Thermo-Responsive Microcapsules with Tunable Molecular Permeability for Controlled Encapsulation and Release

Microcapsules with regulated transmembrane transport are of great importance for various applications. The membranes with a tunable cut-off threshold of permeation provide advanced functionality. Here, thermo-responsive microcapsules are designed, whose hydrogel membrane shows a tunable cut-off threshold of permeation with temperature. To produce the microcapsules, water-in-oil-in-water (W/O/W) double-emulsion droplets are microfluidically produced, whose oil shell contains oil-soluble hydrogel precursor of poly(N, N-diethylacrylamide) copolymerized with benzophenone (PDEAM-BP). The PDEAM hydrogels, crosslinked by BP, show volume-phase transition around 34 °C, which makes the microcapsules with the PDEAM hydrogel membrane thermo-responsive. The microcapsules show temperature-dependent changes in radius and membrane thickness. More importantly, the cut-off threshold of permeation can be reversibly adjusted by temperature control as the degree of swelling decreases with temperature. This enables the molecule-selective encapsulation and the controlled release of the encapsulants in a programmed manner by adjusting the temperature. The microcapsules can be rendered to be photo-responsive by encapsulating photothermal polydopamine nanoparticles during the microfluidic operation, which allows the control of the degree of swelling with near-infrared (NIR) irradiation. The thermo- and photo-responsive microcapsules with a tunable cut-off threshold are appealing as a new platform for drug carriers, microreactors, and microsensors.     

Packing of Emulsion Droplets: Structural and Functional Motifs for Multi‐Cored Microcapsules

Advances in microfluidic emulsification have enabled the creation of multiphase emulsion drops, which have emerged as promising templates for producing functional microcapsules. However, most previous micro‐encapsulation methods have limitations in terms of capsule stability, functionality, and simplicity of fabrication procedures. Here, we report a simple single‐step encapsulation technique that uses an optofluidic platform to efficiently and precisely encapsulate a specific number of emulsion droplets in photocurable shell droplets. In particular, we show, for the first time, that densely confined core droplets within an oily shell droplet rearrange into a unique configuration that minimizes the interfacial energy, as confirmed here from theory. These structures are then consolidated into multi‐cored microcapsules with structural and mechanical stability through in situ photopolymerization of the shell in a continuous mode, which are capable of isolating active materials and releasing them in a controlled manner using well‐defined nanohole arrays or nanoscopic silver architectures on thin membranes.     

Polymer Microparticles with Controllable Surface Textures Generated through Interfacial Instabilities of Emulsion Droplets

A general and versatile route to prepare hierarchical polymer microparticles via interfacial instabilities of emulsion droplets is demonstrated. Uniform emulsion droplets containing hydrophobic polymers and n‐hexadecanol (HD) are generated through microfluidic devices. When organic solvent diffuses through the aqueous phase and evaporates, shrinking emulsion droplets containing HD and polystyrene (PS) will trigger interfacial instabilities to form microparticles with wrinkled surfaces. Interestingly, surface‐textures of the particles can be accurately tailored from smooth to high textures by varying the HD concentration and/or the rate of solvent evaporation. Moreover, composite particles can be generated by suspending different hydrophobic species to the initial polymer solutions. This versatile approach for preparing particles with highly textured surfaces can be extended to other type of hydrophobic polymers which will find potential applications in the fields of drug delivery, tissue engineering, catalysis, coating, and device fabrication.     

Microcapsules: Packing of Emulsion Droplets: Structural and Functional Motifs for Multi‐Cored Microcapsules (Adv. Funct. Mater. 9/2011)

Advances in microfluidic emulsification have enabled the creation of multiphase emulsion drops, which have emerged as promising templates for producing functional microcapsules. However, most previous micro‐encapsulation methods have limitations in terms of capsule stability, functionality, and simplicity of fabrication procedures. Here, we report a simple single‐step encapsulation technique that uses an optofluidic platform to efficiently and precisely encapsulate a specific number of emulsion droplets in photocurable shell droplets. In particular, we show, for the first time, that densely confined core droplets within an oily shell droplet rearrange into a unique configuration that minimizes the interfacial energy, as confirmed here from theory. These structures are then consolidated into multi‐cored microcapsules with structural and mechanical stability through in situ photopolymerization of the shell in a continuous mode, which are capable of isolating active materials and releasing them in a controlled manner using well‐defined nanohole arrays or nanoscopic silver architectures on thin membranes.     

Biasing Buckling Direction in Shape‐Programmable Hydrogel Sheets with Through‐Thickness Gradients

A photocrosslinkable poly( N , N ′‐diethylacrylamide) copolymer allows for the photolithographic fabrication of hydrogel sheets with nonuniform crosslinking density and swelling ratio. Using this material system, different 3D shapes with nonzero Gaussian curvature K are successfully programmed by prescribing a “metric” defined by in‐plane variations in swelling. However, this methodology does not control the direction of buckling adopted by each positive K feature, and therefore cannot controllably select between different isometric shapes defined by a single metric. Here, by introducing gradients in swelling through the thickness of the gel sheet by tuning the absorption of the UV‐light used for crosslinking, a preferential buckling direction is locally specified for each feature by the direction of UV exposure. By also controlling the strength of coupling between neighboring features, this is shown to be an effective method to program buckling direction of each unit within a canonical corrugated surface shape.     

Salt‐Assisted Toughening of Protein Hydrogel with Controlled Degradation for Bone Regeneration

Recently, strong polymer‐based hydrogels have been intensively investigated. However, the development of tough protein hydrogels with controlled degradation for bone regeneration has rarely been reported. Here, regenerated silk fibroin/gelatin (RSF/G) hydrogels with both strength and controlled degradation are prepared via physically and chemically double‐crosslinked networks. As a representative example, the 9%RSF/3%G hydrogel shows approximately 80% elongation and a compressive and tensile modulus of up to 0.25 and 0.21 MPa, respectively. It also shows a degradation rate that can be adjusted to approximately three months in vivo, a value between that of the rapidly degrading gelatin hydrogel and the slowly degrading RSF hydrogel. The 9%RSF/3%G hydrogel has good biocompatibility and promotes the proliferation and differentiation of bone marrow–derived stem cells compared with the control and pure RSF hydrogels. At 12 weeks after implantation of the gel in a calvarial defect, micro‐computed tomography shows greater bone volume and bone mineral density in the 9%RSF/3%G group. More importantly, histology reveals more mineralization and enhancements in the quality and rate of bone regeneration with less of a tissue response in the 9%RSF/3%G group. These results indicate the promising potential of this tough protein hydrogel with controlled degradation for bone regeneration applications.     

Micropatterned Protein for Cell Adhesion through Phototriggered Charge Change in a Polyvinylpyrrolidone Hydrogel

Regulated immobilization of proteins on hydrogels allows for the creation of highly controlled microenvironments to meet the special requirements of cell biology and tissue engineering devices. Light is an ideal stimulus to regulate immobilization because it can be controlled in time, space, and intensity. Here, a photoresponsive hydrogel that enables the patterning of proteins by a combination of electrostatic adsorption and photoregulated charge change on a hydrogel is developed. It is based on a photosensitive cationic monomer ( CLA ), a coumarin caged lysine betaine zwitterion, incorporated into a polyvinylpyrrolidone ( PVP ) hydrogel, which can controllably change the charge from an adhesive positive state to an anti‐adhesive zwitterion state upon irradiation at 365 nm. With this strategy, the immobilization of proteins is regulated and cell adhesion is programmed on hydrogels on demand. This approach should open up new avenues for hydrogels in biomedical applications.     

“Suction Caps”: Designing Anisotropic Core/Shell Microcapsules with Controlled Membrane Mechanics and Substrate Affinity

Core/shell microcapsules with low‐permeability membranes and controlled morphology are crucial for the delivery and controlled release of fragrance molecules, pharmaceuticals, inks, or vitamins. Design criteria for next generation microcapsules must include chemical and mechanical stability, and also provide enhanced substrate interactions to improve deposition onto relevant complex surfaces. Here, a coupled approach is presented to synthesize core/shell delivery systems by interfacial polymerization to enhance both the microcapsule–substrate interactions and the mechanical properties of the capsules to induce a burst‐type release. By combining membrane synthesis, nonlinear mechanics, interfacial rheology, analysis of mass transfer, and capsule morphology generated during interfacial polymerization, large permanent deformations into the capsule geometry are programmed, resulting in chemically stable, yet mechanically rupturing microcapsules with anisotropic geometry. To promote interactions and capsule adhesion onto complex substrates, the capsule contact area is controlled to form prominent “suction cup” shaped rims. These capsules have favorable, far‐reaching electrostatic interactions with oppositely charged substrates such as glass, hair, skin, or fabric. By modulating membrane mechanical properties and morphology during synthesis, formulation‐independent physical criteria are used to improve the overall performance of a functional delivery system while expanding knowledge of the key parameters influencing the interfacial polymerization process and membrane formation.     

3D Printing Hydrogel Scaffolds with Nanohydroxyapatite Gradient to Effectively Repair Osteochondral Defects in Rats

Osteochondral (OC) defects pose an enormous challenge with no entirely satisfactory repair strategy to date. Herein, a 3D printed gradient hydrogel scaffold with a similar structure to that of OC tissue is designed, involving a pure hydrogel-based top cartilage layer, an intermediate layer for calcified cartilage with 40% (w w⁻¹) nanohydroxyapatite (nHA) and 60% (w w⁻¹) hydrogel, and a 70/30% (w w⁻¹) nHA/hydrogel-based bottom subchondral bone layer. This study is conducted to evaluate the efficacy of the scaffold with nHA gradients in terms of its ability to promote OC defect repair. The fabricated composites are evaluated for physicochemical, mechanical, and biological properties, and then implanted into the OC defects in 56 rats. Overall, bone marrow stromal cells (BMSCs)-loaded gradient scaffolds exhibit superior repair results as compared to other scaffolds based on gross examination, micro-computed tomography (micro-CT), as well as histologic and immunohistochemical analyses, confirming the ability of this novel OC graft to facilitate simultaneous regeneration of cartilage-subchondral bone.     

Injectable Hydrogel with NIR Light-Responsive,Dual-Mode PTH Release for Osteoregeneration in Osteoporosis

Effective treatments to overcome osteoblast/osteoclast imbalance are the key to achieving desirable bone regeneration for osteoporosis patients. When used for local bone repair, parathyroid hormone (PTH) often leads to either excessive osteoclasts under continuous exposure or insufficient osteoclasts with pulsatile release of PTH. Herein, an injectable multifunctional in situ-generated calcium phosphate nanoparticle (ICPN)-coordinated poly(dimethylaminoethyl methacrylate-co-2-hydroxyethyl methacrylate) (DHCP) hydrogel loaded with PTH for near-infrared (NIR)-stimulated release is developed to achieve bone regeneration in an ovariectomized (OVX) model. Photothermal-responsive poly(N-acryloyl glycinamide-co-acrylamide) PNAm-indocyanine green ICG-PTH microspheres (PIP MSs) endow a dual-mode release system with a sustained release at low concentrations, a pulse release of PTH, and in situ pore formation properties. The PIP MS-encapsulated DHCP hydrogel (DHCP-10PIP/d) is injected into the bone defects of OVX rats. Under NIR irradiation, the localized photothermal effects trigger on-demand PTH release and in situ micropores formation through the gel–sol transition of PIP MSs, and the repeated treatment is harmless to the bioactivity of PTH. This platform can enhance osteoblast and osteoclast activity at the same time both in vitro and in vivo and repair the cranial defects of OVX rats successfully. Overall, this work provides a promising strategy for PTH delivery to repair osteoporotic bone defects.     

A Bright Two-Photon Lipid Droplets Probe with Viscosity-Enhanced Solvatochromic Emission for Visualizing Lipid Metabolic Disorders in Deep Tissues

The polarity of lipid droplets (LDs) plays an important role in pathological processes associated with abnormal lipid metabolism. Monitoring the variation of LDs polarity in cells and tissues is of great importance in biomedical research and clinical diagnosis. However, developing fluorescent LDs-specific probes with high polarity sensitivity, brightness, and permeability for deep tissue imaging is still challenging. Herein, a push–pull fluorescent luminogen (DPBT) with aggregation-induced emission, strong solvatochromism, large Stokes shift, high solid-state fluorescence efficiency and superior two-photon absorption is facilely developed. The lipophilic DPBT can specifically stain LDs with high biocompatibility and good photostability. The viscosity-enhanced solvatochromic emission property enables DPBT to visualize LDs polarity with high brightness and imaging contrast, and deep penetration depth under two-photon microscopy. DPBT can specifically stain lipids in various mouse tissues (atherosclerotic plaque, liver, and mesenteric adipose tissues) and map their polarity distribution to reflect lipid metabolic states within those tissues. It is found that the lipids deposition as well as their polarity distribution in tissues of hyperlipoidemia mouse are clearly different from the tissues of the normal mouse. Its excellent properties make DPBT a promising candidate for investigating LDs-associated physiological and pathological processes in live biological samples.     

Human Cell Encapsulation in Gel Microbeads with Cosynthesized Concentric Nanoporous Solid Shells

Encapsulation of therapeutic cells in core–shell microparticles has great promise for the treatment of a range of health conditions. Unresolved challenges related to control of the particle morphology, mechanical stability, and immunogenicity hinder dissemination of this promising approach. Here, a novel polymer material for cell encapsulation and a combined novel, easy to control, synthesis method are introduced. Core–shell cell encapsulation is demonstrated with a concentric core–shell morphology formed during a single UV exposure, resulting in particles that consist of a synthetic hydrogel core of polyethylene glycol diacrylate and a solid, but porous, shell of off‐stoichiometric thiol‐ene. The encapsulated human cells in 100 µm diameter particles have >90% viability. The average shell thickness is controlled between 7 and 13 µm by varying the UV exposure, and the shell is measured to be permeable to low molecular weight species (<180 Da) but impermeable to higher molecular weight species (>480 Da). The unique material properties and the orthogonal control of the microparticle core size, shell thickness, shell permeability, and shell surface properties address the key unresolved challenges in the field, and are expected to enable faster translation of novel cell therapy concepts from research to clinical practice.