Shape-Shifting Biomaterials for Tissue Regeneration

Consider the humble pinecone. Found scattered on forest floors and covered in woody scales, the pinecone is a perfect example of nature’s clever shape-shifting engineering. When it is wet and humid, the scales stay closed, protecting the seeds. But when it is dry – ideal conditions for the seeds to disperse – the scales open and they are released.

This naturally occurring shape-shifting structure inspired Skylar Tibbits, associate professor of design research at the Massachusetts Institute of Technology, in 2013 to design similarly ‘smart’ materials for architecture and engineering. Think climate-adaptive building facades that can expand, contract or rotate in response to the outdoor temperature and sunlight, or flatpack furniture that self-assembles when you take it home. Enter the 4D printing revolution.

This approach transcends the limitations of the static structures produced by 3D printing by adding a fourth dimension: time. Similar to the pinecone that closes its scales when wet, 4D materials are designed to autonomously change shape in response to a stimulus in their environment, such as humidity, temperature, light, pressure or magnetism.

These shape-shifting materials are not just for architectural design. In recent years, 4D printing has become a transformative technology in the biomedical field, offering the potential to create smart biomaterials that change shape in response to specific physiological stimuli. In contrast to the passive materials that are traditionally used for tissue engineering, 4D printed materials are dynamic and can adapt to the constantly changing needs of the living body.

So, how are these materials used in healthcare? 4D materials are first fabricated using 3D printing, then triggered by a stimulus to change their shape. This shape shift can be leveraged for deployable medical devices such as stents or orthopedic implants. Rather than undergoing invasive surgery during implantation, materials can take on a temporary compact structure during surgery and then be deployed to their final full-size shape once they have reached the target location in the body.

Some materials also benefit from being printed in a flat 2D configuration first. As Amir Zadpoor, chaired professor of biomaterials and tissue biomechanics at Delft University of Technology explains, “When the initial configuration of these materials is flat, it creates many opportunities for adding surface-related functionalities, including complex nanopatterns and electronic devices.”

This can be particularly useful for creating complex surface nanopatterns that stimulate certain cells, or even kill bacteria; preventing infections upon implantation in the body.

Shape-shifting mechanisms

To create smart biomaterials there are several key requirements. Materials need to be compatible with modern 3D printing techniques e.g. extrusion-based, light-based, bioprinting; be biocompatible; and have the capability to undergo shape change in response to a specific stimulus.

Taking inspiration from the pinecone, hydration is a popular stimulus in 4D printing approaches. Hydrogels are highly absorbent polymer networks that can swell or shrink in response to humidity.¹

Researchers have found that by creating scaffolds with several layers, each with a different swelling mechanism, the material can bend in a controlled way when it is immersed in a liquid, creating tubular or curved structures. Zadpoor’s group recently showed that by using two different hydrogel-based materials with high- and low-swelling formulations, the scaffold could self-bend after liquid immersion, creating a curved structure that mimicked the natural structure of cartilage.² They used this structure to grow bone cells, which were positioned in the hydrogel layers, creating a proof-of-concept for 4D printing multicellular cartilage tissue.

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Transforming geometries in the body

A key benefit of using shape-shifting materials in biomedical applications is the level of adaptability and customization that is possible. For stents and prosthetics, this means that the implanted construct can adapt to the changing needs of the body. For example, a 4D printed intestinal stent was designed to be triggered by near-body temperature, allowing the stent to adjust its shape in direct response to the patient’s internal temperature.³ Similarly, vascular stents have been designed to change shape in response to blood flow or vessel diameter.⁴ These self-adaptive stents are highly customized, responding directly to their environment, which could reduce the need for surgical intervention in the future.

4D printing has also been used to create patches to help repair organ damage in the body. Heart attacks can cause severe damage to the heart tissue, and 4D scaffolds have been developed with a self-adaptive structure to mimic the curved surface and adapt to the contractions of the beating heart.⁵ To improve scaffold integration to the heart tissue, cells were added to fibrous scaffolds, and aligned along the fibers to mimic the cellular architecture of heart tissue. Improving scaffold integration by incorporating cells into 4D scaffolds is a rapidly evolving field of study, with particular focus on which stage of the shape transformation process works best to add cells.⁶

Minimal, targeted delivery

Shape-shifting materials are also advantageous for drug delivery strategies, as 4D-printed devices can be designed to release drugs in response to a specific stimulus at the target location, such as pH or temperature.⁷

In a recent proof-of-concept study, 4D printing technology converged with micro-robotics in a scene perhaps more reminiscent of a sci-fi space movie. The researchers created bioinspired puffball capsules – complete with ‘spores’ containing the drugs and an inbuilt propulsion system – that can be steered to their target site using a rotating magnetic field for on-demand drug release.⁸ This futuristic meld of technologies gives a glimpse into a promising future for drug delivery in healthcare: highly customizable, minimally invasive, targeted care.

Machine learning approaches

Researchers are also starting to use AI and machine learning to fully leverage the adaptability that 4D printing offers. Using modeling and simulation, it is possible to predict the shape transformation of these materials, as well as the physiological responses. This will help to guide the selection of smart materials, as well as the ideal shape-shifting geometry during the design process. This can also inform multi-material printing, where multiple smart materials with different stimuli are used in the same scaffold or construct. Furthermore, the incorporation of sensors could offer real-time monitoring of the constructs, unlocking even more functionality.  

In the clinic

All this sounds exciting and transformative for healthcare, but 4D-printed technologies for tissue engineering have yet to reach the clinic, largely due to some key challenges that still need to be addressed. For example, the 3D fabrication procedures used will need to be optimized to facilitate the large-scale production of these materials, as well as rigorous testing and approval processes that must be implemented before these materials reach the clinic. Each specific application will also have its own unique challenges, as requirements will differ enormously between different tissue engineering projects.

Despite these challenges, it is clear why 4D printing has become a major research focus in the biomedical field. As Zadpoor explains, using shape-shifting materials can lead to a mixture of functionalities and microarchitecture that is not possible to create in any other way. It ultimately creates materials that are much more responsive and customizable to the human body. While several major hurdles will still need to be overcome before we see these technologies in the clinic, this bioinspired shape-shifting revolution will take us towards a new, 4D future in healthcare.