Recently, many studies have explored a new field that integrates 3D and 4D printing with therapeutics. As a result, many pharmaceutical device and formulation concepts that can be printed and possibly tailored to an individual have emerged. 4D Printing technology is rapidly expanding and replacing traditional production in a wide range of industries, including aerospace engineering, automobile, and medical devices. While 3D printing is utilized in a wide variety of sectors, the growing complexity of the materials used has provided an opportunity for technical advancements [1]. One such invention is 4D printing, in which the fourth dimension is time. Smart materials are used in 4D printing to create objects that can self-assemble, be flexible, and adapt to changing conditions. Even though the technology is in the R&D phase, prototypes have been witnessed in various industries, including automotive, medical, and aviation. Although printed in the same way as a 3D-printed shape, a 4D-printed device can change over time. When hot water, light, or heat is added to smart materials (also known as programmable materials), they exhibit different functionalities. This is how a lifeless object changes shape and behavior over time.
The introduction of 3D printing sparked numerous changes in the healthcare industry. However, because 3D printing outputs are rigid in nature, 4D printing technology’s flexible products allow organ parts to be customized based on a patient’s appearance. As a result, 4D printing can be used to create bones, ears, exoskeletons, windpipes, jawbones, eyeglasses, cell cultures, stern cells, blood vessels, vascular networks, tissues, and organs, as well as novel dosage forms and drug delivery devices. The use of 4D printing in healthcare allows for the customization and personalization of medical products, drugs, and equipment, which benefits both healthcare providers and patients. Custom 4D-printed implants, fixtures, and surgical tools, for example, can reduce the time required for surgery and patient recovery while also increasing the success of the surgery or implant.
Smart material is at the core of 4D printing technology, as it allows printed products to be more flexible, expandable, and deformable in response to specific stimuli [2]. In medical devices, the growing interest in 4D printing has been studied in responsive structures such as soft robotics and printed actuators. The concept of 4D printing explores a new branch of additive manufacturing research that has the potential to expand the capabilities of both 3D and 4D printing technologies. This article aims to provide a brief overview of the fundamental aspects of 4D printing technologies and advancing biomedical applications. As 4D Printing may enable the uses of soft robotic technology, such as adaptable sensors and actuators.
The purpose of this article is to provide an overview of various 4D printing techniques and their applications in Healthcare, such as drug delivery systems and bioprinting.
Biomaterials and Smart Materials
The variety of smart materials suitable for printing has grown in recent years as the field has progressed. In 4D printing, smart materials play a significant role in receiving, transferring, and analyzing the applied stimuli. The materials react by undergoing actuation, which involves shape-morphing or functional alteration, culminating in a structural change. The physical characteristics of the printing materials may be used to produce a desired stimulus-response in the final printed structure. As a result, the smart material (or a mix of materials) that is selected is completely dependent on the intended use of the final printed item. Biocompatibility, for example, is a significant concern in the manufacture of biomedical equipment. Fabrication of high-resolution structures that stay stable in both temporary and permanent spatial configurations is another area of increasing attention.
Hydrogels
Cross-linking polymer chains made of hydrophilic monomers form a hydrogel. Hydrogels’ ability to absorb large amounts of water without dissolving is due to the chains’ arrangement in a three-dimensional network. They differ from dry-state polymers in that they expand significantly when exposed to water and then shrink back to their original size once dried [3].
Soft hydrogels’ viscous matrix and high water content enable them to respond to external stimuli such as temperature, light, pH, etc. In the case of 4D bioprinting, the interconnectivity and porosity of the polymeric network system allow controlled permeation of gas and nutrition to cells. Hydrogels also have truly remarkable self-healing properties.
Shape-Memory Polymers
Shape memory polymers (SMPs) are a class of smart materials that may deform inelastically to produce metastable temporary forms in response to external stimuli such as light, moisture, or temperature change. SMPs can regulate and program the SME, making them highly effective for manufacturing dynamic 4D structures. SMPs are suitable for use in a variety of industries, for manufacturing, due to their low cost, lightweight, ease of processing, and high programming flexibility, but it is their biodegradability and biocompatibility that encourage their use in the fabrication of biomedical devices [3].
Recent Advances in 4D Printing
Working heart model is 3D printed using 4D flow MRI images
Technicians and doctors in Colorado, are combining 4D magnetic resonance images of blood flow with 3D printers to create a multicolored functional heart model [4]. 4D flow scans provide doctors with a simple way to visualize exactly where problems are located as blood moves through each section of the heart during a cardiac cycle, from the end of one heartbeat to the beginning of the next, by color-coding the velocity at which blood flows through the heart. This allows them to pinpoint specific problems and plan appropriate surgery. The printed model is based on a Stratasys digital anatomy solution, which includes a suite of new materials that, according to the company, more closely mimic actual tissue density than a rigid model. “This is more about trying to replicate native tissue,” said Scott Drikakis, Stratasys’ medical segment leader. He went on to say that the platform enables greater and more efficient blending to better approximate an organ’s varying physical properties. It evolves from a purely visual model to a functional model for surgical planning.
Magnetically activated system for drug delivery
To build a 4D printed device, magneto-restrictive materials driven by an external magnetic field can be used, which could aid with targeted drugs and appropriate dosing. Li et al., created a micro-robot using a hydrogel bilayer using a standard lithographic approach. There was one layer that changed shape when exposed to certain pH levels, which helped in drug release [5]. This was made possible by using an Iron Oxide coating on the device that allowed it to be magnetically directed and ensured site-specific drug delivery. As a result of this discovery, targeted delivery of anti-cancer medications can be made possible. Tumor tissue with a low partial pressure of oxygen and a certain pH can induce medication release. So-called “drug delivery devices” can administer the maximum amount of beneficial drug therapy while minimizing any unwanted side effects. Before its commercialization, however, further research must be done on this technology.
4D Bioprinting
Artificial hard tissues, such as bone grafts, can also be created using 4D printing. To aid graft mineralization, scientists printed a grid-patterned polymeric bone graft and coated it with MSCs (Mesenchymal stem cells) derived from human nasal inferior turbinate tissue. After a brief culture period, the printed bone graft showed post-printing maturation. The graft’s osteoconductive and osteoinductive properties were improved in both in vitro and in vivo studies. The synthetic graft, on the other hand, lacked the mechanical strength of natural bones. Mini tissues can be prepared using 4D bioprinting, which then integrates and develop into larger tissue over time. Soon, this technology may be advanced to the point where mature tissue and complex organs such as physiological organs can be printed.
4D Printing Healtcare Market
From USD 9 million in 2021 to USD 32 million in 2026, the global 4D printing in the healthcare market is expected to grow at a CAGR of 29.9% over the forecast period. The development of smart, programmable materials, as well as technological advancements in 3D printing technology, is driving this market’s growth. In contrast, 4D printing in the medical market is expected to be constrained by high development and production costs, regulatory and performance standards that will slow product launches, and potential safety hazards.
4D printing in the healthcare market is expected to be dominated by FDM technology by 2021. During the forecast period, however, the PolyJet segment is expected to grow the most. Complex shapes with intricate details and delicate features can be created using this technology. It combines products with a variety of colors and materials into a single model. The ability to use multiple materials and colors, as well as reduced material waste due to higher deposition accuracy, are two major advantages of this process that are driving its demand.
Reference
[1] Greenberg S. 4D Printing in Healthcare. Blog.bccresearch.com. https://blog.bccresearch.com/4d-printing-in-healthcare. Published 2021. Accessed September 1, 2021.
[2] Quanjin M, Rejab M, Idris M, Kumar N, Abdullah M, Reddy G. Recent 3D and 4D intelligent printing technologies: A comparative review and future perspective. Procedia Comput Sci. 2020;167:1210-1219. doi:10.1016/j.procs.2020.03.434
[3] Bajpai A, Baigent A, Raghav S, Brádaigh C, Koutsos V, Radacsi N. 4D Printing: Materials, Technologies, and Future Applications in the Biomedical Field. Sustainability. 2020;12(24):10628. doi:10.3390/su122410628
[4] 4D printing promises biomedical applications – ASME. Asme.org. https://www.asme.org/topics-resources/content/biotechnology-anticipates-4d-printing. Published 2021. Accessed September 13, 2021.
[5] Li H, Go G, Ko S, Park J, Park S. Magnetic actuated pH-responsive hydrogel-based soft micro-robot for targeted drug delivery. Smart Materials and Structures. 2016;25(2):027001. doi:10.1088/0964-1726/25/2/027001
[6] https://www.marketsandmarkets.com/Market-Reports/4d-printing-healthcare-market-196612645.html. Published 2021. Accessed September 13, 2021.
