Hydrogel microparticles (HMPs) are promising for biomedical applications, ranging from the therapeutic delivery of cells and drugs to the production of scaffolds for tissue repair and bioinks for 3D printing. Biologics (cells and drugs) can be encapsulated into HMPs of predefined shapes and sizes using a variety of fabrication techniques (batch emulsion, microfluidics, lithography, electrohydrodynamic (EHD) spraying and mechanical fragmentation). HMPs can be formulated in suspensions to deliver therapeutics, as aggregates of particles (granular hydrogels) to form microporous scaffolds that promote cell infiltration or embedded within a bulk hydrogel to obtain multiscale behaviours. HMP suspensions and granular hydrogels can be injected for minimally invasive delivery of biologics, and they exhibit modular properties when comprised of mixtures of distinct HMP populations. In this Review, we discuss the fabrication techniques that are available for fabricating HMPs, as well as the multiscale behaviours of HMP systems and their functional properties, highlighting their advantages over traditional bulk hydrogels. Furthermore, we discuss applications of HMPs in the fields of cell delivery, drug delivery, scaffold design and biofabrication.

Hydrogel microparticles for biomedical applications.

Droplet microfluidics offers exquisite control over the flows of multiple fluids in microscale, enabling fabrication of advanced microparticles with precisely tunable structures and compositions in a high throughput manner The combination of these remarkable features with proper materials and fabrication methods has enabled high efficiency, direct encapsulation of actives in microparticles whose features and functionalities can be well controlled These microparticles have great potential in a wide range of bio-related applications including drug delivery, cell-laden matrices, biosensors and even as artificial cells In this review, we briefly summarize the materials, fabrication methods, and microparticle structures produced with droplet microfluidics We also provide a comprehensive overview of their recent uses in biomedical applications Finally, we discuss the existing challenges and perspectives to promote the future development of these engineered microparticles

/pdf/microfluidic-fabrication-of-microparticles-for-biomedical-2tsrw0ufu5.pdf

Microfluidic fabrication of microparticles for biomedical applications

The emergence and spread of antibiotic-resistant bacteria are aggravated by incorrect prescription and use of antibiotics. A core problem is that there is no sufficiently fast diagnostic test to guide correct antibiotic prescription at the point of care. Here, we investigate if it is possible to develop a point-of-care susceptibility test for urinary tract infection, a disease that 100 million women suffer from annually and that exhibits widespread antibiotic resistance. We capture bacterial cells directly from samples with low bacterial counts (104 cfu/mL) using a custom-designed microfluidic chip and monitor their individual growth rates using microscopy. By averaging the growth rate response to an antibiotic over many individual cells, we can push the detection time to the biological response time of the bacteria. We find that it is possible to detect changes in growth rate in response to each of nine antibiotics that are used to treat urinary tract infections in minutes. In a test of 49 clinical uropathogenic Escherichia coli (UPEC) isolates, all were correctly classified as susceptible or resistant to ciprofloxacin in less than 10 min. The total time for antibiotic susceptibility testing, from loading of sample to diagnostic readout, is less than 30 min, which allows the development of a point-of-care test that can guide correct treatment of urinary tract infection.

https://www.pnas.org/content/pnas/114/34/9170.full.pdf

Antibiotic susceptibility testing in less than 30 min using direct single-cell imaging

Injectable Microfluidic Hydrogel Microspheres for Cell and Drug Delivery

Hydrogel scaffolds that template the regeneration of tissue structures are widely explored; however, there is often a trade‐off between material properties, such as stiffness and interconnected pore size, that may be equally important in supporting tissue growth. Microporous annealed particle scaffolds are introduced to address this trade‐off while maintaining a flowable precursor; however, manufacturing throughput, reproducibility, and flexibility of hydrogel microparticle building blocks are limited, hindering widespread adoption. The scalable high‐throughput production of bioactive microgels for the formation of microporous tissue scaffolds in situ is presented. Using a parallelized step emulsification device, scalable high‐throughput generation of monodisperse microgels is achieved. Crosslinking is initiated downstream of droplet generation using pH modulation via proton acceptors dissolved in the oil phase. This approach enables continuous production of microgels for over 12 h while ensuring highly uniform physicochemical properties. Using this platform, the effects of local matrix stiffness on cell growth orthogonal to scaffold porosity are studied. Formation of injectable cell‐laden mechanically heterogeneous microporous scaffolds is also demonstrated. This approach is particularly suited for the formation of modular, multimaterial scaffolds in situ, which could be applied to 3D bioprinting or to form more complex scaffolds to enhance regeneration of irregular wounds.

Scalable High‐Throughput Production of Modular Microgels for In Situ Assembly of Microporous Tissue Scaffolds

Microfluidic techniques for high throughput single cell analysis

PEG-based hydrogels have become widely used as drug delivery and tissue scaffolding materials. Common among PEG hydrogel-forming polymers are photopolymerizable acrylates such as polyethylene glycol diacrylate (PEGDA). Microfluidics and microfabrication technologies have recently enabled the miniaturization of PEGDA structures, thus enabling many possible applications for nano- and micro- structured hydrogels. The presence of oxygen, however, dramatically inhibits the photopolymerization of PEGDA, which in turn frustrates hydrogel formation in environments of persistently high oxygen concentration. Using PEGDA that has been emulsified in fluorocarbon oil via microfluidic flow focusing within polydimethylsiloxane (PDMS) devices, we show that polymerization is completely inhibited below critical droplet diameters. By developing an integrated model incorporating reaction kinetics and oxygen diffusion, we demonstrate that the critical droplet diameter is largely determined by the oxygen transport rate, which is dictated by the oxygen saturation concentration of the continuous oil phase. To overcome this fundamental limitation, we present a nitrogen micro-jacketed microfluidic device to reduce oxygen within the droplet, enabling the continuous on-chip photopolymerization of microscale PEGDA particles.

Monodisperse polyethylene glycol diacrylate hydrogel microsphere formation by oxygen-controlled photopolymerization in a microfluidic device

Cell encapsulation within photopolymerized polyethylene glycol (PEG)-based hydrogel scaffolds has been demonstrated as a robust strategy for cell delivery, tissue engineering, regenerative medicine, and developing in vitro platforms to study cellular behavior and fate. Strategies to achieve spatial and temporal control over PEG hydrogel mechanical properties, chemical functionalization, and cytocompatibility have advanced considerably in recent years. Recent microfluidic technologies have enabled the miniaturization of PEG hydrogels, thus enabling the fabrication of miniaturized cell-laden vehicles. However, rapid oxygen diffusive transport times on the microscale dramatically inhibit chain growth photopolymerization of polyethylene glycol diacrylate (PEGDA), thus decreasing the viability of cells encapsulated within these microstructures. Another promising PEG-based scaffold material, PEG norbornene (PEGNB), is formed by a step-growth photopolymerization and is not inhibited by oxygen. PEGNB has also been shown to be more cytocompatible than PEGDA and allows for orthogonal addition reactions. The step-growth kinetics, however, are slow and therefore challenging to fully polymerize within droplets flowing through microfluidic devices. Here, we describe a microfluidic-based droplet fabrication platform that generates consistently monodisperse cell-laden water-in-oil emulsions. Microfluidically generated PEGNB droplets are collected and photopolymerized under UV exposure in bulk emulsions. In this work, we compare this microfluidic-based cell encapsulation platform with a vortex-based method on the basis of microgel size, uniformity, post-encapsulation cell viability and long-term cell viability. Several factors that influence post-encapsulation cell viability were identified. Finally, long-term cell viability achieved by this platform was compared to a similar cell encapsulation platform using PEGDA. We show that this PEGNB microencapsulation platform is capable of generating cell-laden hydrogel microspheres at high rates with well-controlled size distributions and high long-term cell viability.

/pdf/a-microfluidic-based-cell-encapsulation-platform-to-achieve-1pnqb8m28h.pdf

A microfluidic-based cell encapsulation platform to achieve high long-term cell viability in photopolymerized PEGNB hydrogel microspheres

Encapsulating cells within biocompatible materials is a widely pursued and promising element of tissue engineering and cell-based therapies. Recently, extensive interest in microfluidic-enabled cell encapsulation has emerged as a strategy to structure hydrogels and establish custom cellular microenvironments. In particular, it has been shown that the microfluidic-enabled photoencapsulation of cells within PEG diacrylate (PEGDA)-based microparticles can be performed cytocompatibly within gas-permeable, nitrogen-jacketed polydimethylsiloxane microfluidic devices, which mitigate the oxygen inhibition of radical chain growth photopolymerization. Compared to bulk polymerization, in which cells are suspended in a static hydrogel-forming solution during gelation, encapsulating cells via microfluidic processing exposes cells to a host of potentially deleterious stresses such as fluidic shear rate, transient oxygen depletion, elevated pressures, and UV exposure. In this work, we systematically examine the effects of these factors on the viability of cells that have been microfluidically photoencapsulated in PEGDA. It was found that the fluidic shear rate during microdroplet formation did not have a direct effect on cell viability, but the flow rate ratio of oil to aqueous solution would impart harmful effects to cells when a critical threshold was exceeded. The effects of UV exposure time and intensity on cells, however, are more complex, as they contribute unequally to the cumulative rate of peroxy radical generation, which is strongly correlated with cell viability. A reaction-diffusion model has been developed to calculate the cumulative peroxy radical concentration over a range of UV light intensity and radiation times, which was used to gain further quantitative understanding of experimental results. Conclusions drawn from this work provide a comprehensive guide to mitigate the physical and biochemical damage imparted to cells during microfluidic photoencapsulation and expands the potential for this technique.

/pdf/cytocompatible-cell-encapsulation-via-hydrogel-1wgazqohp4.pdf

Cytocompatible cell encapsulation via hydrogel photopolymerization in microfluidic emulsion droplets.

Provided herein are methods utilizing microfluidics for the oxygen-controlled generation of microparticles and hydrogels having controlled microparticle sizes and size distributions and products from provided methods. The included methods provide the generation of microparticles by polymerizing an aqueous solution dispersed in a non-aqueous continuous phase in an oxygen-controlled environment. The process allows for control of size of the size of the aqueous droplets and, thus, control of the size of the generated microparticles which may be used in biological applications.

Methods of generating microparticles and porous hydrogels using microfluidics

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