4D Printing for Biomedical Applications.

4D (bio-)printing endows 3D printed (bio-)materials with multiple functionalities and dynamic properties. 4D printed materials have been recently used in biomedical engineering for the design and fabrication of biomedical devices, such as stents, occluders, microneedles, smart 3D-cell engineered microenvironments, drug delivery systems, wound closures, and implantable medical devices. However, the success of 4D printing relies on the rational design of 4D printed objects, the selection of smart materials, and the availability of appropriate types of external (multi-)stimuli. Here, this work first highlights the different types of smart materials, external stimuli, and design strategies used in 4D (bio-)printing. Then, it presents a critical review of the biomedical applications of 4D printing and discusses the future directions of biomedical research in this exciting area, including in vivo tissue regeneration studies, the implementation of multiple materials with reversible shape memory behaviors, the creation of fast shape-transformation responses, the ability to operate at the microscale, untethered activation and control, and the application of (machine learning-based) modeling approaches to predict the structure-property and design-shape transformation relationships of 4D (bio)printed constructs.

Bone cell response to additively manufactured 3D micro-architectures with controlled Poisson's ratio: Auxetic vs. non-auxetic meta-biomaterials.

The Poisson's ratio and elastic modulus are two parameters determining the elastic behavior of biomaterials. While the effects of elastic modulus on the cell response is widely studied, very little is known regarding the effects of the Poisson's ratio. The micro-architecture of meta-biomaterials determines not only the Poisson's ratio but also several other parameters that also influence cell response, such as porosity, pore size, and effective elastic modulus. It is, therefore, very challenging to isolate the effects of the Poisson's ratio from those of other micro-architectural parameters. Here, we computationally design meta-biomaterials with controlled Poisson's ratios, ranging between -0.74 and +0.74, while maintaining consistent porosity, pore size, and effective elastic modulus. The 3D meta-biomaterials were additively manufactured at the micro-scale using two-photon polymerization (2PP), and were mechanically evaluated at the meso­scale. The response of murine preosteoblasts to these meta-biomaterials was then studied using in vitro cell culture models. Meta-biomaterials with positive Poisson's ratios resulted in higher metabolic activity than those with negative values. The cells could attach and infiltrate all meta-biomaterials from the bottom to the top, fully covering the scaffolds after 17 days of culture. Interestingly, the meta-biomaterials exhibited different cell-induced deformations (e.g., shrinkage or local bending) as observed via scanning electron microscopy. The outcomes of osteogenic differentiation (i.e., Runx2 immunofluorescent staining) and matrix mineralization (i.e., Alizarin red staining) assays indicated the significant potential impact of these meta-biomaterials in the field of bone tissue engineering, paving the way for the development of advanced bone meta-implants. STATEMENT OF SIGNIFICANCE: We studied the influence of Poisson's ratio on bone cell response in meta-biomaterials. While elastic modulus effects are well-studied, the impact of Poisson's ratio, especially negative values found in architected biomaterials, remains largely unexplored. The complexity arises from intertwined micro-architectural parameters, such as porosity and elastic modulus, making it challenging to isolate the Poisson's ratio. To overcome this limitation, this study employed rational computational design to create meta-biomaterials with controlled Poisson's ratios, alongside consistent effective elastic modulus, porosity, and pore size. The study reveals that two-photon polymerized 3D meta-biomaterials with positive Poisson's ratios displayed higher metabolic activity, while all the developed meta-biomaterials supported osteogenic differentiation of preosteoblasts as well as matrix mineralization. The outcomes pave the way for the development of advanced 3D bone tissue models and meta-implants.

Auxeticity as a Mechanobiological Tool to Create Meta-Biomaterials.

Mechanical and morphological design parameters, such as stiffness or porosity, play important roles in creating orthopedic implants and bone substitutes. However, we have only a limited understanding of how the microarchitecture of porous scaffolds contributes to bone regeneration. Meta-biomaterials are increasingly used to precisely engineer the internal geometry of porous scaffolds and independently tailor their mechanical properties (e.g., stiffness and Poisson's ratio). This is motivated by the rare or unprecedented properties of meta-biomaterials, such as negative Poisson's ratios (i.e., auxeticity). It is, however, not clear how these unusual properties can modulate the interactions of meta-biomaterials with living cells and whether they can facilitate bone tissue engineering under static and dynamic cell culture and mechanical loading conditions. Here, we review the recent studies investigating the effects of the Poisson's ratio on the performance of meta-biomaterials with an emphasis on the relevant mechanobiological aspects. We also highlight the state-of-the-art additive manufacturing techniques employed to create meta-biomaterials, particularly at the micrometer scale. Finally, we provide future perspectives, particularly for the design of the next generation of meta-biomaterials featuring dynamic properties (e.g., those made through 4D printing).

Energy Absorption and Mechanical Performance of Functionally Graded Soft-Hard Lattice Structures.

Today, the rational combination of materials and design has enabled the development of bio-inspired lattice structures with unprecedented properties to mimic biological features. The present study aims to investigate the mechanical performance and energy absorption capacity of such sophisticated hybrid soft-hard structures with gradient lattices. The structures are designed based on the diversity of materials and graded size of the unit cells. By changing the unit cell size and arrangement, five different graded lattice structures with various relative densities made of soft and hard materials are numerically investigated. The simulations are implemented using ANSYS finite element modeling (FEM) (2020 R1, 2020, ANSYS Inc., Canonsburg, PA, USA) considering elastic-plastic and the hardening behavior of the materials and geometrical non-linearity. The numerical results are validated against experimental data on three-dimensional (3D)-printed lattices revealing the high accuracy of the FEM. Then, by combination of the dissimilar soft and hard polymeric materials in a homogenous hexagonal lattice structure, two dual-material mechanical lattice statures are designed, and their mechanical performance and energy absorption are studied. The results reveal that not only gradual changes in the unit cell size provide more energy absorption and improve mechanical performance, but also the rational combination of soft and hard materials make the lattice structure with the maximum energy absorption and stiffness, in comparison to those structures with a single material, interesting for multi-functional applications.

Multi-Trigger Thermo-Electro-Mechanical Soft Actuators under Large Deformations.

Dielectric actuators (DEAs), because of their exceptional properties, are well-suited for soft actuators (or robotics) applications. This article studies a multi-stimuli thermo-dielectric-based soft actuator under large bending conditions. In order to determine the stress components and induced moment (or stretches), a nominal Helmholtz free energy density function with two types of hyperelastic models are employed. Non-linear electro-elasticity theory is adopted to derive the governing equations of the actuator. Total deformation gradient tensor is multiplicatively decomposed into electro-mechanical and thermal parts. The problem is solved using the second-order Runge-Kutta method. Then, the numerical results under thermo-mechanical loadings are validated against the finite element method (FEM) outcomes by developing a user-defined subroutine, UHYPER in a commercial FEM software. The effect of electric field and thermal stimulus are investigated on the mean radius of curvature and stresses distribution of the actuator. Results reveal that in the presence of electric field, the required moment to actuate the actuator is smaller. Finally, due to simplicity and accuracy of the present boundary problem, the proposed thermally-electrically actuator is expected to be used in future studies and 4D printing of artificial thermo-dielectric-based beam muscles.