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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 8

Application of three-dimensional bioprinting technology in orthopedics


Department of Orthopaedics, Xuzhou Hospital Affiliated to Jiangsu University, Xuzhou, Jiangsu, China

Date of Submission27-Apr-2021
Date of Decision20-Jun-2021
Date of Acceptance06-Aug-2021
Date of Web Publication21-Apr-2022

Correspondence Address:
Xiao Ouyang
Xuzhou Hospital Affiliated to Jiangsu University, 131 Huancheng Road, Xuzhou, Jiangsu
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/digm.digm_9_21

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  Abstract 


The treatment of bone defects, especially large-area bone defects caused by trauma, congenital malformations, senile diseases, and other factors, is often the key and difficult point of orthopedic diseases, which often brings a lot of troubles in the daily work of orthopedic physicians. Bone tissue engineering attempts to repair bone defects using three-dimensional (3D) bioprinted living tissue, and induces osteoblasts to differentiate and proliferate by placing biological scaffolds, thus finally forming bone tissue commensurate with the original tissue functional structure, reducing the difficulty of surgery. Compared with the traditional bone grafting surgery, it causes less trauma to patients. It is an emerging technology with crossover and cutting edge, and has huge application space and good application prospect in biomedical field. In this article, the clinical application of 3D bioprinting technology in various orthopedic fields in recent 5 years is briefly discussed.

Keywords: 3D Bio-materials, Bone trauma, Cartilage damage, Pediatric orthopedics, Spine surgery, Three-dimensional bioprinting technology


How to cite this article:
Li S, Ouyang X. Application of three-dimensional bioprinting technology in orthopedics. Digit Med 2022;8:8

How to cite this URL:
Li S, Ouyang X. Application of three-dimensional bioprinting technology in orthopedics. Digit Med [serial online] 2022 [cited 2022 Aug 17];8:8. Available from: http://www.digitmedicine.com/text.asp?2022/8/1/8/343719




  Introduction Top


Three-dimensional (3D) biological printing technology accurately arranges various biological materials, tissue cells, and growth factors into a 3D structure according to a specific layout through computer 3D digital imaging and multilevel continuous printing technology so as to interact and exert biological activity, and finally realize biological performance similar to or even better than that of target tissues and organs. Compared with the traditional 3D printing technology, 3D biological printing technology due to the particularity of its materials, in terms of personalized built-in, has an irreplaceable position, as a print built-in essential “biological ink” tends to have the following characteristics: (1) good biocompatibility and biodegradability; (2) certain biomechanical strength; (3) plasticity; (4) ability to induce differentiation and regeneration of cells or tissues and effective surface activity; (5) no toxicity and immunogenicity; (6) appropriate 3D pore size and porosity.[1]

Hydrogels are the most common bio-linked scaffolds that absorb and retain large amounts of water.[2] They are flexible enough for cells, which can sense their existence and move toward them preferentially,[3] then freely migrate and interact in that stereo porou flexible network.[4],[5],[6] Hydrogels with different molecular weights and stimulating factors can recruit stem cells from bone marrow and synovium[7],[8] and promote cell migration and regulate cell proliferation.[9],[10],[11],[12],[13],[14],[15],[16] The gap between each mesh is usually between 100 and 300 nm, even larger, which is beneficial to the formation of new bone and capillary vessels.[17],[18],[19],[20],[21],[22]

The “bio-ink” is printed by a 3D bioprinter into a bioscaffold that fits perfectly with the implanted site and conforms to the stress characteristics, containing a loose porous microstructure, and the surface is adhered with bioactive factors which are convenient for cell adhesion and migration, promote cell differentiation and proliferation and the like, “see cells” will be accurately colonized in that biological scaffold material according to a certain spatial structure to obtain nutrients needed for growth and differentiation. While the scaffold is degraded intracorporeal, the “seed cells” will gradually grow and differentiate into structures with similar biological functions to the original tissues. Although this technology is in its initial stage, many scholars have conducted relevant research in clinical application, the following is a brief overview of the application of 3D bioprinting technology in various subprofessional disciplines of orthopedics and the problems currently faced.


  Application of Three-Dimensional Bioprinting Technology in Joint Surgery Top


Traditional joint replacement is still dominant in treating most middle-aged and elderly joint diseases, especially femoral neck fracture, intertrochanteric fracture, and knee osteoarthritis. However, artificial prostheses have their service life, ranging from 5 to 15 years. When the prostheses are worn to a certain degree, replacement surgery needs to be performed again, but the replacement surgery is more difficult, for this kind of young patients. In order to ensure their quality of life, conservative treatment is the main treatment, and joint replacement can only be performed when they are at a suitable age or must undergo surgery. Using bioactive joint replacement with 3D bioprinting has unique advantages in such situations.

According to the image information collected before operation, the bioactive joint is printed and placed into the biological scaffold–osteoblast complex which matches the local anatomy of the patient and conforms to the stress characteristics of the site. While the bioactive scaffold is gradually degraded in the body, osteoblasts differentiate and proliferate, fuse with the patient's own tissue, and play the same role instead of the original joint. Compared with the traditional joint replacement surgery, it has less damage to the lesion site and its adjacent tissues, and the implanted artificial prosthesis has a higher matching degree. Studies have shown that the bioscaffold–osteoblast complex can be equipped with broad-spectrum antibiotic dressing, which not only meets the anti-loosening requirements of postoperative joints but also provides anti-infection guarantee,[23],[24] it can greatly avoid the possibility of secondary operation after postoperative infection and poor joint reduction. Sun et al.[25] used a GDF5-bound BMSC loaded scaffold in repairing rat osteoarthritis model through 3d bioprinting. Compared with the control group, the GDF5-bound scaffold showed better cartilage repair effect. Meanwhile, in rabbit knee joint transplantation, 3D bioprinted GDF 5-bound scaffold loaded with bone marrow stromal cells provided long-term cartilage protection for rabbit knee joint.[25]

Although the current 3D bioprinting technology has been able to produce osteochondral models similar to human body structure, there are still many problems in practical clinical application due to imperfect material limitations. The harsh conditions such as high temperature and high pressure in the production process may affect the viability of cells,[26] and the mechanical properties of printed cartilage tissue cannot meet the normal load-bearing of human body and the friction between bones, and the control of the degradation rate of bioactive scaffolds and the poor load-bearing of obese patients[27] are the implementation problems that limit the wide application of 3D bioprinting technology. With the development of “bio-ink,” the applicable population and influence of bioactive joint replacement will be wider and wider.


  Application of Biological Three-Dimensional Printing Technology in Cartilage Repair Top


Cartilage is an important part of human body to resist pressure or stretching and reduce the direct friction and impact between bones. However, there are no nourishing blood vessels in adults' cartilage tissue, and its self-healing ability is poor, so the clinical treatment effect of cartilage tissue injury is often unsatisfactory.

With the development of the research on 3D bioprinting technology, various “bio-inks” have been developed and applied in clinical. At present, the “bio-ink” used in cartilage repair is mainly divided into natural biomaterials and synthetic biomaterials.[28]

Natural biomaterials

Agarose, alginate, fibrin, collagen, and hyaluronic acid[29],[30],[31],[32] are all commonly used “bio-inks” in current 3D bioprinting. These substances have good biocompatibility, fast degradation speed, less human reaction, and adverse reactions, which can promote osteoblast migration and produce extracellular molecules through specific surface receptors, and achieve the purpose of cell proliferation. However, their mechanical strength is low, and if they degrade too fast, they cannot achieve the desired therapeutic effect.

Synthetic biomaterials

The most common ones are polyethylene glycol (PEG), polylactic acid (PLA), polycaprolactone (PCL), hydroxyapatite (HA), PLA-glycolic acid, and polyurethane (PU).[33],[34],[35],[36],[37] This kind of material has good mechanical properties, little rejection from human body, but poor water solubility.

Generally speaking, synthetic biomaterials have better biocompatibility than natural ones and are more conducive to cell growth and differentiation.[38] When designing cartilage repair bio-ink, both its mechanical properties and biological benefits should be considered, and a single material often cannot achieve a satisfactory result. Therefore, researchers often mix two or more polymer materials to prepare cartilage bioprinting ink, which plays a complementary role.[39],[40] Taking alginates and HA s as examples, their biocompatibility, toughness, and degradation rate are more conducive to the formation of 3D porous structure.[41],[42] Alginate salt and PEG polymer covalent cross-linked through Ca2+ and decomposed by UV irradiation so as to form a PEG grid with good elasticity.[12],[43],[44] As a knee joint repair material, HA can stimulate chondrocyte metabolism, synthesize cartilage matrix components, and inhibit cartilage degenerative enzymes and inflammatory processes. They are equipped with intra-articular injection gels, and they also have the characteristics of high swelling rate needed to cover the joint surface to meet the requirements of cartilage repair.

This alginate-PEGDA hydrogel also has high stretchability and toughness, and can provide enough strength and rigidity to play a role between bone and cartilage remodeling[45],[46] Cui et al.[47] used the complex of PEG dimethacrylate and gelatin methacrylate to prepare PEG-GeIMA hydrogel scaffold, which was loaded with human mesenchymal stem cells and found that its osteogenic effect and chondrogenic differentiation promotion were stronger than before.

The biological scaffold printed by Li et al. and Wei et al.[48],[49] after mixing silk fibroin, gelatin, and hyaluronic acid with platelet-rich plasma dressing has been proved to be capable of promoting the differentiation and proliferation of adipose-derived mesenchymal stem cells and chondrocytes.

Li et al.[50] used alginate and PEG as 3D bioprinting ink to repair an oval defect with a volume of 39.29 mm3, and printed cartilage highly matched with the defect. The average printing time was only 36.61 s. The results of these studies show that the customized hydrogel printed by 3D biology has great flexibility, can better meet the characteristics needed for cartilage repair,[51],[52] and provides another strategy for cartilage repair.


  Application of Biological Three-Dimensional Printing Technology in Traumatic Orthopedics Top


The repair of bone defects

In our daily life, we often encounter fractures caused by car accidents, falling from a height, severe violence, etc., among which there are many patients with comminuted fractures, which are difficult to treat. Large-scale bone defects, postoperative nonunion or delayed union, and even osteomyelitis are all difficult problems that we need to consider in the treatment process. Zhang et al.[53] used 3D bioprinting technology to print bone matrix gelatin-β-tricalcium phosphate into hierarchical porous scaffolds, which is beneficial to the growth of new blood vessels. Experiments have proved that the newly generated bone cells are highly expressed with the genes related to new blood vessels, which proves that they play an important role in the process of osteoblast formation and angiogenesis. Zhao et al.[54] carried the powder of L-PLA, levofloxacin, and tobramycin on the bone implant, and developed a controlled-release multidrug artificial bone, which achieved good results when used alone, and also achieved satisfactory results when used with titanium mesh. Byambaa et al.[55] co-cultured human bone marrow mesenchymal stem cells and human umbilical vein endothelial cells to develop a new hydrogel, which can promote angiogenesis and bone formation in large bone defects. After 3 weeks of culture in vitro, it showed high cell viability, proliferation rate, and structural stability. The results also showed that mature trabeculae were formed after 21 days in vitro culture. Fedorovich et al.[56] printed alginate gel and cell matrix into vascularized scaffold, filled with endothelial cell precursors and mesenchymal stem cells, and implanted into mice subcutaneous to test the formation of derived bone. Osteoblasts and ectopic bone deposition were found after 6 weeks.

Soft-tissue repair

Fracture is often accompanied by adjacent soft-tissue and skin injury, which often induces inflammation and affects fracture healing. 3D bioprinting technology can print bioactive tissues or organs, and cooperate with bioprinting implants to improve the angiogenesis rate and have a good effect on fracture healing. Such as Tan et al.[57] provided personalized implants for patients with finger or toe defects, which achieved good therapeutic effects and improved the quality of life of patients. Kim et al.[58] added skin-derived extracellular matrix to 3D bioprinting stent, which could observe the formation of new blood vessels and accelerate wound healing. Yokota et al.[59] used 3D bioprinting technology to make keratinocytes and fibroblasts into artificial skin similar in structure and function to human skin, providing a new idea for skin transplantation. Gomez-Barrena et al.[60] combined 3D bioprinting stent with recombinant human growth factor and/or stem cells to solve the problem of insufficient growth of implanted neovascularization. Verboket et al.[61] implanted bone marrow mesenchymal stem cells into bone substitutes, which were used to fill the poor healing caused by unconnected bones after traditional surgery.

Although most experimental studies of 3D bioprinting tissue technology have not been applied to clinical practice, through the unremitting efforts of researchers, its broad development prospects are expected, and it will play the advantages of personalized and precise treatment in the future treatment of traumatic surgical diseases.


  Application of Biological Three-Dimensional Printing Technology in Spinal Surgery Top


The spine is mainly responsible for protecting the spinal cord and bearing part of the weight of human body. The structure of this part is complex, involving many important nerve vessels, and the treatment requirements are very detailed. Spinal surgery patients are more common in spinal cord dysfunction caused by trauma, tumor, intervertebral disc degeneration, etc., among which intervertebral disc degeneration is the most important cause, and some scholars have started relevant research on intervertebral disc substitutes.

Rosenzweig et al.[62] planted articular chondrocytes and nucleus pulposus cells in acrylonitrile butadiene styrene-PLA composite scaffold. After 3 weeks, it was found that many proteoglycans and type II collagen adhered to the scaffold, which reflected that chondrocytes and nucleus pulposus cells grew and differentiated well. The compound may be used as an intervertebral disc substitute to treat various intervertebral disc degenerations. Whatley et al.[63] printed PU as intervertebral disc scaffold. The research shows that this material has a fast degradation rate, which is beneficial to cell adhesion and proliferation. Gluais et al.[64] successfully developed a cell-free PCL fiber scaffold using sheep AF-defects model. This implant could potentially act as a 3D scaffold that induces the production of AF-like tissue and that could prevent IVD recurrent herniation, as well as neural and vascular ingrowth, and that might also slow the IVD degeneration process.

In addition to the intervertebral disc substitute, Gullbrand et al.[65] also carried out the experiment of artificial vertebral replacement. They put an endplate-modified DAPS (eDAPS) into a goat cervical disc replacement model. Results showed that the eDAPS composition and structure were maintained up to 8 weeks within the disc space, the imaging data showed that the position and intervertebral space of the prosthesis were good, and the mechanical function of the eDAPS implants was similar to native disc mechanical properties.

The feasibility of 3D bioprinting technology has been proved by cell experiments and animal experiments, and its development prospect is very optimistic. With more and more animal simulation operations, more and more valuable experience has been accumulated, and 3D bioprinting technology will eventually gain its own place in spinal surgery.


  Application of Biological Three-Dimensional Printing Technology in Pediatric Orthopedics Top


The treatment of bone defects

In the treatment of children's bone tumors, a large area of bone is often removed, even including epiphysis and metaphysis. A few serious comminuted fractures will also lead to the loss of a large area of bone mass, which will make children's bone growth disorder and seriously affect their quality of life. Some researchers solved such problems by using bony inlays. DIPY-3DPBC scaffold was used to repair children's craniofacial defect model. Six months later, the results showed that there was significant bone regeneration in alveolar bone and alveolar bone defect, and there was no significant difference in trabecular thickness among regenerated bone, bone graft, and natural bone.[66] Lu et al.[67] showed that the combination of β-tricalcium phosphate bioceramics and vascularized fibula can restore the function of lower limbs, promote bone healing, and reduce postoperative complications in repairing bone defects after resection of malignant tumors of lower limbs. In another situation, Bose et al. have implanted 3D printed bioabsorbable airway splint into infants.[68]

Repair of metaphyseal injury

Children's metaphyseal end is composed of cancellous bone, which is covered with thin cortical bone, with weak anatomical structure and easy to fracture. If a bone bridge is formed after injury, it is easy to form deformity in future development, which has a great impact on patients. 3D bioprinting technology cannot print out the substitute materials of metaphyseal tissue for the time being, and plays the roles of preoperative simulation, intraoperative positioning, postoperative auxiliary treatment, and so on in metaphyseal injury repair surgery.

Although the short-term treatment effect of 3D bioprinted prosthetic implant is good, the long-term effect is not satisfied because children are still growing.[69] Developing implants that meet the needs of children's bone growth and development is a difficult point for 3D bioprinting technology to make great progress in pediatric orthopedics.

In addition, 3D bioprinting has made some progress in bone tumor research. 3D bioprinting model can simulate cell–cell and cell–matrix interaction in three dimensions, and integrate the vascular system to analyze how cancer cells grow and other carcinogenic events.[70],[71] At present, 3D biomimetic bone matrix has been used to create a bone metastasis model of breast cancer, which has a bone-like microenvironment and can be used to analyze the relationship among breast cancer cells, human bone marrow mesenchymal stem cells, and osteoblasts.[72] Zhu et al.[73] used a 3D printed nano-ink, made of HA nanoparticles suspended in hydrogel, to simulate the specific environment of bone to study the invasion of breast cancer on bone.


  Problems Faced By Three-Dimensional Bioprinting Technology at Present Top


“Bio-ink” is an important part in the process of 3D bioprinting. Although some progress has been made in the research and development of “bio-ink,” there is still a lack of printing materials that can perfectly fit the human body, and the structural strength of the built-in objects generally cannot meet the needs of the human body.

In addition, bio-3D printing technology cannot print cross-category materials at present, and can only produce products with relatively single function and structure. Furthermore, the printing accuracy of 3D printers of different levels and different manufacturers is quite different, especially the commercial desktop 3D printers, whose printing accuracy cannot meet the requirements of orthopedic surgical implants, and such 3D printers are expensive, and their operation processes also require specialized personnel to spend time to learn, and the maintenance and repair of machines is also a huge expense, which makes the price of printed products always high, which is the most important reason for its limited development.[74] Besides, how to ensure the absolute sterility of bone and cartilage tissue substitutes and avoid iatrogenic damage to patients are also the key to the wide application of 3D bioprinting technology in clinical practice.

How to arrange the biological materials, seed cells, and growth factors of the printed tissues and organs so as to ensure the cell activity and meet the basic demands of patients in daily life in the future is another poser for 3D biological printing technology. These requirements may seem simple, but they test the researchers' knowledge storage and the integration ability in various disciplines and technologies. Only after a large number of related experiments, can they obtain a nearly perfect answer. With the improvement of the level of science and technology, improve the precision of equipment at the same time industry personnel operating skills will also be gradually improved, holiday time will be able to overcome the above problems.


  Conclusions Top


As a cutting-edge technology, 3D bioprinting can only print single-cell tissues with no specific biological function now. There are still many problems should to be discussed in the practical application of orthopedics, but it still has potential value that cannot be ignored. Fast, accurate and personalized are the most distinctive features. According to relevant data, there are about 40 million patients with joint diseases in China,[75] and joint replacements are also one of the most common operations in orthopedics today. Due to everyone's body structure and pathophysiology is different, the demand for individualized treatment provides a broad performance stage for 3D bioprinting technology. How to customize personalized hip implant stents and treatment of AIDS according to patients' respective anatomical morphology, pathophysiology and treatment needs is a feasible direction for 3D bioprinting; In addition, because of its degradation–regeneration mechanism, 3D bioprinting stent can get rid of the restriction of built-in objects on children's growth and development, and make a great breakthrough in this field, so as to truly achieve personalized medicine and precise medicine. In addition, 3D bioprinting technology is also full of infinite possibilities in human bone replacement. With the deepening of the research on 3D bioprinting technology, with the cooperation of many researchers, the technology will gradually mature, and more and more valuable experiences will be summarized, which will have a tremendous impact on the treatment of orthopedic diseases in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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