Hard tissues and organs in the human body include the bones, teeth and cartilage, consisting of certain unique cell types and substantial organic and inorganic extracellular matrices (ECMs). For example, the bone is composed of osteoblasts and calcified ECMs, in which the majority inorganic ECM is hydroxyapatite (HA). The tooth is another highly calcified hard tissue. It consists of the enamel, cementum, dentin and endodontium . Whereas the cartilage includes articular gristle, and the main constitutes of noses and ears . These hard tissues and organs take the role of mechanical support with some basic biological functions, such as hematopoiesis and metabolism, which are vitally important in maintaining human lives and activities .
Hard tissue and organ defects, such as bone tumor, tooth fall and ear deformity, have caused tremendous harms to people’s health status and life quality. Generally, the small defects can be cured through host tissue/organ self-regeneration. However, the large defects (e.g., ≥1 cm in length) need intervention therapies, such as implanting grafts to promote healing or repair [4,5,6,7,8,9]. Traditionally, autologous tissue has been considered as gold standard for bridging large hard tissue defects after accidents or cancer surgery. However, the use of autologous tissue always encounters the risks of a second operation after the implantation with some unexpected syndromes. Clinically, there is a great need for novel, stable and resorbable large hard tissue and organ repair materials that are made by 3D printing technologies [10,11].
The production of hard tissue and organ substitutes (also named as implants, grafts, biomaterials, prostheses, precursors and analogues) is an important part of regenerative medicine. Among which, the fabrication of bone repair materials has started earlier and the clinical applications are more successful [4,5,6,7,8,9,10,11]. A special need of the hard tissue and organ substitutes is that they require high content of inorganic ECMs with strong mechanical properties. So, for hard tissue and organ engineering, the material constitutes and structural characteristics of the substitutes have always been the research focuses. Particularly, biomaterials, which have been used frequently as hard tissue and organ implants, have undergone several development stages, such as passive commercial products, no bioactive scaffolds, cell-laden hydrogels, and pre-designed initiative smart composites [12,13,14,15,16]. Additionally, some hard organs, such as the nose and ears, have complex curved surfaces which require specific processing technologies to manufacture. Therefore, the development of new hard tissue and organ substitutes with suitable physical and biological functions based on the bionic principles is an important area of hard tissue and organ engineering [17,18,19,20,21,22,23].
3D printing, also named as solid freeform fabrication (SFF), additive manufacturing (AM), layered manufacturing (LM) or rapid prototyping (RP), is a family of enabling technologies that can produce solid objects layer-by-layer using computer aided design (CAD) models [24,25]. Compared with traditional tissue engineering approaches, 3D printing technologies are often sophisticated, flexible, and automated [26,27,28]. Through the use of 3D printers, the manufacturing procedures can be dramatically simplified. Over the last decade, many industrial 3D printers have been employed to generate porous scaffolds for hard tissue engineering . Whereas some distinctive 3D printers for cell-laden tissue and organ manufacturing have drastically increased [12,13,14,15,16,17,18,19,20,21,22,23,26,27,28]. The 3D printing technologies have been already described as the third industrial revolution with number of new publications increasing rapidly .
The main advantage of 3D printing technologies in large hard tissue and organ engineering is their capability to produce complex 3D objects rapidly from a computer model with varying internal and external structures, such as go-through channels. These complex 3D objects can be either tissue engineering porous scaffolds, cell/biomaterial composites, homogeneous tissues, or multiple tissue contained organs (Figure 1). After printing, the porous 3D scaffolds can be implanted alone or seeded with autologous cells to serve as osteoconductive templates in large tissue engineering. Ideally, new tissue forms along the go-through channels during the scaffolds degrade slowly in the body [31,32]. The cell/biomaterial composites can be used in vitro or in vivo for large hard tissue regenerative research. The homogeneous tissues can be used for large hard tissue defect repair. While the multiple tissue contained organs can be used for customized organ engineering and substitution. Currently, there is a wide range of materials can be used for the 3D printing processes.
Currently, there is a wide range of materials which have been used for the 3D printing processes. For example, 3D printed metal hip joints are considerably lighter than the ones produced by conventional methods. With the go-through channels, the implants can remain longer in the body than conventional implants due to the coalescence of the 3D printed implants with the host bones. Hard tissues can grow easily into the go-through channels and enhance the repair effects. Subsequently, synthetic polymer based scaffolds with similar material properties as natural real bones have been extensively researched. One of the advantages of these synthetic scaffolds is that they—unlike metal implants—behave neutrally in X-ray equipment [33,34]. It is now possible to reconstruct an outline of an ear or a jaw that exactly mimicks the patients’ large tissue and organ contours based on the images acquired by magnetic resonance imaging (MRI) or computerized tomography (CT) scans directly from the patients. The predefined go-through channels have a direct impact on the outcomes of the hard tissue and organ repairs .
During the last three decades, various metal implants have become the main solutions for large hip replacement and long bone graft. Some metal powders have been used for 3D printing. Theses metal powders include titanium, stainless steel, tantalum, aluminum alloys, Inconel, nickel-based alloys, titanium aluminides, and their composites. Xue et al. have employed 3D techniques to make titanium scaffolds with an average pore size of 800 µm and porosity of 17%–58% . This porous titanium scaffold improved the clinical performance of the metal substitutes by promoting osteoblasts to adhere and proliferate inside. When the titanium scaffold was implanted into the target location, osteoblasts migrated into the go-through channels, proliferated and secreted ECMs, leading to the reconstruction of the damaged bone along the gradually degraded metal scaffold. However, metal implants can cause many vice reactions or syndromes for hard tissue and organ regeneration.
As stated above, hard tissues and organs have unique material and structural characteristics that give them their strength. An advantage of 3D printing over traditional tissue engineering strategies is the ability of 3D printing to include these material and structural elements in the fabrication processes of the hard tissue and organ analogues. Especially, many hard organs have soft tissues (such as bone marrow in the bones and pulp in the teeth) that are hard to fabricate using traditional tissue engineering approaches. In this review, we summarized some of the innovative 3D printing technologies for hard tissue and organ engineering obtained over the last three decades with emphasis on functional aspect of each technology, suitable printing materials, strengths and weaknesses in hard tissue and organ engineering.
A team of researchers from Imperial College London and King’s College London has developed a new technique for creating 3D structures that can be used to replicate tissues and biological organs.
The study is published in Scientific Reports.
The study of organ printing uses 3D printing techniques to produce artificially constructed device for organ replacement.
The 3D printing techniques allow for the construction of a particular organ structure layer-by-layer to form a cell scaffold, which is the key component to forming new viable tissues. Scaffolds act as a template for tissue regeneration, where damaged tissues are encouraged to regrow.
Currently, in clinics, organs that are flat, such as the skin, or hollow, such as the bladder, have been successfully printed and implemented. Scientists are working on ways to construct more complex organs, such as the brain and the heart.
The researchers in this study are the first to create 3D structures that are soft enough to replicate the mechanical properties of organs such as the brain and lungs.
“We needed to mimic the complex geometry of the brain and the best way to achieve an accurate geometry was to 3D print it,” said Zhengchu Tan, one of the lead researchers from the Department of Mechanical Engineering at Imperial College London. “Thus, we developed the technique that can print stable, yet super soft when thawed, brain-like material.”
This technique uses a method called cryogenics (in other words, freezing), in which solid carbon dioxide (dry ice) is used to rapidly cool a hydrogel ink as it is extruded from a 3D printer. This instant cooling allows further layers to be built up on the previous layers, building a hydrogel matrix.
So, after being warmed up, unlike in similar techniques previously tested and failed, the gel form of hydrogel ink becomes as soft as body tissues, but doesn’t collapse under its own weight.
“It (3D structure) is able to hold its shape because cross-links have been created to form a hydrogel matrix that keeps the structure together,” Tan said. “However, it should be pointed out that since it is as soft as brain, it does deform under gravity just like brain does.”
The researchers tested the 3D-printed structures by seeding them with dermal fibroblast cells, which generate connective tissue in the skin, and found that there was successful attachment and survival.
“At the moment we have created structures a few centimetres in size, but ideally we’d like to create a replica of a whole organ using this technique,” Tan said in a statement.
With cryogenics, scientists can use these 3D structures to replace body tissues in medical procedures to form scaffolds. By “seeding” porous scaffolds with cells and encouraging them to grow, scientists can regenerate damaged tissues and allow the body to heal without having to face issues that typically affect tissue-replacing transplant procedures, such as rejection by the body.
Future research opportunities
This new technique could lead to further possibilities around the growth of stem cells, which is the key to medical revolution because of its ability to change into different types of cells.
Additionally, this technique could be used to create replica body parts or even entire organs. These could allow scientists to carry out types of experiments, which are not possible on live subjects. And these replica body parts and organs can be used to help with medical training by replacing the need to practice surgeries on animals.
According to Tan, the team is currently using cryogenics to print soft 3D structures, on which they can seed cells to study the effect of substrate stiffness on cell viability. As part of the larger effort to develop a 3D structure of a brain, the team hopes to extend the printing size so as to print an entire brain.
Hyeyeun Jeon is from South Korea and a recent graduate from Carnegie Mellon University with a double major in Professional Writing and International Relations. She is passionate about non-fiction storytelling. She loves reading, watching, writing and producing stories about extraordinary lives of everyday people.