorting techniques based on both physical and biochemical principles.

Microfluidic technologies for isolating cells of interest from a heterogeneous sample have attracted great attentions, due to the advantages of less sample consumption, simple operating procedure, and high separation accuracy. According to the working principles, the microfluidic cell sorting techniques can be categorized into biochemical (labeled) and physical (label-free) methods. However, the inherent drawbacks of each type of method may somehow influence the popularization of these cell sorting techniques. Using the multiple complementary isolation principles is a promising strategy to overcome this problem, therefore there appears to be a continuing trend to integrate two or more sorting methods together. In this review, we focus on the recent advances in microfluidic cell sorting techniques relied on both physical and biochemical principles, with emphasis on the mechanisms of cell separation. The biochemical cell sorting techniques enhanced by physical principles and the physical cell sorting techniques enhanced by biochemical principles, are first introduced. Then, we highlight on-chip magnetic-activated cell sorting, on-chip fluorescence-activated cell sorting, multi-step cell sorting and multi-principle cell sorting techniques, which are based on both physical and biochemical separation mechanisms. Finally, the challenges and future perspectives of the integrated microfluidics for cell sorting are discussed.

A TPMS-based method for modeling porous scaffolds for bionic bone tissue engineering.

In the field of bone defect repair, gradient porous scaffolds have received increased attention because they provide a better environment for promoting tissue regeneration. In this study, we propose an effective method to generate bionic porous scaffolds based on the TPMS (triply periodic minimal surface) and SF (sigmoid function) methods. First, cortical bone morphological features (e.g., pore size and distribution) were determined for several regions of a rabbit femoral bone by analyzing CT-scans. A finite element method was used to evaluate the mechanical properties of the bone at these respective areas. These results were used to place different TPMS substructures into one scaffold domain with smooth transitions. The geometrical parameters of the scaffolds were optimized to match the elastic properties of a human bone. With this proposed method, a functional gradient porous scaffold could be designed and produced by an additive manufacturing method.

Mechanical characterization of 3D printed multi-morphology porous Ti6Al4V scaffolds based on triply periodic minimal surface architectures.

Heterogeneous biomaterials that simultaneously mimic the topological and mechanical properties of nature bone tissues are of great interest in recent years. In this study, multi-morphology porous scaffolds based on the triply periodic minimal surfaces (TPMS) were designed and 3D printed with spatially changing pore patterns. Experiments and numerical analyses were carried out to assess the mechanical properties of the multi-morphology graded porous scaffold. As can be seen from the results, the multi-morphology structure showed a combination of relatively low elastic moduli and high yield strength. This combination allows for simultaneously minimizing the bone damage and increasing the stability of bone-implant interface. Thus the 3D printed multi-morphology porous Ti6AlV scaffold had shown significant promise for orthopedic application.

Application of virtual reality technology in clinical medicine.

The present review discusses the application of virtual reality (VR) technology in clinical medicine, especially in surgical training, pain management and therapeutic treatment of mental illness. We introduce the common types of VR simulators and their operational principles in aforementioned fields. The clinical effects are also discussed. In almost every study that dealt with VR simulators, researchers have arrived at the same conclusion that both doctors and patients could benefit from this novel technology. Moreover, advantages and disadvantages of the utilization of VR technology in each field were discussed, and the future research directions were proposed.

In situ repair of bone and cartilage defects using 3D scanning and 3D printing.

Three-dimensional (3D) printing is a rapidly emerging technology that promises to transform tissue engineering into a commercially successful biomedical industry. However, the use of robotic bioprinters alone is not sufficient for disease treatment. This study aimed to report the combined application of 3D scanning and 3D printing for treating bone and cartilage defects. Three different kinds of defect models were created to mimic three orthopedic diseases: large segmental defects of long bones, free-form fracture of femoral condyle, and International Cartilage Repair Society grade IV chondral lesion. Feasibility of in situ 3D bioprinting for these diseases was explored. The 3D digital models of samples with defects and corresponding healthy parts were obtained using high-resolution 3D scanning. The Boolean operation was used to achieve the shape of the defects, and then the target geometries were imported in a 3D bioprinter. Two kinds of photopolymerized hydrogels were synthesized as bioinks. Finally, the defects of bone and cartilage were restored perfectly in situ using 3D bioprinting. The results of this study suggested that 3D scanning and 3D bioprinting could provide another strategy for tissue engineering and regenerative medicine.

Wavelet Entropy and Directed Acyclic Graph Support Vector Machine for Detection of Patients with Unilateral Hearing Loss in MRI Scanning.

Highlights We develop computer-aided diagnosis system for unilateral hearing loss detection in structural magnetic resonance imaging.Wavelet entropy is introduced to extract image global features from brain images. Directed acyclic graph is employed to endow support vector machine an ability to handle multi-class problems.The developed computer-aided diagnosis system achieves an overall accuracy of 95.1% for this three-class problem of differentiating left-sided and right-sided hearing loss from healthy controls. Aim: Sensorineural hearing loss (SNHL) is correlated to many neurodegenerative disease. Now more and more computer vision based methods are using to detect it in an automatic way. Materials: We have in total 49 subjects, scanned by 3.0T MRI (Siemens Medical Solutions, Erlangen, Germany). The subjects contain 14 patients with right-sided hearing loss (RHL), 15 patients with left-sided hearing loss (LHL), and 20 healthy controls (HC). Method: We treat this as a three-class classification problem: RHL, LHL, and HC. Wavelet entropy (WE) was selected from the magnetic resonance images of each subjects, and then submitted to a directed acyclic graph support vector machine (DAG-SVM). Results: The 10 repetition results of 10-fold cross validation shows 3-level decomposition will yield an overall accuracy of 95.10% for this three-class classification problem, higher than feedforward neural network, decision tree, and naive Bayesian classifier. Conclusions: This computer-aided diagnosis system is promising. We hope this study can attract more computer vision method for detecting hearing loss.

YAP and 14-3-3γ are involved in HS-OA-induced growth inhibition of hepatocellular carcinoma cells: A novel mechanism for hydrogen sulfide releasing oleanolic acid.

Hydrogen sulfide-releasing oleanolic acid (HS-OA) is an emerging novel class of compounds and consists of an oleanolic acid (OA) and a H2S-releasing moiety. Although it exhibits improved anti-inflammatory activity, its potency in human cancers has not been understood yet. In this study, we examined the effects of HS-OA on the growth of liver cancer cell lines and the underlying mechanisms.HS-OA inhibited the growth of all four cancer cell lines studied, with potencies of 10- to 30-fold greater than that of its counterpart (OA). HS-OA induced significant apoptosis and decreased viability, clonogenic activity and migration of Hep G2 cells. Further studies showed that HS-OA resulted in the reduction of YAP expression and its downstream targets, CTGF and CYR 61, thus promoting cell apoptosis. In addition, HS-OA caused a decrease of 14-3-3γ expression, which led to Bad translocation to the mitochondria, ΔΨm loss, cytochrome c release, caspase activation and a recovery of 14-3-3γ reversed these effects induced by HS-OA.These findings indicate that YAP and 14-3-3γ are involved in HS-OA's effects on liver cancer cells and identifying HS-OA as a potential new drug candidate for cancer therapy.

Preliminary research on abnormal brain detection by wavelet-energy and quantum- behaved PSO.

It is important to detect abnormal brains accurately and early. The wavelet-energy (WE) was a successful feature descriptor that achieved excellent performance in various applications; hence, we proposed a WE based new approach for automated abnormal detection, and reported its preliminary results in this study. The kernel support vector machine (KSVM) was used as the classifier, and quantum-behaved particle swarm optimization (QPSO) was introduced to optimize the weights of the SVM. The results based on a 5 × 5-fold cross validation showed the performance of the proposed WE + QPSO-KSVM was superior to ``DWT + PCA + BP-NN'', ``DWT + PCA + RBF-NN'', ``DWT + PCA + PSO-KSVM'', ``WE + BPNN'', ``WE +$ KSVM'', and ``DWT $+$ PCA $+$ GA-KSVM'' w.r.t. sensitivity, specificity, and accuracy. The work provides a novel means to detect abnormal brains with excellent performance.