Emerging 4D Printing Technologies for Biomedical Applications
(Spotlight on Nanowerk) Compared to creating static objects with 3D printing, 4D printing systems add time as a fourth dimension to 3D printing: 4D printing allows a 3D printed structure to change its configuration or its function over time in response to external stimuli such as temperature, light, water, pH, etc. (read more about the concept here in our previous Spotlight on Nanowerk)
The concept of 4D printing is barely 10 years old (the term was first introduced in 2013 in a TED talk) but already researchers have demonstrated a wide range of applications: composite 4D printing that enhances wings drones, 4D printing with structural colors or the extension of 4D printing to nanophotonics, to name but a few.
Although 4D printing is considered very promising for various biomedical applications – such as tissue scaffolds, neural scaffolds, grafts and stents, heart patches and valves, even bionic constructs – its widespread adoption for clinical use and for tissue engineering purposes is complicated by a notable limitation of printable smart materials and the simplistic nature of achievable responses possible with current stimulation sources.
A recent review article in Advanced materials (“Emerging 4D Printing Strategies for Next-Generation Tissue Regeneration and Medical Devices”) begins with a general overview of the state of the 4D printing field, in particular 4D printing technologies, polymeric materials used in these technologies and 4D Shape Deformation Process design (rolling, compressing, twisting, stretching and bending). The authors then summarize representative recent studies on 4D printed biomedical scaffolds/constructs and devices – vascular tissue and stents, heart patches and valves, brain constructs, neural scaffolds and conduits, bone scaffolds, muscle scaffolds, and tracheal implants.
As shown above, researchers used different stimulus response mechanisms to trigger 4D-printed architectures, including temperature, chemical induction, light, magnetism, and multi-stimulation sources.
Generally, the most common stimuli used to trigger the 4D effect are external: chemical, thermal, light and magnetic. Internal stimuli generally only refers to the shape deformation triggered by the internal force which incorporates the phenomenon of “stress relaxation” during the material manufacturing process. The authors discuss these various mechanisms of response to stimuli are discussed at length.
On the road to highly personalized medicine, regenerative medicine in particular has the potential to revolutionize conventional therapeutic strategies by healing or replacing damaged tissues or organs. In this context, 3D and 4D printing is an innovative biofabrication method that can be used to mimic various dynamic processes of living tissues and can facilitate the fabrication of complex tissues/medical products, which can respond to stimulation by biological signals. complexes, such as bioelectrical signals. or biochemical signals.
Due to its ability to generate constructs with distinct self-morphing capabilities, 4D printing may offer a more favorable manufacturing approach than 3D printing, as 4D constructs can respond to internal stimuli and/or external. The unique advantages offered by 4D printing for the manufacture of biomedical devices include, but are not limited to
The process of fabricating dynamic tissue scaffolds involves the use and placement of a 4D ink solution, the filament of a (bio)material or a mixture of several (bio)materials, which directly encapsulates the desired cells with growth factors (or post-print cell loading).
Generally, there are two types of printed fabric scaffolds, namely, cell manager scaffolding and seeded cell scaffolding. Cell-loaded scaffolds are fabricated by the simultaneous deposition of bioinks composed of biocompatible materials and cells. The most commonly used bioink materials include gelatin, collagen, GelMA, alginate, hyaluronic acid (HA), decellularized extracellular matrices (dECM) and their (methyl)acrylate derivatives. Cell-seeded scaffolds are easy to produce, as the printed constructs are simply printed, washed, and then topically administered with cellular sources and/or growth factors.
Vascular regeneration and vascular stents represent one of the first biologically relevant applications for 4D printed constructs, as their tubular structure is simple to achieve through a 4D rolling or stretching process. In addition to blood vessels, various tubular structures can be found in the human body and include tissues such as muscle fibers, nerve bundles, and tendons.
Unlike vascular grafts or stents which are primarily tubular in structure, cardiac scaffolds/patches must achieve curved and aligned architectures to effectively attach to the surface of the heart to repair injured myocardial tissue. Compared to 3D printing for cardiovascular regeneration, 4D printing can enable the fabrication of a physiologically relevant curved surface with integrated dynamic mechanical stimulation.
Through the conversion of patient-specific geometries rendered from diagnostic imaging studies, such as computed tomography and magnetic resonance imaging, into STL files (STL files have become the de facto standard data transmission format for 3D printing) using specific software and hardware, 3D printing has helped develop personalized cerebrovascular 3D printed models in the clinical setting.
Superior to 3D printing, 4D printing has great potential to replicate the development of native complex tissues in a spatio-temporal manner. For example, the folding process of the cerebral cortex of the brain can be mimicked via 4D bioprinting.
Another application of brain tissue 4D printing is to achieve uniform cell distribution on the wrinkled surface of the brain construct.
Nerve regeneration is a complex and poorly understood biological phenomenon. Since nerve damage with a large defect gap has significantly limited regenerative abilities, nerve graft surgery is usually required. Recently, artificial nerve grafting has emerged as one of the most promising strategies for repairing peripheral nerve injury or spinal cord injury. 3D printing of neural conduits, nerve chips and nerve patches has been widely studied to provide new treatments for nerve damage.
The recent development of 4D printed neural scaffolds illustrates the unique characteristics of 4D printing for neural tissue engineering, such as dynamic self-turbulation and seamless integration.
Bone repair is one of the first applications of 3D printing in tissue engineering. However, 4D printing of bone scaffolds has significant advantages in their reconfigurable ability for easy implantation with minimally invasive surgery and perfect form fit in irregularly shaped bone defects.
Skeletal muscle is one of the most abundant tissues in the human body, making up approximately 45% of body mass. 3D printing has become a promising technique that allows the fabrication of modified muscle tissues with heterogeneous structures and mechanical properties. However, it lacks dynamic mechanical signals such as stretching or bending to generate myogenic alignment and functional maturation. As such, 4D printing has become a promising method to solve this problem.
The trachea (trachea) is a cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air. The trachea is surrounded by 16 to 20 C-shaped rings of hyaline cartilage, which are connected by the trachealis muscle. Generating a 4D printed trachea is another important application due to its ability to bend into C-shaped rings. Researchers have already demonstrated the excellent therapeutic effect of 4D printing in the regeneration of the trachea .
Bioproducts and medical devices made by 4D printing or other technologies are subject to regulation by regulatory bodies such as the FDA in the United States. With the development of 3D printing technology for biomedical applications, regulatory requirements prompted the FDA to establish a working group to evaluate technical and regulatory considerations regarding 3D printing of medical devices.
To date, no FDA-approved 4D biomedical products are available.
Michael is the author of three Royal Society of Chemistry books: Nano-Society: Pushing the Boundaries of Technology, Nanotechnology: The Future is Tiny and Nanoengineering: The Skills and Tools Making Technology Invisible Copyright ©
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