Modular and Versatile Spatial Functionalization of Tissue Engineering Scaffolds through Fiber‐Initiated Controlled Radical Polymerization

Native tissues are typically heterogeneous and hierarchically organized, and generating scaffolds that can mimic these properties is critical for tissue engineering applications. By uniquely combining controlled radical polymerization (CRP), end‐functionalization of polymers, and advanced electrospinning techniques, a modular and versatile approach is introduced to generate scaffolds with spatially organized functionality. Poly‐ε‐caprolactone is end functionalized with either a polymerization‐initiating group or a cell‐binding peptide motif cyclic Arg‐Gly‐Asp‐Ser (cRGDS), and are each sequentially electrospun to produce zonally discrete bilayers within a continuous fiber scaffold. The polymerization‐initiating group is then used to graft an antifouling polymer bottlebrush based on poly(ethylene glycol) from the fiber surface using CRP exclusively within one bilayer of the scaffold. The ability to include additional multifunctionality during CRP is showcased by integrating a biotinylated monomer unit into the polymerization step allowing postmodification of the scaffold with streptavidin‐coupled moieties. These combined processing techniques result in an effective bilayered and dual‐functionality scaffold with a cell‐adhesive surface and an opposing antifouling non‐cell‐adhesive surface in zonally specific regions across the thickness of the scaffold, demonstrated through fluorescent labelling and cell adhesion studies. This modular and versatile approach combines strategies to produce scaffolds with tailorable properties for many applications in tissue engineering and regenerative medicine.     

Programmed Shape‐Morphing Scaffolds Enabling Facile 3D Endothelialization

Rapid formation of a confluent endothelial monolayer is the key to the success of small‐diameter vascular grafts, which is significantly important for treating dangerous and even sometimes deadly vascular disorders. However, the difficulty to homogenously locate endothelial cells onto the lumen of small‐diameter tubular scaffolds makes 3D endothelialization greatly challenging. Here, novel shape‐morphing scaffolds enabling programmed deformation from planar shapes to small‐diameter tubular shapes are designed and developed by combining biocompatible shape memory polymer and electrospun nanofibrous membrane. Endothelial cells can be conveniently seeded and attached on the 2D surface of the scaffolds and subsequently self‐rolled into 3D organization at physiological temperature. Endothelial cell responses and functions are varied on the shape‐morphing scaffolds with different nanofibrous electrospun membranes as the inner layer, arisen from the inducement of scaffolds with different morphological, physical, and biochemical characteristics. Owing to excellent properties of the nanofibrous membrane fabricated by the coelectrospinning of poly‐ε‐caprolactone (PCL) and gelatin methacrylate (GelMA), the shape‐morphing scaffolds with a nanofibrous PCL/GelMA inner layer support desirable homogeneous endothelial cell attachment as well as the rapid formation of biomimetic cell–scaffold interaction and cell–cell interaction under the 3D cell culture condition, therefore offering a visible approach for facile 3D endothelialization.     

Controllable Underwater Oil‐Adhesion‐Interface Films Assembled from Nonspherical Particles

A controllable underwater oil‐adhesion‐interface is presented based on colloidal crystals assembled from nonspherical latex particles. The underwater oil‐adhesive force of the as‐prepared film can be effectively controlled from high to low adhesion by varying the latex structures from spherical or cauliflower‐like to single cavity, which effectively adjusts the solid/liquid contact mode/wetting state of oil droplets on the films. This facile fabrication of functional films with special underwater oil‐adhesion properties based on a flexible design of a latex structure will offer significant insight for the design and creation of novel underwater antifouling materials.     

Fabrication of Reversibly Crosslinkable, 3‐Dimensionally Conformal Polymeric Microstructures

Multifaceted porous materials were prepared through careful design of star polymer functionality and properties. Functionalized core crosslinked star (CCS) polymers with a low glass transition temperature (T_g) based on poly(methyl acrylate) were prepared having a multitude of hydroxyl groups at the chain ends. Modification of these chain ends with 9‐anthracene carbonyl chloride introduces the ability to reversibly photocrosslink these systems after the star polymers were self‐assembled by the breath figure technique to create porous, micro‐structured films. The properties of the low T_g CCS polymer allow for the formation of porous films on non‐planar substrates without cracking and photo‐crosslinking allows the creation of stabilized honeycomb films while also permitting a secondary level of patterning on the film, using photo‐lithographic techniques. These multifaceted porous polymer films represent a new generation of well‐defined, 3D microstructures.     

Fractal Inorganic−Organic Interfaces in Hybrid Membranes for Efficient Proton Transport

A facile method for preparing highly conductive hybrid organic?inorganic membranes is reported. These membranes are synthesized using an electrospinning process with a sol?gel‐based solution containing PVDF?HFP (polyvinylidenefluoride‐hexafluoropropylene), functionalized or not functionalized silicon alkoxides, and additives. Proton conduction measurements highlight that these hybrid membranes exhibit conductivity value of 101 mS/cm at 120 °C under 80% RH (relative humidity), comparable to the best Nafion measured under the same conditions. These membranes have a proton conductivity‐humidity variation close to Nafion and a modulus value higher than that for Nafion above 80 °C. Their proton conductivity value is about 15 mS/cm under 50% RH, and it constitutes one of the highest values reported. These interesting properties are related to the microstructure of the electrospun membranes that have been characterized using field emission scanning electron microscopy (FE‐SEM) and small angle neutron scattering (SANS). The electrospun membranes are made composed of a bundle of fibers surrounded by a functionalized silica network. The bundle of fibers corresponds to the assembly of small polymer fibers surrounded by small anisotropic functionalized silica domains. Coupling the reactive chemistry of the sol–gel‐based process with electrospinning allows the design of hybrid membranes with fractal hydrophobic/hydrophilic interfaces exhibiting different length scales.     

Ethanol‐Dispersed Polymer Nanofibers as a Highly Selective Cell Isolation and Release Platform for CD4+ T Lymphocytes

A novel cell isolation and release platform using electrospun polystyrene‐poly(styrene‐co‐maleic anhydride) (PS‐PSMA) nanofibers is presented. Ethanol treatment of PS‐PSMA nanofibers, employed for the purpose of sterilization, significantly increases their inter‐fiber space for both antibody conjugation and subsequent cell separation. For the selective isolation of CD4⁺ T cells from heterogeneous mixtures of mouse lymph nodes, capture efficiencies of up to 100% are achieved while maintaining cellular integrity and viability. Once captured, CD4⁺ T lymphocytes can also be released from the NF scaffolds, further demonstrating its potential functionality as an immune cell‐supporting and releasing matrix. This is the first demonstration of lymphocyte‐culture scaffolds enabling selective isolation, accommodation, and sustained release of CD4⁺ T cells for the purpose of cell therapies.     

Spray Layer‐by‐Layer Electrospun Composite Proton Exchange Membranes

Polymer electrolyte films are deposited onto highly porous electrospun mats using layer‐by‐layer (LbL) processing to fabricate composite proton conducting membranes. By simply changing the assembly conditions for generation of the LbL film on the nanofiber mat substrate, three different and unique composite film morphologies can be achieved in which the electrospun mats provide mechanical support; the LbL assembly produces highly conductive films that coat the mats in a controlled fashion, separately providing the ionic conductivity and fuel blocking characteristics of the composite membrane. Coating an electrospun mat with the LbL dipping process produces composite membranes with “webbed” morphologies that link the fibers in‐plane and give the composite membrane in‐plane proton conductivities similar to that of the pristine LbL system. In contrast, coating an electrospun mat using the spray‐LbL process without vacuum produces a uniform film that bridges across all of the pores of the mat. These membranes have methanol permeability similar to free‐standing poly(diallyl dimethyl ammonium chloride)/sulfonated poly(2,6‐dimethyl 1,4‐phenylene oxide) (PDAC/sPPO) thin films. Coating an electrospun mat with the vacuum‐assisted spray‐LbL process produces composite membranes with conformally coated fibers throughout the bulk of the mat with nanometer control of the coating thickness on each fiber. The mechanical properties of the LbL‐coated mats display composite properties, exhibiting the strength of the glassy PDAC/sPPO films when dry and the properties of the underlying electrospun polyamide mat when hydrated. By combining the different spray‐LbL fabrication techniques with electrospun fiber supports and tuning the parameters, mechanically stable membranes with high selectivity can be produced, potentially for use in fuel cell applications.     

Fabrication of Biofunctionalized Quasi‐Three‐Dimensional Microstructures of a Nonfouling Comb Polymer Using Soft Lithography

This paper describes a simple set of patterning methods that are applicable to diverse substrates and allow the routine and rapid fabrication of protein patterns embedded within a background that consists of quasi‐three‐dimensional microstructures of a cell‐resistant polymer. The ensemble of methods reported here utilizes three components to create topographically nonfouling polymeric structures that present cell‐adhesive protein patterns in the regions between the microstructures: the first component is an amphiphilic comb polymer that is comprised of a methyl methacrylate backbone and pendant oligo(ethylene glycol) moieties along the side chain, physically deposited films of which are protein‐ and cell‐resistant. The second component of the fabrication methodology involves the use of different variants of soft lithography, such as microcontact printing to create nonfouling topographical features of the comb polymer that demarcate cell‐adhesive regions of the third component: a cell‐adhesive extracellular protein or peptide. The ensemble of methods reported in this paper was used to fabricate quasi‐three‐dimensional patterns that present topographical and biochemical cues on a variety of substrates, and was shown to successfully maintain cellular patterns for up to two months in serum‐containing medium. We believe that this, and other such methods under development that allow independent and systematic control of chemistry, topography and substrate compliance will provide versatile “test‐beds” for fundamental studies in cell biology as well as allow the discovery of rational design principles for the development of biomaterials and tissue‐engineering scaffolds.     

Jellyfish‐Based Smart Wound Dressing Devices Containing In Situ Synthesized Antibacterial Nanoparticles

Although the negative consequences of the global phenomenon of jellyfish (JF) swarms are well recognized, the use of their biomass for practical applications is mostly limited to a niche in the Asian food industry. This fact is quite surprising since JF's biomass comprises useful biomaterials such as Q‐mucin glycoprotein and collagen. In this work, the JF biomass, collected from two different species, is used to prepare electrospun scaffolds composed of nanometric “core–shell”‐type fibers, in which adjustment of the electrospinning process parameters can easily control their mechanical, morphological, and chemical properties. This nonwoven scaffold shows excellent biocompatibility and biodegradability, indicating suitability for biomedical research contexts. Performed cell proliferation assays show that the scaffold could support the growth of cardiac cells, fitting the requirement of tissue engineering. Additional incorporation of in situ‐generated silver nanoparticles in these nanofibers produced mats with potent antibacterial properties. Preclinical trials with the resulted mats on porcine wound healing models exhibit fast and complete healing of wounds.     

Biomimetic Scaffolds for Tissue Engineering

Biomimetic scaffolds mimic important features of the extracellular matrix (ECM) architecture and can be finely controlled at the nano‐ or microscale for tissue engineering. Rational design of biomimetic scaffolds is based on consideration of the ECM as a natural scaffold; the ECM provides cells with a variety of physical, chemical, and biological cues that affect cell growth and function. There are a number of approaches available to create 3D biomimetic scaffolds with control over their physical and mechanical properties, cell adhesion, and the temporal and spatial release of growth factors. Here, an overview of some biological features of the natural ECM is presented and a variety of original engineering methods that are currently used to produce synthetic polymer‐based scaffolds in pre‐fabricated form before implantation, to modify their surfaces with biochemical ligands, to incorporate growth factors, and to control their nano‐ and microscale geometry to create biomimetic scaffolds are discussed. Finally, in contrast to pre‐fabricated scaffolds composed of synthetic polymers, injectable biomimetic scaffolds based on either genetically engineered‐ or chemically synthesized‐peptides of which sequences are derived from the natural ECM are discussed. The presence of defined peptide sequences can trigger in situ hydrogelation via molecular self‐assembly and chemical crosslinking. A basic understanding of the entire spectrum of biomimetic scaffolds provides insight into how they can potentially be used in diverse tissue engineering, regenerative medicine, and drug delivery applications.     

Microribbon‐Like Elastomers for Fabricating Macroporous and Highly Flexible Scaffolds that Support Cell Proliferation in 3D

Hydrogel‐based scaffolds are widely used for culturing cells in three dimensions due to their tissue‐like water content and tunable biochemical and physical properties. Most conventional hydrogels lack the macroporosity desirable for efficient cell proliferation and migration and have limited flexibility when subject to mechanical load. Here microribbon‐like elastomers that, when photocrosslinked, can form macroporous and highly flexible scaffolds that support cell proliferation in 3D are developed. These microribbons are produced by wet‐spinning gelatin solution into microfibers, followed by drying in acetone, which causes asymmetrical collapse of microfibers to form microribbon‐like structures. Gelatin microribbons are then modified using methacrylate anhydride to allow further photocrosslinking into 3D scaffolds. The macroporosity and mechanical properties of the microribbon‐based scaffold may be tuned by varying wet‐spinning rate, drying temperature, choice of drying agent, level of glutaraldehyde crosslinking, and microribbon density. When encapsulated in the microribbon‐based scaffold, human adipose‐derived stromal cells proliferated up to 30‐fold within 3 weeks. Furthermore, microribbons‐based scaffold demonstrate great flexibility and can sustain up to 90% strain and 3 MPa stress without failing. The unique mechanical properties of microribbon‐based scaffolds make them promising tools for engineering shock‐absorbing tissues such as cartilage and intervertebral discs.     

Forming Covalent Crosslinks between Polymer‐Grafted Nanoparticles as a Route to Highly Filled and Mechanically Robust Nanocomposites

Filler aggregation in polymer matrix nanocomposites leads to inhomogeneity in particle distribution and deterioration of mechanical properties. The use of polymer‐grafted nanoparticles (PGNPs) with polymers directly attached to the particle surfaces precludes aggregation of the filler. However, solids composed of PGNPs are mechanically weak unless the grafted chains are long enough to form entanglements between particles, and requiring long grafts limits the achievable filler density of the nanocomposite. In this work, long, entangled grafts are replaced with short reactive polymers that form covalent crosslinks between particles. Crosslinkable PGNPs, referred to as XNPs, can be easily processed from solution and subsequently cured to yield a highly filled yet mechanically robust composite. In this specific instance, silica nanoparticles are grafted with poly(glycidyl methacrylate), cast into films, and crosslinked with multifunctional amines at elevated temperatures. Indentation and scratch experiments show significant enhancement of hardness, modulus, and scratch resistance compared to non‐crosslinked PGNPs and to crosslinked polymer films without nanoparticle reinforcement. Loadings of up to 57 wt% are achieved while yielding uniform films that deform locally in a predominantly elastic manner. XNPs therefore potentially allow for the formulation of robust nanocomposites with a high level of functionality imparted by the selected filler particles.     

Electrospun Extracellular Matrix: Paving the Way to Tailor‐Made Natural Scaffolds for Cardiac Tissue Regeneration

Biomimetic scaffolds generally aim at structurally and compositionally imitating native tissue, thus providing a supportive microenvironment to the transplanted or recruited cells in the tissue. Native decellularized porcine extracellular matrix (ECM) is becoming the ultimate bioactive material for the regeneration of different organs. Particularly for cardiac regeneration, ECM is studied as a patch and injectable scaffolds, which improve cardiac function, yet lack reproducibility and are difficult to control or fine‐tune for the desired properties, like most natural materials. Seeking to harness the natural advantages of ECM in a reproducible, scalable, and controllable scaffold, for the first time, a matrix that is produced from whole decellularized porcine cardiac ECM using electrospinning technology, is developed. This unique electrospun cardiac ECM mat preserves the composition of ECM, self‐assembles into the same microstructure of cardiac ECM ,and ,above all, preserves key cardiac mechanical properties. It supports cell growth and function, and demonstrates biocompatibility in vitro and in vivo. Importantly, this work reveals the great potential of electrospun ECM‐based platforms for a wide span of biomedical applications, thus offering the possibility to produce complex natural materials as tailor‐made, well‐defined structures.     

Direct‐Write Assembly of Microperiodic Silk Fibroin Scaffolds for Tissue Engineering Applications

Three–dimensional, microperiodic scaffolds of regenerated silk fibroin have been fabricated for tissue engineering by direct ink writing. The ink, which consisted of silk fibroin solution from the Bombyx mori silkworm, was deposited in a layer‐by‐layer fashion through a fine nozzle to produce a 3D array of silk fibers of diameter 5 µm. The extruded fibers crystallized when deposited into a methanol‐rich reservoir, retaining a pore structure necessary for media transport. The rheological properties of the silk fibroin solutions were investigated and the crystallized silk fibers were characterized for structure and mechanical properties by infrared spectroscopy and nanoindentation, respectively. The scaffolds supported human bone marrow‐derived mesenchymal stem cell (hMSC) adhesion, and growth. Cells cultured under chondrogenic conditions on these scaffolds supported enhanced chondrogenic differentiation based on increased glucosaminoglycan production compared to standard pellet culture. Our results suggest that 3D silk fibroin scaffolds may find potential application as tissue engineering constructs due to the precise control of their scaffold architecture and their biocompatibility.     

Creating a Living Hyaline Cartilage Graft Free from Non‐Cartilaginous Constituents: An Intermediate Role of a Biomaterial Scaffold

A novel living hyaline cartilage graft (LhCG) with controllable dimensions and free of non‐cartilaginous constituents for articular regeneration is developed. As a living graft for regenerative medicine, LhCG is purely living tissue based and truly scaffold‐free. The process of neotissue formation in LhCG is mediated by an interim biomaterial‐based novel scaffolding system. This design highlights a philosophy of using biomaterials in engineered regenerative medicine as a transient guiding facility rather than a permanent part of substitute. The fabrication is designed and practiced in a continuous and integrated process, which attributes to its simplicity in operation. Because of the intrinsic non‐cell‐adhesive property of hydrogel scaffolds, articular chondrocytes’ phenotype is always preserved throughout the whole procedure, which has been tested and approved both in vitro and in vivo. In situ grafting trials in a rabbit model showcase high success rates in both cartilage repair and graft‐host integration. Beyond cartilage repair, this LhCG model may provide a living‐tissue‐based open platform or niche for multi‐tissue regenerations.     

Recent Advances in Electrospun Nanofibrous Scaffolds for Cardiac Tissue Engineering

Cardiovascular diseases remain the leading cause of human mortality worldwide. Some severe symptoms, including myocardial infarction and heart failure, are difficult to heal spontaneously or under systematic treatment due to the limited regenerative capacity of the native myocardium. Cardiac tissue engineering has emerged as a practical strategy to culture functional cardiac tissues and relieve the disorder in myocardium when implanted. In cardiac tissue engineering, the design of a scaffold is closely relevant to the function of the regenerated cardiac tissues. Nanofibrous materials fabricated by electrospinning have been developed as desirable scaffolds for tissue engineering applications because of the biomimicking structure of protein fibers in native extra cellular matrix. The versatilities of electrospinning on the polymer component, the fiber structure, and the functionalization with bioactive molecules have made the fabrication of nanofibrous scaffolds with suitable mechanical strength and biological properties for cardiac tissue engineering feasible. Here, an overview of recent advances in various electrospun scaffolds for engineering cardiac tissues, including the design of advanced electrospun scaffolds and the performance of the scaffolds in functional cardiac tissue regeneration, is provided with the aim to offer guidance in the innovation of novel electrospun scaffolds and methods for improving their potential for cardiac tissue engineering applications.     

Layer‐by‐Layer Assembly of 3D Tissue Constructs with Functionalized Graphene

Carbon‐based nanomaterials have been considered promising candidates to mimic certain structure and function of native extracellular matrix materials for tissue engineering. Significant progress has been made in fabricating carbon nanoparticle‐incorporated cell culture substrates, but only a limited number of studies have been reported on the development of 3D tissue constructs using these nanomaterials. Here, a novel approach to engineer 3D multilayer constructs using layer‐by‐layer (LbL) assembly of cells separated with self‐assembled graphene oxide (GO)‐based thin films is presented. The GO‐based structures are shown to serve as cell adhesive sheets that effectively facilitate the formation of multilayer cell constructs with interlayer connectivity. By controlling the amount of GO deposited in forming the thin films, the thickness of the multilayer tissue constructs could be tuned with high cell viability. Specifically, this approach could be useful for creating dense and tightly connected cardiac tissues through the co‐culture of cardiomyocytes and other cell types. In this work, the fabrication of stand‐alone multilayer cardiac tissues with strong spontaneous beating behavior and programmable pumping properties is demonstrated. Therefore, this LbL‐based cell construct fabrication approach, utilizing GO thin films formed directly on cell surfaces, has great potential in engineering 3D tissue structures with improved organization, electrophysiological function, and mechanical integrity.     

Efficient Perovskite Light‐Emitting Diodes Using Polycrystalline Core–Shell‐Mimicked Nanograins

Making small nanograins in polycrystalline organic–inorganic halide perovskite (OIHP) films is critical to improving the luminescent efficiency in perovskite light‐emitting diodes (PeLEDs). 3D polycrystalline OIHPs have fundamental limitations related to exciton binding energy and exciton diffusion length. At the same time, passivating the defects at the grain boundaries is also critical when the grain size becomes smaller. Molecular additives can be incorporated to shield the nanograins to suppress defects at grain boundaries; however, unevenly distributed molecular additives can cause imbalanced charge distribution and inefficient local defect passivation in polycrystalline OIHP films. Here, a kinetically controlled polycrystalline organic‐shielded nanograin (OSN) film with a uniformly distributed organic semiconducting additive (2,2′,2′′‐(1,3,5‐benzinetriyl)‐tris(1‐phenyl‐1‐H‐benzimidazole), TPBI) is developed mimicking core–shell nanoparticles. The OSN film causes improved photophysical and electroluminescent properties with improved light out‐coupling by possessing a low refractive index. Finally, highly improved electroluminescent efficiencies of 21.81% ph el^?1 and 87.35 cd A^?1 are achieved with a half‐sphere lens and four‐time increased half‐lifetime in polycrystalline PeLEDs. This strategy to make homogeneous, defect‐healed polycrystalline core–shell‐mimicked nanograin film with better optical out‐coupling will provide a simple and efficient way to make highly efficient perovskite polycrystal films and their optoelectronics devices.     

Hybrid 3D Printing of Synthetic and Cell‐Laden Bioinks for Shape Retaining Soft Tissue Grafts

Despite recent advances in clinical procedures, the repair of soft tissue remains a reconstructive challenge. Current technologies such as synthetic implants and dermal flap autografting result in inefficient shape retention and unpredictable aesthetic outcomes. 3D printing, however, can be leveraged to produce superior soft tissue grafts that allow enhanced host integration and volume retention. Here, a novel dual bioink 3D printing strategy is presented that utilizes synthetic and natural materials to create stable, biomimetic soft tissue constructs. A double network ink composed of covalently cross‐linked poly(ethylene) glycol and ionically cross‐linked alginate acts as a physical support network that promotes cell growth and enables long‐term graft shape retention. This is coupled with a cell‐laden, biodegradable gelatin methacrylate bioink in a hybrid printing technique, and the composite scaffolds are evaluated in their mechanical properties, shape retention, and cytotoxicity. Additionally, a new shape analysis technique utilizing CloudCompare software is developed that expands the available toolbox for assessing scaffold aesthetic properties. With this dynamic 3D bioprinting strategy, complex geometries with robust internal structures can be easily modulated by varying the print ratio of nondegradable to sacrificial strands. The versatility of this hybrid printing fabrication platform can inspire the design of future multimaterial regenerative implants.