Sichuan University “Science Advances”: Non-invasive bioprinting directly in the organism

Source: Jiangsu Laser Industry Technology Innovation Strategic Alliance

Introduction: 3D printing technology has very important potential and application in clinical medicine. The currently implemented biological 3D printing is basically in vitro printing, and then clinically implanted through surgery. Therefore, in vivo 3D printing is still very limited as an implanted device product. There are no reports of cases where in-situ printing is performed on the body or the wounded area.

In the past, all the areas that needed to be exposed were printing. Here, researchers from Sichuan University reported that the near-infrared photopolymerization-based 3D printing technology enables non-invasive 3D printing of in vivo tissue reconstruction. In this technology, a digital micro-mirror device is used to modulate the near-infrared laser into a customized mode for printing, and at the same time, spatial dynamic projection printing is achieved through monomer solution polymerization. By using near-infrared laser radiation in vitro, the bio-injected bio-ink can achieve in-situ non-invasive printing at customized tissue reconstruction sites. This new technology can be used without surgical implantation. A personalized ear-shaped tissue structure and a mouse cell-conformal scaffold tissue repair case were verified using non-invasive in vivo bioprinting. This work proves that in-vivo 3D printing is feasible.

In the past few years, the news of the successful experiment of Sichuan University Kang Yujian implanting 3D bioprinted blood vessels into rhesus monkeys has caused industry shocks. Now, Sichuan University has made new progress in bioprinting and pioneered non-invasive bioprinting in vivo. This achievement was published in the recently published top issue “Sciecne Advances”.

Basic principles of non-invasive biological printing in vivo
As shown in Figure 1, the digitized personalized CAD model is first delivered to the computer-controlled DMD biochip. A 980nm light plate is irradiated through the optical lens, and the tissue on the biological ink is non-invasively transported into the body through a channel made by living tissue in the body. The biological ink includes a nanometer catalyst to convert the near-infrared laser light into 365nm wavelength light, and the amount of heat uses this wavelength of 365nm light to polymerize the monomer.

As we all know, 3D printing is an advanced manufacturing technology, which has unparalleled advantages in the application of the medical industry for manufacturing personalized and complex structures. Bioprinting, that is, the use of cell-containing biological ink for 3D printing of tissues and organs, still has certain obstacles, but breakthroughs in this field have very important potential applications in the medical industry, especially for tissue regenerative medicine. Today, the commonly used biological 3D printers mainly include printing technologies such as inkjet printing, extrusion printing, light-assisted printing, and laser direct writing. In today’s clinical 3D printing applications are mainly implanted using surgery or in situ printing at the location of exposed wounds. However, there are many times when it is necessary to minimize clinical surgery and try not to carry out or less trauma treatment. If there is an injury inside the skin, the use of trauma surgery will destroy the surrounding tissue and cause secondary injury. As in plastic surgery, non-invasive surgery is very important and ideal. These important clinical needs cannot be applied with current 3D printing technology. This urged us to develop a non-invasive in vivo 3D printing technology, which can realize the full coverage of non-invasive manufacturing tissue bio-ink printing personalized products, including in situ printing of living tissue.

The use of digital light processing technology (DLP) biological 3D printing technology, light-assisted printing technology, has recently received widespread attention because of the relatively high cell activity ability after printing, while also having a very high printing speed and printing resolution . Today, the technology has been used to reconstruct or repair multiple tissues, such as spinal cord, peripheral nerves, and vascular injury. Traditionally, ultraviolet or blue light is often used for bioprinting by photopolymerization. However, it is difficult to achieve non-invasive manufacturing and printing with ultraviolet light or blue light, because these two kinds of light have very poor approval penetration ability. NIR light penetrates deeper skin and can be used to control drug release, photodynamic therapy, in vivo imaging, 3D image visualization, in vivo optogenetics, etc. Moreover, similar to ultraviolet light or blue light, near infrared light has the potential to initiate photopolymerization.

The induction effect of near infrared light can realize the conversion made in vivo. The photopolymerization effected by the precise control induced by the near-infrared can promote the non-invasive manufacturing of the bio-ink fully covered by the tissues in the body, and this feature can be used for potential clinical or medical research. Here, by inputting the CAD model, the digitized near-infrared laser is continuously generated by connecting the digital micromirror device biochip and predicts the non-invasive printing in time, and the printing is achieved by the photopolymerization of the injected biological ink layer in space. This eliminates the need for clinical surgery and enables personalized reconstruction of living tissue. This work has created a new path for 3D printing of teeth and noninvasive upper body printing in the medical field.

Graphic: (A) Normal ear image. (B) Mirror image of A. (C) Optimized ear profile of B image). (D) Image scale after ear reconstruction using DNP technology without destroying approval It is 2 mm. (E) The image obtained after 7 days of reconstruction of living/dead ears after bioprinting in vivo, with a scale of 2 mm. (F) The reconstruction of the shape of the nondestructive 3D bioprinted ears using DNP technology, using subcutaneous in the experiment Injections were used to print BALB/c thymic nude mice with a scale of 5 mm. (G) Reconstructed images of ear shape bioprinted after 1 month, scale is 5 mm. (H) H&E and (I) Collagen type Ⅰ The result of the immunostaining method after November, the scale is 50 μm.

Graphic: (A) Schematic diagram of a conformal ASC-trapezoidal scaffold for repairing muscle defects; (B) Comparison of DNP printed wounded area healing and controllable printing; scale is 5mm; (C) Muscle injured area after 10 days Percent closure P<0.01, n = 5. (D) H&E histological analysis of muscle healing 10 days after treatment, the scale is 50 μm.

Background of the biological 3D printing market: According to the statistics of the World Health Organization, the number of patients with cardiovascular and cerebrovascular diseases in 2012 has exceeded 1.7 billion people, accounting for a quarter of the global population. “Now from a global perspective, at least 100 million people need such technology every year.” Kang Yujian said that in the next three to five years, it will be applied to the human body.

The status of bioprinting: in the R&D stage, it will take time for profit
Medical treatment is also an important field of 3D printing applications. The prospect of 3D printing of human organs is very exciting, but at present they are basically in the research stage, even if 3D printing dentures are still far from large-scale application.

Helen Meese, head of healthcare at the Institution of Mechanical Engineers in London, said it is estimated that it will take at least 20 years for more complex 3D printed organs such as the heart or kidney to be transplanted into human patients.

Take Organovo, a leading company that bioprints human tissue, as an example. The company printed the first whole-cell engineered human artery, implanted the bioprinted tissue into a living body (animal) for the first time, and printed a human liver with all biological activities and functions. The organization also launched 3D printed human kidney tissue products and provided commercial services in September this year.

Ali Khademhosseini, a bioengineering professor specializing in tissue engineering and bioprinting at the University of California, Los Angeles, and his team have developed a new and innovative technology for bioprinting to simulate the tubular structure of complex vascular networks and pipes. This breakthrough research was recently published in the journal Advanced Materials and can be used for tissue bioprinting of implants or drug testing.

Reference materials: 36 krypton, anet3d.cn, etc.

Article Source:
Noninvasive in vivo 3D bioprinting, Yuwen Chen, Jiumeng Zhang, Xuan Liu,, Shuai Wang, Jie Tao, Yulan Huang, Wenbi Wu, Yang Li, Kai Zhou, Xiawei Wei, Shaochen Chen, Xiang Li, Xuewen Xu, Ludwig Cardon, Zhiyong Qian,†Maling Gou,Science Advances 03 Jun 2020:Vol. 6, no. 23, eaba7406, DOI: 10.1126/sciadv.aba7406