Engineering Natural Pollen Grains as Multifunctional 3D Printing Materials

The development of multifunctional 3D printing materials from sustainable natural resources is a high priority in additive manufacturing. Using an eco-friendly method to transform hard pollen grains into stimulus-responsive microgel particles, we engineered a pollen-derived microgel suspension that can serve as a functional reinforcement for composite hydrogel inks and as a supporting matrix for versatile freeform 3D printing systems. The pollen microgel particles enabled the printing of composite inks and improved the mechanical and physiological stabilities of alginate and hyaluronic acid hydrogel scaffolds for 3D cell culture applications. Moreover, the particles endowed the inks with stimulus-responsive controlled release properties. The suitability of the pollen microgel suspension as a supporting matrix for freeform 3D printing of alginate and silicone rubber inks was demonstrated and optimized by tuning the rheological properties of the microgel. Compared with other classes of natural materials, pollen grains have several compelling features, including natural abundance, renewability, affordability, processing ease, monodispersity, and tunable rheological features, which make them attractive candidates to engineer advanced materials for 3D printing applications.     

Surface-Triggered In Situ Gelation for Tunable Conformal Hydrogel Coating of Therapeutic Cells and Biomedical Devices

Hydrogel coatings have been proposed as a promising strategy to improve the biocompatibility of therapeutic cells and biomedical devices. However, developed coating methods are only applicable for simple geometries, typical sizes, and limited substrates. In addition, its applications in therapeutic cell encapsulation are hampered by inadequate construction of the hydrogel capsules such as off-center encapsulation, immense volume, and lack of control over the thickness of capsules. Here, a method called surface-triggered in situ gelation (STIG) for universal hydrogel coating of multiscale objects ranging from single cells to mini-organs to biomedical devices with arbitrary shapes and heterogeneous components is reported. By covering cells or devices with calcium carbonate particles, progressive propagation of alginate hydrogel from their surface under the stimulation of GDL is achieved. The thickness of the hydrogel layers can be easily controlled from several micrometers to hundreds of micrometers by adjusting the gelation time and the release rate of calcium ions. Importantly, STIG facilitates accurate, complete, and individual cell encapsulation, which potentially overcomes the pitfalls of conventional strategies. It is further proven that the low-cost and facile method can potentially lead to advances in different fields by rendering precisely controlled microscale alginate layers on a wide variety of biomedical substrates.     

Bioorthogonal Strategies for Engineering Extracellular Matrices

Hydrogels are commonly used as engineered extracellular matrix (ECM) mimics in applications ranging from tissue engineering to in vitro disease models. Ideal mechanisms used to crosslink ECM‐mimicking hydrogels do not interfere with the biology of the system. However, most common hydrogel crosslinking chemistries exhibit some form of crossreactivity. The field of bioorthogonal chemistry has arisen to address the need for highly specific and robust reactions in biological contexts. Accordingly, bioorthogonal crosslinking strategies are incorporated into hydrogel design, allowing for gentle and efficient encapsulation of cells in various hydrogel materials. Furthermore, the selective nature of bioorthogonal chemistries can permit dynamic modification of hydrogel materials in the presence of live cells and other biomolecules to alter matrix mechanical properties and biochemistry on demand. This review provides an overview of bioorthogonal strategies used to prepare cell‐encapsulating hydrogels and highlights the potential applications of bioorthogonal chemistries in the design of dynamic engineered ECMs.     

Injectable Microfluidic Hydrogel Microspheres for Cell and Drug Delivery

Microfluidic hydrogel microspheres have been broadly studied across a wide range of industries and applications, and their use in the medical field, including control cells and drug delivery, is increasing. The usual design of these materials is intended to enable the efficient and smart encapsulation of cells and/or drugs in microspheres in which the functionalities and features are effectively controlled, lending itself some unique properties. These characteristics promote exchanges and cooperation in multiple disciplines and boost the development of precision medicine, new manufacturing technologies, and applied materials. This review begins with a discussion of microfluidic hydrogel microspheres and then introduces the preparation equipment, main principles, and related characteristics of the microspheres. Furthermore, the medical applications of microfluidic hydrogel microspheres for delivering cells and drugs are emphasized. Finally, this review discusses perspectives and future directions for accelerating the development and application of microfluidic hydrogel microspheres for controlled delivery.     

Novel Biocompatible Polysaccharide‐Based Self‐Healing Hydrogel

A novel biocompatible polysaccharide‐based self‐healing hydrogel, CEC‐l‐OSA‐l‐ADH hydrogel (“l” means “linked‐by”), is developed by exploiting the dynamic reaction of N‐carboxyethyl chitosan (CEC) and adipic acid dihydrazide (ADH) with oxidized sodium alginate (OSA). The self‐healing ability, as demonstrated by rheological recovery, macroscopic observation, and beam‐shaped strain compression measurement, is attributed to the coexistence of dynamic imine and acylhydrazone bonds in the hydrogel networks. The CEC‐l‐OSA‐l‐ADH hydrogel shows excellent self‐healing ability under physiological conditions with a high healing efficiency (up to 95%) without need for any external stimuli. In addition, the CEC‐l‐OSA‐l‐ADH hydrogel exhibits good cytocompatibility and cell release as demonstrated by three‐dimensional cell encapsulation. With these superior properties, the developed hydrogel holds great potential for applications in various biomedical fields, e.g., as cell or drug delivery carriers.     

Poly(N‐isopropylacrylamide)‐Clay Nanocomposite Hydrogels with Responsive Bending Property as Temperature‐Controlled Manipulators

Novel poly(N‐isopropylacrylamide)‐clay (PNIPAM‐clay) nanocomposite (NC) hydrogels with both excellent responsive bending and elastic properties are developed as temperature‐controlled manipulators. The PNIPAM‐clay NC structure provides the hydrogel with excellent mechanical property, and the thermoresponsive bending property of the PNIPAM‐clay NC hydrogel is achieved by designing an asymmetrical distribution of nanoclays across the hydrogel thickness. The hydrogel is simply fabricated by a two‐step photo polymerization. The thermoresponsive bending property of the PNIPAM‐clay NC hydrogel is resulted from the unequal forces generated by the thermoinduced asynchronous shrinkage of hydrogel layers with different clay contents. The thermoresponsive bending direction and degree of the PNIPAM‐clay NC hydrogel can be adjusted by controlling the thickness ratio of the hydrogel layers with different clay contents. The prepared PNIPAM‐clay NC hydrogels exhibit rapid, reversible, and repeatable thermoresponsive bending/unbending characteristics upon heating and cooling. The proposed PNIPAM‐clay NC hydrogels with excellent responsive bending property are demonstrated as temperature‐controlled manipulators for various applications including encapsulation, capture, and transportation of targeted objects. They are highly attractive material candidates for stimuli‐responsive “smart” soft robots in myriad fields such as manipulators, grippers, and cantilever sensors.     

Hydration-Induced Void-Containing Hydrogels for Encapsulation and Sustained Release of Small Hydrophilic Molecules

Efficient encapsulation and sustained release of small hydrophilic molecules from traditional hydrogel systems are challenging due to the large mesh size of 3D networks and high water content. Furthermore, the encapsulated molecules are prone to early release from the hydrogel prior to use, resulting in a short shelf life of the formulation. Here, a hydration-induced void-containing hydrogel (HVH) based on hyperbranched polyglycerol-poly(propylene oxide)-hyperbranched polyglycerol (HPG-PPG-HPG) as a robust and efficient delivery system is presented for small hydrophilic molecules. Specifically, after the HPG-PPG-HPG is incubated overnight at 4 °C in the drug solution, it is hydrated into a hydrogel containing micron-sized voids, which can encapsulate hydrophilic drugs and achieve 100% drug encapsulation efficiency. In addition, the voids are surrounded by a densely packed polymer matrix, which restricts drug transport to achieve sustained drug release. The hydrogel/drug formulation can be stored for several months without changing the drug encapsulation and release properties. HVH hydrogels are injectable due to shear thinning properties. In rats, a single injection of the HPG-PPG-HPG hydrogel containing 8 µg of tetrodotoxin (TTX) produces sciatic nerve block lasting up to 10 h without any TTX-related systemic toxicity nor local toxicity to nerves and muscles.     

Functionalized Microparticles Producing Scaffolds in Combination with Cells

The development of biologically instructive biomaterials with application for tissue regeneration has become the focus of intense research over the last years. This work reports a novel approach for the production of three‐dimensional constructs for tissue engineering applications based on the assembly of chitosan microparticles exhibiting specific biological response with cells. Chitosan microparticles with a size range between 20 and 70 μm are functionalized with platelet derived growth factor (PDFG‐BB). The functionalization is achieved by previous immobilization of an anti‐PDGF‐BB antibody, using a water‐soluble carbodiimide. When incubated with a cocktail of growth factors‐platelet lysates, the previously functionalized particles are able to target PDGF‐BB from the protein mixture. In vitro studies are carried out focusing on the ability of these systems to promote the assembly into a stable 3D construct triggered by the presence of human adipose stem cells, which act as crosslinker agents and induce the formation of a hydrogel network. The presence of immobilized growth factors gives to this system a biological functionality towards control on cell function. It is also bioresponsive, as cells drive the assembly process of the microgel. These versatile biomimetic microgels may provide a powerful tool to be used as an injectable system for non‐invasive tissue engineering applications with additional control over cellular function by creating specific microenvironments for cell growth.     

Bioinspired Multifunctional Hybrid Hydrogel Promotes Wound Healing

Inspired by the coordinated multiple healing mechanism of the organism, a four‐armed benzaldehyde‐terminated polyethylene glycol and dodecyl‐modified chitosan hybrid hydrogel with vascular endothelial growth factor (VEGF) encapsulation are presented for efficient and versatile wound healing. The hybrid hydrogel is formed through the reversible Schiff base and possesses self‐healing capability. As the dodecyl tails can insert themselves into and be anchored onto the lipid bilayer of the cell membrane, the hybrid hydrogel has outstanding tissue adhesion, blood cell coagulation and hemostasis, anti‐infection, and cell recruitment functions. Moreover, by loading in and controllably releasing VEGF from the hybrid hydrogel, the processes of cell proliferation and tissue remodeling in the wound bed can be significantly improved. Based on an in vivo study of the multifunctional hybrid hydrogel, it is demonstrated that acute tissue injuries such as vessel bleeding and liver bleeding can be repaired immediately because of the outstanding adhesion and hemostasis features of the hydrogel. Moreover, the chronic wound‐healing process of an infectious full‐thickness skin defect model can also be significantly enhanced by promoting angiogenesis, collagen deposition, macrophage polarization, and granulation tissue formation. Thus, this multifunctional hybrid hydrogel is potentially valuable for clinical applications.     

A Universal and Facile Approach for the Formation of a Protein Hydrogel for 3D Cell Encapsulation

A universal and facile approach to modifying proteins so that they can rapidly form hydrogel upon mixing with crosslinkers is presented. The concept of it is to introduce maleimide, which is highly reactive with dithiol‐containing crosslinkers via thiol‐ene click chemistry, onto proteins. Bovine serum albumin (BSA) is used as a model protein due to its good stability and low cost. The results here show that a protein hydrogel can be readily formed by blending modified BSA and resilin‐related peptide crosslinker solutions at a proper ratio. The hydrogel exhibits good elasticity and tunable mechanical as well as biochemical properties. Moreover, it allows convenient 3D cell encapsulation and shows good biocompatibility. Muscle cells embedded in the hydrogel are promoted to spread by incorporating arginyl‐glycyl‐aspartic acid (RGD)‐containing peptide into the system, thus warranting a bright future of it in regenerative medicine.     

Complex Tuning of Physical Properties of Hyperbranched Polyglycerol‐Based Bioink for Microfabrication of Cell‐Laden Hydrogels

Microfabrication technology has emerged as a valuable tool for fabricating structures with high resolution and complex architecture for tissue engineering applications. For this purpose, it is imperative to develop “bioink” that can be readily converted to a solid structure by the modus operandi of a chosen apparatus, while optimally supporting the biological functions by tuning their physicochemical properties. Herein, a photocrosslinkable hyperbranched polyglycerol (acrylic hyperbranched glycerol (AHPG)) is developed as a crosslinker to fabricate cell‐laden hydrogels. Due to its hydrophilicity as well as numerous hydroxyl groups for the conjugation of reactive functional groups (e.g., acrylate), the mechanical properties of resulting hydrogels could be controlled in a wide range by tuning both molecular weight and degree of acrylate substitution of AHPG. The control of mechanical properties by AHPG is highly dependent on the type of monomer, due to the hydrophilic/hydrophobic balance of polyglycerol backbone and acrylate as well as the dynamic conformational flexibility based on the molecular weight of polyglycerol. The cell encapsulation studies demonstrate the biocompatibility of the AHPG‐linked hydrogels. Eventually, the AHPG‐based hydrogel precursor solution is employed as a bioink for a digital light processing based printing system to generate cell‐laden microgels with various shapes and sizes for tissue engineering applications.     

Microphysiological Systems as Enabling Tools for Modeling Complexity in the Tumor Microenvironment and Accelerating Cancer Drug Development

Tumor cell heterogeneity with distinct phenotypes, genotypes, and epigenetic states as well as the complex tumor microenvironment is major challenges for cancer diagnosis and treatment. There have been substantial advances in our knowledge of tumor biology and in the capabilities of available biological analysis tools; however, the absence of physiologically relevant in vitro testing platforms limits our ability to gain an in‐depth understanding of the role of the tumor microenvironment in cancer pathology. In this review, recent advances in engineered tumor microenvironments to advance cancer research and drug discovery are presented, including tumor spheroids, microfluidic chips, paper scaffolds, hydrogel‐based engineered tissues, 3D bioprinted scaffolds, and multiscale topography. Furthermore, how these technologies address the specific characteristics of the native tumor microenvironment is described. Through the comparison of these biomimetic 3D tumor models to conventional 2D culture models, the validity and physiological relevance of these platforms for fundamental in vitro studies of the tumor biology, as well as their potential use in drug screening applications, is also discussed.     

Self‐Rupturing and Hollow Microcapsules Prepared from Bio‐polyelectrolyte‐Coated Microgels

This paper reports on microcapsules obtained by layer‐by‐layer deposition of bio‐polyelectrolyte multilayers at the surface of biodegradable dextran microgels. The behavior of the layer‐by‐layer coating upon degradation of the microgel core strongly depends on the bio‐polyelectrolytes used. Two types of microcapsules, “self‐rupturing” microcapsules and “hollow” microcapsules, are presented. Self‐rupturing microcapsules are obtained when the swelling pressure of the degrading microgel core is strong enough to rupture the surrounding bio‐polyelectrolyte membrane. Self‐rupturing microcapsules could be of interest as a pulsed drug delivery system. Hollow microcapsules are obtained after applying multiple layers of bio‐polyelectrolyte that can withstand the swelling pressure of the degrading microgel core. Biomacromolecules (such as albumin and dextran) spontaneously accumulate in the hollow microcapsules prepared from dex‐HEMA microgels, which could be of interest for drug‐encapsulation purposes.     

Skin‐Inspired Antibacterial Conductive Hydrogels for Epidermal Sensors and Diabetic Foot Wound Dressings

Recently, artificial intelligence research has driven the development of stretchable and flexible electronic systems. Conductive hydrogels are a class of soft electronic materials that have emerging applications in wearable and implantable biomedical devices. However, current conductive hydrogels possess fundamental limitations in terms of their antibacterial performance and a mechanical mismatch with human tissues, which severely limits their applications in biological interfaces. Here, inspired by animal skin, a conductive hydrogel is fabricated from a supramolecular assembly of polydopamine decorated silver nanoparticles (PDA@Ag NPs), polyaniline, and polyvinyl alcohol, namely PDA@Ag NPs/CPHs. The resultant hydrogel has many desirable features, such as tunable mechanical and electrochemical properties, eye‐catching processability, good self‐healing ability as well as repeatable adhesiveness. Remarkably, PDA@Ag NPs/CPHs exhibit broad antibacterial activity against Gram‐negative and Gram‐positive bacteria. The potential application of this versatile hydrogel is demonstrated by monitoring large‐scale movements of the human body in real time. In addition, PDA@Ag NPs/CPHs have a significant therapeutic effect on diabetic foot wounds by promoting angiogenesis, accelerating collagen deposition, inhibiting bacterial growth, and controlling wound infection. To the best of the authors' knowledge, this is the first time that conductive hydrogels with antibacterial ability are developed for use as epidermal sensors and diabetic foot wound dressing.     

High-Throughput Screening of Self-Healable Polysulfobetaine Hydrogels and their Applications in Flexible Electronics

Hydrogels are promising materials in the applications of wound adhesives, wearable electronics, tissue engineering, implantable electronics, etc. The properties of a hydrogel rely strongly on its composition. However, the optimization of hydrogel properties has been a big challenge as increasing numbers of components are added to enhance and synergize its mechanical, biomedical, electrical, and self-healable properties. Here in this work, it is shown that high-throughput screening can efficiently and systematically explore the effects of multiple components (at least eight) on the properties of polysulfobetaine hydrogels, as well as provide a useful database for diverse applications. The optimized polysulfobetaine hydrogels that exhibit outstanding self-healing and mechanical properties, have been obtained by high-throughput screening. By compositing with poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), intrinsically self-healable and stretchable conductors are achieved. It is further demonstrated that a polysulfobetaine hydrogel-based electronic skin, which exhibits exceptionally fast self-healing capability of the whole device at ambient conditions. This work successfully extends high-throughput synthetic methodology to the field of hydrogel electronics, as well as demonstrates new directions of healable flexible electronic devices in terms of material development and device design.     

Color Tunable Poly (N‐Isopropylacrylamide)‐co‐Acrylic Acid Microgel–Au Hybrid Assemblies

A new class of materials that are capable of color tunability over 300 nm with a 15 °C temperature change is introduced. The materials are assembled from thermoresponsive poly (N‐isopropylacrylamide)‐co‐acrylic acid (pNIPAm‐co‐AAc) microgels, which are deposited on Au coated glass substrates. The films are also pH responsive; the temperature‐induced color change was suppressed at high pH and is consistent with the behavior of a solution of suspended microgels. The mechanism proposed to account for the observed optical properties suggests that they result from the two Au layers being separated from each other by the “monolithic” microgel film, much like a Fabry‐Pérot etalon or interferometer. It is the modulation of the distance between these two layers, facilitated by the microgel collapse transition at high temperature, that allows the color to be tuned. The sensitivity of the system presented here will be used for future sensing and biosensing applications, as well as for light filtering applications.     

A Highly Elastic and Rapidly Crosslinkable Elastin‐Like Polypeptide‐Based Hydrogel for Biomedical Applications

Elastin‐like polypeptides (ELPs) are promising for biomedical applications due to their unique thermoresponsive and elastic properties. ELP‐based hydrogels have been produced through chemical and enzymatic crosslinking or photocrosslinking of modified ELPs. Herein, a photocrosslinked ELP gel using only canonical amino acids is presented. The inclusion of thiols from a pair of cysteine residues in the ELP sequence allows disulfide bond formation upon exposure to UV light, leading to the formation of a highly elastic hydrogel. The physical properties of the resulting hydrogel such as mechanical properties and swelling behavior can be easily tuned by controlling ELP concentrations. The biocompatibility of the engineered ELP hydrogels is shown in vitro as well as corroborated in vivo with subcutaneous implantation of hydrogels in rats. ELP constructs demonstrate long‐term structural stability in vivo, and early and progressive host integration with no immune response, suggesting their potential for supporting wound repair. Ultimately, functionalized ELPs demonstrate the ability to function as an in vivo hemostatic material over bleeding wounds.     

A Review on Encapsulation Technology from Organic Light Emitting Diodes to Organic and Perovskite Solar Cells

Organic light emitting diodes (OLEDs) employing organic thin-film based emitters have attracted tremendous attention due to their widespread applications in lighting and as displays in mobile devices and televisions. The novel thin-film photovoltaic techniques using organic or organic–inorganic hybrid materials such as organic photovoltaics (OPVs) and perovskite solar cells (PSCs) have become emerging competitive candidates with regard to the traditional photovoltaic techniques on account of high-efficiency, low-cost, and simple manufacturing processing properties. However, OLEDs, OPVs, and PSCs are vulnerable to the undesired degradation induced by moisture and oxygen. To afford long-term stability, a robust encapsulation technique by employing materials and structures that possess high barrier performance against oxygen and moisture must be explored and employed to protect these devices. Herein, the recent progress on specific encapsulation materials and techniques for three types of devices on the basis of fundamental understanding of device stability is reviewed. First, their degradation mechanisms, as well as, influencing factors are discussed. Then, the encapsulation technologies and materials are classified and discussed. Moreover, the advantages and disadvantages of various encapsulation technologies and materials coupled with their encapsulation applications in different devices are compared. Finally, the ongoing challenges and future perspectives of encapsulation frontier are provided.     

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.     

Inherent Photodegradability of Polymethacrylate Hydrogels: Straightforward Access to Biocompatible Soft Microstructures

Hydrogels are important functional materials useful for 3D cell culture, tissue engineering, 3D printing, drug delivery, sensors, or soft robotics. The ability to shape hydrogels into defined 3D structures, patterns, or particles is crucial for biomedical applications. Here, the rapid photodegradability of commonly used polymethacrylate hydrogels is demonstrated without the need to incorporate additional photolabile functionalities. Hydrogel degradation depths are quantified with respect to the irradiation time, light intensity, and chemical composition. It can be shown that these parameters can be utilized to control the photodegradation behavior of polymethacrylate hydrogels. The photodegradation kinetics, the change in mechanical properties of polymethacrylate hydrogels upon UV irradiation, as well as the photodegradation products are investigated. This approach is then exploited for microstructuring and patterning of hydrogels including hydrogel gradients as well as for the formation of hydrogel particles and hydrogel arrays of well‐defined shapes. Cell repellent but biocompatible hydrogel microwells are fabricated using this method and used to form arrays of cell spheroids. As this method is based on readily available and commonly used methacrylates and can be conducted using cheap UV light sources, it has vast potential to be applied by laboratories with various backgrounds and for diverse applications.