Abstract
The continued rise in patients suffering from organ failure has raised the need for additional sources for replacement organs to improve the quality of life for these patients. Organ transplantation is the standard of care for end-stage organ disease, and as such, there has been an ever-increasing need worldwide to find suitable grafts for those patients.
In the last decade, the field of biomedical engineering has made important technological advances in tissue bioengineering through the use of three-dimensional bioprinting. These innovative advances have contributed to developing biocompatible materials and supporting scaffolds that allow the production of functional tissues and printed organ models. 3D printing in medicine could eventually allow the application of printed tissues and organs to replace damaged or irreparable grafts from trauma or disease. Using these new and emerging additive-manufacturing technologies, it is hoped to be able to implant printed synthetics for end-stage organ disease (ESOD) and help with the shortage of viable organs for transplantation.
Multiple bioprinter configurations for tissue printing along with printing techniques have emerged to revolutionize the creation of 3D biostructures. Current advances of tissue bioengineering strive to allow for self-assembly of cells and tissues to become a reality, which would augment the possibility of generating new graft models. Around the world, scientists have developed vascular grafts, liver, kidney, and heart models that are in various stages of development and in some cases have been implanted in animal models. Many years of work are still to come in order for these basic models to be useful for human implantation.
Ultimately, the goal of developing bioprinted tissues and organs is to overcome the shortage of available grafts. Furthermore, these replacement tissues could be made of cells from the donor, thereby reducing the risk of rejection and the levels of immunosuppressive agents being used.
Keywords
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11.1 Introduction
For more than three decades, the field of organ transplantation has made great strides on improved organ graft outcomes, saving thousands of patients with end-stage organ disease (ESOD) [27]. Improved surgical techniques and new antirejection drugs have helped pave the way toward increased success in organ transplantation. Yet, even with these advancements, the waiting list for transplantation remains extremely long and outpaces the number of donations. Organs continue to be a scarce resource, and even with potential changes in organ allocation in the United States and in some areas in the world, the number of people in need far exceeds the availability of these limited assets.
However, recent innovations in technology and new developing fields in science can potentially bring a change to the unmet organ demand. The field of biomedical engineering is among the most important areas, already bringing new solutions to medicine and will potentially provide game-changing results to the transplantation world. Creation of functional tissues in the lab setting became a reality by the end of 1980s. With this basis, the concept of organogenesis was born with the idea of creating not only tissues but also whole organs with the use of cells and a support system to allow them to thrive. Since then, tissue graft assembly employing synthetic materials for the creation of synthetic scaffolds became a reality. This process called decellularization functions as the support system that designates specific roles to living cells [29].
Most recently, a new concept, known as 3D bioprinting (3DB), where the use of a 3D printer is capable of transferring cellular material onto an extracellular matrix in a tridimensional fashion, has become the most modern technology for tissue bioengineering. Multiple research centers around the world are adopting this technique for research with the idea of building a biostructure that resembles and works as a real organ [21]. This chapter will focus on the origins of 3DB and the basics of how bioprinting works and will describe the current efforts and early developments in 3DB.
11.2 Background
Charles Hull described a technique known as stereolithography, which dates back to the 1980s and is considered the early origins of 3D printing. Stereolithography is a form of printing, where a laser is used to solidify a polymer material being extruded from a needle to form a solid 3D structure. The instructions for the design of the 3D-printed structure come from computer software connected directly to the printer [17].
The field of medicine originally adopted 3D printing from the basic anatomical standpoint. One of the early purposes for the use of 3D printing was for presurgical evaluation based on imaging models that would allow an integral visualization of the organs [6]. The ability to reproduce an organ in a 3D digital format based on computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound images led to the idea of printing synthetic organs (e.g., hepatic models) with the primary purpose of reproducing the internal anatomy of the organ to determine surgical approaches [25]. The digitized information of the CT or MRI is transferred to standard 3D printer computer software that allows printing the organ as desired [31]. In the field of transplantation, this allows an ideal preoperative evaluation of patients that are candidates for living donor liver transplantation, for example, the assessment of the liver anatomy, its biliary system, and blood supply before taking the donor to the operating room [1].
Parallel to printing synthetic organs for presurgical evaluation, 3D printing of synthetic organs or bone structures has been adopted by fields such as orthopedics; ears, nose, and throat; and facial and dental surgery, for the creation of anatomic molds, devices, and implants that can replace anatomical parts [14, 25, 32].
With the creation of 3D-printed synthetic organs, a step further was taken. 3D-printed synthetic scaffolds were created, seeded with live cells, and used for implantation in the human body with the ability to function as a tissue or organ. The first successful attempt at this approach was on patients with bladder cancer, with the use of a synthetic scaffold of human bladder by the Wake Forest group [2, 22]. Decellularization came along, a technique that involves the use of natural or biological scaffolds obtained from allogenic or xenogeneic organs or tissues. Along with the application of a detergent that removes the cellular elements, decellularization maintains the extracellular matrix and provides a support structure that can be seeded with new cells and create a new functional organ [29].
Finally, in the early 2000s, the group of Forgacs et al. from the University of Missouri-Columbia and Mironov from the University of South Carolina began working on the idea of 3D organ printing with a three-step principle: preprocessing or development of blueprints for organs, processing or actual organ printing, and post-processing or organ conditioning and accelerated organ maturation [12, 19]. The first patent application for a bioprinting platform was filed based on this initial work, and in 2007, Organovo, Inc. was established as the first 3D bioprinting company. Based on the research performed by Mironov and Forgacs’ group, they soon devised the first commercially available 3D bioprinter. In 2010, with the support of an NIH grant, Organovo was able to print the first fully cellular blood vessel [20].
With this brief review on the recent history of 3DB, we continue to the next section where we describe the basic principles of how 3DB works.
11.3 Basic Principles
The bases for reconstruction of tissues and organs through 3DB consist of a set of techniques that transfer biologically active material onto a substrate. These techniques should include a high-resolution tridimensional printer able to inject or deposit cellular structures and biocompatible materials (e.g., agar gels) that can support building blocks of cells. The use of microstructures with simple geometry planning and orientation, along with computerized technology, helps create a macrostructure that is functional [19]. The basic concept of 3DB allows the building process to be able to create cellular patterns, which are the systematical organization of cell-to-cell interactions and produce mechanical and chemical signaling. These patterns confined in a tridimensional structure hope to achieve cellular functionality and become a viable tissue or whole organ.
Important concepts to understand the basics of 3DB are described in this following section.
11.3.1 Basic Components of 3DB
11.3.1.1 3D Bioprinter
11.3.1.1.1 Hardware
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Printer head: Metal plate with attached printheads that are remotely controlled by a series of motors that allow them to function along the x, y, and z axes. The printhead function is to inject or deposit the bioink (biomaterial composed of living cells, intended to create the 3D structure) or biogel (extracellular matrix, agar gel to provide support to the cells). The printheads (syringe shaped) contain either a glass capillary that works as a fine needle that will deposit or inject the biomaterial. Depending on the manufacturer, the printer heads can contain a reservoir where the bioink/biogel is contained. Other manufacturers rely on continuous reloading of glass capillaries or needles.
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Printing platform: Flat surface where the biogel container (or petri dish) is placed to allow the printer heads to deposit the bioink/biogel (Fig. 11.1).
11.3.1.1.2 Biologic Material
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Bioink: Biomaterial composed of living cells intended to be the main functioning cells of the 3D structure.
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Biogel: Supporting extracellular matrix that is present in the container where the 3D biostructure is created. This biogel is also injected or deposited by the printer head to support the cellular layers in order to support the tridimensional structure.
11.3.2 Types of Bioprinters
Currently, the 3DB process can be achieved through three different modalities:
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Micro-extrusion bioprinting: Characterized by a temperature-controlled biomaterial dispensing system, based on a standard 3D printer, contains a fiber-optic light-illuminated deposit in area for photo-initiator activator and a piezoelectric humidifier. The system generates continuous biomaterial beads that are deposited in two dimensions; layers are placed along the x- and z-axes and then move higher in the y-axis. The final product is a tridimensional structure. The process is guided by computational software. The micro-extrusion printers have proven its value for creation of aortic valves and vascular structures [30].
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Inkjet bioprinting: Works by thermal or acoustic forces that promote the ejection of the bioink onto a scaffold or biogel base [9]. Thermal inkjet printers produce pulses of pressure via electricity to heat the printhead and thus stimulate droplets of bioink to fall from the nozzle into the biogel. These printers are high speed and low cost and they are widely available. Acoustic inkjet bioprinters have a piezoelectric crystal that creates an acoustic wave in the printhead that stimulates the deployment of cells into the biogel base. Printers such as these are very precise and uniform in terms of the bioink droplet deposition size. Overall, inkjet bioprinters are limited to low cell density deposition in order to prevent nozzle clogging. They have proven their value for printing functional skin and cartilage.
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Laser-assisted bioprinting: Consists of a pulsed laser beam that promotes the deployment of the bioink into the biogel plate. The laser bioprinter is compatible with a wide range of bioink viscosities. These printers are high cost, and their availability is limited (Fig. 11.2).
11.3.3 Creation of 3D Biostructures
Although each type of printer might have slight differences in the steps of creating a tridimensional biostructure, the common basic steps of fabricating a 3D tissue or organ are described below [4]:
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1.
Preprocessing: Creation of a biological structure in a computer software, also considered the “blueprint.”
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2.
Processing: Consists of preparing the materials that will be required to create the biostructure, as well as the steps to produce it.
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(a)
Layer of hydrogel or hydrogel container – Series of steps to create an extracellular matrix structure that is contained in a petri dish or container that will serve as the foundation base or support where the desired printer tissue will be deposited.
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(b)
Bioink – Cultured cells or tissue spheroids that are obtained from standardized methods for tissue/cell cultures. The bioink is loaded into the printer heads or printer head needles (glass capillaries). The bioink is eventually disposed on the hydrogel container.
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(c)
Hydrogel – The same material used to support the cells that are in the container will also be used for dispensation in between the layers of bioink in order to support the multiple cellular layers.
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(d)
Bioink dispensation process – The bioink or hydrogel is dispensed repeatedly depending on the amount of desired layers based on the blueprint design. As the layers are deposited, the bioink will fuse, eventually forming a 3D structure containing cells and extracellular matrix.
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(a)
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3.
Maturation: The 3D biostructure is placed in an incubator and left to mature for a certain period of time (will depend on the materials and type of tissue created).
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Application: Once the printed biostructure is mature, it can be used for pharmaceutical drug testing, in vitro models or animal models. Eventually the printed tissues/organs will potentially be used for human transplantation.
11.4 Current Research on 3DB
The field of tissue engineering and the recent application of 3D printing to medicine can potentially provide game-changing solutions to transplantation in the near future. Several examples of tissue and organ replacements are being described, designed, and applied around the world [12, 21]. As already mentioned in this chapter, multiple approaches are being investigated such as the use of natural or artificial scaffolds, decellularized organs to ultimately build 3DB. The key for success seems to be providing an ideal microenvironment allowing integration of tissue cells and development of a full organ. Although scaffolds provide an adequate structure for a 3D organ, they can be problematic in terms of immunological reactions and degradation of the extracellular matrix. Thus, the ideal approach is to rely on self-assembly and self-organization of the cells and tissues, which can be achieved with 3DB [12]. The field of whole-organ bioprinting is still in early stages, and many years of complex research will be required to obtain substantial results. Fortunately, multiple institutions around the world are focusing on different aspects of tissue engineering and 3DB process, which could lead to future applications. We continue to describe some of the relevant aspects that are being researched by different groups around the world including the aforementioned scaffolds, decellularization, and the advances achieved in some areas of real 3DB.
11.4.1 Steps Toward 3D Bioprinting
The advances on scaffolding and decellularization are described below as they have set the foundation for ideas to further develop the 3DB grounds.
One of the earliest stories of success in scaffolding development was achieved by one of the leading groups in 3D printing in medicine. The Wake Forest group [2] was able to engineer a three-dimensional bladder scaffold intended for patients with nonfunctional bladders. A biodegradable 3D scaffold was created and then seeded with autologous bladder urothelial and muscle cells grown in vitro, and once mature, the structure was anastomosed to the native bladder. Another example by Mannoor et al., with the use of cybernetics and tissue engineering, proved they were able to create a three-dimensional bionic ear, by printing a hydrogel matrix, seeding cells, and inter-wined conducting polymers with infused silver nanoparticles. This allowed in vitro culturing of cartilage tissue around an inductive coil antenna in the ear that was capable of detecting sound waves [16] (Fig. 11.3).
Another school of thought focuses on the use of scaffolds as template for developing 3D tissues/organs based on a decellularization technique, which is based on the use of detergents that are perfused through the vasculature of the organ/tissue to remove cellular elements, but the extracellular matrix remains intact. The scaffold obtained after decellularization can then be seeded combined with cellular components with different techniques (including 3D bioprinters) in order to incorporate epithelial cells (liver, lung, heart) and endothelial (intra-organ vasculature). Song et al. developed an in vitro model and were able to incorporate endothelial and epithelial cells into a decellularized kidney scaffold with promising results [28]. Yagi et al. described a technique on a porcine liver model that can support functional hepatocytes maintaining the vascular and biliary network of the original organ [34].
Various approaches that preceded 3DB have been developed for vascular grafts. Niklason et al. developed a human-cultured smooth muscle cell model with a polyglycolic acid scaffold to generate a functional artery, demonstrating the importance of pulsatile stretching and improving strength of the vessel, but limitations were noted with the polymer remnants [8]. Dahl et al. reported a human vascular graft using cadaveric smooth muscle cells and the implantation onto baboon vessels after decellularization; these vessels were able to maintain blood flow for 6 months; after their animal model, a clinical trial in human was started in Poland in 2012 in patients with kidney failure as AV grafts [7].
Although animal tissues and organs are widely available for the use of scaffold techniques, it comes with the caveat that these scaffolds can potentially host infectious agents or trigger an immune response. Unrecovered organ donor organs could serve as a source of scaffolds as well, but ethical issues could potentially set a barrier. In terms of synthetic scaffolds, limitations due to polymer/synthetic available materials will remain. Overall, the use of scaffolds has been great in setting the scenario for creating 3D biological tissues and organs, but the use of these synthetic or natural scaffolds comes with their own limitation. Ideally the 3D biostructure should be allowed a natural interaction between the epithelial cells and the support cells, with a natural maturation process of the tissue in order to become fully functional.
11.4.2 True 3D Bioprinting Advances
The use of scaffoldings to develop 3D biostructures has set the scenario for real 3D bioprinting, since, for an organ to really achieve its functions, it requires an intricate network of tridimensional systems in order to thrive. Thus, the idea of creating tissues and organs from scratch to create a native functional biostructure is now feasible with the transformation of 3D printers to 3D bioprinters. Here we review the work of several institutions on bioprinting technologies and their strategies.
11.4.2.1 Vascular
One of the most important challenges of successful bioprinting for organ creation is the establishment of vascular networks that are essential to the organ, since without adequate organ supply, the desired tissue cannot survive. Kolesky et al. described a method for fabricating 3D biostructures with vasculature, multiple types of cells, and ECM, with the use of four different bioinks in vitro [15]. They designed a 2D vascular network with bifurcations found in natural biostructures that provide nutrient transportation and waste removal. Their model was originally proposed for drug screening, wound healing, and angiogenesis, but it also sets the scenario for manufacturing 3D tissues and organs.
In the field of transplantation, one of the determinant factors for a successful graft implantation is to have optimal vascular structures attached to the donor organ in order to perform an adequate anastomosis and to prevent thrombosis, stenosis, or leaks in the implanted organ. Often the vasculature of these organs is not usable due to their length, diameter, and integrity or due to inherent disease of the vessel. With the development of bioengineered constructs and the special interest in developing vessels for many vascular diseases, synthetic vascular grafts were created for repairing or replacing vessels. However, synthetic grafts often come with complications, thrombosis, and infection in the majority of cases. Tissue-specific engineered vascular grafts offer an attractive alternative.
In terms of 3DB vascular structures, some centers have developed their own models. Norotte et al. [23] described a layer-by-layer printing technique with the use of multicellular spheroids containing smooth cells and fibroblasts along with agarose rods, resulting in single- and double-layer small diameter vascular structures. This is one of the early examples of fully biological vascular tubular grafts and provides high expectations for the advancement in the vascular areas that will benefit the cardiovascular and transplantation field. Potential applications of 3D-bioprinted vascular grafts in the field of transplantation are meso-rex bypass from the superior mesenteric vein to left portal vein for the treatment of portal vein thrombosis. These vascular grafts could also prove useful in living donor liver transplantation where many times there is a need to extend vasculature for the drainage of segments V and VIII of the liver to the middle hepatic vein or vena cava to prevent outflow issues in right lobe grafts (Fig. 11.4).
11.4.2.2 Liver
The importance of the liver in terms of its role in drug metabolism has fueled multiple interests around the world to develop liver biostructures to test the biopharmacology of many drugs. Research to develop 3D liver structures will eventually benefit the field of transplantation. To date, only reports of early data in in vitro models are available. Robbins et al. [26] with the use of the NovoGen MMX Bioprinter ™ printed a metabolically functional 3D liver biostructure that showed cell-to-cell interaction, protein production, and enzymatic activity [24]. Their structure also contained stellate cells as well as endothelial cells. Chang et al. [5] created an in vitro device that had a 3D liver biostructure housed in a chamber that resembled the natural microenvironment of the hepatocyte, including a perfusion system that allowed assessing the metabolic function of the biostructure as well as the interaction with drugs. This model was developed with NASA support to assess drug pharmacokinetic profiles in planetary environments. As mentioned above, the success of these 3D liver biostructures relies on providing a vascular network. Miller et al. [18] were able to print 3D filament networks made of carbohydrate glass in a cylindrical shape that were lined with endothelial cells and perfused with blood. This model was tested in a rat hepatocyte model, maintaining the metabolic function of the cells.
11.4.2.3 Intestine
Although GI tract models have been developed with diverse bioengineering techniques, the 3D bioprinting world has not focused on the development of GI tract models. The complexity of creating an intestine requires the creation of vasculature, neural, and lymphoid tissue along with epithelial tissue with absorptive and secretory functions. At our institution, efforts are being focused on the creation of a muscular graft onto which all the functions previously mentioned are added [33].
11.4.2.4 Kidney
Drug nephrotoxicity is estimated to cause 25% of acute renal failure. However, this is just an estimated number, and the real percentage is hard to determine. As in liver, the creation of 3D-bioprinted kidney models is being fueled by the need to understand better the interaction between the kidney and multiple drugs. This again will benefit the field of kidney transplantation with the subsequent development of fabricated human kidney tissue models.
King et al. [13] created an in vitro model of multicellular, 3D-bioprinted proximal tubules. In their model, the interface between tubular epithelium and renal interstitial cells was observed. Also an extensive endothelial network was described. Homan et al. [11] created a 3D-bioprinted human renal proximal tubule model in vitro within an extracellular matrix and housed in perfusable tissue chips that allowed the model to survive for more than 2 months. Their model exhibits enhanced epithelial morphology and functional properties. Cyclosporine (known nephrotoxin but also used for immunosuppression in transplantation) demonstrated disruption of the epithelial barrier in a dose-dependent manner, proving the utility of the in vitro model. Even with these advances, the development of a kidney model is far from being accomplished (Fig. 11.5).
11.4.2.5 Heart
The complexity of the heart tissue poses a barrier that only few researchers are willing to confront. Zhang and Zhang [35] created a hybrid strategy based on 3D bioprinting and scaffolding with an Organovo NovoGen MMX Bioprinter (Organovo Holdings) [24]. First with the use of bioink containing endothelial cells, they injected microfibrous hydrogel scaffolds. The endothelial cells migrated toward the periphery to form a layer of endothelium. This endothelial layer was then seeded with cardiomyocytes in order to generate aligned myocardium capable of spontaneous and synchronous contractions. Even though cell migration was achieved, the overall composite demonstrated a lack of structure and functionality. This is one of the earliest demonstrations of 3D-bioprinted heart tissue [36] (Fig. 11.6).
11.5 Barriers to Overcome
Every organ with potential 3DB creation presents with its own complex barriers. Replicating the cell-to-cell interaction requires establishment of a vascular network and neurohumoral response. Efforts to achieve organogenesis, as it occurs in the human body, must be attempted. More “out of the box” approaches might need to be performed along with much needed interinstitutional collaborations.
Currently, bioprinters are able to deliver biomaterials, micromolecules, and viable cells to generate experimental constructs, but lack sufficient organizational integrity and stability for surgical graft replacement. Experimental biomaterial mixtures are still being tested to find the adequate median for cell carriers and to provide appropriate machine-driven support and cell-specific cues and eliminate toxicity. The requirements to fulfill a stable construct are limited by the small amount of biomaterials available in our era to apply in 3DB. Such requirements comprehend thermoregulation, gel stabilization, and an adequate environment for cell adhesion and proliferation, which should be accomplished with dispensing uniformity and preventive nozzle clogging.
With the eventual development of mature bioengineered tissues or organs for transplantation, addressing the implantation stage will be a complex task as well. New drugs will have to be tested and developed to promote the adaptation and function of the implanted tissue or organ to fully achieve what is desired.
11.6 Conclusion
Although most of the aforementioned advances in the 3DB field are in the early stages, the current improvements achieved every year in different aspects of 3D biostructure development are remarkable. So far, achievements in synthetic 3D printing, scaffolds, gel prints, and cellular prints have allowed significant progress of 3DB. We hope in a near future to achieve structure stability and develop organs that will be used as universal replacements. The next step for tissue engineering and 3DB is to establish networks of collaboration between interested groups to merge the areas of research that will allow the integration of fully functional 3D biostructures, first at the in vitro stage and eventually at the in vivo stage. Academic institutions interested in physiology and transplantation, as well as private entities, share a final endpoint, the creation of 3D-bioprinted tissues and organs that can address unmet needs for the patients with ESOD.
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Munoz-Abraham, A.S., Ibarra, C., Agarwal, R., Geibel, J., Mulligan, D.C. (2017). 3D Bioprinting in Transplantation. In: Nadig, S., Wertheim, J. (eds) Technological Advances in Organ Transplantation. Springer, Cham. https://doi.org/10.1007/978-3-319-62142-5_11
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