Impact of bio-printing

The bio-printing is a biomedical application of processes additive manufacturing to produce artificial biological tissues. Bio-printing can be defined as the spatial structuring of living cells and other biological products by stacking and assembling them using a layer-by-layer computer-assisted deposition method to develop living tissues and organs for tissue engineering, regenerative medicine, pharmacokinetics and more generally biology research. This is a recent innovation that simultaneously positions living cells andlayer-by-layer biomaterials to make living tissue. The main use of printed organs is transplantation. Research is currently being conducted on artificial structures of the heart, kidneys, liver and other vital organs. For more complex organs such as the heart, smaller constructs such as heart valves have also been investigated. Some printed organs have already reached clinical implementation but mainly involve hollow structures such as the bladder as well as vascular structures.

In 1938 Alexis Carrell, Nobel Prize in Medicine, and Charles Lindbergh, the aviation pioneer and passionate inventor, proposed to grow organs. And we must wait for the appearance of regenerative medicine that seeks to replace the damaged cells of the human body with healthy organs to see appear first transplants. Nevertheless the risk of rejection by the patient is important and requires precautions on the part of the medical profession.

This is the 21th century that the technology of bio-printing. It allows the custom manufacturing of tissues or organs with the cells of the patient, thus minimizing the risk of rejection. It consists of an assembly of constituents of biological tissues (cells) predefined by digital design. The goal is to seek to reproduce the three-dimensional organization of cells as naturally done by the human body. This technology uses the layer – by – layer principle of 3D printing. Bio-printing is defined as a disruptive technology because it results from the grouping of knowledge in physics, biology,mechanical and computer. Applications are limited today because of the recent discovery of this technology but in the long term, the expected applications are many and innovative.

3D organ printing was first used in 2003 by Thomas Boland of Clemson University who patented the use of ink jet printing for cells. The method used a modified system for deposition of cells in three-dimensional matrices placed on a substrate.

Since Boland’s first experiments, 3D printing of biological structures, also known as bioprinting, has developed. New printing techniques have been developed, for example, extrusion printing.

The organ printing was quickly seen as a potential solution to the global shortage of organs for transplantation. Printed organs have already been successfully transplanted. In particular, tissues such as skin, vascular tissue, such as blood vessels, or hollow organs, such as the bladder. The artificial organs are most often made from the recipient’s own cells, which eliminates the problems related to the risks of rejection.

The printing of more complex organs is the subject of intense research around the world. For example for the heart, pancreas, liver or kidneys. Beginning 2017, this research had not yet led to transplantation.

A bioprinter works in a similar way to a 3D printer based on the FDM process. An extruder builds molds from the fabric, in this case no thermoplastic such as ABS, but a polymeric gel, for. B. on alginate basis, with encapsulated living cells. Organovos Bioprinter drops droplets using another promising technology, each containing about 10,000 to 30,000 single cells. These are later to be stimulated by suitable growth factors even in functional tissue structures.

Bioprinters have special components, such as temperature regulation, which is very important for proper printing.

Medical use
For medical purposes, bioprinters (in the experimental field) have been known since 2000. Even today it is not yet possible experimentally to print organs consisting of several tissue types. The research tends to be more in the direction of building relatively coarse cell aggregations through the printing process, which then “mature” into organs through biological self-assembly. A major problem is, for example, the generation of a functioning blood vessel system.

However, it seems quite conceivable that bioprinters or organs created with them can someday replace donor organs. An advantage of bioprinter organs is the precise tuning to the intended body. For donor organs it is necessary to wait until an organ is available which fits as well as possible. That a donor organ is available at all, however, is usually unlikely. The “pressure time” of an artificial organ lasting several hours can be a barrier in acute accident injuries. Transplants that are printed with a regular 3D printer and made of metal or plasticdo not count as bioprinting because no cells are used. Smaller bone fragments or dental prostheses made of calcium phosphate are already produced in the 3D printing process. However, it is customary to use the material of specially bred cattle for bones.

Synthetic Biology
In synthetic biology, bioprinters could be used to print novel forms of life. A sensational result in synthetic biology was a “medusoid,” an artificial ” jellyfish ” of rat and silicone muscle cells that could swim. However, this was not only generated by a Bioprinter.

Food industry
Also, to produce foods such as meat, bioprinters could be used on a massive scale. According to the company, Modern Meadow has already printed tasty meat, which was produced with less effort than livestock and slaughter. The company wants to put an end to slaughter. Currently, no “printed” meat is commercially available, although this would already be possible in terms of flavor and health. Professor Stampfl from the Institute of Materials Science and Technology of the Vienna University of Technology estimated the cost of a printed piece of meat to be at least 50,000 euros in 2013.

The satire of such a food industry was already presented in the film ” Brust oder Keule ” in 1976, in which Louis de Funès plays the leading role and secretly invades a factory in which, for example, chicken is artificially produced.

In 2017, the achievements of the biological printer remain limited, scientists seek to improve and develop existing technologies. The hypothesis of a functional bio-printing technology would offer many perspectives of applications.

The main goal remains surgical grafting. Printing organs from the recipient’s cells also helps to avoid the risk of rejection. This would save thousands of lives, lower the cost of medical care and meet ever-increasing organ demands. It should be noted that the number of organ requesters almost doubled between 2006 (12,531 applicants) and 2014 (20,311). But it takes time and experience to get there because you have to create a complex vascularization to oxygenate and feed the organ. And currently, it is difficult to reconstitute complex blood vessels. Also, created organs are only viable for a limited time and are for the moment of a tiny size. They are then unusable in humans. To create and respond to the shortage of organs will then wait a few more years.

The objective of the skin print is especially able to treat large burnt by creating fabrics adapted to the patient’s wound 38. Currently, transplants are performed by removing undamaged tissue from the patient’s body (autograft) or by using skin donations. This operation is often painful or sanctioned by rejection from the immune system. According to D r Marc Jeschke: “90% of burns occur in low- and middle-income, with greater mortality and morbiditypoorly equipped health care systems and inadequate access to burn treatment facilities. Regenerating the skin using the patient’s own stem cells can significantly reduce the risk of death in developing countries. “. It should be noted that the number of transplants carried out in France is increasing: 4,428 in 2006 and 5,357 in 2014, but these figures are still very low compared to the requests because only a quarter in 2006 and just over a third in 2014 of applicants could have been grafted.

Improvement and diffusion of the printers would allow printing individual cell tissues from the patient’s stem cells for grafting onto the patient. Then, with the installation of biological printers in hospitals to print living tissue on demand and custom. But also the direct printing of tissues on or in the human body by printing sequences of layers of cells is envisaged: to produce grafts, tissues that can be implanted directly in the patient. So bio-printing would be a solution to create tissue from the patient’s cells.

Bio-printed Prostheses: Printing using bio-prosthesis and implant materials would limit the risk of rejection and infection of the recipient. Researchers rely on using all-organic materials and stem cells to achieve this. Note that this type of transplant would be used only for certain pathologies such as tracheotomies, which leave serious after-effects such as speech loss and a high risk of infection.

Medical research
Bio-printing makes it possible to produce biological tissues for experimentation in medical, pharmaceutical and toxicological research. The goal is to create individualized tissues, made from the patient’s cells, allowing to select in vitro on these tissues the treatments and to develop personalized therapeutic solutions. “One of the major problems facing these companies is the ability to accurately assess the toxicity of new treatments on human cells, particularly those of the liver. Between 1990 and 2010, 25% of treatments were either withdrawn from the market or stranded in phase 3 because of toxic effects on the liver “. This type of application could also lead to lowering the cost of searches.

In the field of cancer for example: it could be possible through the 3D reconstruction of the patient’s own tissues (taking into account the cellular environment of the tumor) to test chemotherapy. Serial printing of cancerous tumors would allow researchers to test compounds and thus target the most effective molecules for a given mutation. For the moment, patients are used as guinea pigs for these tests. The current development time of treatments is long and could accelerate by bio-printing diseased tissue.

The use of bio-printed fabrics could reduce the cost and process of research and development of new treatments. According to a study, “Between 1997 and 2011, the top 12 pharmaceutical companies spent $ 802.5 billion on research and development to finally approve 139 new treatments. The process leading to the commercialization of a single drug therefore cost an average of $ 5.77 billion. In other words, 40% of the money invested did not go beyond the laboratory stage “. Cosmetics and pharmaceutical companies provide significant financial support to bio-printing research laboratories.

In vivo printing
Printing in vivo is to print directly tissue from the patient. For example, BioPen is able to repair fractures and wounds by injecting a mixture of stem cells with a biopolymer gel (algae extract: proteins that accelerate regeneration). This mixture is combined in the BioPen, it is sufficient to superimpose successive layers on the surface of the bone or missing cartilage to fill the damaged area. An ultra-violet source attached to the pen instantly solidifies the substance. Over time, the protective gel degrades and cells multiply and dissociate to become nerve, muscle, bone cells to repair the area. This technique allows greater accuracy and reduces the time of surgery. She has appeared at the University of Wollongong in Australia and the laboratory tests are conclusive but clinical trials will begin shortly at St Vincent Hospital in Melbourne. It may then be possible to repair a fracture instantly and why not also repair skin and organs. Printing in vivo notably been tested on large wounds burned with the hope of cure serious wounds soldiers directly on the battlefield, for example.

Synthetic meat
A US startup, Modern Meadow, gathered $ 350 000 to create a 3D printer capable of printing meat. This technology could avoid killing animals to feed humans and make meat production greener and more economical.

The implantation of prostheses could increase life expectancy by replacing human body parts and even creating superhuman bodies such as the bionic ear created by scientists from Princeton University.

3D bioprinting contributes to significant advances in the medical field of tissue engineering by allowing for research to be done on innovative materials called biomaterials. Biomaterials are the materials adapted and used for printing three-dimensional objects. Some of the most notable bioengineered substances are usually stronger than the average bodily materials, including soft tissue and bone. These constituents can act as future substitutes, even improvements, for the original body materials. Alginate, for example, is an anionic polymer with many biomedical implications including feasibility, strong biocompatibility, low toxicity, and stronger structural ability in comparison to some of the body’s structural material. Synthetic hydrogels are also commonplace, including PV-based gels. The combination of acid with a UV-initiated PV-based cross-linker has been evaluated by the Wake Forest Institute of Medicine and determined to be a suitable biomaterial. Engineers are also exploring other options such as printing micro-channels that can maximize the diffusion of nutrients and oxygen from neighboring tissues In addition, the Defense Threat Reduction Agency aims to print mini organs such as hearts, livers, and lungs as the potential to test new drugs more accurately and perhaps eliminate the need for testing in animals.

Legal Aspects
As bio-printing is a relatively new technology and not yet successful, its legal aspects still contain broad issues. This includes regulations, patents, issues related to these as well as intellectual property law.

Bio-printing (and most bio-manufacturing technologies in general) are not yet available to the general public. Thus the suggested solutions about the various legal problems of this technology in the following paragraphs are only propositions.

Policies and Regulations
The intervention of the State in research and regulatory aspects of new technology is crucial to the future of the latter. Regarding bio-printing, overly restrictive regulations could result in the creation of a black market of printed organs. For if access to bio-functional printed products is too hard, it could indeed lead to a secondary market where neither the service nor the quality of products would be guaranteed.

The following propositions come from Jaspar L. Tran and are taken from his article “To bioprint or not to bioprint”:

The simplest solution would probably be to ban all activities around bio-printing but this will have the effect of ending a technology that has the potential to save a lot of human lives in the long run. Another solution would be a ban with an exception for research and emergencies. It is a solution similar to the previous one but, this time, with permission to continue research and experimentation. However, the questions of qualified people to conduct research work, sources of funding (private / public) etc. remain to be debated.

A solution diametrically opposed to the ban would be to put in place, no regulation at all. So the state counts on its citizens and their ability to regulate the market themselves. This is based on the assumption that individuals will do “righteous” and ethical things. In the case of bio-printing, this may possibly be considered because bio-printing carries little risk. The state could still support this technology through education and dissemination of safety instructions to the general public for example. However, this would remove the possibility of having patents for new inventions in this area, which could decrease the research budget. There is always the possibility of funding research via the.

Granting Patents and Intellectual Property
The patents and intellectual property dominate any new technology with great potential for commercialization and bio-printing is of course part of this kind of technology. According to we can identify five main categories to which the different patents on bio-printing can belong:

Hydrogel / Extracellular Matrix Materials (ECM)
Isolation and cell growth
Manufacturing / distribution methods
New 3D printing methods

Patent Pro Reasons
We must be able to file patents on bio-printing in order to promote innovation and allow inventors to recover a return on their investment. Note that bio-printing is still in its infancy and without additional research and development of such technology is likely to stagnate as did the technology of cloning for example.

The problem with the patenting of bio-printing is the fact that the law generally prohibits the patenting of a human organism (see patentability of life). But things are not so simple in the case of bio-printing. It should be known that a product is patentable if it is created by the man and does not appear conveniently in the nature.

Technically everything that is related to bio-printing is a result of ingenuity and human creation: the manufacturing processes as well as the bio-printed organs. The point that is more difficult to prove is the fact that a bio-printed product does not appear naturally in nature. If an organ or printed tissue is an exact replica of a human organ or tissue, then the bio-printed product can not be patented. Thus bio-printed tissues, although they are very similar to human tissues (at the functional level), are (for the moment) structurally different from the latter, which allows them to be patentable.

A solution that could avoid the various challenges and opposition to the patentability of bio-printed products, would be to only patent the manufacturing process and not the product as such.

Ethical and Social Debate
Bio-printing is a topic that is of interest to more and more researchers, as evidenced by the scientific literature whose number of articles on the subject is increasing rapidly, from in 2012 to 202 in 2015. However, bio-printing is a technology that could trigger many ethical debates and raise a number of moral issues.

In 2016, researchers from the National University of Singapore published an article proposing a methodical and comprehensive approach to bring ethical issues to the forefront of bio-printing research.

Social stratification
Bio-printing is a recent and potentially expensive technology. It may be accessible only to a small fraction of the better-off population. Unequal access to this technology could lead to social stratification dividing people on the basis of their income and enable richer live longer and in better health.

Use of stem cells
Bio-printing is based in particular on the use of stem cells which have the advantage of being able to multiply and to specialize. Depending on the origin of these cells (embryos), ethical and social questions may arise.

The use of stem cells and the intense cell multiplication necessary for the creation of synthesis organs suggest that certain risks of cell proliferation are not excluded. These risks include the formation of teratomas or cancers, as well as the dislodgement or migration of implants. Most bio-printing studies have shown convincing results in the short term but it is necessary to conduct in vivo studies to assess long-term risks.

Debate on embryonic stem cells (ESC)
The embryos are a very interesting source of pluripotent stem cells for tissue engineering but the collection and use of embryos hotly debated topic. These debates are influenced in particular by cultural and religious factors.

Different positions of religions
In 2003, a study published in Advances in Experimental Medicine and Biology in February 2003 reports how different religions perceive research on embryonic stem cells and therapeutic and reproductive cloning.

The Catholic and Orthodox prohibit research on CSE and refuse all forms of cloning.

The Protestants accept research on CSE and therapeutic cloning if they are conducted reasonably and ethically but refuse reproductive cloning.

The Muslims, like the Protestants accept research and therapeutic cloning, provided that this is done on embryos of less than 4 months. They refuse, however, reproductive cloning.

The Jews, for their part, accept the research and cloning as long as the clone is sterile and that embryos have used less than 40 days.

Finally, with regard to Buddhists, they oppose research on ESCs and therapeutic cloning. On the other hand, they accept reproductive cloning provided that no genetic modification is made.

Differences in Perceptions by Country
A report (Beyond the permissibility of embryonic and stem cell research: substantive requirements and procedural safeguards) containing a comparative analysis of current regulations concerning the use and research on ESCs in more than countries was published in 2006. notes that the regulation of therapeutic cloning and embryonic stem cell research varies greatly from one country to another.

Therapeutic cloning is prohibited in France, Germany, Spain, Italy, Austria, Ireland, Israel, Sweden, Belgium, India, Canada and Australia. On the contrary, it is authorized in the United Kingdom, Denmark, Japan, the Netherlands and Korea. It can be seen that positions vary from country to country despite their geographical proximity, therapeutic cloning being prohibited in Ireland but allowed in the UK.

Most countries that have adopted a regulation prohibiting research and the use of embryos use as ethical justification that only one of the manipulations to improve the conditions of development and the health of the embryo are acceptable. Thus, by allowing only the research that benefits embryos and leaving aside any other scientific purpose, this policy confers a legal status to embryos.

On the contrary, some countries broadly accept research on embryos and their stem cells because they consider it more important to reduce the suffering and death of humans (as opposed to human embryos). Thus this research is considered and regulated as a therapeutic research. In several countries, such as Switzerland, Japan, France, Brazil and Iceland, we accept in vitro embryo research as long as it contributes to major advances in the therapeutic field.

These strong differences in perceptions could strongly influence how bio-printing could be accepted. It is therefore important to study and reflect these perceptions are complex and largely related to religion and culture and politics influencées.

Source from Wikipedia