Application of 3D Printing Bioinks Tissue Repair and Regenerative Medicine

Introduction to 3D Printing

In the 1980s, American engineer Charles Hull developed rapid prototyping technology by combining points and surfaces and then using light reinforcement. After numerous failures, he finally invented stereolithography technology. Based on this technology, the world’s The first 3D printer came into being. By the end of the 1990s, researchers combined 3D printing technology with the field of medical care to create substitutes for human organs for adjuvant treatment, which created a new field – 3D bioprinting.

3D bioprinting is a novel technology that can create structures that can combine living cells or biomaterials and control cell proliferation, differentiation, and migration on this structure. At present, 3D bioprinting technologies based on scaffold materials are mainly divided into three categories: extrusion, droplet, and laser-assisted, each of which has its own advantages and disadvantages. Droplet bioprinting technology is widely used in tissue engineering and regenerative medicine because of its high rate, high cell survival rate, and low cost. It mainly includes inkjet printing, microvalve printing, acoustic printing, laser-assisted three-dimensional imaging, Main printing technologies such as electrospinning/electrofluid jet printing. Depending on the printing method, the choice of bio-ink will also change accordingly, often based on the rheology, viscosity, cross-linking chemistry and biocompatibility of the ink. The suitability of bioinks for bioprinting processes mainly depends on their physical and chemical properties under the conditions imposed by specific bioprinting parameters; extrusion bioprinting usually requires shear-thinning bioinks, while droplet bioprinting requires low viscosity liquid material, otherwise it will easily cause the nozzle to become clogged. The choice of bio-ink is crucial for 3D printing, and an ideal bio-ink should have suitable physical and chemical properties, such as suitable rheology, mechanical properties and biocompatibility. Currently existing bioinks are derived from countless biomaterials, such as natural materials such as gelatin, alginate, silk, collagen, chitosan, etc., as well as synthetic materials such as polyethylene glycol, polycaprolactone, etc. The advantages of natural biomaterials come from their excellent biological activity, which can be well adapted to the environment in the human body; but the disadvantages are also obvious, such as poor mechanical properties and limited freedom of customization. Compared with natural biomaterials, the mechanical properties and biological activities of synthetic biomaterials can be easily adjusted, and they are currently widely used. In addition, the use of cell particles or aggregates to prepare bioinks for scaffold-free tissue fabrication is becoming more and more widespread.

Types of Bioinks

• Hydrogel-based Bioink

The most important role of bioink is to protect cells from the external environment during printing, so bioink must be biocompatible. Hydrogel is a commonly used scaffold material in 3D printing. It provides a tissue-specific microenvironment that can support cell growth and maturation, while also dominating the physical and chemical properties of bioinks. Most hydrogels have specific cell-binding sites that are necessary for cell attachment, spreading, growth, and differentiation. At present, through long-term exploration and demonstration by scientific researchers, several commonly used bioinks have been developed, such as synthetic hydrogel polyethylene glycol, polycaprolactone, etc., as well as natural hydrogel collagen (type I), alginate, hyaluronic acid, gelatin, chitosan, silk, etc. The 3D bioprinting capabilities of these hydrogel bioinks have been demonstrated in the regeneration of several damaged tissues, including heart, cartilage, bone, muscle, skin, kidney, blood vessels, adipose tissue, liver, and other engineered biological tissues.

Due to the limitations of current bioprinting technology, hydrogels can only exist in liquid or paste form during printing, which imposes great restrictions on subsequent bioink formation to support cell proliferation. In addition, the thickness of the hydrogel will affect the diffusion of signaling molecules, oxygen, and nutrients inside the gel, which also poses challenges to the design of the hydrogel.

• Polyethylene Glycol

Polyethylene glycol is a component of bioink commonly used in 3D bioprinting. Its chemical structural formula is H-(O-CH2-CH2)_n-OH. It is a linear polyether compound with good hydrophilicity and water absorption. The material itself is non-toxic and can be used in clinical medicine after approval by the FDA. It is often used to modify proteins, liposomes and other biomolecules as excipients, support materials for scaffolds, and drug delivery carriers through 3D bioprinting. The polyethylene glycol/polylactic acid-co-glycolic acid nanofibrous membrane prepared by electrospinning can act as a barrier between the cecum and surrounding tissues, thereby effectively preventing abdominal adhesion. In addition, in order to solve the common problems of damage to the printing unit and frequent clogging of the print head when printing biological bone and cartilage tissue using inkjet bioprinter, some scholars have co-produced acrylated peptides with acrylated polyethylene glycol hydrogels. At the same time, bone marrow-derived human mesenchymal stem cells are accurately printed during the scaffold manufacturing process, and multiple steps are successfully synthesized into one step, so that the polyethylene glycol peptide scaffold and human mesenchymal stem cells to form strong bone and cartilage under minimal clogging.

• Collagen

The structure and remodeling of collagen in the human body is crucial for pathological research on many human diseases as well as normal tissue development and regeneration. Collagen-based biomaterials are recognized as a promising option as a bioink that can serve an ideal purpose, mainly for the regeneration of several tissues with high cell activation properties.

• Alginate

Alginates are a very important family of polysaccharides. Because they can be used to prepare hydrogels under mild pH and temperature conditions, they are suitable for the preparation of sensitive biomolecules such as proteins and nucleic acids, and even for the preparation of living cells. As a new type of bio-ink, alginate is suitable for printing technologies such as inkjet printing, laser-assisted printing, and micro-valve printing. At the same time, alginate has the advantages of rapid gelation and good mechanical properties. However, there are also disadvantages such as poor cell adhesion due to the natural inertness of the biomaterial.

• Gelatin

Gelatin is a biopolymer with excellent biocompatibility, hemostasis, low cytotoxicity and low antigenicity, and can promote cell attachment and growth. However, it has poor mechanical properties and antibacterial activity, so it can be cross-linked with other polymers to enhance its mechanical properties. Chitosan is the most commonly used chemical cross-linking agent for gelatin. It is often used to make electrospun gelatin/chitosan nanofiber scaffolds. The scaffolds are slightly spindle-shaped and have good tensile properties. The gelatin/chitosan scaffolds also have relatively good tensile properties. Long term (7 d) shape retention.

• Hyaluronic Acid

Hyaluronic acid is an immunoneutral linear non-sulfated glycosaminoglycan that is widely found in connective tissue and skin tissue of the human body. Hyaluronic acid directly affects the physiological functions of human cells and tissues, and has a 30-year history of clinical use. As a component of synovial fluid and articular cartilage, hyaluronic acid has biocompatibility and the ability to support cell growth and chondrogenic differentiation of encapsulated stem cells. In the treatment of osteoarthritis, hyaluronic acid can enhance joint retention and control drugs release can effectively improve the therapeutic effect of osteoarthritis.

• Chitosan

Chitosan is a linear polysaccharide, which can be obtained from shrimp shells or crustaceans, and its molecular mass is between 10-1 000 kD. As a readily available biological material, chitosan has great development potential. Chitosan has inherent bacteriostatic, fungistatic, hemostatic and analgesic properties and is a promising material for the development of formulations and devices suitable for surgical applications. Chitosan is an excellent support material in tissue engineering due to its excellent biocompatibility, biodegradability and low immunogenicity.

• Silk/silk Fibroin

Silk is a natural fibrous protein polymer spun by silkworms and spiders. Scientists have discovered that silk fibroin can be extracted from the cocoon of B. mori silkworm, and then synergized with other biological materials to form biopolymer composites, which can be widely used in research in the fields of biomedicine and technology. The FDA has approved silk medical devices for use in sutures and as support structures during reconstructive surgery. The artificially developed recombinant method for the production of silk protein can reduce the variability and rapid degradation of natural silk, and effectively increase the yield. As a natural protein with outstanding mechanical properties, biodegradability, biocompatibility and bioabsorbability, silk fibroin is widely used in tissue engineering, including bone, cartilage, ligament, tendon, skin, wound healing and tympanic membrane etc.

Functional Composite Materials

Composite materials are divided into chemical composite materials and physical composite materials, and their synthesis methods are divided into chemical synthesis methods and physical synthesis methods. The properties of composite materials after synthetic treatment will change accordingly, making them suitable for applications in bioengineering. Synthetic composite materials have strong mechanical properties, and materials can be matched according to needs to meet people’s needs in biomedicine and regenerative medicine. Printable polymer hydrogels The printable hydrogels required in bioengineering have extremely high requirements for biocompatibility and mechanical strength, and traditional biopolymer hydrogels often cannot meet the requirements for printing. Therefore, biomaterials that use a variety of organic and inorganic substances to be polymerized and then polymerized by physical methods or chemical methods have attracted people’s attention.

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