Regenerative Medicine Technologies to Treat Dental, Oral, and Craniofacial Defects

Abstract

Additive manufacturing (AM) is the automated production of three-dimensional (3D) structures through successive layer-by-layer deposition of materials directed by computer-aided-design (CAD) software. While current clinical procedures that aim to reconstruct hard and soft tissue defects resulting from periodontal disease, congenital or acquired pathology, and maxillofacial trauma often utilize mass-produced biomaterials created for a variety of surgical indications, AM represents a paradigm shift in manufacturing at the individual patient level. Computer-aided systems employ algorithms to design customized, image-based scaffolds with high external shape complexity and spatial patterning of internal architecture guided by topology optimization. 3D bioprinting and surface modification techniques further enhance scaffold functionalization and osteogenic potential through the incorporation of viable cells, bioactive molecules, biomimetic materials and vectors for transgene expression within the layered architecture. These computational design features enable fabrication of tissue engineering constructs with highly tailored mechanical, structural, and biochemical properties for bone. This review examines key properties of scaffold design, bioresorbable bone scaffolds produced by AM processes, and clinical applications of these regenerative technologies. AM is transforming the field of personalized dental medicine and has great potential to improve regenerative outcomes in patient care.

Keywords: 3D printing; biocompatibility; bioresorbable scaffolds; bone regeneration; periodontal diseases/therapy; regenerative medicine; tissue engineering.

FIGURE 1

Principles and current endeavors for periodontal regeneration with tissue bioengineering. (A) Key components of periodontal regeneration with tissue engineering. Cells, growth factors, scaffold, mechanical loading, pathogen control, and ideal blood supply are the key for periodontal regeneration. (B) Examples of micropatterned scaffold, which enhances the orientation of fiber in periodontal regeneration. Left panel: SEM image of a micropatterned scaffold with grooves. Center: Viral Gene delivery (Ad-BMP-7) with chemical vapor deposition. Right: human PDL cells aligned along with the grooves of micropattern. (C) Left: prospective sources of stem cells in dental and maxillofacial region. BMSCs, bone marrow-derived mesenchymal stem cells from orofacial bone; DPSCs, dental pulp stem cells; SHED, stem cells from human exfoliated deciduous teeth; PDLSCs, periodontal ligament stem cells; DFSCs, dental follicle stem cells; TGPCs, tooth germ progenitor cells; SCAP, stem cells from the apical papilla; OESCs, oral epithelial progenitor/stem cells; GMSCs, gingiva-derived MSCs; PSCs, periosteum-derived stem cells; SGSCs, salivary gland-derived stem cells. Right: autologous PDL-derived a three-layered cell sheet with woven PGA. Adapted with permission from Egusa et al. (2012), Iwata et al. (2018), Pilipchuk et al. (2018), and Yu et al. (2019).

FIGURE 2

Key determinants of cell-scaffold interactions. Resorbable scaffolds for the regeneration of functional dental, oral, and craniofacial tissues require tailored, biomimetic features that consider structural design, internal geometry, and surface topography to promote cell-scaffold interactions. Additive manufacturing facilitates optimization of physical properties of scaffold substrates to promote overall mechanical performance and fine tune biomechanical regulation of cell behavior. Intrinsic material properties such as degradation rate and surface chemistry are key biochemical considerations, and various exogenous agents with bioactive properties may be incorporated for scaffold functionalization to further enhance regenerative outcomes.

FIGURE 3

Paradigm shift in scaffold production. Additive manufacturing has introduced a departure from design for conventional manufacturing processes to additive manufacturing driven by design for the individual patient. The generalized design approach utilizes traditional product specification and engineering processes to facilitate large-scale production for distribution to a target population. Disadvantages of conventional manufacturing include limited capacity for complex designs and less customization. Additive manufacturing (AM) utilizes individual patient data processed by computer-aided design (CAD)/computer-aided manufacturing (CAM) software to perform virtual planning, design optimization, and fabrication of highly personalized scaffolds for bone regeneration. This design process begins and ends with direct patient interaction. AM has enormous potential to improve accessibility to personalized regenerative medicine in everyday clinical dentistry.

FIGURE 4

Overview of major types of additive manufacturing processes for bone tissue engineering applications. Additive manufacturing (AM) falls into three major categories: laser-based, extrusion-based, or binder jetting processes. Stereolithography apparatus (SLA) and selective laser sintering (SLS) are the predominant forms of laser-assisted techniques for production of non-metallic bone scaffolds. Fused deposition modeling (FDM) is the main extrusion-based method and binder-jetting is the last method. Melt electrospinning or bioprinting are similar, but distinct scaffold fabrication processes that may be used in conjunction with traditional methods of AM.

FIGURE 5

Biomaterials for bone scaffold fabrication. A variety of candidate materials are available for scaffold fabrication using additive manufacturing or bioprinting processes. Additive manufacturing typically employs polymers, to which ceramic materials may be added to form composites. Bioprinting incorporates all three elements of the tissue engineering triad: cells, scaffold (hydrogel), and growth factors. Exogenous agents are often incorporated either with pre-loading or post-processing methods.