A Self-Assembled 3D Model Demonstrates How Stiffness Educates Tumor Cell Phenotypes and Therapy Resistance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense and stiff extracellular matrix (ECM) associated with tumor progression and therapy resistance. To further the understanding of how stiffening of the tumor microenvironment (TME) contributes to aggressiveness, a three-dimensional (3D) self-assembling hydrogel disease model is developed based on peptide amphiphiles (PAs, PA-E3Y) designed to tailor stiffness. The model displays nanofibrous architectures reminiscent of native TME and enables the study of the invasive behavior of PDAC cells. Enhanced tuneability of stiffness is demonstrated by interacting thermally annealed aqueous solutions of PA-E3Y (PA-E3Yh) with divalent cations to create hydrogels with mechanical properties and ultrastructure similar to native tumor ECM. It is shown that stiffening of PA-E3Yh hydrogels to levels found in PDAC induces ECM deposition, promotes epithelial-to-mesenchymal transition (EMT), enriches CD133+/CXCR4+ cancer stem cells (CSCs), and subsequently enhances drug resistance. The findings reveal how a stiff 3D environment renders PDAC cells more aggressive and therefore more faithfully recapitulates in vivo tumors.

DNA Crosslinked Mucin Hydrogels Allow for On-Demand Gel Disintegration and Triggered Particle Release.

Whereas hydrogels created from synthetic polymers offer a high level of control over their stability and mechanical properties, their biomedical activity is typically limited. In contrast, biopolymers have evolved over billions of years to integrate a broad range of functionalities into a single design. Thus, biopolymeric hydrogels can show remarkable capabilities such as regulatory behavior, selective barrier properties, or antimicrobial effects. Still, despite their widespread use in numerous biomedical applications, achieving a meticulous control over the physical properties of macroscopic biopolymeric networks remains a challenge. Here, a macroscopic, DNA-crosslinked mucin hydrogel with tunable viscoelastic properties that responds to two types of triggers: temperature alterations and DNA displacement strands, is presented. As confirmed with bulk rheology and single particle tracking, the hybridized base pairs governing the stability of the hydrogel can be opened, thus allowing for a precise control over the hydrogel stiffness and even enabling a full gel-to-sol transition. As those DNA-crosslinked mucin hydrogels possess tunable mechanical properties and can be disintegrated on demand, they can not only be considered for controlled cargo release but may also serve as a role model for the development of smart biomedical materials in applications such as tissue engineering and wound healing.

Attenuating Epithelial-to-Mesenchymal Transition in Cancer through Angiopoietin-Like 4 Inhibition in a 3D Tumor Microenvironment Model.

Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastatic cancer progression, and current research, which relies heavily on 2D monolayer cultures, falls short in recapitulating the complexity of a 3D tumor microenvironment. To address this limitation, a transcriptomic meta-analysis is conducted on diverse cancer types undergoing EMT in 2D and 3D cultures. It is found that mechanotransduction is elevated in 3D cultures and is further intensified during EMT, but not during 2D EMT. This analysis reveals a distinct 3D EMT gene signature, characterized by extracellular matrix remodeling coordinated by angiopoietin-like 4 (Angptl4) along with other canonical EMT regulators. Utilizing hydrogel-based 3D matrices with adjustable mechanical forces, 3D cancer cultures are established at varying physiological stiffness levels. A YAP:EGR-1 mediated up-regulation of Angptl4 expression is observed, accompanied by an upregulation of mesenchymal markers, at higher stiffness during cancer EMT. Suppression of Angptl4 using antisense oligonucleotides or anti-cAngptl4 antibodies leads to a dose-dependent abolishment of EMT-mediated chemoresistance and tumor self-organization in 3D, ultimately resulting in diminished metastatic potential and stunted growth of tumor xenografts. This unique programmable 3D cancer cultures simulate stiffness levels in the tumor microenvironment and unveil Angptl4 as a promising therapeutic target to inhibit EMT and impede cancer progression.

Tadpole-Like Flexible Microswimmers with the Head and Tail Both Magnetic.

In analogy to eukaryotic cells that move by beating the flagella, magnetically powered micro/nanorobots with flexible filaments are capable of eluding the limitation of the scallop theorem to generate net displacement in a three-dimensional space, but they are limited by complicated fabrication and low speed. Here, we demonstrate a tadpole-like flexible microswimmer with a head and tail that are both magnetic by developing a magnetically assisted in situ polymerization method. The flexible microswimmer consists of a magnetic-bead head fixed to a nanochain bundle of magnetic nanoparticles (tail), and the tail length and stiffness can be adjusted simply by changing the duration and strength of the applied magnetic field during fabrication, respectively. For the microswimmer under an oscillating magnetic field, the magnetic head generates an undulatory motion, which can be further increased by the flexible magnetic tail. The magnetically induced undulation of the head and tail generates a traveling wave propagating through its flexible tail, resulting in efficient tadpole-like propulsion of the microswimmer. The flexible microswimmer runs at a maximum motion speed when the tail length is ∼5 times the diameter of the magnetic head, corresponding to ∼half the wavelength of the undulatory motion. The flexible microswimmers reported here are promising for active sensing and drug delivery, as the tails can be designed with various responsive hydrogels, and the results are expected to advance flexible micro/nanorobots.

Tunable, Textile-Based Joint Impedance Module for Soft Robotic Applications.

The design of soft actuators is often focused on achieving target trajectories or delivering specific forces and torques, rather than controlling the impedance of the actuator. This article outlines a new soft, tunable pneumatic impedance module based on an antagonistic actuator setup of textile-based pneumatic actuators intended to deliver bidirectional torques about a joint. Through mechanical programming of the actuators (select tuning of geometric parameters), the baseline torque to angle relationship of the module can be tuned. A high bandwidth fluidic controller that can rapidly modulate the pressure at up to 8 Hz in each antagonistic actuator was also developed to enable tunable impedance modulation. This high bandwidth was achieved through the characterization and modeling of the proportional valves used, derivation of a fluidic model, and derivation of control equations. The resulting impedance module was capable of modulating its stiffness from 0 to 100 Nm/rad, at velocities up to 120°/s and emulating asymmetric and nonlinear stiffness profiles, typical in wearable robotic applications.

Partial Liquid Alloy Microdroplet Sedimentation Induced a Gradient Porous Structured Elastomer with a Tunable Property for an Anisotropic Robotic Bulk.

With the confrontation of ever increasing complicated working objects and unstructured environments, it is necessary for soft robots to be equipped with diverse intelligent mechanical structures, for example, anisotropically motorial bulk and timely proprio/exteroceptive sensing with programmable morphologies. Owing to abundant pores inside, porous media are promising to host various intelligent functions as interfaces/structures of robots yet challenging because of a limited anisotropic response inherited from a random hierarchical pore distribution. Here, an electron competition between Ga, N, and Pt is found and used to tune the polymerization of a gradient liquid alloy and NH4HCO3-suspended silicone precursor mixture and, thus, decompose gas movements in gradient pore formation under high-temperature heating (120 °C). By such a competition-collaboration effect, we present here an interconnected gradient porous structure (GPS) that can serve as an anisotropically robotic motorial bulk. Moreover, the mechanical stiffness and piezoresistive/capacitive property of GPS can be further tuned and reconfigured via so-called self-sucked coating, following solvent erasing. Such new structures provide a dynamic tactile recognition with an ultrabroad sensing range (from 135 Pa to 2.3 MPa) and a reconfigurable biomimetic elephant trunk with monolithic proprioceptive sensing-integrated bulks.

3D-Printed Soft Sensors for Adaptive Sensing with Online and Offline Tunable Stiffness.

The stiffness of a soft robot with structural cavities can be regulated by controlling the pressure of a fluid to render predictable changes in mechanical properties. When the soft robot interacts with the environment, the mediating fluid can also be considered an inherent information pathway for sensing. This approach to using structural tuning to improve the efficacy of a sensing task with specific states has not yet been well studied. A tunable stiffness soft sensor also renders task-relevant contact dynamics in soft robotic manipulation tasks. This article proposes a type of adaptive soft sensor that can be directly three-dimensional printed and controlled using pneumatic pressure. The tunability of such a sensor helps to adjust the sensing characteristics to better capturing specific tactile features, demonstrated by detecting texture with different frequencies. We present the design, modeling, Finite Element Simulation, and experimental characterization of a single unit of such a tunable stiffness sensor. How the sensing characteristics are affected by adjusting its stiffness is studied in depth. In addition to the tunability, the results show that such types of adaptive sensors exhibit good sensitivity (up to 2.6 KPa/N), high sensor repeatability (average std <0.008 KPa/N), low hysteresis (<6%), and good manufacturing repeatability (average std = 0.0662 KPa/N).

A Stretchable Fiber with Tunable Stiffness for Programmable Shape Change of Soft Robots.

All soft robots require the same functionality, that is, controlling the shape of a structure made from soft materials. However, existing approaches for shape control of soft robots are primarily dominated by modular pneumatic actuators, which require multichambers and complex flow control components. Nature shows exciting examples of manipulation (shape change) in animals, such as worms, using a single-chambered soft body and programmable stiffness changes in the skin; controlling the spatial distribution of changes in stiffness enables achieving complex shape evolutions. However, such stiffness control requires a drastic membrane stiffness contrast between stiffened and nonstiffened states. Generally, this is extremely challenging to accomplish in stretchable materials. Inspired by longitudinal muscle fibers in the skin of worms, we developed a new concept for fabricating a hybrid fiber with tunable stiffness, that is, a fiber comprising both stiff and soft parts connected in a series. A substantial change in membrane stiffness was then observed by the locking/unlocking of the soft part. Our proposed hybrid fiber cyclically produced a membrane stiffness contrast of more than 100 × in less than 6 s using an input power of 3 W. A network of these hybrid fibers with tunable stiffness could manipulate a single-chambered soft body in multiple directions and transform it into a complex shape by selectively varying the stiffness at different locations.

Tunable Stiffness and Damping Study on Flexible PVC Cantilever Structure Embedded with MR Fluid.

The stiffness and damping of a flexible smart cantilever structure controlled by a magnetic field is investigated in this research. The cantilever structure is fabricated by using flexible polyvinyl chloride as a host structure of rectangular cross-section embedded with magnetorheological (MR) fluid. The deflection of the cantilever structure at the free end is used to analyze the stiffness change of the cantilever structure. The stiffness of the specimen with MR fluid at magnetic flux density of 0.171 T is greater than that of the specimen without subjected to magnetic field. The strength of the applied magnetic field is directly related to the structure's stiffness. Under the influence of a magnetic field, the MR fluid embedded inside the flexible PVC cantilever structure significantly dampens the vibrations of the structure.

Materials with Electroprogrammable Stiffness.

Stiffness is a mechanical property of vital importance to any material system and is typically considered a static quantity. Recent work, however, has shown that novel materials with programmable stiffness can enhance the performance and simplify the design of engineered systems, such as morphing wings, robotic grippers, and wearable exoskeletons. For many of these applications, the ability to program stiffness with electrical activation is advantageous because of the natural compatibility with electrical sensing, control, and power networks ubiquitous in autonomous machines and robots. The numerous applications for materials with electrically driven stiffness modulation has driven a rapid increase in the number of publications in this field. Here, a comprehensive review of the available materials that realize electroprogrammable stiffness is provided, showing that all current approaches can be categorized as using electrostatics or electrically activated phase changes, and summarizing the advantages, limitations, and applications of these materials. Finally, a perspective identifies state-of-the-art trends and an outlook of future opportunities for the development and use of materials with electroprogrammable stiffness.

Printed miniature robotic actuators with curvature-induced stiffness control inspired by the insect wing.

Stimuli-responsive actuating materials offer a promising way to power insect-scale robots, but a vast majority of these material systems are too soft for load bearing in different applications. While strategies for active stiffness control have been developed for humanoid-scale robots, for insect-scale counterparts for which compactness and functional complexity are essential requirements, these strategies are too bulky to be applicable. Here, we introduce a method whereby the same actuating material serves not only as the artificial muscles to power an insect-scale robot for load bearing, but also to increase the robot stiffness on-demand, by bending it to increase the second moment of area. This concept is biomimetically inspired by how insect wings stiffen themselves, and is realized here with manganese dioxide as a high-performing electrochemical actuating material printed on metallized polycarbonate films as the robot bodies. Using an open-electrodeposition printing method, the robots can be rapidly fabricated in one single step in ∼15 minutes, and they can be electrochemically actuated by a potential of ∼1 V to produce large bending of ∼500° in less than 5 s. With the stiffness enhancement method, fast (∼5 s) and reversible stiffness tuning with a theoretical increment by ∼4000 times is achieved in a micro-robotic arm at ultra-low potential input of ∼1 V, resulting in an improvement in load-bearing capability by about 4 times from ∼10µN to ∼41µN.

A novel design of printable tunable stiffness metamaterial for bone healing.

A tunable stiffness bone rod was designed, optimized, and 3D printed to address the shortcomings of existing bone fixation devices, such as stress shielding and bone nonunion in the healing of fractured bones. Current bone plates/rods have constant and high stiffness. High initial stiffness prevents the micromotion of newly formed bone and results in poor bone healing. Our novel design framework provides surgeons with a ready-for-3D-printing, patient-specific design, optimized to have the desired force-displacement response with a stopping mechanism for preventing further deformation under higher-than-normal loads, such as falling. The computational framework is a design optimization based on the multi-objective genetic algorithm (GA) optimization with the FE simulation to quantify the objectives: tuning the varied stiffness while minimizing the maximum von Mises stress of the model to avoid plastic and permanent deformation of the bone rod. The computational framework for optimum design of tunable stiffness metamaterial presented in this paper is not specific for a tibia bone rod, and it can be used for any application where bilinear stiffness is desirable.

Biomimicking Fiber Platform with Tunable Stiffness to Study Mechanotransduction Reveals Stiffness Enhances Oligodendrocyte Differentiation but Impedes Myelination through YAP-Dependent Regulation.

A key hallmark of many diseases, especially those in the central nervous system (CNS), is the change in tissue stiffness due to inflammation and scarring. However, how such changes in microenvironment affect the regenerative process remains poorly understood. Here, a biomimicking fiber platform that provides independent variation of fiber structural and intrinsic stiffness is reported. To demonstrate the functionality of these constructs as a mechanotransduction study platform, these substrates are utilized as artificial axons and the effects of axon structural versus intrinsic stiffness on CNS myelination are independently analyzed. While studies have shown that substrate stiffness affects oligodendrocyte differentiation, the effects of mechanical stiffness on the final functional state of oligodendrocyte (i.e., myelination) has not been shown prior to this. Here, it is demonstrated that a stiff mechanical microenvironment impedes oligodendrocyte myelination, independently and distinctively from oligodendrocyte differentiation. Yes-associated protein is identified to be involved in influencing oligodendrocyte myelination through mechanotransduction. The opposing effects on oligodendrocyte differentiation and myelination provide important implications for current work screening for promyelinating drugs, since these efforts have focused mainly on promoting oligodendrocyte differentiation. Thus, the platform may have considerable utility as part of a drug discovery program in identifying molecules that promote both differentiation and myelination.

Lightweight Highly Tunable Jamming-Based Composites.

Tunable-impedance mechanisms can improve the adaptivity, robustness, and efficiency of a vast array of engineering systems and soft robots. In this study, we introduce a tunable-stiffness mechanism called a "sandwich jamming structure," which fuses the exceptional stiffness range of state-of-the-art laminar jamming structures (also known as layer jamming structures) with the high stiffness-to-mass ratios of classical sandwich composites. We experimentally develop sandwich jamming structures with performance-to-mass ratios that are far greater than laminar jamming structures (e.g., a 550-fold increase in stiffness-to-mass ratio), while simultaneously achieving tunable behavior that standard sandwich composites inherently cannot achieve (e.g., a rapid and reversible 1800-fold increase in stiffness). Through theoretical and computational models, we then show that these ratios can be augmented by several orders of magnitude further, and we provide an optimization routine that allows designers to build the best possible sandwich jamming structures given arbitrary mass, volume, and material constraints. Finally, we demonstrate the utility of sandwich jamming structures by integrating them into a wearable soft robot (i.e., a tunable-stiffness wrist orthosis) that has negligible impact on the user in the off state, but can reduce muscle activation by an average of 41% in the on state. Through these theoretical and experimental investigations, we show that sandwich jamming structures are a lightweight highly tunable mechanism that can markedly extend the performance limits of existing structures and devices.

A New Biomimetic Composite Structure with Tunable Stiffness and Superior Toughness via Designed Structure Breakage.

Mimicking natural structures has been highly pursued recently in composite structure design to break the bottlenecks in the mechanical properties of the traditional structures. Bone has a remarkable comprehensive performance of strength, stiffness and toughness, due to the intricate hierarchical microstructures and the sacrificial bonds within the organic components. Inspired by the strengthening and toughening mechanisms of cortical bone, a new biomimetic composite structure, with a designed progressive breakable internal construction mimicking the sacrificial bond, is proposed in this paper. Combining the bio-composite staggered plate structure with the sacrificial bond-mimicking construction, our new structure can realize tunable stiffness and superior toughness. We established the constitutive model of the representative unit cell of our new structure, and investigated its mechanical properties through theoretical analysis, as well as finite element modeling (FEM) and simulation. Two theoretical relations, respectively describing the elastic modulus decline ratio and the unit cell toughness promotion, are derived as functions of the geometrical parameters and the material parameters, and validated by simulation. We hope that this work can lay the foundation for the stiffness tunable and high toughness biomimetic composite structure design, and provide new ideas for the development of sacrificial bond-mimicking strategies in bio-inspired composite structures.

A review of recent advancements in soft and flexible robots for medical applications.

BACKGROUND: Soft and flexible robots for medical applications are needed to change their flexibility over a wide range to perform tasks adequately. The mechanism and theory of flexibility has been a scientific issue and is of interest to the community. METHODS: Recent advancements of bionics, flexible actuation, sensing, and intelligent control algorithms as well as tunable stiffness have been referenced when soft and flexible robots are developed. The benefits and limitations of these relevant studies and how they affect the flexibility are discussed, and possible research directions are explored. RESULTS: The bionic materials and structures that demonstrate the potential capabilities of the soft medical robot flexibility are the fundamental guarantee for clinical medical applications. Flexible actuation that used to provide power, intelligent control algorithms which are the exact executors, and the wide range stiffness of the soft materials are the three important influence factors for soft medical robots. CONCLUSION: Some reasonable suggestions and possible solutions for soft and flexible medical robots are proposed, including novel materials, flexible actuation concepts with a built-in source of energy or power, programmable flexibility, and adjustable stiffness.

A foldable manipulator with tunable stiffness based on braided structure.

Minimally invasive surgery (MIS) has recently seen a surge in clinical applications due to its potential benefits over open surgery. In MIS, a long manipulator is placed through a tortuous human orifice to create a channel for surgical tools and provide support when they are operated. Currently the relative large profile and low stiffness of the manipulators limit the effectiveness and accuracy of MIS. Here we propose a new foldable manipulator with tunable stiffness. The manipulator takes a braided skeleton to enable radial folding, whereas membrane is used to seal the skeleton so as to adjust stiffness through creating negative pressure. We demonstrated experimentally, numerically, and analytically that, a flexible and a rigid state were obtained, and the ratio of bending stiffness in the rigid state to that in the flexible state reached 6.85. In addition, the manipulator achieved a radial folding ratio of 1.95. The proposed manipulator shows great potential in the design of surgical robots for MIS. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B, 2019.

2D Gelatin Methacrylate Hydrogels with Tunable Stiffness for Investigating Cell Behaviors.

Cellular microenvironment has played a critical role in cell behavior regulation, natural tissue formation, and development. Specifically, the stiffness of extracellular matrix (ECM) not only helps cells to maintain their morphology and location but also provides physical cues to regulate cellular functions. Nevertheless, it is still hard for conventional matrix materials to explore cell behaviors and functions under their physical microenvironments due to potential long-term cytotoxicity or unphysiological stiffness. Herein, a biocompatible stiffness-tunable 2D gelatin methacryloyl (GelMA) hydrogel matrix is fabricated to explore the influence of ECM stiffness on cell morphology as well as cellular gene expression. GelMA, as a derivative of gelatin, can not only serve as cell culture matrixes due to the existence of bioactive peptide sequences and biocompatibility, but also mimic the stiffness of native ECMs. As a result, the stiffness of GelMA matrix can regulate cytoskeleton assembly and cell morphology via mechanotransduction-related genetic pathways (RhoA/ROCK and PI3K/Rac1 signaling pathway). Therefore, the 2D GelMA hydrogel matrix with tunable stiffness can be regard as an alternative cellular matrix, and has a potential to reveal the fundamental principle of ECM defect-associated diseases.

A Novel Fabric-Based Versatile and Stiffness-Tunable Soft Gripper Integrating Soft Pneumatic Fingers and Wrist.

This work presents the design and test of a novel fabric-based versatile and stiffness-tunable soft gripper integrating soft pneumatic fingers and wrist. The morphology is designed into a compact tuning fork shape (130 × 110 × 260 mm, 389 g) with two bidirectional sheet-shaped soft fingers and a biaxial bidirectional (universal) cylinder-shaped soft wrist. The multi-degree of freedom of soft fingers and wrist makes the gripper versatile and adaptable to gripping objects of various shapes, sizes, and orientations in a wide range. The bidirectional fingers with double-side inflatable chambers can tune their gripping stiffness and force by varying the common and differential pressure of the two sides. The wrist can tune its deflecting stiffness and force in the same way. Therefore, the gripper can grip objects of various stiffness and weights. The soft gripper is tested to characterize its workspace, stiffness, gripping force, and dynamic response time. Gripping function tests are also performed to evaluate the achieved degree of functions of the gripper. Tests show that the proposed gripper can grip objects in the size of 0-245 mm and in the orientation of -88.2°-90.8° (pitch/roll) with a maximum gripping force of 40 N and a response time of 1.22-1.60 s to force and 0.56-2.61 s to motion, respectively. The gripping stiffness can be tuned in the range of 0.029-0.137 N/mm (i.e., the tunable scope is 79%) by varying common pressure in the range of 0-0.2 MPa. Functional tests verify that the proposed soft gripper is versatile and adaptable to gripping objects of various shapes, sizes, weights, and orientations. Therefore, the proposed soft gripper has great potential applications in production and daily life.

Custom 3D Printable Silicones with Tunable Stiffness.

Silicone elastomers have broad versatility within a variety of potential advanced materials applications, such as soft robotics, biomedical devices, and metamaterials. A series of custom 3D printable silicone inks with tunable stiffness is developed, formulated, and characterized. The silicone inks exhibit excellent rheological behavior for 3D printing, as observed from the printing of porous structures with controlled architectures. Herein, the capability to tune the stiffness of printable silicone materials via careful control over the chemistry, network formation, and crosslink density of the ink formulations in order to overcome the challenging interplay between ink development, post-processing, material properties, and performance is demonstrated.