Soft Biomaterials Research Articles

Physics of droplet impact on flexible materials: A review

Droplet impact on a flexible substrate is a prevalent phenomenon in nature and various advanced technologies such as soft bio-printing, tissue engineering, smart biomaterials and flexible electronics. Recent rapid advancement in new functional surfaces, ultra-high-speed imaging, nanotechnology, deep learning, advanced computational strength and the relation between fluid dynamics and interfacial science have intensified the physical understanding of droplet impact on soft materials. Once a droplets impacts on a solid surface, it deposits, spreads, rebounds or splashes. Given the importance of the droplet impact onto soft substrates in biotechnology, medicine and advanced flexible electronics, a deep physical understanding of such complex phenomenon is vital. This review initially presents the liquid-solid interaction physics and relevant interfacial science. Next, this review discusses the physics of droplet impact on soft materials with different physical and interfacial characteristics. Moreover, this review presents advancements in droplet impact on elastic materials relevant to new technologies such as soft electronics, elastic smart biomaterials, tissue engineering and the fight against COVID-19 pandemic. Finally, this review lays out future research directions related to current problems in such complex physical phenomenon.

Impact of doubling peptide length on in vivo hydrogel stability and sustained drug release

Peptide-based hydrogels represent promising systems for the sustained release of different types of drugs, ranging from small molecules to biologicals. Aiming at subcutaneous injection, which is a desirable parenteral administration route, especially for biologicals, we herein focus on physically crosslinked systems possessing thixotropic behaviour. The purpose of this study was to evaluate the in vitro and in vivo properties of hydrogels based on the amphipathic hexapeptide H-FQFQFK-NH2, which served as the lead sequence. Upon doubling the length of this peptide, the dodecapeptide H-FQFQFKFQFQFK-NH2 gave a significant improvement in terms of in vivo stability of the hydrogel post-injection, as monitored by nuclear SPECT/CT imaging. This increased hydrogel stability also led to a more prolonged in vivo release of encapsulated peptide cargoes. Even though no direct link with the mechanical properties of the hydrogels before injection could be made, an important effect of the subcutaneous medium was noticed on the rheological properties of the hydrogels in post in vivo injection measurements. The results were validated in vivo for a therapeutically relevant analgesic peptide using the hot-plate test as an acute pain model. It was confirmed that elongation of the hydrogelator sequence induced more extended antinociceptive effects. Altogether, this simple structural modification of the hydrogelating peptide could provide a basis for reaching longer durations of action upon use of these soft biomaterials.

A Polyanionic Tartrate‐containing Temperature‐responsive Hydrogel

Thermogels, a class of hydrogels which show spontaneous sol-gel phase transition when warmed, are an important class of soft biomaterials. To date, however, most amphiphilic polymers that are able to form thermogels in aqueous solution are uncharged, and the influence of ionisable groups on thermogelation are largely unknown. Herein, we report the first example of a polyanionic amphiphilic multi-block copolymer, containing multiple pendant carboxylate groups, that can form transparent thermogels spontaneously when warmed up to physiological temperature. We demonstrate that introducing negative charges onto thermogelling polymers could significantly alter the properties of the micelles and thermogels formed. Furthermore, the polymer's polyanionic character provides new options for modulating the gel rheological properties, such as stiffness and gelation temperatures, through electrostatic interactions with different cations. We also demonstrated that the polyanionic thermogel allowed slower sustained release of a cationic model drug compound compared to an anionic one over 2 weeks. The findings from our study demonstrate exciting new possibilities for advanced biomedical applications using charged polyelectrolyte thermogel materials.

Regulable Supporting Baths for Embedded Printing of Soft Biomaterials with Variable Stiffness.

Three-dimensional (3D) embedded printing is emerging as a potential solution for the fabrication of complex biological structures and with ultrasoft biomaterials. For the supporting medium, bulk gels can support a wide range of bioinks with higher printing resolution as well as better finishing surfaces than granular microgel baths. However, the difficulties of regulating the physical properties of existing bulk gel supporting baths limit the further development of this method. This work has developed a bulk gel supporting bath with easily regulable physical properties to facilitate soft-material fabrication. The proposed bath is composed based on the hydrophobic association between a hydrophobically modified hydroxypropylmethyl cellulose (H-HPMC) and Pluronic F-127 (PF-127). Its rheological properties can be easily regulated; in the preprinting stage by varying the relative concentration of components, during printing by changing the temperature, and postprinting by adding additives with strong hydrophobicity or hydrophilicity. This has made the supporting bath not only available for various bioinks with a range of printing windows but also easy to be removed. Also, the removal strategy is independent of printing conditions like temperature and ions, which empowers the bath to hold great potential for the embedded printing of commonly used biomaterials. The adjustable rheological properties of the bath were leveraged to characterize the embedded printing quantitatively, involving the disturbance during the printing, filament cross-sectional shape, printing resolution, continuity, and the coalescence between adjacent filaments. The match between the bioink and the bath was also explored. Furthermore, low-viscosity bioinks (with 0.008-2.4 Pa s viscosity) were patterned into various 3D complex delicate soft structures (with a 0.5-5 kPa compressive modulus). It is believed that such an easily regulable assembled bath could serve as an available tool to support the complex biological structure fabrication and open unique prospects for personalized medicine.

Tailored Biocompatible Polyurethane-Poly(ethylene glycol) Hydrogels as a Versatile Nonfouling Biomaterial.

Polyurethane-based hydrogels are relatively inexpensive and mechanically robust biomaterials with ideal properties for various applications, including drug delivery, prosthetics, implant coatings, soft robotics, and tissue engineering. In this report, a simple method is presented for synthesizing and casting biocompatible polyurethane-poly(ethylene glycol) (PU-PEG) hydrogels with tunable mechanical properties, nonfouling characteristics, and sustained tolerability as an implantable material or coating. The hydrogels are synthesized via a simple one-pot method using commercially available precursors and low toxicity solvents and reagents, yielding a consistent and biocompatible gel platform primed for long-term biomaterial applications. The mechanical and physical properties of the gels are easily controlled by varying the curing concentration, producing networks with complex shear moduli of 0.82-190kPa, similar to a range of human soft tissues. When evaluated against a mechanically matched poly(dimethylsiloxane) (PDMS) formulation, the PU-PEG hydrogels demonstrated favorable nonfouling characteristics, including comparable adsorption of plasma proteins (albumin and fibrinogen) and significantly reduced cellular adhesion. Moreover, preliminary murine implant studies reveal a mild foreign body response after 41 days. Due to the tunable mechanical properties, excellent biocompatibility, and sustained in vivo tolerability of these hydrogels, it is proposed that this method offers a simplified platform for fabricating soft PU-based biomaterials for a variety of applications.

The Systems Chemistry of Nucleic‐acid‐Peptide Networks

AbstractLiving cells use chemical building blocks (biopolymers) to form fascinatingly complex architectures, which in turn display multiple functions necessary for the cell life cycle. The mechanisms and order of events by which forerunners of these extant biopolymers formed on the early earth remains under intensive investigation. Prebiotic chemistry research has recently provided ample evidence that both peptide and nucleic‐acid (NA) precursors could be formed in a primordial environment through common synthetic routes. However, until recently, studies directed at the design of functional supramolecular structures have focused primarily on assemblies made of either peptides or NAs. The emerging discipline of Systems Chemistry now develops dynamic supramolecular interactions to capture the complex emergent properties of reaction networks. Accordingly, we review here recent work that reveals mutualistic nucleic acid/peptide co‐assembly, and approaches toward utility of these architectures as functional materials capable of substrate binding, catalysis, replication, and translation. Many of these new approaches to smart soft biomaterials and functional bio‐nanotechnology provide insight and extend our understanding of the possible origins of living systems.

Patternable Gelatin Methacrylate/PEDOT/Polystyrene Sulfonate Microelectrode Coatings for Neuronal Recording.

This manuscript addresses the need for new soft biomaterials that can be fabricated on the surface of microelectrodes to reduce the mechanical mismatch between biological tissues and electrodes and improve the performance at the neural interface. By electrochemical polymerization of poly(3,4-dioxythiophene) (PEDOT)/polystyrene sulfonate (PSS) through a gelatin methacrylate (GelMA) hydrogel, we demonstrate the synthesis of a conducting polymer hydrogel (CPH) to meet the performance criteria of bioelectrodes. The hybrid material can be photolithographically patterned and covalently attached to gold microelectrodes, forming an interpenetrating network, as confirmed by infrared spectroscopy. The GelMA/PEDOT/PSS coatings were found to be reversibly electroactive by cyclic voltammetry and had low impedance compared to bare gold and GelMA-coated microelectrodes. The CPH coatings showed impedance at levels similar to conventional PEDOT/PSS coatings at a frequency of 1000 Hz. CPH exhibited electrochemical stability over 1000 CV cycles, and its performance was maintained over 14 days. Biocompatibility of the CPH coatings was confirmed by primary hippocampal neuronal cultures via a neuronal viability assay. The CPH-coated microelectrode arrays (MEAs) successfully recorded neuronal activity from primary hippocampal neuronal cells. The CPH GelMA/PEDOT/PSS is a highly promising coating material to enhance microelectrode performance at the neural interface.

Visible-light controlled supramolecular transformations of donor-acceptor Stenhouse adducts amphiphiles at multiple length-scale

Designing responsive, adaptive, and dynamic supramolecular systems in water, the incorporation of photoresponsive units in amphiphilic molecular structures enables functional responses in a non-invasive way by using light. However, in aqueous media, vast majority of reported synthetic photoresponsive molecular amphiphiles are commonly driven by high energy and bio-damaging UV-light for supramolecular transformation at multiple length-scale. Herein, we present newly designed visible-light controlled supramolecular assembly of donor-acceptor Stenhouse adducts amphiphiles (DA) with excellent stability and solubility in aqueous media. The excellent photoswitchability in organic media and photoresponsiveness in aqueous media driven by visible-light are found, as confirmed with UV–vis absorption and NMR spectroscopies. Supramolecular assembly at multiple length-scale of DAs is investigated with electron microscopies and X-ray diffraction to show large aspect-ratio of nanostructures assembled into macroscopic soft scaffolds. Upon visible-light irradiation, the large geometrical transformation of DAs enables supramolecular transformations, and subsequently destabilizes the macroscopic soft scaffold to release fluorophores from the scaffolds. These results provide the feasibility in developing the next generation of visible-light controlled macroscopic soft functional scaffold from supramolecular assembly across multiple length-scale without and offer ample opportunity to design future soft robotic materials and functional biomaterials.

Simulations of Extrusion 3D Printing of Chitosan Hydrogels

Extrusion-based three-dimensional (3D) printing has recently become a major field that provides significant benefits, as it is principally employed to fabricate 3D scaffolds, exploiting soft biomaterials. The 3D printing hydrogel-based ink requires crucial properties, such as printability and printing fidelity to fabricate the appropriate structure. However, it typically uses trial and error techniques to achieve a three-dimensional structure, which wastes material and time. This study employed multiphysics simulation to predicate the potential printability of chitosan hydrogel as a desirable biomaterial used in tissue engineering. The flow was presumed to be laminar and two-phased in the simulations. Furthermore, the impact of different velocities and viscosities in extrusion-based chitosan 3D printing was investigated. Moreover, the model validation of the printed chitosan hydrogel was investigated to confirm the simulation outcomes for high-quality printing. The effect of different printing settings was studied during the experimental test. The results obtained from the simulation and experiments provide information for deciding the optimum parameters for printing chitosan-based ink with high quality.

Soft Biomaterials Based Flexible Artificial Synapse for Neuromorphic Computing

AbstractArtificial synapses are vital for neuromorphic computing chips that can potentially revolutionize von Neumann systems. Biomaterials‐based bio‐memristors have been investigated as synaptic emulators to develop neuromorphic computing chips due to their biocompatibility, degradability, flexibility, and low costs. However, the existing biomaterials‐based artificial synapses suffer from limited biological synapse functions, insufficient reliability, and poor endurance. Particularly, protein‐based artificial synapse with stable synaptic performances of long‐term potentiation/depression (LTP/LTD) for neuromorphic computing is challenging. Here, the soft material of egg albumen@CuO are employed to develop an artificial synapse. The device can mimic bio‐synaptic functionalities, including the excitatory postsynaptic current (EPSC), spike‐number‐dependent plasticity (SNDP), paired‐pulse facilitation (PPF), and LTP/LTD. High accuracy of 95% has been obtained by the neuromorphic computing simulation for pattern recognition. Combining with density functional theory calculations, multiphysics simulations, and electrical measurements, the analog resistive switching mechanism is attributed to electron hopping. In addition, the device is flexible and can be used to develop wearable systems. The results shed light on the biocompatible and wearable neuromorphic computing chips.

Computational indentation in highly cross-linked polymer networks

Indentation is a common experimental technique to study the mechanics of polymeric materials. The main advantage of using indentation is this provides a direct correlation between the microstructure and the small-scale mechanical response, which is otherwise difficult within the standard tensile testing. The majority of studies have investigated hydrogels, microgels, elastomers, and even soft biomaterials. However, a less investigated system is the indentation in highly cross-linked polymer (HCP) networks, where the complex network structure plays a key role in dictating their physical properties. In this work, we investigate the structure-property relationship in HCP networks using the computational indentation of a generic model. We establish a correlation between the local bond breaking, network rearrangement, and small-scale mechanics. The results are compared with the elastic-plastic deformation model. HCPs harden upon indentation.

Measuring the elastic modulus of soft biomaterials using nanoindentation

The measurement of the elastic modulus of soft biomaterials via nanoindentation relies on the accurate determination of the zero-point of the tip-sample interaction on which the depth of penetration into the sample is based. Non-cantilever based nanoindentation systems were originally designed for hard materials, and therefore monitoring the zero-point contact presents a significant challenge for the characterisation of very soft biomaterials. This study investigates the ability of non-cantilever based nanoindentation to differentiate between hydrogels with elastic moduli on the order of single kiloPascals (kPa) using a bespoke soft contact protocol and low flexural stiffness of instrument. Polyethylene glycol (PEG) hydrogels were fabricated as a model system with a range of elastic moduli by varying the polymer concentration and degree of crosslinking. Elastic modulus values were calculated using the Oliver-Pharr method, Hertzian contact model, as well as a viscoelastic model to account for the time-dependent behaviour of the gels. The stiffness measurements were validated by measuring cantilever beams with the equivalent flexural stiffness to that of the PEG hydrogels being tested. The results demonstrated a high repeatability of the measurements, enabling differentiation between hydrogels with elastic moduli in the single kPa to hundreds of kPa range.

Optimal Design and Analysis for a New 1-DOF Compliant Stage Based on Additive Manufacturing Method for Testing Medical Specimens

In situ nanoindentation is extensively employed for online observing deformation and mechanical behaviors of bio-materials. However, the existing designs of the positioning stages have limited performances for testing soft or hard biomaterials. Consequently, this paper proposes a new structural design of a compliant one degree of freedom (01-DOF) stage with faster response. In addition to a new design, this article applies an analytical method to estimate the kinematic and dynamic behaviors of the stage. Firstly, the 01-DOF stage is designed with two modules, including a displacement amplifier with six levers and a symmetric parallelogram mechanism. Secondly, a kinetostatic diagram of the stage is built by pseudo-rigid-body method. Then, the dynamic equation of the proposed stage is formulated using the Lagrange method. In order to speed up the response of the indentation system, the structural optimization of the stage is conducted via the Firefly algorithm. The results showed that the theoretical first-order resonant frequency is found at about 226.8458 Hz. The theoretical consequences are nearby to the verified simulation. Besides, this achieved frequency of the presented stage is greater than that of previous stages. In an upcoming study, the prototype will be fabricated by additive manufacturing method or a computerized wire cutting method in order to verify the analytical results with experimental results.

Biocompatible Chemically Fueled Transient Polymer Nanoparticles for Temporally Programmable in Vivo Imaging

Biocompatible Chemically Fueled Transient Polymer Nanoparticles for Temporally Programmable in Vivo Imaging

Application Status of Sacrificial Biomaterials in 3D Bioprinting.

Additive manufacturing, also known as three-dimensional (3D) printing, relates to several rapid prototyping (RP) technologies, and has shown great potential in the manufacture of organoids and even complex bioartificial organs. A major challenge for 3D bioprinting complex org unit ans is the competitive requirements with respect to structural biomimeticability, material integrability, and functional manufacturability. Over the past several years, 3D bioprinting based on sacrificial templates has shown its unique advantages in building hierarchical vascular networks in complex organs. Sacrificial biomaterials as supporting structures have been used widely in the construction of tubular tissues. The advent of suspension printing has enabled the precise printing of some soft biomaterials (e.g., collagen and fibrinogen), which were previously considered unprintable singly with cells. In addition, the introduction of sacrificial biomaterials can improve the porosity of biomaterials, making the printed structures more favorable for cell proliferation, migration and connection. In this review, we mainly consider the latest developments and applications of 3D bioprinting based on the strategy of sacrificial biomaterials, discuss the basic principles of sacrificial templates, and look forward to the broad prospects of this approach for complex organ engineering or manufacturing.

Fluorescent DNA thermotropic liquid crystal showing thermostability and water-resistance

Solvent-free soft biomaterials with fluorescent property are highly attractive because of their wide prospective applications in bioimaging and anticounterfeiting. However, in solvent-free condition, developing soft fluorescent DNA materials is very challenging. In this study, a type of fluorescent solvent-free DNA thermotropic liquid crystal (DNA-TPEA) is developed via the electrostatic complexation of DNA and tetraphenylethene-containing ammonium surfactant TPEA. Under UV light, DNA-TPEA could give bright luminescence with good quantum yield, which has been tested as an anticounterfeiting labeling biomaterial working at high temperatures and in aqueous condition. An investigation on the photoluminescence lifetime of DNA-TPEA indicates that the TPEA molecules are in two different environments, and for which a working mechanism is illustrated. This work provides a new strategy for developing fluorescent biomaterials in solvent-free condition by fusing AIE surfactants and biomolecules together via electrostatic force, which gains synthetic convenience compared to the covalent modification of biomolecules with fluorescent proteins.

Self-Assembling Peptide Hydrogels as Functional Tools to Tackle Intervertebral Disc Degeneration.

Low back pain (LBP), caused by intervertebral disc (IVD) degeneration, is a major contributor to global disability. In its healthy state, the IVD is a tough and well-hydrated tissue, able to act as a shock absorber along the spine. During degeneration, the IVD is hit by a cell-driven cascade of events, which progressively lead to extracellular matrix (ECM) degradation, chronic inflammation, and pain. Current treatments are divided into palliative care (early stage degeneration) and surgical interventions (late-stage degeneration), which are invasive and poorly efficient in the long term. To overcome these limitations, alternative tissue engineering and regenerative medicine strategies, in which soft biomaterials are used as injectable carriers of cells and/or biomolecules to be delivered to the injury site and restore tissue function, are currently being explored. Self-assembling peptide hydrogels (SAPHs) represent a promising class of de novo synthetic biomaterials able to merge the strengths of both natural and synthetic hydrogels for biomedical applications. Inherent features, such as shear-thinning behaviour, high biocompatibility, ECM biomimicry, and tuneable physiochemical properties make these hydrogels appropriate and functional tools to tackle IVD degeneration. This review will describe the pathogenesis of IVD degeneration, list biomaterials requirements to attempt IVD repair, and focus on current peptide hydrogel materials exploited for this purpose.

Quantitative analysis of the effect of radiation on mitochondria structure using coherent diffraction imaging with a clustering algorithm.

Radiation damage and a low signal-to-noise ratio are the primary factors that limit spatial resolution in coherent diffraction imaging (CDI) of biomaterials using X-ray sources. Introduced here is a clustering algorithm named ConvRe based on deep learning, and it is applied to obtain accurate and consistent image reconstruction from noisy diffraction patterns of weakly scattering biomaterials. To investigate the impact of X-ray radiation on soft biomaterials, CDI experiments were performed on mitochondria from human embryonic kidney cells using synchrotron radiation. Benefiting from the new algorithm, structural changes in the mitochondria induced by X-ray radiation damage were quantitatively characterized and analysed at the nanoscale with different radiation doses. This work also provides a promising approach for improving the imaging quality of biomaterials with XFEL-based plane-wave CDI.

Experimental and Data Analysis Workflow for Soft Matter Nanoindentation.

Nanoindentation refers to a class of experimental techniques where a micrometric force probe is used to quantify the local mechanical properties of soft biomaterials and cells. This approach has gained a central role in the fields of mechanobiology, biomaterials designand tissue engineering, to obtain a proper mechanical characterization of soft materials with a resolution comparable to the size of single cells (μm). The most popular strategy to acquire such experimental data is to employ an atomic force microscope (AFM); while this instrument offers an unprecedented resolution in force (down to pN) and space (sub-nm), its usability is often limited by its complexity that prevents routine measurements of integral indicators of mechanical properties, such as Young's Modulus (E). A new generation of nanoindenters, such as those based on optical fiber sensing technology, has recently gained popularity for its ease of integration while allowing to apply sub-nN forces with µm spatial resolution, therefore being suitable to probe local mechanical properties of hydrogels and cells. In this protocol, a step-by-step guide detailing the experimental procedure to acquire nanoindentation data on hydrogels and cells using a commercially available ferrule-top optical fiber sensing nanoindenter is presented. Whereas some steps are specific to the instrument used herein, the proposed protocol can be taken as a guide for other nanoindentation devices, granted some steps are adapted according to the manufacturer's guidelines. Further, a new open-source Python software equipped with a user-friendly graphical user interface for the analysis of nanoindentation data is presented, which allows for screening of incorrectly acquired curves, data filtering, computation of the contact point through different numerical procedures, the conventional computation of E, as well as a more advanced analysis particularly suited for single-cell nanoindentation data.

Development of Soft Interface Biomaterials from Data of Protein Adsorption and Cell Adhesion

Development of Soft Interface Biomaterials from Data of Protein Adsorption and Cell Adhesion