Background
Developmental or acquired craniofacial deformities may impose a negative psychological impact on affected individuals [
1]. Such deformities affect the soft and the hard tissues of the craniofacial complex to varying extents. Managing such patients requires multidisciplinary care, with the patient under the care of a team of specialists that may involve a cranio-maxillofacial surgeon, plastic and reconstructive surgeon, otorhinolaryngological surgeon, neurosurgeon, pediatrician, orthodontist, psychologist and speech and language therapist. Combined specialists’ effort is needed to improve function and aesthetics.
Surgery and bone grafting are considered crucial pillars for repair when missing large amounts of bone [
2]. Bone grafts may be harvested from the patient as an autologous graft, which has the advantage of being biocompatible and not eliciting an immune response or provoking graft rejection. Alternatively, allogenic bone can be harvested from cadavers and transplanted into recipients, which carries the risk of rejection. Bone can also be replaced using natural or synthetic bone substitutes [
3]. Grafts provide support to the soft tissue overlaying it, improving the aesthetics and allowing for the healing process to occur by “creeping substitution,” which is the resorption of graft and its replacement with new bone [
4]. This is accomplished by the ability of the graft to osteoinduce and osteoconduct the healing process. Osteoinduction entails stimulation of progenitor cells to differentiate into osteoblasts and enhance bone deposition, while osteoconduction means providing a surface on which the new bone will be deposited to direct the bone growth and restore its shape [
5,
6].
For the bone graft to be successful, it should match the shape and size of the replaced bone, in order to offer the support and conduct the new bone formation [
7]. Craniofacial bones have a complex architecture that encompasses spaces and contains delicate organs, and shaping a bone graft in the traditional way with bone trimming requires burs that will not allow replication of the exact facial bone intended to be replaced [
8]. Transplanting a graft that does not mimic the original shape of the bone will negatively affect the outcome of the facial reconstructive surgery. Therefore, developing an appropriate scaffold material to replace bone along with the appropriate technique has been the focus of ongoing research in the last decade.
Bone tissue engineering has been an avenue of scientific interest since the 1980s [
9,
10]. It aims to fabricate substitutes for bone grafts using a scaffold from a biocompatible material that carries the osteogenic cells needed for healing along with the growth factors that will help the osteodifferentiation and angiogenesis to aid in the healing process [
11]. Since then, many biomaterials have been developed and tested to fulfill the requirement needed for safety, adequate mechanical properties and designs to mimic the replaced bone [
12,
13].
Many methods have been utilized to fabricate scaffolds for tissue engineering, including solvent casting and particulate leaching (SCPL), phase separation, gas foaming, microsphere sintering and electrospinning [
14,
15]. Though these methods are able to produce a scaffold out of biomaterial, they are unable to precisely depict the design they are intended to replace. Fortunately, the collaboration between scientists and engineers, together with interdisciplinary research, led to significant developments. Early in the 1970s, advances in design and manufacturing technology led to the development of the CAD/CAM system (computer-aided design/computer-aided manufacturing), which was adopted and implemented heavily in the automotive and aerospace industries [
16]. The system produces a digital design using software, and then with the assistance of the computer, a prototype is manufactured. The technology made its way into dentistry where it is still utilized for the fabrication of various fixed partial dentures and restorations requiring better aesthetic appearance and durability [
17]. Manufacturing those prototypes depends on carving the design from an ingot or a block of material using the CAM system [
18,
19]. Scaffolds, on the other hand, require having interconnected pores to ensure infiltration with nutrients and ensure cell migration within the material to allow for replacement with healing cells [
20].
Advances in manufacturing continued, and additive manufacturing (AM) or three-dimensional (3D) printing, was introduced into industry and biology. The AM technology fabricates the prototype or scaffold by depositing bioink in a layer by layer manner rather than subtracting from an ingot [
21,
22]. Bioink is a material that resembles the extracellular matrix containing cells encapsulated within, which is then deposited with precision and polymerizes or cross-links either before or after deposition to form the scaffold [
23]. Previously, the technology was used to deposit a single bioink but nowadays and with the advancement of the field, multicomponent bioinks may now be deposited in high accuracy to mimic the complex architecture of human tissue [
24]. Recently, the CAD technology combined with the advances in the AM and 3D bioprinting technology has succeeded in the construction of scaffolds for tissue regeneration that was translated and implanted in patients for the repair of the blood vessels, urethra, urinary bladder, and trachea [
25].
The present review introduces both the bioink material and the technology used in 3D bioprinting in relation to maxillofacial plastic and reconstructive surgery.
Bioink material
The first generation of bioinks are materials that show bioinert behavior and biocompatibility, which do not elicit an immune response or rejection. In contrast, the body only responds by forming a thick fiber capsule; thus, the scaffold remains implanted without degrading and continues to provide mechanical support, e.g. metals (stainless steel and titanium) and polymers (silicone and polymethylmethacrylate) [
26]. The second generation of bioinks are materials demonstrating both biocompatibility and being bioactive. They allow mineralization, i.e. hydroxyapatite formation and are able to be biodegradable for healing cells to replace the scaffold [
27]. The third generation of bioinks is the bioresponsive materials, which incorporate growth factors and stimulatory molecules that stimulate osteoblast differentiation including bone morphogenetic proteins (BMP) and fibroblast growth factors (FGF) [
28]. Nowadays, a multicomponent bioink is used, as it combines the mechanical and functional properties to meet the complex need within the replaced tissue [
24].
Stem cells and bioactive molecules
For the biomaterial to be a bioink, they should encapsulate stem cells that can differentiate into different lineages and assist in the body healing and regeneration [
43]. Stem cells may be embryonic (ESC) in origin, which carry the ethical considerations of harvesting them using embryos [
44]. Alternatively, adult stem cells may be found in specific niches within the adult body, such as the bone marrow, umbilical cord, amniotic tissue, dental pulp and adipose tissue. Shen et al. compared the osteogenic differentiation potential of different mesenchymal stem cell (MSC) sources and determined that MSC derived from the amniotic membrane and umbilical cord tissue has the highest osteogenic potential compared with other MSC-derived cells [
45]. Bioactive molecules incorporated within the bioink are growth factors that enhance angiogenesis, as in vascular endothelial growth factor (VEGF), or may also improve osteogenic differentiation and bone formation, as in BMP, FGF and insulin-like growth factor-1 (IGF-1) [
23].
Conclusion
Scaffold fabrication for bone tissue engineering depends on many physical and chemical factors that cue simultaneously to ensure cell migration, proliferation, vascularization, osteogenic differentiation and scaffold degradation [
83]. 3D bioprinting has proved to create the interconnected pores and the surface topography needed for bone tissue engineering, thereby overcoming one of the main challenges and barriers that faced the translation of technology [
84]. Biomaterial combination, as well as methods and techniques for every organ, still need to be tested and assessed prior to their translation into patient care [
85].
ClinicalTrials.gov lists only one clinical trial investigating the safety and efficacy of treating bone injuries using 3D scaffolds made from demineralized bone matrix and seeded with bone marrow-derived stem cells [
86]. Apart from the bone tissue engineering, several organs have been successfully engineered and successfully transplanted into patients, such as the trachea, urethra and blood vessels [
87,
88].
One of the barriers that hinders the translation of the technology is its high cost. However, once a bioprinter is owned, fabricating scaffolds using the 3D printing is relatively cost-effective as only the necessary material is used with minimal waste [
89]. A bioengineering research group has overcome this barrier by describing a method to modify an off-the-shelf 3D printer into a printer for bio-fabrication use [
90].
The technology of 3D printing is promising and allows for individualized medicine that is currently progressing. Researchers are continuing to improve and develop the deficits seen with tissue 3D bioprinting. Ultimately, 3D printing technology is likely to become, not far from now, an essential tool for maxillofacial, plastic and reconstructive surgeons potentially to improve facial reconstruction surgical outcomes, along with patient satisfaction and the quality of life of patients.
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