Bioprinting future possibilities

BIOPRINTING: DIRECTED TISSUE SELF-ASSEMBLY
Chemical Engineering Progress, Dec 2007 by Mironov, Vladimir, Kasyanov, Vladimir, Markwald, Roger
Imagine eliminating patient waiting lists for organ transplants. Bioprinting holds the promise of making this happen, but, much research must be done first. Traditional or classic tissue engineering is based on fabrication of porous solid biodegradable scaffolds with sequential cell seeding in bioreactors. The main rationale behind this approach is a need to maintain, at least initially, the shape and mechanical properties of the tissueengineered construct and to provide a substrate for cell attachment However, there are limitations to this approach - primarily the low level of precision in cell placement, especially when engineering multicellular constructs, an intrinsic problem with vascularization of thick tissue constructs, and the extremely laborious, slow and costly nonautomated tissue assembly process. Bioprinting is a transforming technology with potential for surpassing the traditional solid-scaffold-based approach in tissue engineering. Bioprinting, in essence, is a biomedical application of rapid prototyping technology or computeraided layered additive biofabrication. The main conceptual foundation of bioprinting technology is a directed tissue selfassembly (Figure 1). Tissue self-assembly is the forming of tissue and next-level biological structures, such as organs from single cells, cell aggregates, cell sheets, tissue spheroids, tissue rods, tissue tubes or more-complex 3D microtissue modules, tissue segments or tissue blocks and extracellular matrices or biomimetic hydrogels. Self-assembly is the autonomous organization of components into patterns or structures without human intervention (1). The term "directed" means precise automated robotic placement and positioning of cells and tissue spheroids according to computer-aided design. Direction or precise robotic placement of two tissue spheroids in close contact creates permissive, but not instructive, conditions for tissue fusion - since tissue fusion is an autonomous self-assembly process driven by surface tension. In other words, placing two cell aggregates into direct contact is necessary, but not sufficient, for tissue fusion. Self-assembly is an emerging concept in tissue engineering. Examples of various tissue self-assembly approaches include cell-sheet technology (rolling or stacking) (2-5), the fusion of linear rod-like structures (6), centrifugal casting (7) and magnetically driven tissue engineering (8, 9). What makes the bioprinting approach different is using selfassembled rounded tissue spheroids as building blocks. Tissue spheroids can be roboticalry dispensed and they have the capacity, when placed close to each other as hanging drops or in permissive hydrogel, to fuse into large tissue constructs of desirable geometrical shape due to their fluidic nature (10-13) and intrinsic capacity for tissue fusion.
The bioprinting process
Step 1 - Pre-processing. In order to build anything for example, a bridge or a house - one must first develop a blueprint. This is also true in the case of organ printing. Before building an organ, we must have a blueprint in the form of a computer-aided design of the desired organ. This gives the precise spatial information about the localization of cells in the 3D organ or, in other words, the "address" of each cellular or extracellular component of the tissue or organ that we want to build. There are several ways in which we can get the information about the anatomy, histological structure, composition and topology of human organs necessary for computer-aided design of printed organs. Recent progress in clinical bioimaging and ultrasound make it possible for us to discern the gross anatomical characteristics of organs, even while they are still inside their owner. The advantage of this approach lies in its capacity to demonstrate the patient's specific anatomical information as well that of his organs, not to mention the fact that we do not need to remove the individual's organ in order to examine it (a fact that many patients might well appreciate). However, resolution of this technique has not yet reached the histological and cellular level. More importantly, tissue composition and cell redistribution cannot be precisely identified. This method is not yet refined enough to be utilized in the process of organ printing. A second approach is based on computer-aided reconstruction of serial histological sections. This method provides a high level of resolution and information about the size and shape of the organ, as well as details about its composition. The problem inherent in this method lies in the fact that human organs are available for this sort of inspection only after death, and are, hence, subject to change and distortion. Other limitations of the histological approach are that it is enormously labor-intensive and is not patient-specific. However, considering that organs have a polymeric structure and consist of repeating structural functional units, one can reconstruct a typical organ unit, and then assemble the whole organ in silico by adding a reconstructed unit based on the gross anatomical structure or by filling the available space. A third approach is based on a mathematical-computational-anatomical model. For example, by knowing the mathematics of vascular branching, it is possible to reconstruct a very realistic model of the vascular tree found inside the organ using computer simulation. In fact, several commercially available pieces of software permit the creation of a realistic anatomical model from bioimages. Furthermore, several laboratories around the world have developed virtual cadavers with gross-anatomical and microanatomical-level resolution and have made them available through the Internet. These successes suggest that the computer-aided design of printed organs is feasible, although prior to finalizing the task of printing a viable organ, the existing software will need to be upgraded to embody more capacities and greater flexibility. One potential problem is post-printing tissue fusion, compaction and remodeling. It means that software for the organ blueprint must be able to incorporate post-processing changes. Our research has demonstrated that tissue compaction and tissue retraction after a fusion process can be very dramatic (11). Tissue maturation and remodeling can lead to additional changes. In other words, blueprints for printing organ constructs can be 2-3 times larger than the actual organ size. However, we do not see these as insurmountable technical challenges. Step 2 - Processing. Processing or actual printing of tissue and organ constructs can be physically carried out by various material-transfer dispensing and deposition devices. One of most promising technologies is inkjet printers, because they are inexpensive and operate at fast speeds of several thousand drops per second or more. Several research groups have already demonstrated that cells survive the process of printing, and that one drop can contain a single cell. Utilizing cell aggregates in inkjet printers is a trickier proposition, but may be possible if the former are enhanced by the inclusion of a highly porous scaffold or using mechanically enforced tissue spheroids. The relatively morestable, and thus more-processible, tissue spheroids or encapsulated living cells (e.g., enzymatically removable hydrogel) could be another possible option. Rapid prototyping technologies offer another possibility, although the use of high temperatures, toxic resin, or resin and plastic with a toxic catalyst is a counter-indication. It has been reported that several rapid prototyping systems can be used to design solid biodegradable scaffolds for tissue engineering with sequential bioreactor-based scaffold seeding with cells or printed scaffold embedding, or injection with hydrogel containing living cells. The biggest problem with this approach is the limited extent to which we can control the position of cells in the 3D scaffold. What makes the direct bioprinting approach different from printed scaffold-based techniques is simultaneous (one-step procedure) layer-by-layer deposition of cells and stimuli-sensitive hydrogel. The rapid prototyping technology that matches this description is stereolithography, using cells in a photo-sensitive hydrogel. The cells are positioned in the gel by using a special mask and dielectrophoresis, or by directing the cells using a special laser with a different light frequency than that used for the polymerization of photosensitive hydrogel (14,15).
A popular bioprinting method employs an automatic robotic deposition device - basically a syringe and a robotic hand. This allows the deposition of biological material, such as a hydrogel containing living cells, in a very precise manner. Initial cell density in this case is not optimal, but it has been reported that after incubation, the printed construct's cell density increases (16). Spraying a layer of hydrogel with sequential, precise punching of cell aggregates and tissue spheroids in this layer holds a great deal of promise. The repeating cycles of in situ cross-linkable hydrogel spraying and tissue spheroids placed by punching could allow us to build a multilayer construct with the tissue spheroids precisely positioned. Step 3 - Post-processing. After printing, we have nothing more than printed tissue and organ constructs. They are not yet mature, functional tissues and organs, and do not represent finished products. In order to be functional organs, they must undergo a rapid process of self-assembly, maturation and differentiation, or post-processing. Biophysically, they have the physical properties of a viscoelastic fluid, whereas mature organs usually have physical properties of an elastic solid. The process of becoming solid organs may be referred to as "accelerated tissue maturation." If printed constructs are to become viable organs, they require a wet environment that can only be achieved by using a special perfusion device - a bioreactor that allows the cells to survive. As yet, we have not solved the problem as to whether or not the bioreactor should be an essential, integrated component of the bioprinter. From both the perspective of cost and engineering, it is preferable that the organ be removed from the printer and placed in a separate environment for further post-processing in order to use the bioprinter more productively. Another factor essential to accelerated tissue maturation is the chemical and mechanical conditioning of the printed tissue and organ construct. In this case, each specific organ will require a specially designed perfusion media and regime of perfusion. Finally, it must be possible during post-printing to provide for the non-invasive, non-destructive biomonitoring of the maturation of the printed tissue and organ construct.
The top 10 challenges
The general challenges in the field of tissue engineering are clearly outlined in several publications (17). Here, we will focus on ten specific challenges. 1. Organ blueprint - The organ blueprint, especially in "bioprinter-friendly" stereolithography (STL) format, is basically a software-based computer program providing detailed instruction for layer-by-layer placement of specific biocomponents using a dispensing device in accordance with the original computer-aided design (CAD). The main challenge for organ blueprint design, as previously noted, is post-processing fusion, retraction, remodeling and compaction of the printed soft-tissue construct (11,18). Thus, in order to get the desirable mature organ size and shape, the organ blueprint must be larger and probably have a slightly different shape. The CAD must include experimentally estimated and validated coefficients of specific tissue compaction, retraction and remodeling. Effective collaboration of mathematical biologists, biophysicists, computer scientists, biologists and tissue engineers could lead to the development of novel software and organ blueprints. CAD or blueprints for 3D soft-organ printing could not be automatically derived from a 3D clinical imaging file, as is the case for CAD for solid-organ scaffolds.
2. In silico tissue self-assembly - Decoupling of design and fabrication is one of the main principles of engineering. Detailed computational simulation of the tissue self-assembly process based on predictive mathematical modeling and packing theory is a prerequisite for organ printing. Initial data strongly demonstrate that this is not only a desirable goal, but also a feasible task (19). Moreover, in silico tissue assembly is necessary for designing mechanical engineering aspects of the entire robotic biomanufacturing process. So-called computational tissue engineering is still focusing predominantly on CAD of rigid solid scaffolds (20-22). Thus, computer simulation of dynamic tissue self-assembly and post-processing remodeling of bioprinted 3D soft-tissue constructs are important tasks for the rapidly evolving field of computational tissue engineering. 3. Design of the biofabrication process - It is becoming increasingly obvious that fabrication of complex 3D organs, such as the kidney, will require several steps and a broad spectrum of specially designed equipment. The future organ-printing plant will likely resemble assembly plants for cars or planes. Modern software will allow one to design the whole organ biomanufacturing process and the corresponding robotic biofabrication equipment, as well as sequential and/or parallel fabrication steps. 4. Biopaper - Biopaper can be defined as bioprocessible biomimetic hydrogels that are specially designed for the bioprinting process. The first comprehensive review about hydrogels as extracellular matrices for organ printing was recently published (23). Criteria for ideal hydrogels for organ printing technology include:
* bioprocessible (dispensible and fast solidification)
* biomimetic (with functional peptide and growth factors)
* biocompatible (non-toxic, high cell viability)
* intelligent (stimuli-sensitive, in situ cross-linkable)
* tissue-fusion permissive (optimal physicochemical properties)
* shape maintenance
* hydrophilic (efficient diffusion)
* biodegradable (removable on demand)
* naturally derived hydrogels (collagen, fibrin, hyaluronan based)
* pro-angiogenic and loaded with anti-apoptotic and angiogenic factors
* affordable
Bioink - Bioink is defined as the standardized modular tissue and organ building blocks. The fundamental biological principle of organ printing technology is the tissue fusion process. The large-scale fabrication of self-assembled tissue spheroids with viscoelastic, fusogenic fluid-like properties is essential for reproducible organ printing (10, 24, 25). Smallscale fabrication of tissue spheroids and cell aggregates is well-established and can be achieved by different approaches, such as hanging drop, shaking, rentrifugation and cutting, extrusion and cutting (26-29), and many other techniques. However, scalable fabrication of standardized tissue spheroids suitable for robotic dispensing is still an important challenge in developing organ printing technology. Possible novel tools and devices for developing scalable technologies include a coaxial extruder, spinning disk atomizer, acoustic excitator, chaotic advection stirrer and mixer, and microfluidic device. Designing cartridges for bioink is another serious challenge
6. Bioprinters - Design and fabrication of the bioprinter or robotic dispenser and a biologically friendly rapid prototyping rnachine are important challenges for engineers involved in the development of organ printing technology and adaptation of existing rapid prototyping technologies for bioprinting and biofabrication. Organ bioprinting can also be considered as an integral part of the ongoing desktop manufacturing revolution. Some engineers define a desktop rapid prototyping system as a "personal fabricator,"analogous to a personal computer. A group at Cornell Univ. designed the first affordable, easy-to-assemble personal fabricator (29). If mass produced, it was predicted that the price of a personal fabricator could be as low as $250. It has already been shown that this personal fabricator can be used for rapid prototyping of tissue-engineered cartilage (29). An affordable personal biofabricator or bioprinter is an important accomplishment, and it will definitely enable and enhance further development, expansion and broad applications of robotic biofabrication technology.
7. Bioreactors - Bioreactors are one of the enabling tools in the field of tissue engineering. However, a bioreactor for bioprinted 3D thick-tissue constructs must have certain essential characteristics that are different from bioreactors used in traditional tissue engineering. First, it must be a perfused bioreactor that will allow perfusion of the intraorgan branched vascular tree. second, it must provide a temporal, removable irrigation system that will give the necessary time until the bioprinted intraorgan branched vascular system becomes mature and functional enough for initiation of intravascular perfusion (Figure 2). Third, it must provide dynamic bio-mechanical conditioning for accelerated tissue maturation during post-processing (30). Finally, the bioreactor must be seamlessly integrated with the bioprinter or rapid prototyping machine and allow easy placing and damage-free removal of bioprinted tissue constructs in sterile wet conditions. 8. Viability and vascularization - The viability of printed tissue constructs depends on several factors: preprocessing cell survival during loading of bioprinter cartridges; cell survival during processing; and tissue construct survival during post-processing. The last factor can be addressed by a combination of technological approaches: rapid assembly of a perfusable branched vascular tree using solid vascular tissue spheroids, and uni-lumenal vascular tissue spheroids (Figure 3); using special hydrophilic hydrogels loaded with survival factors coupled with a special bioreactor with temporal removable irrigation system; and, finally, by mathematical modeling and precisely controlling the tissue compaction process and construct diffusion properties. Simultaneously printing the organ with a "built-in" intraorgan branched macrovascular tree is probably the most challenging engineering task. Preliminary data strongly suggest that it is technically possible. There are also several evolving approaches for microvascular bed self-assembly when using endothelialized and microvascularized tissue spheroids as building blocks in organ printing technology (Figure 4). The effectiveness of these approaches in ensuring adequate perfusion and viability of bioprinted 3D thicktissue constructs and organs remains to be demonstrated.
9. Accelerated tissue maturation - Due to the fluidic nature of additive biomanufacturing processes and the absence of solid scaffolding, accelerated tissue maturation is one of the most important biological challenges of organ printing technology. Bioprinting technology is based on the assumptions that precisely placed cell populations at high density can rapidly form and assemble authentic tissues through cell adhesion, cell sorting and tissue fusion processes, and then start to synthesize the tissue and organ-specific extracellular matrices, which will provide and maintain the desirable geometrical shape and mechanical properties of the organ. Identification of biologically effective and econo-mically reliable accelerated tissue maturation procedures and so-called "maturogens," or physical, chemical and biological factors that accelerate post-printing or post-processing tissue maturation and assembly, is not only essential and integral, but also poses one of the biggest challenges in organ-printing technology development. 10. Non-invasive biomonitoring - Development of non-invasive, non-destructive quantitative methods and biosensors for monitoring the kinetics of post-processing tissue self-assembly, remodeling and maturation is another important challenge. It includes development of objective and reliable criteria, or "tissue maturation biomarkers," for achieving sufficient levels of tissue maturation and organ functionality using genomics and proteomics technologies. Optical, biomechanical and physical methods, as well as biochemical analysis of perfusate fluid, could be used for non-destructive biomonitoring of tissue maturation and for identification of structural and functional tissue maturation biomarkers. A combination of predictive mathematical models and computer simulations as a reference point with real-time registration of tissue-maturation biomarkers will provide an intelligent and automated tissue maturation biomonitoring system.
Practical applications
There are several potential biomedical applications of bioprinting technology. Biopatteming of 2D cell-based in vitro assays can create cell-based assays for cellomics and high-throughput and high-content drug discovery and drug toxicity assays. Precision Therapeutics is already using ex vivo 2D assays from patient tumor biopsies for personalized medicine or testing patient-specific sensitivity or responsiveness to anti-tumor drugs. Theoretically, printed 3D patient-specific morecomplex tumor assays are more predictive and could improve the effectiveness of anti-tumor therapy. Bioprinted complex authentic 3D human tissue-based in vitro drug discovery and drug toxicity assays can potentially be more predictable than small-animal or even largeanimal testing. It can dramatically reduce the cost of drug development and improve drug safety. 3D human tissue-based in vitro assays can also be used as models of human disease both for basic and applied therapeutic research. In vitro robotic biofabrication of organ printing from autologous cells can make allogenic organ transplantation obsolete, and once and forever eliminate patient waiting lists for organ transplantation. In situ robotic biofabrication of tissue and organs can revolutionize and reinvent surgery (31). Sciperio/nScript as well as The Pittsburgh Robotic Institute are seriously considering this direction.
Acknowledgement
This work was funded by NSF FIBR Grant (EF-0526854) and the MUSC Bioprinting Research Center Grant.
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VLADIMIR MIRONOV
MEDICAL UNIV. OF SOUTH CAROLINA
VLADIMIR KASYANOV
RIGA STRADINS UNIV.
ROGER MARKWALD
MEDICAL UNIV. OF SOUTH CAROLINA
VLADIMIR MIRONOV. MD, PhD, is an associate professor in the Dept. of Cell Biology and Anatomy at the Medical Univ. of South Carolina (MUSC; Charleston, SC 29425; Emalt: mironow@musc.edu). He is a director of the MUSC Bioprinting Research Center. He received his MD at the Ivanovo State Medical Institute in Russia and PhD in developmental biology at the second Moscow Pirogov Medical Institute. His research interests are in cardiovascular developmental biology, vascular tissue engineering and bioprinting. Mironov is the author of several books and 150 publications. He holds three patents, is a co-founder of two biotech companies, and does consulting work for several biotech companies. He serves on the editorial boards of two journals and is a vice president of the World Academy for Bioprinting.
VLADIMIR A. KASYANOV, PhD, is a professor in the Institute of Anatomy and Anthropology at the Riga Stradins Univ. in Latvia and head of the Laboratory of Biomechanics at the Institute of Biomaterials and Biomechanics at Riga Technical Univ. He earned an MS in civil engineering at the Riga Polytechnic Institute and a PhD in engineering sciences at the Institute of Polymer Mechanics, Latvian Academy of Science. His research interests are in biomaterials, biomechanics of the cardiovascular system, cardiovascular tissue engineering and perfusion bioreactor technologies. He is the author of 150 papers and the monograph "Biomechanics of Human Large Blood Vessels." He holds 13 patents, serves on the editorial boards of two journals, and is a member of the Latvian Academy of Sciences.
ROGER MARKWALD, PhD, is a distinguished university professor and chair of the Dept. of Cell Biology and Anatomy at the MUSC. He is also the MUSC Cardiovascular Developmental Biology Center director. He completed his BS in biology and chemistry at California Polytechnic Institute and then received both his MS and PhD from Colorado State Univ.
He is a leading expert in cardiovascular developmental biology, and author of several books on heart development and more than 150 peer-reviewed publications. Markwald is the recipient of numerous awards, including the South Carolina Governor's Award for Excellence in Science and the MERIT award from the National Heart, Lung & Blood Institute. He also completed a 10-yr stint as the Anatomical Record's editor-in-chief, and serves on the editorial boards of Tissue and Cell Research, Circulation Research and Endothelium.
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