A Review of 3D Polymeric Scaffolds for Bone Tissue Engineering: Principles, Fabrication Techniques, Immunomodulatory Roles, and Challenges

Abstract

Over the last few years, biopolymers have attracted great interest in tissue engineering and regenerative medicine due to the great diversity of their chemical, mechanical, and physical properties for the fabrication of 3D scaffolds. This review is devoted to recent advances in synthetic and natural polymeric 3D scaffolds for bone tissue engineering (BTE) and regenerative therapies. The review comprehensively discusses the implications of biological macromolecules, structure, and composition of polymeric scaffolds used in BTE. Various approaches to fabricating 3D BTE scaffolds are discussed, including solvent casting and particle leaching, freeze-drying, thermally induced phase separation, gas foaming, electrospinning, and sol-gel techniques. Rapid prototyping technologies such as stereolithography, fused deposition modeling, selective laser sintering, and 3D bioprinting are also covered. The immunomodulatory roles of polymeric scaffolds utilized for BTE applications are discussed. In addition, the features and challenges of 3D polymer scaffolds fabricated using advanced additive manufacturing technologies (rapid prototyping) are addressed and compared to conventional subtractive manufacturing techniques. Finally, the challenges of applying scaffold-based BTE treatments in practice are discussed in-depth.

Keywords: additive manufacturing; biopolymers; customized therapy 3D scaffolds; nanofabrication techniques; rapid prototyping; tissue engineering and regenerative medicine.

Figure 1

Schematic representation of the basic structure of bone tissue: (A) hierarchical structure of the bone; (B) anatomical features of the bone; (C) elemental composition of the bone. The image was created using Biorender.

Figure 2

Main stages of secondary bone healing. (A) A hematoma forms after the fracture. (B) In the first stage of regeneration, the fibrin is gradually replaced by fibrous-cartilaginous tissue forming woven bone. (C) At a later stage of the regeneration phase, ossification of the cartilaginous tissue occurs, and more neocartilaginous tissue is formed. (D) Once the bone has grown back together over bony calluses, the original morphology of the bone cortex is restored by remodeling [48]. The image was created using Biorender.

Figure 3

SEM images of adhesion of MG63 cells to the PC membrane surfaces with different surface roughnesses: (A) 0.2, (B) 0.4, (C) 1.0, (D) 3.0, (E) 5.0, and (F) 8.0 mm [78]. © Elsevier, 2004.

Figure 4

The properties of ideal bone tissue engineering scaffold. The image was created using Biorender.

Figure 5

Preparation of chitosan-PCL biocomposite scaffolds displaying “shish kebab-like” morphology [120].

Figure 6

PPGmM and PEGmM were chemically crosslinked to form hydrogels using MA as a crosslinking agent. The resulting hydrogels (nanoporous hydrogels) and hydrogels freeze-dried to microscopic pores (microporous hydrogels) were incubated in mSBF to induce biomineralization [129]. The image was created using Biorender.

Figure 7

A flow chart showing the preparatory steps for manufacturing HPC-2, HPB-3, and HPCB-1~5 and in vivo investigations carried out on an 8 mm induced defect of rabbit calvaria [130]. The image was created using Biorender.

Figure 8

Classification of polymeric scaffolds used in bone tissue engineering according to their geometry and composition. The image was created using Biorender.

Figure 9

Solvent casting and particulate leaching technique and its processing parameters. The image was created using Biorender.

Figure 10

Freeze-drying technique and its processing parameters and additives. The image was created using Biorender.

Figure 11

The thermally induced phase separation technique and its processing parameters and additives. The image was created using Biorender.

Figure 12

The gas foaming technique and its processing parameters. The image was created using Biorender.

Figure 13

The sol–gel formation technique and its processing parameters and additives. The image was created using Biorender.

Figure 14

The electrospinning technique and its processing parameters, additives, and nanofiber types. The image was created using Biorender.

Figure 15

Stereolithography technique and its processing parameters and additives. The image was created using Biorender.

Figure 16

The 3D printing technique and its processing parameters and additives. The image was created using Biorender.

Figure 17

The 3D bioprinting technique and its processing parameters and additives. The image was created using Biorender.

Figure 18

Tissue engineering (TE) triad comprising of three main components: cells, scaffolds, and stimulating signals. The image was created using Biorender.

Figure 19

(A): (a) A 3D CT scan of a bone cranial defect. The first step to a customized graft is to acquire a patient-specific CT scan image of the defect. (b) Anatomically shaped HA scaffold that perfectly fits the defect in a skull model. A prototype acrylic resin model was fabricated by 1:1 stereolithography, replicating the skull with the defect. A custom HAp prosthesis was then fabricated and accurately refined based on the defect that the resin model exhibited [247]. (B): Multilayered composite scaffold with three gradients that replicates the entire articular osteochondral compartment and can initiate osteochondral regeneration. The nanostructured, biomimetic, porous, three-layer gradient composite scaffold mimics (a) the cartilage layer (type I collagen), (b) the tidemark (a combination of type I collagen and non-stoichiometric, magnesium-enriched HA), and (c) the subchondral bone (a mineralized blend of type I collagen and magnesium HA) [248]. (C): Method for the preparation of vascular channels using a cell-gelatin mixture. (a) Schematic description of the process. (b) Custom-made flow chamber consisting of three transparent polycarbonate parts and two O-shaped rings for sealing. (c) Image of the flow chamber connected to the perfusion system via side-mounted needles [249].