Biocompatible Soft Materials Research Articles

Alkaline cations dramatically control molecular hydrogelation by an amino acid-derived anionic amphiphile

Understanding the factors that control the formation of (supra)molecular hydrogels permits a rational tuning of their properties and represents a primary challenge for developing smart biocompatible soft materials. Hydrogel formation by molecular amphiphilic anions at millimolar concentrations is counterintuitive, considering the solubility of these species in water. Here we report hydrogel formation by a simple anionic molecular amphiphile and a rationale for the fibrillisation process observed. The studied molecule, DodValSuc, consists of a 12C alkyl chain, an l-valine unit and a terminal succinic acid moiety. Hydrogelation depends to a large degree on the nature and concentration of the alkaline cations present in the medium (Li+, Na+ or K+). As a result, gelation efficiency and properties like thermal stability or rheology are highly tunable using the alkaline cation present or its concentration as variables.A detailed study is reported, which includes the determination of minimum gelation concentration (MGC) by tabletop rheology, critical micelle concentration (CMC) using pyrene as a fluorescent probe, thermal stability (solubility) by 1H NMR, the morphology of the fibres by transmission electron microscopy (TEM), crystallinity by X-ray diffraction (XRD) and gel strength by oscillatory rheology. Additionally, dynamic light scattering (DLS) was used to evaluate the size of the micelles and permitted monitoring of the fibrillisation process.Altogether, the results are consistent with the formation of micelles that experience head crystallisation and subsequent aggregation into crystalline fibres. The alkaline cations play a crucial role in providing the cement that glues together the gelator molecules, making their concentration a critical parameter for gelation efficiency and properties. Furthermore, the gelation-promoting effects are inversely correlated with the size of the cations so that the highest thermal stability and rheological strength were found for the hydrogels formed in the presence of Li+.

Visualization of Solvent-Induced Structure Evolution in Cyclodextrin Polyrotaxane Gels.

Cyclodextrin (CD)-based polyrotaxanes (PR) are widely used to construct high-mechanical-performance materials because of the high degree of conformational freedom. However, strong hydrogen bonds between CDs greatly limit the application of CD-PR in the preparation of ductile neutral hydrogels. In this work, spiropyrane (SP) into α-CD-based PR is introduced to "visualize" the segment motion of the network in neutral water. The aggregation-induced cohesion and critical factors for the force transmission are disclosed. This system offers a new approach for the fundamental research for the complicated topologically cross-linked structures, which is important for the design of CD-PR-based biocompatible soft materials.

Recent Advances on Hybrid Piezo-Triboelectric Bio-Nanogenerators: Materials, Architectures and Circuitry

Nanogenerators, based on piezoelectric or triboelectric materials, have emerged in the recent years as an attractive cost-effective technology for harvesting energy from renewable and clean energy sources, but also for human sensing and biomedical wearable/implantable applications. Advances in materials engineering have enlightened new opportunities for the creation and use of novel biocompatible soft materials as well as micro/nano-structured or chemically-functionalized interfaces. Hybridization is a key concept that can be used to enhance the performances of the single devices, by coupling more transducing mechanisms in a single-integrated micro-system. It has attracted plenty of research interest due to the promising effects of signal enhancement and simultaneous adaptability to different operating conditions. This review covers and classifies the main types of hybridization of piezo-triboelectric bio-nanogenerators and it also provides an overview of the most recent advances in terms of material synthesis, engineering applications, power-management circuits and technical issues for the development of reliable implantable devices. State-of-the-art applications in the fields of energy harvesting, in vitro/in vivo biomedical sensing, implantable bioelectronics are outlined and presented. The applicative perspectives and challenges are finally discussed, with the aim to suggest improvements in the design and implementation of next-generation hybrid bio-nanogenerators and biosensors.

Application of X-ray Microcomputed Tomography for the Static and Dynamic Characterization of the Microstructure of Oleofoams.

Oleofoams are a novel, versatile, and biocompatible soft material that finds application in drug, cosmetic or nutraceuticals delivery. However, due to their temperature-sensitive and opaque nature, the characterization of oleofoams’ microstructure is challenging. Here, synchrotron X-ray microcomputed tomography and radiography are applied to study the microstructure of a triglyceride-based oleofoam. These techniques enable non-destructive, quantitative, 3D measurements of native samples to determine the thermodynamic and kinetic behavior of oleofoams at different stages of their life cycle. During processing, a constant bubble size distribution is reached after few minutes of shearing, while the number of bubbles incorporated keeps increasing until saturation of the continuous phase. Low amounts of solid triglycerides in oleofoams allow faster aeration and a more homogeneous microstructure but lower thermodynamic stability, with bubble disproportionation and shape relaxation over time. Radiography shows that heating causes Ostwald ripening and coalescence of bubbles, with an increase of their diameter and sphericity.

(Invited) 3D Printing of Soft-Matter Mono Pump in Infant Ventricular Assist Device (VAD) for Blood Pumping

We want to develop a soft-matter Mono pump for infant Ventricular Assist Device (VAD). In this research, we have developed the Mono pump, which is made of soft materials and hard materials to study the effect of applying the soft materials to the Mono pump. The stator of the 3D printed Mono pump was made with biocompatible soft materials called Inter Cross-linking Network (ICN) gels. We believe that ICN gels have not only specific toughness and low friction but also excellent biocompatibility that can prevent blood cell trauma and the transplant rejection. Moreover, the rotor is made of hard materials using commercial resin or filament based 3D printers, (Form 2 and Flashforge Creator). Finally, we will compare the practical and theoretical displacement from the flow rate measurement to implement the best performance of the Mono pump in practical use. Figure 1

(Invited) 3D Printing of Soft-Matter Mono Pump in Infant Ventricular Assist Device (VAD) for Blood Pumping

We want to develop a soft-matter Mono pump for infant Ventricular Assist Device (VAD). In this research, we have developed the Mono pump, which is made of soft materials and hard materials to study the effect of applying the soft materials to the Mono pump. The stator of the 3D printed Mono pump was made with biocompatible soft materials called Inter Cross-linking Network (ICN) gels. We believe that ICN gels have not only specific toughness and low friction but also excellent biocompatibility that can prevent blood cell trauma and the transplant rejection. Moreover, the rotor is made of hard materials using commercial resin or filament based 3D printers, (Form 2 and Flashforge Creator). Finally, we will compare the practical and theoretical displacement from the flow rate measurement to implement the best performance of the Mono pump in practical use.

4D printing soft robotics for biomedical applications

Abstract Soft robotics has grown rapidly as an attractive manufacturing technique at micro/nanoscales, especially in the field of biomedical engineering, due to its mobility and compact size. As an emerging additive manufacturing technique, four-dimensional (4D) printing can replicate natural physio-mechanical changes over time leading the transition from static to dynamic. As such, 4D printing is widely investigated and applied in fields ranging from mechanical engineering and material science, to biomedical engineering. By combining the unique ability of 4D printing to create dynamic morphological changes under certain stimuli and biocompatible soft material based micro-/nanorobots, a new promising platform with precise controllability and unlimited reversible actuation is expected to enhance the role of 4D printing for biomedical applications. In this review, we systematically introduce soft robots and further summarize current 4D printing approaches to fabricate soft robots. Moreover, a broad scope of potential applications of 4D soft robots in biomedical engineering is exclusively discussed. We finally conclude with current challenges and limitations, as well as future directions, for 4D printing soft robot technology.

Protein Microgel-Stabilized Pickering Liquid Crystal Emulsions Undergo Analyte-Triggered Configurational Transition.

Herein, we report a novel approach that involves Pickering stabilization of micometer-sized liquid crystal (LC) droplets with biocompatible soft materials such as a whey protein microgel (WPM) to facilitate the analysis of analyte-induced configurational transition of the LC droplets. The WPM particles were able to irreversibly adsorb at the LC-water interface, and the resulting WPM-stabilized LC droplets possessed a remarkable stability against coalescence over time. Although the LC droplets were successfully protected by a continuous network of the WPM layer, the LC-water interface was still accessible for small molecules such as sodium dodecyl sulfate (SDS) that could diffuse through the meshes of the adsorbed WPM network or through the interfacial pores and induce an LC response. This approach was exploited to investigate the dynamic range of the WPM-stabilized LC droplet response to SDS. Nevertheless, the presence of the unadsorbed WPM in the aqueous medium reduced the access of SDS molecules to the LC droplets, thus suppressing the configuration transition. An improved LC response to SDS with a lower detection limit was achieved after washing off the unadsorbed WPM. Interestingly, the LC exhibited a detection limit as low as ∼0.85 mM for SDS within the initial WPM concentration ranging from 0.005 to 0.1 wt %. Furthermore, we demonstrate that the dose-response behavior was strongly influenced by the number of droplets exposed to the aqueous analytes and the type of surfactants such as anionic SDS, cationic dodecyltrimethylammonium bromide (DTAB), and nonionic tetra(ethylene glycol)monododecyl ether (C12E4). Thus, our results address key issues associated with the quantification of aqueous analytes and provide a promising colloidal platform toward the development of new classes of biocompatible LC droplet-based optical sensors.

Membrane Engineering: Phase Separation in Polymeric Giant Vesicles.

Cell membranes exhibit elaborate lipidic patterning to carry out a myriad of functions such as signaling and trafficking. Domain formation in giant unilamellar vesicles (GUVs) is thus of interest for understanding fundamental biological processes and to provide new prospects for biocompatible soft materials. Lipid rearrangements in lipidic GUVs and lipid/polymer GUVs are extensively studied whereas polymer/polymer hybrid GUVs remain evasive. Here, the focus is on the thermodynamically driven phase separation of amphiphilic polymers in GUVs. It is demonstrated that polymer phase separation is entropically dictated by hydrophobic block incompatibilities and that films topology can help to determine the outcome of polymeric phase separation in GUVs. Lastly, Janus-GUVs are obtained and GUVs exhibit a single large domain by using a compatibilizing hydrophobic block copolymer.

A disulfide based low molecular weight gel for the selective sustained release of biomolecules.

Constructing biocompatible soft materials via supramolecular approaches remains an important challenge for in vivo applications. Substantial efforts have been made to develop biocompatible non-polymeric materials allowing sustained release of biomolecules and/or drugs in vivo. Herein, we introduce disulfide based low molecular weight gels (LMWGs) allowing the in vitro selective sustained release of proteins containing thiol residues. The novel glycosylated nucleoside based bola-amphiphile (GNBA), which features a disulfide bond inserted in the hydrophobic segment, self-assembles to stabilize the resulting hydrogel. Rheological studies show the dominant elastic character and thixotropic properties of the disulfide LMWG demonstrating its injectability. In vitro and in vivo biodegradation investigations reveal that the disulfide LMWG is stable for several weeks. Importantly, disulfide bonds can be cleaved through the thiol-disulfide exchange reactions with small redox molecules such as dithiothreitol (DTT). The disulfide LMWG loaded with a thiol-containing protein (bovine serum albumin) features sustained release in vitro, whereas a dextran of the same molecular weight, lacking a thiol biomolecule, shows quick release. The disulfide GNBA is the first example of a LMWG allowing selective long term sustained release in vitro via a disulfide reshuffling mechanism.

Water-Alcohol Bigels from Fatty Acylated Dipeptides.

Peptide-based gels are emerging as an interesting class of biocompatible soft materials. 9-Fluorenylmethoxycarbonyl-protected amino acids and short peptides have gained considerable attention as promising gelators. Peptide amphiphiles, wherein an alkyl chain is appended to a polar peptidic moiety, are another important class of peptide-based gelators. Here, we report the alcohol/water bigels formed by the rather simple fatty acylated dipeptides wherein the peptidic moiety is made up of hydrophobic amino acids, viz., Val, Ile, and Leu. Lauroyl, myristoyl, and palmitoyl were investigated as the N-terminal fatty acyl groups. None of the lauroylated peptides caused gelation of methanol/water and ethanol/water mixtures up to 2 wt % peptide concentration. Eight out of the 27 peptides resulted in distinct bigels. The gels are composed of fibrous aggregates as characterized by electron microscopy. Infrared spectroscopy suggests the β-sheet conformation of the peptidic region in the gels. Using the Ma-IV ethanol/water bigel as the representative gel, entrapment and steady release of the anticancer drug docetaxel are demonstrated. Such bigels from rather simple amphipathic peptides that are easily synthesized and purified through solvent extraction could be attractive gelator candidates with potential application in drug delivery.

Thermoreversible Siloxane Networks: Soft Biomaterials with Widely Tunable Viscoelasticity

AbstractPolysiloxane elastomers represent a widely utilized soft material with excellent rubber‐like elasticity, biocompatibility, and biodurability; however, there is a lack of an effective and straightforward approach to manipulate the material's viscoelastic response. A facile hydrosilylation reaction is employed to integrate ureidopyrimidinone hydrogen‐bonding side‐groups into linear and crosslinked siloxane polymers to achieve biocompatible soft materials with a highly tunable viscoelastic relaxation timescale. Stacking of H‐bonded moieties is avoided in the designed macromolecular architectures with tight, side‐groups substituents. The obtained siloxane network features the presence of both covalent crosslinks and truly thermoreversible crosslinks, and can be formulated across a broad material design space including elastic solids, recoverable viscoelastic solids, and viscous liquids. The elastomers exhibit unique temperature‐dependent shape‐memory capability and show good cytocompatibility. Importantly, a deformed material's shape‐recovery occurs regardless of external triggering, and through manipulation of network formulations, the shape‐recovery timescale can be easily tuned from seconds to days, opening new possibilities for biomedical, healthcare, and soft material applications.

Facile tuning of the mechanical properties of a biocompatible soft material

Herein, we introduce a method to locally modify the mechanical properties of a soft, biocompatible material through the exploitation of the effects induced by the presence of a local temperature gradient. In our hypotheses, this induces a concentration gradient in an aqueous sodium alginate solution containing calcium carbonate particles confined within a microfluidic channel. The concentration gradient is then fixed by forming a stable calcium alginate hydrogel. The process responsible for the hydrogel formation is initiated by diffusing an acidic oil solution through a permeable membrane in a 2-layer microfluidic device, thus reducing the pH and freeing calcium ions. We characterize the gradient of mechanical properties using atomic force microscopy nanoindentation measurements for a variety of material compositions and thermal conditions. Significantly, our novel approach enables the creation of steep gradients in mechanical properties (typically between 10–100 kPa/mm) on small scales, which will be of significant use in a range of tissue engineering and cell mechanosensing studies.

Biocompatible Lipopeptide-Based Antibacterial Hydrogel.

A biocompatible hydrogel containing a hexapeptide as a key unit has been designed and fabricated. Our design construct comprises a β-sheet-rich short hexapeptide in the center with a hydrophobic long chain and hydrophilic triple lysine unit attached at the N- and C-terminals, respectively. Thus, it is this amphiphilic nature of the molecule that facilitates gelation. It can capture solvent molecules in the three-dimensional cross-linked fibrillar networks. The amphiphilic character of the construct has been modulated to produce an excellent biocompatible soft material for the inhibition of bacterial growth by rupturing the bacterial cell membrane. This hydrogel is also stable against enzymatic degradation (proteinase K) and, most importantly, offers a biocompatible environment for the growth of normal mammalian cells due to its noncytotoxic nature as observed through the cell viability assay. From the hemolytic assay, the morphology of the human red blood cells is found to be almost intact, which suggests that the hydrogel can be used in biomedical applications. Thus, this newly designed antibacterial hydrogel can be used as both an antibacterial biomaterial and a biocompatible scaffold for mammalian cell culture.

Dynamics of amphiphilic block copolymers in an aqueous solution: direct imaging of micelle formation and nanoparticle encapsulation.

Micelles formed through the aggregation of amphiphilic block copolymers are ideal drug nanocarriers. Despite their importance in nanomedicine, the detailed mechanisms through which micelles form and copolymers encapsulate the target nanomaterials are unclear. Here, using in situ liquid cell transmission electron microscopy imaging, we capture both the dynamics of micelle formation and their encapsulation of gold nanoparticles (NPs) in an aqueous solution. Our observations reveal that the amphiphilic block copolymers aggregate and rearrange to form a micelle with a hydrophobic and rigid core, surrounded by a corona of hydrophilic blocks that extend into the solution. These micelles are stable against coalescence, and once mature, they do not merge. We also show that the encapsulation of hydrophobic NPs is a self-limiting process, which occurs through gradual adsorption of block copolymers; the growth of a polymeric shell around the NPs, shielding them from water, ceases when the NPs are fully covered by the adsorbed copolymers. The insights from these observations are of fundamental importance for the design of biocompatible soft materials.

Injectable Hybrid Hydrogels, with Cell-Responsive Degradation, for Tumor Resection.

Biocompatible soft materials have recently found applications in interventional endoscopy to facilitate resection of mucosal tumors. When neoplastic lesions are in organs that can be easily damaged by perforation, such as stomach, intestine, and esophagus, the formation of a submucosal fluid cushion (SFC) is needed to lift the tumor from the underlying muscle during the resection of neoplasias. Such procedure is called endoscopic submucosal dissection (ESD). We describe an injectable, biodegradable, hybrid hydrogel able to form a SFC and to facilitate ESD. The hydrogel, based on polyamidoamines, contains breakable silica nanocapsules covalently bound to its network and able to release biomolecules. To promote degradation, the hydrogel is composed of cleavable disulfide moieties that are reduced by the cells through secretion of glutathione. The same stimulus triggers the breaking of the silica nanocapsules; therefore, the entire hybrid material can be completely degraded and its decomposition depends entirely on the presence of cells. Interestingly, the hydrogel precursor solution showed rapid gelation when injected in vivo and afforded a long-lasting high mucosal elevation, keeping the cushion volume constant during the dissection. This novel material can provide a solution to ESD limitations and promote healing of tissues after surgery.

Green Reduced Graphene Oxide Toughened Semi-IPN Monolith Hydrogel as Dual Responsive Drug Release System: Rheological, Physicomechanical, and Electrical Evaluations.

Macroporous hydrogel monoliths having tailor-made features, conductivity, superstretchability, excellent biocompatibility, and biodegradability, have become the most nurtured field of interest in soft biomaterials. Green method assisted reduced graphene oxide has been inserted by in situ free radical gelation into semi-IPN hydrogel matrix to fabricate conducting hydrogel. Mechanical toughness has been implemented for the graphene-polymer physisorption interactions with graphene basal planes. Moreover, the as-prepared 3D scaffold type monolith hydrogel has been rheologically superior regarding their high elastic modulus and delayed gel rupturing. κ-Carragenaan, one of the components of the hydrogel, has biodegradable nature. The most significant outcome is their low electrical percolation threshold and reversibly ductile nature. Reversible ductility provides them with rubber-like consistency in flow conditions. Surprising, the hydrogels showed dual stimuli-responsiveness, that is, environmental pH and external electrical stimulation. Electro-stimulation has been adopted here for the first time in semi-IPN systems, which could be an ideal alternative for iontopheretic devices and pulsatile drug release through skin. Regarding this, the hydrogel also has been passed to biocompatibility assay; they are noncytotoxic and show cell proliferation without negligible cell death in live-dead assay. The porosity of the nanocomposite scaffold-like gels was also analyzed by microcomputed tomography (μ-CT), which exhibited their connectivity in cell/voids inside the matrix. Thus, the experimentations are on the support of biocompatible soft material for dual-responsive tunable drug delivery.

Biodegradable Neuro-Compatible Peptide Hydrogel Promotes Neurite Outgrowth, Shows Significant Neuroprotection, and Delivers Anti-Alzheimer Drug.

A novel neuro-compatible peptide-based hydrogel has been designed and developed, which contains microtubule stabilizing and neuroprotective short peptide. This hydrogel shows strong three-dimensional cross-linked fibrillary networks, which can capture water molecules. Interestingly, this hydrogel serves as excellent biocompatible soft material for 2D and 3D (neurosphere) neuron cell culture and provides stability of key cytoskeleton filaments such as microtubule and actin. Remarkably, it was observed that this hydrogel slowly enzymatically degrades and releases neuroprotective peptide, which promotes neurite outgrowth of neuron cell as well as exhibits excellent neuroprotection against anti-NGF-induced toxicity in neuron cells. Further, it can encapsulate anti-Alzheimer and anticancer hydrophobic drug curcumin, releases slowly, and inhibits significantly the growth of a 3D spheroid of neuron cancer cells. Thus, this novel neuroprotective hydrogel can be used for both neuronal cell transplantation for repairing brain damage as well as a delivery vehicle for neuroprotective agents, anti-Alzheimer, and anticancer molecules.

3D printing of concentrated emulsions into multiphase biocompatible soft materials.

3D printing via direct ink writing (DIW) is a versatile additive manufacturing approach applicable to a variety of materials ranging from ceramics over composites to hydrogels. Due to the mild processing conditions compared to other additive manufacturing methods, DIW enables the incorporation of sensitive compounds such as proteins or drugs into the printed structure. Although emulsified oil-in-water systems are commonly used vehicles for such compounds in biomedical, pharmaceutical, and cosmetic applications, printing of such emulsions into architectured soft materials has not been fully exploited and would open new possibilities for the controlled delivery of sensitive compounds. Here, we 3D print concentrated emulsions into soft materials, whose multiphase architecture allows for site-specific incorporation of both hydrophobic and hydrophilic compounds into the same structure. As a model ink, concentrated emulsions stabilized by chitosan-modified silica nanoparticles are studied, because they are sufficiently stable against coalescence during the centrifugation step needed to create a bridging network of droplets. The resulting ink is ideal for 3D printing as it displays high yield stress, storage modulus and elastic recovery, through the formation of networks of droplets as well as of gelled silica nanoparticles in the presence of chitosan. To demonstrate possible architectures, we print biocompatible soft materials with tunable hierarchical porosity containing an encapsulated hydrophobic compound positioned in specific locations of the structure. The proposed emulsion-based ink system offers great flexibility in terms of 3D shaping and local compositional control, and can potentially help address current challenges involving the delivery of incompatible compounds in biomedical applications.

Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing.

Biomedical research has relied on animal studies and conventional cell cultures for decades. Recently, microphysiological systems (MPS), also known as organs-on-chips, that recapitulate the structure and function of native tissues in vitro, have emerged as a promising alternative1. However, current MPS typically lack integrated sensors and their fabrication requires multi-step lithographic processes2. Here, we introduce a facile route for fabricating a new class of instrumented cardiac microphysiological devices via multi-material 3D printing. Specifically, we designed six functional inks, based on piezo-resistive, high conductance, and biocompatible soft materials that enable integration of soft strain gauge sensors within micro-architectures that guide the self-assembly of physio-mimetic laminar cardiac tissues. We validated that these embedded sensors provide non-invasive, electronic readout of tissue contractile stresses, inside cell incubator environments. We further applied these devices to study drug responses, as well as the contractile development of human stem cell derived laminar cardiac tissues over four weeks.