4D bioprinting is the next-generation additive manufacturing-based fabrication platform employed to construct intricate, adaptive, and dynamic soft and hard tissue structures as well as biomedical devices. It is achieved by using stimuli-responsive materials, especially shape memory polymers (SMPs) and hydrogels, which possess desirable biomechanical characteristics. In the last few years, numerous efforts have been made by 4D printing community to develop novel stimuli-responsive polymeric materials by considering their biomedical perspective. This review presents an up-to-date overview of 4D bioprinting technology incorporating bioprinting materials, functionalities of biomaterials as well as the focused approach towards different tissue engineering and regenerative medicine (TERM) applications. It includes bone, cardiac, neural, cartilage, drug delivery systems, and other high-value biomedical devices. This review also addresses current limitations and challenges in 4D bioprinting technology to provide a basis for foreseeable advancements for TERM applications that could be helpful for their successful utilization in clinical settings. • A compendium review of 4D bioprinting technology. • Development of scaffolds for tissue regeneration through 4D bioprinting. • Fabrication of biomedical devices by stimuli-responsive polymers and hydrogels. • Addressing current limitations and challenges in 4D bioprinting. 

4D bioprinting of smart polymers for biomedical applications: recent progress, challenges, and future perspectives

The development of programmable functional biomaterials makes 4D printing add a new dimension, time (t), based on 3D structures (x, y, z), therefore, 4D printed constructs could transform their morphology or function over time in response to environmental stimuli. Nowadays, highly efficient bone defect repair remains challenging in clinics. Combining programmable biomaterials, living cells, and bioactive factors, 4D bioprinting provides greater potential for constructing dynamic, personalized, and precise bone tissue engineering scaffolds by complex structure formation and functional maturation. Therefore, 4D bioprinting has been regarded as the next generation of bone repair technology. This review focuses on 4D printing and its advantages in orthopedics. The applications of different smart biomaterials and 4D printing strategies are briefly introduced. Furthermore, one summarizes the recent advancements of 4D printing in bone tissue engineering, uncovering the addressed and unaddressed medical requirements. In addition, current challenges and future perspectives are further discussed, which will offer more inspiration about the clinical transformation of this emerging 4D bioprinting technology in bone regeneration.

Harnessing 4D Printing Bioscaffolds for Advanced Orthopedics.

Nature's material systems during evolution have developed the ability to respond and adapt to environmental stimuli through the generation of complex structures capable of varying their functions across direction, distances and time. 3D printing technologies can recapitulate structural motifs present in natural materials, and efforts are currently being made on the technological side to improve printing resolution, shape fidelity, and printing speed. However, an intrinsic limitation of this technology is that printed objects are static and thus inadequate to dynamically reshape when subjected to external stimuli. In recent years, this issue has been addressed with the design and precise deployment of smart materials that can undergo a programmed morphing in response to a stimulus. The term 4D printing was coined to indicate the combined use of additive manufacturing, smart materials, and careful design of appropriate geometries. In this review, we report the recent progress in the design and development of smart materials that are actuated by different stimuli and their exploitation within additive manufacturing to produce biomimetic structures with important repercussions in different but interrelated biomedical areas.

4D printing in biomedical applications: emerging trends and technologies

Highly stretchable, high efficiency room temperature self-healing polyurethane adhesive based on hydrogen bonds – applicable to solid rocket propellants

The rapid development of 3D printing has led to considerable progress in the field of biomedical engineering. Notably, 4D printing provides a potential strategy to achieve a time-dependent physical change within tissue scaffolds or replicate the dynamic biological behaviors of native tissues for smart tissue regeneration and the fabrication of medical devices. The fabricated stimulus-responsive structures can offer dynamic, reprogrammable deformation or actuation to mimic complex physical, biochemical, and mechanical processes of native tissues. Although there is notable progress made in the development of the 4D printing approach for various biomedical applications, its more broad-scale adoption for clinical use and tissue engineering purposes is complicated by a notable limitation of printable smart materials and the simplistic nature of achievable responses possible with current sources of stimulation. In this review, the recent progress made in the field of 4D printing by discussing the various printing mechanisms that are achieved with great emphasis on smart ink mechanisms of 4D actuation, construct structural design, and printing technologies, is highlighted. Recent 4D printing studies which focus on the applications of tissue/organ regeneration and medical devices are then summarized. Finally, the current challenges and future perspectives of 4D printing are also discussed. 

Emerging 4D Printing Strategies for Next‐Generation Tissue Regeneration and Medical Devices

4D Printing of Multi-Responsive Membrane for Accelerated In Vivo Bone Healing Via Remote Regulation of Stem Cell Fate

Realization of muscle‐like actuation for a liquid crystal elastomer (LCE) requires mesogen alignment, which is typically achieved/fixed chemically during the synthesis. Post‐synthesis regulation of the alignment in a convenient and repeatable manner is highly desirable yet challenging. Here, a dual‐phase LCE network is designed and synthesized with a crystalline melting transition above a liquid crystalline transition. The crystalline phase can serve as an “alignment frame” to fix any mechanical deformation via a shape memory mechanism, leading to corresponding mesogen alignment in the liquid crystalline phase. The alignment can be erased by melting, which can be the starting point for reprogramming. This strategy that relies on a physical shape memory transition for mesogen alignment permits repeated reprogramming in a timescale of seconds, in stark contrast to typical methods. It further leads to unusual versatility in designing 3D printed LCE with unlimited programmable actuation modes.

Rapidly and Repeatedly Reprogrammable Liquid Crystalline Elastomer via a Shape Memory Mechanism

Soft machines can offer remote-powering mechanisms and mechanical flexibility unmatched by conventional rigid machines. However, the molecular integration of powering and actuation functions in a simple yet versatile format has remained challenging. We achieve this with a semi-crystalline supramolecular metallo-network. The dynamic metallo-bonds offer a flexible mechanism for programming the network anisotropy, which gives rise to stress-free reversible actuation using the crystalline transition as the actuation phase. In addition, the proper choice of metallo-bonds provides suitable photo-thermal capabilities for remote powering without endangering the cyclic actuation stability, despite the supramolecular nature. Based on these principles, we illustrate that the supramolecular network can be programmed into a reptile-style device remotely powered by light. The molecularly integrated dual functionality based on supramolecular metallo-bonds provides an attractive option for the future design of soft machines with sophisticated morphing behaviors yet simple powering mechanisms.

Guancong Chen

Papers

4D Printing of Multi-Responsive Membrane for Accelerated In Vivo Bone Healing Via Remote Regulation of Stem Cell Fate

Rapidly and Repeatedly Reprogrammable Liquid Crystalline Elastomer via a Shape Memory Mechanism

A photo-driven metallo-supramolecular stress-free reversible shape memory polymer

An overview of nanomaterial-based novel disinfection technologies for harmful microorganisms: Mechanism, synthesis, devices and application.

A thermadapt epoxy based on borate ester crosslinking and its carbon fiber composite as rapidly processable prepreg