We will not be changing spare parts soon
The natural desire for artificial organs: we print with living cells
Andrey Vasilkov, Computerra
3D printing technology and bioprinters in medicine are associated with many developments that seem fantastic. Rapid healing of extensive wounds, reconstruction of vessels, valves, articular surfaces and, in the future, layer–by-layer printing of entire organs. What is possible now and what areas are relevant in medical 3D printing?
What is bioprinting? According to the theses of the International Conference 3B’09 (Bioprinting is coming of age: report from the International Conference on Bioprinting and Biofabrication in Bordeaux), bioprinting is the use of automated processes when assembling certain flat or volumetric structures from biological materials for the needs of regenerative medicine, pharmacological and cytobiological research.
In parallel, another term (tracing paper from English), bioprinting, has taken root in the Russian–language press. The process really resembles inkjet printing, in which live cells are used instead of pigments. It can be a monoculture of cells with a finite function (for example, cells of the inner lining of blood vessels) or a suspension of pluripotent stem cells capable of forming any tissue.
3D bioprinter in the laboratory (photo: Wiired)Layer-by-layer printing of tissues and organs creates a basis for the development of transplantology.
This direction is able to solve many urgent medical problems. First of all, the issues of long waiting for donor organs, the risk of rejection and complications due to suppression of immunity are removed.
Background of the issueThe idea to use cell cultures instead of ink and create biological tissues using modified inkjet printing originated at the end of the last century.
One of the first publications about its successful development can be considered an article by Vladimir Mironov and co-authors of Organ printing: computer-aided jet-based 3D tissue engineering, published in April 2003 in the journal Trends in Biotechnology.
The 3D prefix was used in it rather as an indication of the prospects of work, since at that time in the study itself it was possible to create one layer of endothelial cells, and the resulting structure could not be called volumetric. The main achievement of the conducted research was the demonstration of the very possibility of accurately placing living cells by inkjet printing methods while preserving their viability.
Over the following years, each group of researchers used their own version of the bioprinter and various variations of the cell distribution technique. The first mass-produced bioprinter appeared at the end of 2009. It was manufactured by the Australian company Invetech by order of the American Organovo. The latter firm was founded in 2007 and five years later was mentioned in the MIT survey among the most innovative companies. Take a look at the following video.
Organovo recently signed a contract with Autodesk. In well-known computer-aided design systems, organs will be drawn in much the same way as parts for cars and robots.
Problems and solutionsThere are no special issues with the design stage, but the printing process itself has an important difference.
"Biological ink" consists of several components that must be precisely dosed so that the "print heads" do not interfere with each other. AMTecH is actively working on the development of multicomponent printing.
The concept of a multicomponent bioprinting printing system (image: pcmweb.nl )Now the technology of printing with living cells is constrained by a lot of factors.
It is naive to believe that in a year or two they will start printing organs, and the donor procurement service can be abolished. In addition to specific difficulties, there are a number of common problems in the procedure of 3D printing with different cells.
For example, each organ requires a "connection" to the nervous system and an extensive network of blood vessels. If the problem of reinervation is somehow solved by modern transplantology, then a feeding network of vessels is needed already at the stage of organ formation. The circulatory system, even in some areas, is literally riddled with intricacies. There are own vessels in the outer shells of arteries and veins, and the order of branches inside the organ often exceeds ten levels.
Models of the circulatory system of the kidneys and liver (image: sciencephoto.com , anatomikmodeller.com )It is still difficult to print a blood vessel even at the concept level.
This is not an elastic tube of a given diameter, as it seems to most people with a technical education. Vessels of each type have important features that need to be able to reproduce.
Arteries and veins consist of layers of different cells that form a specific spatial structure. It allows each vessel to interact with others and with the body as a whole. Even the diameter of the pores in the walls and the local tone are regulated very difficult.
Currently, within the framework of proof-of-concept studies, it is possible to print only single small vessels and individual fragments of large ones. Until the problem of full-fledged vascularization of organs in the process of volumetric printing is solved, it is useless to try to make them.
When talking about more realistic tasks, skin is often mentioned. Sometimes it is cited as an example of a promising direction of two-dimensional bioprinting, but the skin seems to be a simple fabric only until you try to recreate it. The epidermis alone consists of five layers. Their structure is different, as is the morphology of keratinocytes. You can't just take, print and implant a flap of skin, although you will find many articles describing "successful experiments". Why does this happen?
This artificial skin is mainly composed of bovine collagen (photo: Dan McCoy – Rainbow/Science Faction/Corbis)One of the reasons is that the cell culture in the bioprinter is mixed with hydrogel.
Recently, certain successes have been associated with hydrogels. They have learned to make them with a lot of interesting properties, including physical antibacterial and fungicidal.
Once on the wound surface, the hydrogel performs the same function as in the cell culture from the bioprinter. It creates a voluminous porous microstructure for cell migration and serves as a support for them. Regeneration is more efficient, and the wound heals outwardly much faster and more accurately.
Scanning electron microscopy of a hydrogel fragment (photo: Nanoscale Informational Science Education Network)If there was also some part of the multiplied cells in the applied mixture, perhaps they will also play some positive role.
However, today it is more likely that they will slow down regeneration and pure hydrogel will be preferable. Printing patches for wound surfaces is the destiny of the future, but not yet the present.
It is planned to solve the voiced problems primarily by using the property of self-organization of living matter and strengthening regenerative capabilities. Hydrogel and other compounds now perform an important function of support, but in the future we need to gradually get rid of these crutches. It is believed that it is enough to recreate the basic structure of the organ, and more specific details in it will be formed independently. The main question is how to make an artificial organ "ripen" properly outside the body.
Main directions Existing achievements are not just a foundation for the future.
In addition to the promising task of organ manufacturing, bioprinting has other applications. The main direction that is already bearing fruit today is toxicological studies of various substances and new pharmaceutical preparations without the use of laboratory animals.
The point here is not so much ethics as expediency. Toxicological experiments on laboratory animals are characterized by a relatively low reproducibility of the results. In addition, they require empirical conversion methods to account for differences in human structure.
Organovo 3D bioprinter (photo: Wired)A conceptually similar research technique is the modeling of pathological processes in order to study the key mechanisms of their development.
It is unproductive to do this on animals, and an identical fabric will be almost an ideal model. The aforementioned Organovo in 2013 began to cooperate in this direction with the Institute of Cancer Problems at the University of Oregon.
In general, bioprinting allows us to evaluate many aspects of the influence of various substances and processes directly on those cells that are the main targets for new drugs. This can be done most fully within the framework of the "laboratory-on-a-chip" concept, which Computerra has already written about.
The prospects
The greatest interest is shown in grants for the layered creation of a functioning and suitable kidney from living cells. In second place is the task of bioprinting the liver and pancreas. These projects have been relatively generously funded by NASA, DARPA, other major agencies and non-governmental organizations in recent years. However, first they will try to create simple hollow organs, and only then the turn of more complex ones – parenchymal ones - will come. Currently, researchers note that at the current rate of development of the industry, the shares of the first organs can be printed no earlier than by 2030 (Regenerative Medicine and 3D Bioprinting: Polymers Sow the Seed of Life, Medical Plastics news, March 21, 2013). Take care of yourself! We will not be able to change spare parts under warranty for a long time.
Portal "Eternal youth" http://vechnayamolodost.ru26.03.2013