Microfluidic strategies for engineering oxygen-releasing biomaterials.

In the field of tissue engineering, local hypoxia in large-cell structures (larger than 1 mm3) poses a significant challenge. Oxygen-releasing biomaterials supply an innovative solution through oxygen ⁠ delivery in a sustained and controlled manner. Compared to traditional methods such as emulsion, sonication, and agitation, microfluidic technology offers distinct benefits for oxygen-releasing material production, including controllability, flexibility, and applicability. It holds enormous potential in the production of smart oxygen-releasing materials. This review comprehensively covers the fabrication and application of microfluidic-enabled oxygen-releasing biomaterials. To begin with, the physical mechanism of various microfluidic technologies and their differences in oxygen carrier preparation are explained. Then, the distinctions among diverse oxygen-releasing components in regards for oxygen-releasing mechanism, oxygen-carrying capacity, and duration of oxygen release are presented. Finally, the present obstacles and anticipated development trends are examined together with the application outcomes of oxygen-releasing biomaterials based on microfluidic technology in the biomedical area. STATEMENT OF SIGNIFICANCE: Oxygen is essential for sustaining life, and hypoxia (a condition of low oxygen) is a significant challenge in various diseases. Microfluidic-based oxygen-releasing biomaterials offer precise control and outstanding performance, providing unique advantages over traditional approaches for tissue engineering. However, comprehensive reviews on this topic are currently lacking. In this review, we provide a comprehensive analysis of various microfluidic technologies and their applications for developing oxygen-releasing biomaterials. We compare the characteristics of organic and inorganic oxygen-releasing biomaterials and highlight the latest advancements in microfluidic-enabled oxygen-releasing biomaterials for tissue engineering, wound healing, and drug delivery. This review may hold the potential to make a significant contribution to the field, with a profound impact on the scientific community.

Programmable Photoswitchable Microcapsules Enable Precise and Tailored Drug Delivery from Microfluidics.

The development of precision personalized medicine poses a significant need for the next generation of advanced diagnostic and therapeutic technologies, and one of the key challenges is the development of highly time-, space-, and dose-controllable drug delivery systems that respond to the complex physiopathology of patient populations. In response to this challenge, an increasing number of stimuli-responsive smart materials are integrated into biomaterial systems for precise targeted drug delivery. Among them, responsive microcapsules prepared by droplet microfluidics have received much attention. In this study, we present a UV-visible light cycling mediated photoswitchable microcapsule (PMC) with dynamic permeability-switching capability for precise and tailored drug release. The PMCs were fabricated using a programmable pulsed aerodynamic printing (PPAP) technique, encapsulating an aqueous core containing magnetic nanoparticles and the drug doxorubicin (DOX) within a poly(lactic-co-glycolic acid) (PLGA) composite shell modified by PEG-b-PSPA. Selective irradiation of PMCs with ultraviolet (UV) or visible light (Vis) allows for high-precision time-, space-, and dose-controlled release of the therapeutic agent. An experimentally validated theoretical model was developed to describe the drug release pattern, holding promise for future customized programmable drug release applications. The therapeutic efficacy and value of patternable cancer cell treatment activated by UV radiation is demonstrated by our experimental results. After in vitro transcatheter arterial chemoembolization (TACE), PMCs can be removed by external magnetic fields to mitigate potential side effects. Our findings demonstrate that PMCs have the potential to integrate embolization, on-demand drug delivery, magnetic actuation, and imaging properties, highlighting their immense potential for tailored drug delivery and embolic therapy.

Enhancing safety in small confined spaces with thermally triggered fire-extinguishing microcapsules from microfluidics.

Fires in small confined spaces have problems such as difficulty extinguishing, fast burning speed, long duration, strong concealment, and untimely warning. Perfluorohexanone-based fire-extinguishing microcapsule technology provides an important solution to overcome these problems. However, due to the poor solubility and high volatility of perfluorohexanone, the preparation of perfluorohexanone fire-extinguishing microcapsules (FEMs) with a high encapsulation rate, good homogeneity, and low processing costs is still a great challenge. Here, we propose a microfluidic flow-focusing technique to realize efficient encapsulation of perfluorohexanone. It is shown that FEMs can spray fire-extinguishing agents at high speeds in the presence of external heat, and only one FEM is needed to extinguish a candle flame much larger than its size. Meanwhile, the extension of FEMs to two-dimensional fire-extinguishing patches (FEPs) has achieved significant results in suppressing fire and preventing fire spread, which is expected to further expand its application in various fire suppression scenarios.

Free-Boundary Microfluidic Platform for Advanced Materials Manufacturing and Applications.

Microfluidics, with its remarkable capacity to manipulate fluids and droplets at the microscale, has emerged as a powerful platform in numerous fields. In contrast to conventional closed microchannel microfluidic systems, free-boundary microfluidic manufacturing (FBMM) processes continuous precursor fluids into jets or droplets in a relatively spacious environment. FBMM is highly regarded for its superior flexibility, stability, economy, usability, and versatility in the manufacturing of advanced materials and architectures. In this review, a comprehensive overview of recent advancements in FBMM is provided, encompassing technical principles, advanced material manufacturing, and their applications. FBMM is categorized based on the foundational mechanisms, primarily comprising hydrodynamics, interface effects, acoustics, and electrohydrodynamic. The processes and mechanisms of fluid manipulation are thoroughly discussed. Additionally, the manufacturing of advanced materials in various dimensions ranging from zero-dimensional to three-dimensional, as well as their diverse applications in material science, biomedical engineering, and engineering are presented. Finally, current progress is summarized and future challenges are prospected. Overall, this review highlights the significant potential of FBMM as a powerful tool for advanced materials manufacturing and its wide-ranging applications.

Controlled Latent Heat Phase-Change Microcapsules for Temperature Regulation.

Microencapsulation of phase-change materials (PCMs) is of great value and significance for improving energy efficiency and reducing carbon dioxide emissions. Here, highly controllable phase-change microcapsules (PCMCs) with hexadecane as the core material and polyurea as the shell material were developed for precise temperature regulation. A universal liquid-driven active flow focusing technique platform was used to adjust the diameter of PCMCs, and the shell thickness can be controlled by adjusting the monomer ratio. In synchronized regime, the droplet size is only related to the flow rate and excitation frequency, which can be accurately predicted by the scaling law. The fabricated PCMCs have uniform particle size with a coefficient of variation (CV) under 2%, smooth surface, and compact structure. Meanwhile, under the good protection of a polyurea shell, PCMCs exhibit fair phase-change performance, strong heat storage capacity, and good thermal stability. The PCMCs with different sizes and wall thickness show obvious differences in thermal properties. The feasibility of the fabricated hexadecane phase-change microcapsules in phase-change temperature regulation was verified by thermal analysis. These features indicate that the developed PCMCs by the active flow focusing technique platform have broad application prospects in thermal energy storage and thermal management.

Magnetic Targeting and Ultrasound Activation of Liposome-Microbubble Conjugate for Enhanced Delivery of Anticancer Therapies.

Effective delivery of chemotherapeutics with minimal toxicity and maximal outcome is clinically important but technically challenging. Here, we synthesize a complex of doxorubicin (DOX)-loaded magneto-liposome (DOX-ML) microbubbles (DOX-ML-MBs) for magnetically responsive and ultrasonically sensitive delivery of anticancer therapies with enhanced efficiency. Citrate-stabilized iron oxide nanoparticles (MNs) of 6.8 ± 1.36 nm were synthesized, loaded with DOX in the core of oligolamellar vesicles of 172 ± 9.2 nm, and covalently conjugated with perfluorocarbon (PFC)-gas-loaded microbubbles to form DOX-ML-MBs of ∼4 µm. DOX-ML-MBs exhibited significant magnetism and were able to release chemotherapeutics and DOX-MLs instantly upon exposure to ultrasound (US) pulses. In vitro studies showed that DOX-ML-MBs in the presence of US pulses promoted apoptosis and were highly effective in killing both BxPc-3 and Panc02 pancreatic cancer cells even at a low dose. Significant reduction in the tumor volume was observed after intravenous administration of DOX-ML-MBs in comparison to the control group in a pancreatic cancer xenograft model of nude mice. Deeply penetrated iron oxide nanoparticles throughout the magnetically targeted tumor tissues in the presence of US stimulation were clearly observed. Our study demonstrated the potential of using DOX-ML-MBs for site-specific targeting and controlled drug release. It opens a new avenue for the treatment of pancreatic cancer and other tissue malignancies where precise delivery of therapeutics is necessary.

Coaxial oblique interface shearing: tunable generation and sorting of double emulsions for spatial gradient drug release.

We propose a coaxial oblique interface shearing (COIS) process for one-step generation of double emulsions which are synchronously sorted with spatial gradient distributions. As a coaxial needle supplying the inner and outer liquids obliquely vibrates across an air-liquid interface, the pinch-off of the compound liquid neck arises and the resultant double emulsions moves with tunable lateral displacements in the receiving phase. In the COIS process, the morphology and size of the double emulsions are heavily dependent on the vibration frequency and the inner and outer liquid flow rates. The lateral droplet displacements changing with process parameters can be precisely controlled in experiments and predicted theoretically by the Stokes drift model. Furthermore, the feasibility of the COIS process in spatial gradient drug release is verified. The double emulsions sorted along a specific direction are available for spatial gradient release under thermal and chemical environments, respectively. The COIS technique has great potential in fields of sensors, spatial gradient materials, advanced drug delivery and biomedical applications.

Synthesis of a functionalized dipeptide for targeted delivery and pH-sensitive release of chemotherapeutics.

Targeted delivery of chemotherapeutics to tumor cells is one of the biggest challenges in cancer treatment. Herein, we synthesized smart dipeptide nanoparticles for cancer-specific targeting and intracellular pH-sensitive release of chemotherapeutics. Diphenylalanine peptide was synthesized and further developed as nanoparticles (NPs), which were functionalized with folic acid utilizing the carbodiimide reaction. Doxorubicin (Dox) was loaded to self-assembled non-functionalized (FF-Dox) and folate functionalized peptides NPs (FA-FF-Dox). Moreover, the experiments revealed the pH-sensitive release of Dox for both FA-FF-Dox and FF-Dox due to the protonation of the Schiff base and the amines present in the peptides at low pH, enhancing intracellular release subsequent to receptor-mediated endocytosis. Further, biodistribution and the pharmacokinetics study revealed enhanced targeting efficiency of FA-FF-Dox with high accumulation in tumor cells.

On-Demand Generation of Double Emulsions Based on Interface Shearing for Controlled Ultrasound Activation.

Stimuli-responsive microcarriers (SRMs) based on multiple emulsions can be widely used in advanced drug delivery, tissue engineering, biosensing, and cell biology. Here a simple and effective compound interface shearing (CIS) method is proposed to one-step produce SRMs for controlled ultrasound (US) activation. In the CIS process, a coaxial needle supplying the core and shell liquids vibrates periodically across a free gas-liquid surface, resulting in the pinch-off of a compound liquid neck for on-demand generation of multiple emulsions. The CIS process is free of confined walls with a pure interface shearing mechanism. Perfectly uniform SRMs with tunable core-shell volume ratios can be produced, following a scaling law of their size as a function of the liquid flow rates and the vibration frequency. US- and magnetic-responsive microcapsules are prepared for magnetic-guided site-targeting delivery, and acid-aided sequential US activation realizes the synergistic delivery of hydrophilic and hydrophobic payloads. It can be concluded that the CIS technique is able to generate multifunctional SRMs at low cost, high uniformity, high flexibility, and effective process control for various fields of potential applications.

Engineered multifunctional biodegradable hybrid microparticles for paclitaxel delivery in cancer therapy.

Ovarian cancer is one of the most lethal gynecologic malignancies due to its rapid proliferation, frequent acquisition of chemoresistance, and widespread metastasis within the peritoneal cavity. Intraperitoneal (IP) chemotherapy has demonstrated significant anti-cancer potential but its broad clinical application is hindered by several drug delivery limitations. Herein, we engineer paclitaxel (PTX) laden hybrid microparticles (PTX-Hyb-MPs) for improved delivery of chemotherapy in ovarian cancer. The PTX-Hyb-MPs are comprised of a lipid-coated shell of poly (lactic acid-co-glycolic acid) (PLGA) encapsulating hydrophobic PTX. A co-axial electrohydrodynamic (CEH) process is used for one-step and scalable production of the PTX-Hyb-MP agent with controlled particles size, uniform size distribution, tunable thickness, and high encapsulation rate (92.17 ±â€¯6.9%). The multi-layered structure of the PTX-Hyb-MPs is verified by transmission electron microscopy and confocal fluorescence microscopy. The effect of lipid coating on the enhancement of particle interactions with cancer cells is studied by flow cytometry and confocal fluorescence microscopy. The anti-cancer effect of the PTX-Hyb-MPs is evaluated in SKOV-3 ovarian cancer cells in vitro and a cancer xenograft model in vivo, in comparison with conventional drug delivery methods. Our studies reveal that the PTX-Hyb-MP agent can be potentially used for locoregional treatment of ovarian cancer and other tissue malignancies with sustained drug release, tunable release profiles, enhanced drug uptake, and reduced systemic toxicity.

Oblique interface shearing (OIS): single-step microdroplet generation and on-demand positioning.

A new process for simultaneous generation and positioning of microdroplets within a single step named oblique interface shearing (OIS) is reported based on the observation that liquid microdroplets generated by vibrating a thin capillary across the air-liquid interface at an oblique angle exhibit notable lateral displacements. An analytical model is established to describe the lateral droplet displacement induced by the Stokes drift effect. The dependency of the lateral displacement on typical operating parameters allows for on-demand droplet positioning while they are produced. The efficacy of the process is validated through delivering microdroplets with the same size to different positions as well as size-dependent positioning of these microdroplets.