Emerging 4D Printing Technologies for Biomedical Applications

June 07, 2022

(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.

The manufacturing process of 4D printing is mainly based on existing 3D printing technologies. The classification of 4D printing can be sorted by stimulation sources, including two categories: internal stimuli and external stimuli, and subtypes into five subcategories: internal, magnetic, light, thermal and chemical stimuli . (Reproduced with permission from Wiley-VCH Verlag)

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

  • ease of obtaining uniform cell distribution on irregular 3D microstructures thanks to its ability to transform from a temporary flat 2D structure into a complex and irregular 3D structure (original shape) under a certain stimulus,
  • facilitation of minimally invasive surgery and seamless integration into tissue defects,
  • replicating dynamic biological behaviors (e.g., tissue growth, joint flexion, and muscle contraction/relaxation) of native tissues,
  • robust biocompatible responsiveness to stimuli, and
  • autonomous transformation and form/functional change.
  • Schematic illustration of 4D printing for tissue regeneration Schematic illustration of 4D printing for tissue regeneration. A) Most commonly used 4D printing technologies: FDM or DIW, SLA and DLP. B) Biomaterial and bio-ink strategy applied to tissue/organ regeneration. C) 4D transformation process of printed scaffolds triggered by external stimuli. (Reproduced with permission from Wiley-VCH Verlag)

    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 grafts and stents

    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.

    Heart patches and valves

    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.

    Bionic brain constructs

    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.

    Scaffolds and neural conduits

    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 regeneration

    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.

    Regeneration of muscle tissue

    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.

    Tracheal repair

    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 .

    Tiny and complex biomedical structure printed in 3D A tiny and complex biomedical structure created with the NEST3D technique that allows structures to be 3D printed that can measure only 200 microns in diameter. Read more. (Image: RMIT University)

    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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