From 3D printing to 3D organ printing, how far is human beings from printing life?

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From the 1980s to today, 3D printing has come a long way. As an important branch of 3D printing, bio-3D printing has made great progress since it was proposed around 2000.

Of course, bio-3D printing also has many levels, including the manufacture of structures without biocompatibility requirements, such as the 3D printing of products for surgical path planning that are currently widely used, and the manufacture of non-degradable products with biocompatibility requirements, such as Titanium alloy joints, silicone prostheses for defect repair, etc., as well as the manufacture of degradable products with biocompatibility requirements, such as active ceramic bone, degradable vascular stents, etc., but the most important, and the most concerned, is still Organ 3D printing in manipulating living cells to construct biomimetic 3D tissues.

Due to the desire of human beings for the continuation of life, it can be said that organ printing has been the dream of human beings for thousands of years, and printing life is the ultimate desire of human beings. Right now, people are trying to run wild towards the ultimate human aspiration.

Why is 3D organ printing needed?

The realization of 3D bioprinting is closely related to tissue engineering and regenerative medicine. Tissue regeneration is the end, and tissue engineering is the means.

Among them, the concept of tissue engineering was proposed by Feng Yuanzhen, a Chinese-American scientist, and was confirmed by the National Science Foundation of the United States in 1987. Tissue engineering refers to first depositing cells on biological scaffolds to form cell-material complexes, and then implanting cell-containing scaffolds into the body, using the in vivo environment to induce the formation of corresponding tissues or organs to achieve wound repair and functional reconstruction. Conventional tissue engineering practice is to separate scaffold fabrication from cell adhesion, but this makes it difficult to achieve deposition of different types and densities of cells at different locations on the scaffold. 3D bioprinting, on the other hand, can realize the spatially directional manipulation of multi-cells and the controllable deposition of different cell densities, which just solves the problems currently faced by tissue engineering .

For a long time, the production of living tissues or organs in vitro has been the goal of people's tireless pursuit. The reason is that, on the one hand, there is a huge gap in organ transplantation at present. So far, many medical problems such as renal failure, malignant tumors, etc., the clinically effective treatment is still organ transplantation. However, allogeneic organ transplantation has always had the problem of insufficient donors. Whether domestically or internationally, due to insufficient organ donations, the success rate of matching is not high, and patients who need organ transplants can only wait.

In the United States, according to the U.S. Network for Organ Sharing (UNOS), one patient dies every 1.5 hours because they cannot wait for a suitable organ transplant, and more than 8 million patients need tissue repair-related surgeries every year. In China, according to statistics, about 1.5 million people need organ transplants every year due to end-stage organ failure, but only about 10,000 people receive organ transplants every year. The limited source of living organs cannot meet the needs of patients.

Taking kidney transplantation as an example, the number of transplant patients is 3,000 every year, and the demand is as high as 300,000. Most patients can only deteriorate or even die while waiting for the ligand. At the same time, the number of patients in need of organ transplants in China is increasing by more than 10% every year. In addition, there is still immune rejection after organ transplantation, which requires long-term immunosuppressive therapy.

In view of this, there is an urgent need for an effective method to solve the shortage of donor organs and the rejection of organ transplantation. The emergence and rapid development of 3D bioprinting technology has provided a new solution to the problem of tissue or organ shortage. Print living organs or tissues to replace those that have lost their function.

At present, 3D bioprinting has achieved certain achievements in the field of organ transplantation, and has been applied to the regeneration and reconstruction of skin, bone, artificial blood vessels, vascular splints, cardiac tissue and cartilage structures.

On the other hand, the current medical mechanism research needs more accurate in vitro models . Traditional solutions are often based on two-dimensional cell culture and animal experiments. However, the method based on 2D cell culture is very different from the real 3D environment in vivo, and in some cases there may be conflicting results, which makes the reference value limited. In addition to many ethical issues in animal experiments, the most important thing is that the internal environment of animals is very different from the human environment.

That is to say, if human cells can be used to reconstruct the three-dimensional environment of tissues or organs in vitro, the shortcomings of existing solutions can be well compensated, and the construction of in vitro tissues or organs can undoubtedly be widely used in drug screening and Research on the mechanism of disease.

What this will bring to people is a leap forward in precision medicine and personalized medicine. After all, each person's body structure and pathological conditions are unique and differentiated, especially for patients with complex and rare conditions. Considering the high risk of surgery, doctors can use 3D printing technology to make the lesions of patients according to a 1:1 ratio. The scale is completely printed out, and preoperative planning and precise drills are carried out for complex, rare and difficult cases.

This not only provides accurate three-dimensional structural data for doctors to design surgical plans, but also previews the entire surgical process under the premise of being more intuitive and more realistic, and improves surgical planning, thereby improving the accuracy of real surgery and reducing surgical risks. In addition, for different patients, 3D printing personalized surgical guides can effectively reduce the trauma and blood loss of the operation, greatly shorten the operation time, and improve the accuracy of the operation.

Therefore, compared with traditional medical technology, on the basis of respecting and mastering individual differences, 3D printing technology can realize real personalized customization and make medical treatment more precise.

The future is getting brighter

In 2003, Thomas Boland and others of Clemson University in the United States used a modified HP printer (H550C) and ink cartridge (HP51626a) to use PBS buffer containing Chinese hamster ovary cells (CHO) and mouse embryonic motor neuron cells as "bioink". The soy agar/collagen gel "biopaper" has successfully achieved live cell printing, and published the first paper on cell bioprinting, which was reported by the American Journal of Science, CNN and other media. In 2004, the research group applied for the first cell and organ printing patent, and obtained the patent authorization in 2006. Later, the technology was authorized to Organovo, a well-known bio-printing company listed on Nasdaq .

Since then, 3D printed organs have also officially entered the development lane and brought many hopes to regenerative medicine. In December 2010, Organovo produced the first bioprinted human blood vessel using a NovoGen MMX. Since then, the company has also printed small samples of skeletal muscle, bone and liver tissue, successfully implanted nerves in the spine, and has finalized long-term plans to create human transplant tissue. Initially, this on-demand printing has focused on myocardial repair, nerve grafts, or arterial segments, because these tissues are relatively smaller, easier to print, and more likely to have clinical applications.

In 2012, Scottish scientists used human cells to print artificial liver tissue for the first time with a 3D printer. In the same year, the University of Michigan Public Medical Center manufactured an artificial trachea through 3D printing technology, and performed the world's first 3D printed organ transplant. This is the first time humans have used 3D-printed parts to help reorganize tissue, and was published in the May 2013 issue of the New England Journal of Medicine.

In a completely different R&D in December 2012, Organovo announced that it had partnered with Autodesk to produce the first 3D design software for bioprinting. It opens up NovoGen MMX to more users, thereby improving the usability and functionality of bioprinting.

As Organovo Chairman and CEO Keith Murphy puts it, the long-term goal of the company's new partnership with Autodesk is "to give customers the ability to design their own 3D tissue and then have Organovo produce it." Just as a sculptor can now upload a new piece of jewelry to jewelry makers to 3D print a plastic or metal object, in the future physicians can send an artery graft or an electronic model of an entire organ to Organovo for bioprinting, and Organovo will then The finished product will be returned by express. In 2012, MIT Technology Review named Organovo one of the world's top 50 most innovative companies, and in 2010, Time Magazine named the NovoGen MMX one of the best inventions of the year.

In 2013, the world's first personalized 3D printed product PEEK skull implant (OPM, USA) was approved by the FDA. In February of the same year, researchers at Cornell University in the United States published a report saying that they used bovine ear cells to print artificial ears in a 3D printer, which could be used for organ transplantation in children with congenital malformations.

In November 2014, Organovo launched its commercially available 3D printed human liver tissue exVive3DTM for preclinical drug testing.

In April 2015, Organovo presented data on the world's first 3D bioprinted whole-cell kidney tissue at the Experimental Biology conference in Boston. Whereas current kidney tissue survives only a few days under normal laboratory conditions, Organovo's 3D printed kidney tissue can last "at least two weeks."

In China, Professor Yan Yongnian of Tsinghua University took the lead in carrying out research on bio-3D printing technology around 2002, and in 2004, he led a team to complete the cell direct writing system and cell printing, and established an internationally advanced biomanufacturing engineering laboratory. , known as "the first person in 3D printing in China".

In August 2013, Hangzhou Jienuofei Biotechnology Co., Ltd. (Regenovo, referred to as Jienuofei Company) cooperated with scientists from Hangzhou Dianzi University and other universities to successfully develop a 3D printer that can print biological materials and living cells at the same time. In October 2015, Genofei launched the third-generation biological 3D printing workstation. Using this biological 3D printing equipment, it successfully "printed" liver units in batches for drug screening.

Today, with the advancement and maturity of 3D bioprinting technology, the prospect of 3D bioprinting is becoming increasingly bright.

Before 3D printing organs

However, the bright future does not mean the process is smooth. After all, 3D bioprinting is an interdisciplinary industry such as medicine, life sciences, materials science, information technology, tissue engineering, manufacturing, and clinical trials. The three most important conditions for printing a living organ are cells, scaffolds and induction.

Direct cell assembly technology refers to the direct assembly of cells or cell matrix materials into the required structure according to the 3D data model, and through subsequent culture, a living tissue or organ is finally formed.

Indirect cell assembly technology refers to first building a cell culture scaffold with biological materials, then attaching cells to the corresponding position of the scaffold according to the required structure through a 3D model, and then inducing the cells to survive to cultivate into living tissues and organs.

However, you must know that the structure of the organ itself is very complex, and there are more than one type of cells in an organ. How to realize the complex arrangement of multiple cells and maintain their growth is still a difficult problem faced by the current organ printing . Taking blood vessels as an example, blood vessels look like The structure is simple, but in fact, in addition to the multi-layered cell structure (typical blood vessels are mainly composed of endothelium, smooth muscle and fibroblasts), the blood vessel wall also has functions such as selective permeability, elasticity of the blood vessel wall and anticoagulation. , all of which make it quite difficult to manufacture active blood vessels in vitro to replace diseased blood vessels in vivo.

In addition, how to ensure that the scaffold material is non-toxic and adaptable to the human body, so that cells can grow normally, and how to induce cell growth, activate the printed organ and make it completely replace the original organ are also difficult problems to be solved.

Finally, there will be a series of human and moral considerations surrounding the use of such organs, and a tolerant public opinion environment that allows the application of related technologies is still being built . This skepticism about printing organs has been amply reflected in Neddy Okorafer's short science fiction novel "The Event Center."

In the novel, news of Nigerian President Toyohiya's heart transplant operation spread like wildfire, causing a national uproar. Different from the current scientists' assumptions, the artificial heart prepared for the president by "Event Center" no longer obtains raw materials from animals, but is based on plant tissue and obtained using autologous stem cells and 3D printing technology.

Even though the technology has matured in the novel, in the novel, Izzy, the chief surgeon from the United States, is still concerned about the effectiveness of the operation. If Izzy's doubts are mainly about the success or failure of the technology itself, then the coup d'état by the president's nephew Sibi and former general Ochchuku touched on another question posed by the technology: whether the heart will change its temperament after a heart transplant. Is it even possible to be controlled? This speculation is not unfounded speculation. In the real world, many liver transplant patients do experience personality changes within a certain period of time, and the root cause may be the changes in endocrine regulation caused by rejection.

The crux of this worry is: what exactly is a human being? With a set of primitive organs, or with a body and mind that can think and act independently? Although the development of technology is almost independent of human will, it is still necessary to be cautious about the two sides of technology. It needs to be admitted that a series of questions about whether technology is good or bad is often the road that must be experienced in the process of technology popularization, that is, "the past was whimsical, now it is difficult, and the future is accustomed to it". After all, when a technology is created, how to best use it is what we most need to care about .

3D printing organs may have promised us a bright future, but before the future arrives, what we still need to do is to correctly understand this technology, and give this technology ethics and usage rules - in fact, biological 3D Printing is still far from the vision of the original organ printing, and there is still a long way to go to print live organs that can be used for transplantation in vitro.