Photocontrolled Healable Structural Color Hydrogels.

Structural color hydrogels with healable capability are of great significance in many fields, however the controllability of these materials still needs optimizing. Thus, this work presents a healable structural color hydrogel with photocontrolling properties. The component parts of the hydrogel are a graphene oxide (GO) integrated inverse opal hydrogel scaffold and a hydrogel filler with reversible phase transition. The inverse opal scaffold provides stable photonic crystal structure and the hydrogel filler is the foundation of healing. Taking advantage of the prominent photothermal conversion efficiency of GO, the healable structural color material is imparted with photocontrolled properties. It is found that the structural color hydrogel shaped in complex patterns can heal under near-infrared (NIR) irradiation. These features indicate that the optical controllable healable structural color hydrogel can be employed in various applications, such as constructing complex objects, repairing tissues, and so on.

Droplet Microarray on Patterned Butterfly Wing Surfaces for Cell Spheroid Culture.

Three-dimensional (3D) cell spheroids have a demonstrated value for in vitro biological research and therapeutics development. Attempts to this technique focus on the development of effective methods for fabricating cell spheroids. Here, inspired by the heterogeneously textured wettability bumps (with hydrophilic peaks and hydrophobic bases) of Stenocara beetle, we present a biotemplated substrate with wettable hydrogel arrays for culturing the cell spheroids. The biotemplates were Morpho butterfly wings with chitin and protein components, which could provide a natural superhydrophobic surface without any modification. The droplet microarrays could be formed for cell spheroid culture on this bioinspired wing substrate by using the hydrogel patterns to hanging droplets. The hanging drop culture method on hydrogel-covered wings has the advantages of high speed, uniform size, and controllable diameter for the formation of 3D cell spheroids. It was demonstrated that drugs produced distinct responses in the 3D cell spheroids compared to conventional two-dimensional cell cultures. As the presented system does not require complex instruments and chemical modifications, our method can simply construct the desired wettability substrates with high biocompatibility for cell culture, drug testing, and other biomedical applications.

Bioinspired Photonic Barcodes with Graphene Oxide Encapsulation for Multiplexed MicroRNA Quantification.

Multiplexed microRNA (miRNA) quantification has a demonstrated value in clinical diagnosis. In this paper, novel mussel-inspired photonic crystal (PhC) barcodes with graphene oxide (GO) encapsulation for multiplexed miRNA detection are presented. Using the excellent adhesion capability of polydopamine, the dispersed GO particles can be immobilized on the surfaces of the PhC barcodes to form an additional functional layer. The GO-decorated PhC barcodes have constant characteristic reflection peaks because the GO immobilization process not only maintains their periodic microstructure but also enhances their stability and anti-incoherent light-scattering capability. The immobilized GO particles are shown to enable high-sensitivity miRNA screening on the surface of the PhC barcodes by integration with a hybridization chain reaction amplification strategy. Because the PhC barcodes have stable encoding reflection peaks, multiplexed low-abundance miRNA quantification can also be achieved rapidly, accurately, and reproducibly by employing different GO-decorated PhC barcodes. These features should make GO-encapsulated PhC barcodes ideal for many practical applications.

Synthesis, antitumor activity and pharmacokinetic study of 10-propionyloxy camptothecin in rats.

In the present study, a 10-position modified of camptothecin, 10-propionyloxy camptothecin (PCPT) was esterified from 10-hydroxcamptothecin (HCPT), which could metabolize to HCPT in vivo. PCPT displayed a relatively stronger antitumor activity in vitro and in vivo. Thereafter a simple, sensitive and rapid HPLC method coupled with a fluorescence detector was developed and validated for the assay of PCPT and its active metabolite HCPT in rat plasma. The method was validated for accuracy, precision, linearity, selectivity and recovery. The validated method was successfully applied to the pharmacokinetic study of PCPT in rats after intravenous administration. The results showed that PCPT could be mainly converted to HCPT in plasma with the AUC0-∞ value of 3.69 ± 4.44 and 311.16 ± 188.81 ng h/mL for PCPT and HCPT, respectively.

In vitro vascularized liver tumor model based on a microfluidic inverse opal scaffold for immune cell recruitment investigation.

Liver cancer, characterized as a kind of malignant tumor within the digestive system, poses great health harm, and immune escape stands out as an important reason for its occurrence and development. Chemokines, pivotal in guiding immune cells' migration, is necessary to initiate and deliver an effective anti-tumor immune response. Therefore, understanding the chemotactic environment and identifying chemokines that regulate recruitment of immune cells to the tumor microenvironment (TME) are critical to improve current immunotherapy interventions. Herein, we report a well-defined inverse opal scaffold generated with a microfluidic emulsion template for the construction of a vascularized liver tumor model, offering insights into immune cells' recruitment. Due to the excellent 3D porous morphology of the inverse opal scaffold, human hepatocellular carcinoma cells can aggregate in the pores of the scaffold to form uniform multicellular tumor spheroids. More attractively, the vascularized liver tumor model can be achieved by constructing a 3D co-culture system involving endothelial cells and hepatocellular carcinoma cells. The results demonstrate that the 3D co-cultured tumor cells increase the neutrophil chemokines remarkably and recruit neutrophils to tumor tissues, then promote tumor progression. This approach opens a feasible avenue for realizing a vascularized liver tumor model with a reliable immune microenvironment close to that of a solid tumor of liver cancer.

Droplet microfluidics-based biomedical microcarriers.

Droplet microfluidic technology provides a new platform for controllable generation of microdroplets and droplet-derived materials. In particular, because of the ability in high-throughput production and accurate control of the size, structure, and function of these materials, droplet microfluidics presents unique advantages in the preparation of functional microcarriers, i.e., microsized liquid containers or solid particles that serve as substrates of biomolecules or cells. These microcarriers could be extensively applied in the areas of cell culture, tissue engineering, and drug delivery. In this review, we focus on the fabrication of microcarriers from droplet microfluidics, and discuss their applications in the biomedical field. We start with the basic principle of droplet microfluidics, including droplet generation regimes and its control methods. We then introduce the fabrication of biomedical microcarriers based on single, double, and multiple emulsion droplets, and emphasize the various applications of microcarriers in biomedical field, especially in 3D cell culture, drug development and biomedical detection. Finally, we conclude this review by discussing the limitations and challenges of droplet microfluidics in preparing microcarriers. STATEMENT OF SIGNIFICANCE: Because of its precise control and high throughput, droplet microfluidics has been employed to generate functional microcarriers, which have been widely used in the areas of drug development, tissue engineering, and regenerative medicine. This review is significant because it emphasizes recent progress in research on droplet microfluidics in the preparation and application of biomedical microcarriers. In addition, this review suggests research directions for the future development of biomedical microcarriers based on droplet microfluidics by presenting existing shortcomings and challenges.

Erratum to "Responsive Inverse Opal Scaffolds with Biomimetic Enrichment Capability for Cell Culture".

[This corrects the article DOI: 10.34133/2019/9783793.].

Biomimetic Alveolus-on-a-Chip for SARS-CoV-2 Infection Recapitulation.

SARS-CoV-2 has caused a severe pneumonia pandemic worldwide with high morbidity and mortality. How to develop a preclinical model for recapitulating SARS-CoV-2 pathogenesis is still urgent and essential for the control of the pandemic. Here, we have established a 3D biomimetic alveolus-on-a-chip with mechanical strain and extracellular matrix taken into consideration. We have validated that the alveolus-on-a-chip is capable of recapitulating key physiological characteristics of human alveolar units, which lays a fundamental basis for viral infection studies at the organ level. Using virus-analogous chemicals and pseudovirus, we have explored virus pathogenesis and blocking ability of antibodies during viral infection. This work provides a favorable platform for SARS-CoV-2-related researches and has a great potential for physiology and pathophysiology studies of the human lung at the organ level in vitro.

Porous carbon nanotube microspheres with tailorable surface wettability areas for oil adsorption.

HYPOTHESIS: Oil adsorption is significant for water purification and environmental protection. However, the conventional bulk sorbents face the predicament of uncontrollable motion as well as hydrophobic nature the whole body, which largely restricts their uptake capacity underwater. Hence, novel adsorbent material for high-efficient oil uptake both at the surface and under the water is urgently required. EXPERIMENTS: We presented a phase-transition lysozyme coating approach to fabricate porous carbon nanotube microspheres with tailorable surface wettability areas for versatile oil adsorption. Because of the existence of magnetic nanoparticle in one hemisphere, the multi-sites coating was easily achieved by constantly changing orientations of the magnetic field. Owing to the integration of various hydrophilic functional groups in lysozyme as well as remarkable adhesion to virtually arbitrary materials, the intrinsically hydrophobic surface of the microspheres was partially modified hydrophilic on multiple sites. FINDINGS: It was demonstrated that the unique surface wettability feature and the porous structure enabled the microspheres to adsorb multiple contaminants both floating on the water and underwater. Besides, the magnetic-responsive ability allowed for controllable collection of oil contaminants. These features, along with the reusability, make the porous carbon nanotube microspheres excellent adsorbents for water purification.

Hierarchical Hydrogels with Ordered Micro-Nano Structures for Cancer-on-a-Chip Construction.

In the drug therapy of tumor, efficient and stable drug screening platforms are required since the drug efficacy varies individually. Here, inspired by the microstructures of hepatic lobules, in which hepatocytes obtain nutrients from both capillary vessel and the central vein, we present a novel hierarchical hydrogel system with ordered micro-nano structure for liver cancer-on-a-chip construction and drug screening. The hierarchical hydrogel system was fabricated by using pregel to fill and replicate self-assembled colloidal crystal arrays and microcolumn array template. Due to the synergistic effect of its interconnected micro-nano structures, the resultant system could not only precisely control the size of cell spheroids but also realize adequate nutrient supply of cell spheroids. We have demonstrated that by integrating the hierarchical hydrogel system into a multichannel concentration gradients microfluidic chip, a functional liver cancer-on-a-chip could be constructed for high-throughput drug screening with good repeatability and high accuracy. These results indicated that the hierarchical hydrogel system and its derived liver cancer-on-a-chip are ideal platforms for drug screening and have great application potential in the field of personalized medicine.

Chinese herb microneedle patch for wound healing.

Traditional Chinese medicine and Chinese herbs have a demonstrated value for disease therapy and sub-health improvement. Attempts in this area tend to develop new forms to make their applications more convenient and wider. Here, we propose a novel Chinese herb microneedle (CHMN) patch by integrating the herbal extracts, Premna microphylla and Centella asiatica, with microstructure of microneedle for wound healing. Such path is composed of sap extracted from the herbal leaves via traditional kneading method and solidified by plant ash derived from the brine induced process of tofu in a well-designed mold. Because the leaves of the Premna microphylla are rich in pectin and various amino acids, the CHMN could be imparted with medicinal efficacy of heat clearing, detoxicating, detumescence and hemostatic. Besides, with the excellent pharmaceutical activity of Asiatic acid extracted from Centella asiatica, the CHMN is potential in promoting relevant growth factor genes expression in fibroblasts and showing excellent performance in anti-oxidant, anti-inflammatory and anti-bacterial activity. Taking advantages of these pure herbal compositions, we have demonstrated that the derived CHMN was with dramatical achievement in anti-bacteria, inhibiting inflammatory, collagen deposition, angiogenesis and tissue reconstruction during the wound closure. These results indicate that the integration of traditional Chinese herbs with progressive technologies will facilitate the development and promotion of traditional Chinese medicine in modern society.

Bio-inspired wettability patterns for biomedical applications.

Benefiting from the remarkable wettability heterogeneity, bio-inspired wettability patterns present a progressive and versatile platform for manipulating and patterning liquids, which provides an emerging strategy for operating liquid samples with crucial values in biomedical applications. In this review, we present a general summary of bio-inspired wettability patterns. After a compendious introduction of natural wettability phenomena and their underlying mechanisms, we summarize the general design principles and fabrication methods for preparing artificial wettability materials. Next, we shift to patterned surface wettability with an emphasis on the fabrication approaches. Then, we discuss in detail the various practical applications of wettability patterns in the biomedical field, including cell culture, drug screening and biosensors. Critical thinking about the current challenges and future outlook is also provided. We believe that this review would propel the prosperous development of bio-inspired wettability patterns to flourish in the field of biomedical engineering.

Bioinspired Helical Micromotors as Dynamic Cell Microcarriers.

Micromotors have exhibited great potential in multidisciplinary nanotechnology, environmental science, and especially biomedical engineering due to their advantages of controllable motion, long lifetime, and high biocompatibility. Marvelous efforts focusing on endowing micromotors with novel characteristics and functionalities to promote their applications in biomedical engineering have been taken in recent years. Here, inspired by the flagellar motion of Escherichia coli, we present helical micromotors as dynamic cell microcarriers using simple microfluidic spinning technology. The morphologies of micromotors can be easily tailored because of the highly controllable and feasible fabrication process including microfluidic generation and manual dicing. Benefiting from the biocompatibility of the materials, the resultant helical micromotors could be ideal cell microcarriers that are suitable for cell seeding and further cultivation; the magnetic nanoparticle encapsulation imparts the helical micromotors with kinetic characteristics in response to mobile magnetic fields. Thus, the helical micromotors could be applied as dynamic cell culture blocks and further assembled to complex geometrical structures. The constructed structures out of cell-seeded micromotors could find practical potential in biomedical applications as the stack-shaped assembly embedded in the hydrogel may be used for tissue repairing and the tube-shaped assembly due to its resemblance to vascular structures in the microchannel for organ-on-a-chip study or blood vessel regeneration. These features manifest the possibility to broaden the biomedical application scope for micromotors.

Antibacterial and angiogenic chitosan microneedle array patch for promoting wound healing.

A patch with the capability of avoiding wound infection and promoting tissue remolding is of great value for wound healing. In this paper, we develop a biomass chitosan microneedle array (CSMNA) patch integrated with smart responsive drug delivery for promoting wound healing. Chitosan possesses many outstanding features such as the natural antibacterial property and has been widely utilized for wound healing. Besides, the microstructure of microneedles enables the effective delivery of loaded drugs into the target area and avoids the excessive adhesion between the skin and the patch. Also, vascular endothelial growth factor (VEGF) is encapsulated in the micropores of CSMNA by temperature sensitive hydrogel. Therefore, the smart release of the drugs can be controllably realized via the temperature rising induced by the inflammation response at the site of wounds. It is demonstrated that the biomass CSMNA patch can promote inflammatory inhibition, collagen deposition, angiogenesis, and tissue regeneration during the wound closure. Thus, this versatile CSMNA patch is potentially valuable for wound healing in clinical applications.

The development and validation of an LC-MS/MS method for the quantification of CZ112, a prodrug of 9-Nitrocamptothecin in rat plasma.

9-Nitrocamptothecin-20-O-propionate (CZ112) and 9-Nitrocamptothecin (9NC) are the bioactive derivatives of camptothecin (CPT), an alkaloid isolated from Camptotheca acuminata, and have been confirmed to possess high anti-cancer properties. In the present study, 9NC was identified as the major metabolite of CZ112 in rat plasma through HPLC/photodiode array detection (PDA) and liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. A highly sensitive LC-MS/MS method was developed and validated for the simultaneous analysis of CZ112 and 9NC in rat plasma, and camptothecin-20-O-acetate (CZ44) was used as an internal standard (IS). The calibration curves were linear (r2 > 0.999) over concentrations from 2.5 to 320 ng/mL for both CZ112 and 9NC. The method had an accuracy of 96.7-109.6%, and the intra- and inter-day precision (RSD%) were 10.9% or less for CZ112 and 9NC. The stability data showed no significant degradation occurred under the experimental conditions. This method was successfully applied to the pharmacokinetic study of CZ112 and its metabolite 9NC in rat plasma after intravenous and intragastric administration. The oral bioavailability of CZ112 was 6.2 ±â€¯3.3% (n = 6).

Superwettable colloidal crystal micropatterns on butterfly wing surface for ultrasensitive detection.

HYPOTHESIS: Ultrasensitive detections with enrichment approaches based on hydrophilic-hydrophobic patterns have attracted increasing attention in the early diagnosis and treatment of diseases. However, most of these techniques involve complicated micro-fabrications and chemical modifications to achieve their specific pattern substrate wettability. Hence, the development of a simple and effective approach for the construction of new surface wettability techniques for ultrasensitive detection is with great expectations. EXPERIMENTS: We present a simple approach to fabricate the superwettable colloidal crystal (CC) micropatterns on superhydrophobic Morpho butterfly wing surface for the ultrasensitive detection. The superwettable CC micropatterns were easily obtained by infiltrating and self-assembling monodispersed silica colloidal nanoparticles on the plasma treated butterfly wing patterns. The analytes could be enriched onto the hydrophilic CC area due to the wettability difference between the hydrophilic CC area and the superhydrophobic substrate. FINDINGS: It was demonstrated that the detection limit of thrombin was down to 1.8 × 10-13 mol L-1 based on the fluorophore-labeled aptamer. Moreover, with two-dimensional position codes of these CC micropatterns for different probes, the multiplex detection capability was also demonstrated with great accuracy. As the elimination of complex instruments and chemical modifications, this proposed platform offers a simple strategy for ultrasensitive multiplex detection in practical applications.

Responsive Inverse Opal Scaffolds with Biomimetic Enrichment Capability for Cell Culture.

Three-dimensional (3D) porous scaffolds have a demonstrated value for tissue engineering and regenerative medicine. Inspired by the predation processes of marine predators in nature, we present new photocontrolled shrinkable inverse opal graphene oxide (GO) hydrogel scaffolds for cell enrichment and 3D culture. The scaffolds with adjustable pore sizes and morphologies were created using a GO and N-isopropylacrylamide dispersed solution as a continuous phase of microfluidic emulsions for polymerizing and replicating. Because of the interconnected porous structures and the remotely controllable volume responsiveness of the scaffolds, the suspended cells could be enriched into the inner spaces of the scaffolds through predator-like swallowing and discharging processes. Hepatocyte cells concentrated in the scaffold pores could form denser 3D spheroids more quickly via the controlled compression force caused by the shrinking of the dynamic scaffolds. More importantly, with a program of scaffold enrichment with different cells, an unprecedented 3D multilayer coculture system of endothelial-cell-encapsulated hepatocytes and fibroblasts could be generated for applications such as liver-on-a-chip and bioartificial liver. It was demonstrated that the resultant multicellular system offered significant improvements in hepatic functions, such as albumin secretion, urea synthesis, and cytochrome P450 expression. These features of our scaffolds make them highly promising for the biomimetic construction of various physiological and pathophysiological 3D tissue models, which could be used for understanding tissue level biology and in vitro drug testing applications.

Magnetically responsive colloidal crystals with angle-independent gradient structural colors in microfluidic droplet arrays.

Magnetically responsive colloidal crystal films with gradient structural colors have a significant value in optical applications via controllable external stimuli. Herein, we propose a practical method for fabricating colloidal crystal hydrogel films with continuous gradient structural colors by using superparamagnetic colloidal nanoparticles. The colloidal nanoparticles could self-assemble into chain-like non-close-packed arrays to present structural colors under the stimuli of external magnetic fields. And structural colors with gradient changes could be achieved when subjected to a spatial magnetic field with a remarkable variation in field strength and direction. By integrating with a microfluidic droplet array template with spherical symmetry morphology, we have demonstrated convenient fabrication of free-standing colloidal crystal films with angle-independent gradient structural colors, which could be utilized for the fabrication of optical devices.

Photoresponsive Delivery Microcarriers for Tissue Defects Repair.

Intelligent responsive microcarriers have emerged as a promising class of biomaterials for therapeutic delivery and tissue regeneration, since they can respond to external stimuli and release the loaded drugs in an active manner. Among various available stimuli, near-infrared (NIR) light is particularly attractive because it can penetrate biotic tissues with sufficient intensity and minimal damage. In this work, a kind of photoresponsive delivery microcarriers (PDMs) is developed using microfluidics. The microcarriers consist of NIR-absorbing graphene oxide, thermosensitive poly(N-isopropylacrylamide), and biocompatible gelatin methacrylate. Under NIR light, the PDMs exhibit an evident volume shrinkage and effectively trigger the drug release. After the NIR light is switched off, the shrunken microcarriers return to their original size. This reversible process can be stably repeated for many cycles. An in vitro experiment demonstrates that the NIR-radiated PDMs can actively release vascular endothelial growth factors and improve the tube formation of human umbilical vein endothelial cells. The results from the in vivo experiment also show an obvious photothermal effect and superior therapeutic efficacy of these PDMs in a rat model of tissue defects. These features make the PDMs an excellent drug delivery system and represent a great potential for clinical applications in tissue repair.

Cardiomyocyte-Driven Structural Color Actuation in Anisotropic Inverse Opals.

Biohybrid actuators composed of living tissues and artificial materials have attracted increasing interest in recent years because of their extraordinary function of dynamically sensing and interacting with complex bioelectrical signals. Here, a compound biohybrid actuator with self-driven actuation and self-reported feedback is designed based on an anisotropic inverse opal substrate with periodical elliptical macropores and a hydrogel filling. The benefit of the anisotropic surface topography and high biocompatibility of the hydrogel is that the planted cardiomyocytes could be induced into a highly ordered alignment with recovering autonomic beating ability on the elastic substrate. Because of the cell elongation and contraction during cardiomyocyte beating, the anisotropic inverse opal substrates undergo a synchronous cycle of deformation actuations, which can be reported as corresponding shifts of their photonic band gaps and structural colors. These self-driven biohybrid actuators could be used as elements for the construction of a soft-bodied structural color robot, such as a biomimetic guppy with a swinging tail. Besides, with the integration of a self-driven biohybrid actuator and microfluidics, the advanced heart-on-a-chip system with the feature of microphysiological visuality has been developed for integrated cell monitoring and drug testing. This anisotropic inverse opal-derived biohybrid actuator could be widely applied in biomedical engineering.