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Lung‐on‐chips (LoCs) are advanced microsystems designed to culture pulmonary cells under physiologically relevant conditions, including air–liquid interface, cell stretch, and shear stress. As the most promising preclinical models, the LoCs are aimed to reduce and ultimately replace conventional ineffective animal studies. Biomimetic and functional LoCs lead to more translational preclinical studies that effectively address unmet needs across therapeutic areas. A variety of cell‐ and scaffold‐based techniques are employed to establish biomimetic pulmonary cell models that closely resemble their in vivo counterparts, which is a challenging yet critical aspect of LoCs. Herein, the challenges encountered in biomimetic LoCs are discussed, and the future perspectives toward higher biomimicry using advanced biofabrication approaches are explored. [ABSTRACT FROM AUTHOR]

Light‐based 3D printing techniques represent powerful tools, enabling the precise fabrication of intricate objects with high resolution and control. An innovative addition to this set of printing techniques is Optical Fiber‐Assisted Printing (OFAP) introduced in this article. OFAP is a platform utilizing an LED‐coupled optical fiber (LOF) that selectively crosslinks photopolymer resins. It allows change of parameters like light intensity and LOF velocity during fabrication, facilitating the creation of structures with progressive features and multi‐material constructs layer‐by‐layer. An optimized formulation based on allyl‐modified gelatin (gelAGE) with food dyes as photoabsorbers is introduced. Additionally, a novel gelatin‐based biomaterial, alkyne‐modified gelatin (gelGPE), featuring alkyne moieties, demonstrates near‐visible light absorption thus fitting OFAP needs, paving the way for multifunctional hydrogels through thiol‐yne click chemistry. Besides 2D patterning, OFAP is transferred to embedded 3D printing within a resin bath demonstrating the proof‐of‐concept as a novel printing technology with potential applications in tissue engineering and biomimetic scaffold fabrication, offering rapid and precise freeform printing capabilities. [ABSTRACT FROM AUTHOR]

Atherosclerosis is the primary cause of cardiovascular disease, resulting in mortality, elevated healthcare costs, diminished productivity, and reduced quality of life for individuals and their communities. This is exacerbated by the limited understanding of its underlying causes and limitations in current therapeutic interventions, highlighting the need for sophisticated models of atherosclerosis. This review critically evaluates the computational and biological models of atherosclerosis, focusing on the study of hemodynamics in atherosclerotic coronary arteries. Computational models account for the geometrical complexities and hemodynamics of the blood vessels and stenoses, but they fail to capture the complex biological processes involved in atherosclerosis. Different in vitro and in vivo biological models can capture aspects of the biological complexity of healthy and stenosed vessels, but rarely mimic the human anatomy and physiological hemodynamics, and require significantly more time, cost, and resources. Therefore, emerging strategies are examined that integrate computational and biological models, and the potential of advances in imaging, biofabrication, and machine learning is explored in developing more effective models of atherosclerosis. [ABSTRACT FROM AUTHOR]

The current barrier to clinical translation of small‐caliber tissue‐engineered vascular grafts (TEVGs) is the long‐term patency upon implantation in vivo. Key contributors are thrombosis and stenosis caused by inadequate mechanical graft properties and mismatch of hemodynamic conditions. Herein, the authors report on an approach for the fabrication of a mechanically tunable bilayered composite TEVGs. Using a combination of solution electrospinning (SES) and melt electrowriting (MEW), it is shown that the mechanical properties can be tailored and the natural J‐shape of the stress–strain relationship can be recapitulated. Upon cell seeding, the luminal surface of the composite SES layers permits the formation of a confluent mature endothelium. MEW fibers provide structural support to promote stacking and orientation of MSCs in a near‐circumferential native vessel like direction. By adjusting the ratios of poly(ε‐caprolactone) and poly(ester‐urethane) during the SES process, TEVGs with a range of tunable mechanical properties can be manufactured. Notably, this hybrid approach permits modulation of the radial tensile properties of TEVGs to approximate different native vessels. Overall, a strategy for the fabrication of TEVGs with mechanical properties resembling those of native vessels which can help to accommodate long‐term patency of TEVGs at various treatment sites in future applications is demonstrated. [ABSTRACT FROM AUTHOR]

Low back pain is among the main issues in vertebral orthopaedics. Intervertebral disk degeneration can be severe, up to requiring the replacement of the damaged disk by substitutes to achieve spine fusion. Disk removal results in critical size defects, so fusion does not occur naturally, but synthetic bone grafts are needed. Since the surgical procedure is time‐consuming, high infection rates occur. Hence, in spine fusion, bone regeneration enhancement and infection prevention are needed. Here, a new dual‐component system is proposed, to tackle both issues at one time. To enable spine fusion, 3D extrusion‐based printing is employed to develop coherent custom magnesium phosphate (CaMgP)‐based cages. The 3D‐printed scaffolds are hardened, and the structural properties are evaluated to be within the ranges of physiological bone. To prevent infection, an in‐house ice‐templating device is employed in combination with a 3D‐printed ceramic scaffold, to develop tailored porous alginate structures loaded with vancomycin. Results show that CaMgP can be printed into complex geometries and that the geometry influences the pore orientation during ice‐templating. These structures loaded with vancomycin have antibacterial properties against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) strains. [ABSTRACT FROM AUTHOR]

Digital light processing (DLP) enables the fabrication of complex 3D structures based on a photopolymerizable resin usually containing a photo initiator and an UV or photo absorber. The resin and thus the final properties of the printed structures can be adjusted by adding fillers like bioceramic powders relevant for bone‐regeneration applications. Herein, a water‐based and biocompatible poly(ethylene glycol diacrylate) (PEGDA) resin containing the photo initiator lithium‐phenyl‐2,4,6‐trimethylbenzoylphosphinate (LAP) enables the production of 3D structures via DLP. The addition of calcium magnesium phosphate cement (CMPC) powder, acting as photo absorber, leads to higher accuracy of the final structures. After curing the printed construct in a diammonium–hydrogen phosphate (DAHP) bath for hardening, the resulting mechanical properties can be adjusted without post‐process sintering. Solid loading of up to 40 wt% CMPC powder is possible, and the resins are investigated regarding their rheological behavior and printability. The resulting constructs are analyzed in respect to their surface morphology using scanning electron microscope (SEM), porosity, phase composition using X‐ray diffraction (XRD) methods, as well as mechanical properties influenced by the hardening process using DAHP for different durations. [ABSTRACT FROM AUTHOR]

Melt electrowriting (MEW) is an additive manufacturing process that produces highly defined constructs with elements in the micrometer range. A specific configuration of MEW enables printing tubular constructs to create small‐diameter tubular structures. The small pool of processable materials poses a bottleneck for wider application in biomedicine. To alleviate this obstacle, an acrylate‐endcapped urethane‐based polymer (AUP), using a poly(ε‐caprolactone) (PCL) (molar mass: 20 000 g mol−1) (AUP PCL20k) as backbone material, is synthesized and utilized for MEW. Spectroscopic analysis confirms the successful modification of the PCL backbone with photo‐crosslinkable acrylate endgroups. Printing experiments of AUP PCL20k reveal limited printability but the photo‐crosslinking ability is preserved post‐printing. To improve printability and to tune the mechanical properties of printed constructs, the AUP‐material is blended with commercially available PCL (AUP PCL20k:PCL in ratios 80:20, 60:40, 50:50). Print fidelity improves for 60:40 and 50:50 blends. Blending enables modification of the constructs' mechanical properties to approximate the range of blood vessels for transplantation surgeries. The crosslinking‐ability of the material allows pure AUP to be manipulated post‐printing and illustrates significant differences in mechanical properties of 80:20 blends after crosslinking. An in vitro cell compatibility assay using human umbilical vein endothelial cells also demonstrates the material's non‐cytotoxicity. [ABSTRACT FROM AUTHOR]

Several manufacturing technologies beneficially involve processing from the melt, including extrusion‐based printing, electrospinning, and electrohydrodynamic jetting. In this study, (AB)n segmented copolymers are tailored for melt‐processing to form physically crosslinked hydrogels after swelling. The copolymers are composed of hydrophilic poly(ethylene glycol)‐based segments and hydrophobic bisurea segments, which form physical crosslinks via hydrogen bonds. The degree of polymerization was adjusted to match the melt viscosity to the different melt‐processing techniques. Using extrusion‐based printing, a width of approximately 260 µm is printed into 3D constructs, with excellent interlayer bonding at fiber junctions, due to hydrogen bonding between the layers. For melt electrospinning, much thinner fibers in the range of about 1–15 µm are obtained and produced in a typical nonwoven morphology. With melt electrowriting, fibers are deposited in a controlled way to well‐defined 3D constructs. In this case, multiple fiber layers fuse together enabling constructs with line width in the range of 70 to 160 µm. If exposed to water the printed constructs swell and form physically crosslinked hydrogels that slowly disintegrate, which is a feature for soluble inks within biofabrication strategies. In this context, cytotoxicity tests confirm the viability of cells and thus demonstrating biocompatibility of this class of copolymers. [ABSTRACT FROM AUTHOR]

Die bisher größtenteils unerforschte Kombination aus Biofabrikation und Nanotechnologie ermöglicht eine örtlich und zeitlich aufgelöste Freisetzung von Wirkstoffen aus hierarchischen, zellbeladenen Biomaterialien. Als ein erster Schritt in Richtung der Verknüpfung dieser beiden Forschungsgebiete wird hier gezeigt, dass die Einstellung der elektrostatischen Nanopartikel ‐ Polymer ‐ und Nanopartikel ‐ Nanopartikel ‐ Wechselwirkungen verwendet werden kann, um die Freisetzungskinetik von Nanopartikeln aus gedruckten 3D Hydrogelgerüsten zu steuern. Diese grundlegende Strategie kann für die räumliche und zeitliche Kontrolle der Freisetzungskinetik von nanopartikulären Wirkstoffträgern in biofabrizierten Konstrukten verwendet werden. Formulierungen von positiv und negativ geladenen Silika ‐ Nanopartikeln oder sphärischen Gold ‐ Nanopartikeln mit einer Hydrogel ‐ Biotinte wurden für die Biofabrikation verwendet. Die schnelle Freisetzung der negativ geladenen Partikel sowie das gegensätzliche Verhalten der positiv geladenen Partikel werden demonstriert. Dieses allgemeine Prinzip könnte als Strategie für die Implementierung von Nanopartikeln in die Biofabrikation für die örtliche und zeitliche Kontrolle der Wirkstofffreisetzung dienen. [ABSTRACT FROM AUTHOR]

The convergence of biofabrication with nanotechnology is largely unexplored but enables geometrical control of cell-biomaterial arrangement combined with controlled drug delivery and release. As a step towards integration of these two fields of research, this study demonstrates that modulation of electrostatic nanoparticle-polymer and nanoparticle-nanoparticle interactions can be used for tuning nanoparticle release kinetics from 3D printed hydrogel scaffolds. This generic strategy can be used for spatiotemporal control of the release kinetics of nanoparticulate drug vectors in biofabricated constructs. [ABSTRACT FROM AUTHOR]

Additive manufacturing with electrohydrodynamic direct writing is a promising approach for the production of polymeric microscale objects. In this study we investigate the stability of one such process, melt electrospinning writing, to maintain accurate placement of the deposited fibre throughout the entire print. The influence of acceleration voltage and feeding pressure on the deposited poly(ε-caprolactone) fibre homogeneity is described, and how this affects the variable lag of the jet drawn by the collector movement. Three classes of diameter instabilities were observed that led to poor printing quality: (1) temporary pulsing, (2) continuous pulsing, and (3) regular long bead defects. No breakup of the electrified jet was observed for any of the experiments. A simple approach is presented for the melt electrospinning user to evaluate fibre writing integrity, and adjust the processing parameters accordingly to achieve reproducible and constant diameter fibres. [ABSTRACT FROM AUTHOR]

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Melt electrospinning writing is a direct-writing additive manufacturing process that involves depositing a continuous, viscous and electrohydrodynamically stabilised molten jet onto a collector. Here, molten threads of medical-grade polycaprolactone ( PCL) are directed towards stationary/rotating cylindrical collectors (0-6600 rpm), including very slow revolutions well below the critical translation speed (approximately 600 mm min−1) of the molten jet. In this slow-rotation region, the speed of the jet is faster than the movement of the collector and buckled/coiled fibres are produced due to compressive viscoelastic forces. The results are porous PCL tubes with wall morphologies often associated with viscoelastic liquids impinging onto a surface. The curvature of the collector affects how the fibre is deposited, with preferential fibre deposition along the axis of the cylinder. When the collector rotation speed is increased to greater than the speed of the jet, then straight fibres are produced. Such tubular structures have applications in tissue engineering. © 2015 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Despite significant investment in tissue engineering over the past 20 years, few tissue engineered products have made it to market. One of the reasons is the poor control over the 3D arrangement of the scaffold's components. Biofabrication is a new field of research that exploits 3D printing technologies with high spatial resolution for the simultaneous processing of cells and biomaterials into 3D constructs suitable for tissue engineering. Cell-encapsulating biomaterials used in 3D bioprinting are referred to as bioinks. This review consists of: (1) an introduction of biofabrication, (2) an introduction of 3D bioprinting, (3) the requirements of bioinks, (4) existing bioinks, and (5) a specific example of a recombinant spider silk bioink. The recombinant spider silk bioink will be used as an example because its unmodified hydrogel format fits the basic requirements of bioinks: to be printable and at the same time cytocompatible. The bioink exhibited both cytocompatible (self-assembly, high cell viability) and printable (injectable, shear-thinning, high shape fidelity) qualities. Although improvements can be made, it is clear from this system that, with the appropriate bioink, many of the existing faults in tissue-like structures produced by 3D bioprinting can be minimized. [ABSTRACT FROM AUTHOR]

To facilitate true regeneration, a vascular graft should direct the evolution of a neovessel to obtain the function of a native vessel. For this, scaffolds have to permit the formation of an intraluminal endothelial cell monolayer, mimicking the tunica intima. In addition, when attempting to mimic a tunica media‐like outer layer, the stacking and orientation of vascular smooth muscle cells (vSMCs) should be recapitulated. An integral scaffold design that facilitates this has so far remained a challenge. A hybrid fabrication approach is introduced by combining solution electrospinning and melt electrowriting. This allows a tissue‐structure mimetic, hierarchically bilayered tubular scaffold, comprising an inner layer of randomly oriented dense fiber mesh and an outer layer of microfibers with controlled orientation. The scaffold supports the organization of a continuous luminal endothelial monolayer and oriented layers of vSM‐like cells in the media, thus facilitating control over specific and tissue‐mimetic cellular differentiation and support of the phenotypic morphology in the respective layers. Neither soluble factors nor a surface bioactivation of the scaffold is needed with this approach, demonstrating that heterotypic scaffold design can direct physiological tissue‐like cell organization and differentiation. [ABSTRACT FROM AUTHOR]

Bioprinting has emerged as a valuable three-dimensional (3D) biomanufacturing method to fabricate complex hierarchical cell-containing constructs. Spanning from basic research to clinical translation, sterile starting materials are crucial. In this study, we present pharmacopeia compendial sterilization methods for the commonly used bioink component alginate. Autoclaving (sterilization in saturated steam) and sterile filtration followed by lyophilization as well as the pharmacopeia noncompendial method, ultraviolet (UV)-irradiation for disinfection, were assessed. The impact of the sterilization methods and their effects on physicochemical and rheological properties, bioprinting outcome, and sterilization efficiency of alginate were detailed. Only sterile filtration followed by lyophilization as the sterilization method retained alginate's physicochemical properties and bioprinting behavior while resulting in a sterile outcome. This set of methods provides a blueprint for the analysis of sterilization effects on the rheological and physicochemical pattern of bioink components and is easily adjustable for other polymers used in the field of biofabrication in the future., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Bioengineered grafts have the potential to overcome the limitations of autologous and non-resorbable synthetic vessels as vascular substitutes. However, one of the challenges in creating these living grafts is to induce and maintain multiple cell phenotypes with a biomimetic organization. Our biomimetic grafts with heterotypic design hold promises for functional neovessel regeneration by guiding the layered cellular and tissue organization into a native-like structure. In this study, a perfusable two-compartment bioreactor chamber was designed for the further maturation of these vascular grafts, with a compartmentalized exposure of the graft's luminal and outer layer to cell-specific media. We used the system for a co-culture of endothelial colony forming cells and multipotent mesenchymal stromal cells (MSCs) in the vascular grafts, produced by combining electrospinning and melt electrowriting. It was demonstrated that the targeted cell phenotypes (i.e. endothelial cells (ECs) and vascular smooth muscle cells (vSMCs), respectively) could be induced and maintained during flow perfusion. The confluent luminal layer of ECs showed flow responsiveness, as indicated by the upregulation of COX-2, KLF2, and eNOS, as well as through stress fiber remodeling and cell elongation. In the outer layer, the circumferentially oriented, multi-layered structure of MSCs could be successfully differentiated into vSM-like cells using TGFβ, as indicated by the upregulation of αSMA, calponin, collagen IV, and (tropo)elastin, without affecting the endothelial monolayer. The cellular layers inhibited diffusion between the outer and the inner medium reservoirs. This implies tightly sealed cellular layers in the constructs, resulting in truly separated bioreactor compartments, ensuring the exposure of the inner endothelium and the outer smooth muscle-like layer to cell-specific media. In conclusion, using this system, we successfully induced layer-specific cell differentiation with a native-like cell organization. This co-culture system enables the creation of biomimetic neovessels, and as such can be exploited to investigate and improve bioengineered vascular grafts.

In this study, we evaluate hydrogels based on oxidized hyaluronic acid, cross-linked with adipic acid dihydrazide, for their suitability as bioinks for 3D bioprinting. Aldehyde containing hyaluronic acid (AHA) is synthesized and cross-linked via Schiff Base chemistry with bifunctional adipic acid dihydrazide (ADH) to form a mechanically stable hydrogel with good printability. Mechanical and rheological properties of the printed and casted hydrogels are tunable depending on the concentrations of AHA and ADH cross-linkers.

The development and formulation of printable inks for extrusion-based 3D bioprinting has been a major challenge in the field of biofabrication. Inks, often polymer solutions with the addition of crosslinking to form hydrogels, must not only display adequate mechanical properties for the chosen application but also show high biocompatibility as well as printability. Here we describe a reproducible two-step method for the assessment of the printability of inks for bioprinting, focussing firstly on screening ink formulations to assess fibre formation and the ability to form 3D constructs before presenting a method for the rheological evaluation of inks to characterise the yield point, shear thinning and recovery behaviour. In conjunction, a mathematical model was formulated to provide a theoretical understanding of the pressure-driven, shear thinning extrusion of inks through needles in a bioprinter. The assessment methods were trialled with a commercially available crème, poloxamer 407, alginate-based inks and an alginate-gelatine composite material. Yield stress was investigated by applying a stress ramp to a number of inks, which demonstrated the necessity of high yield for printable materials. The shear thinning behaviour of the inks was then characterised by quantifying the degree of shear thinning and using the mathematical model to predict the window of printer operating parameters in which the materials could be printed. Furthermore, the model predicted high shear conditions and high residence times for cells at the walls of the needle and effects on cytocompatibility at different printing conditions. Finally, the ability of the materials to recover to their original viscosity after extrusion was examined using rotational recovery rheological measurements. Taken together, these assessment techniques revealed significant insights into the requirements for printable inks and shear conditions present during the extrusion process and allow the rapid and reproducible characterisation of a wide variety of inks for bioprinting.