Towards Polycaprolactone-Based Scaffolds for Alveolar Bone Tissue Engineering: A Biomimetic Approach in a 3D Printing Technique

Abstract

The alveolar bone is a unique type of bone, and the goal of bone tissue engineering (BTE) is to develop methods to facilitate its regeneration. Currently, an emerging trend involves the fabrication of polycaprolactone (PCL)-based scaffolds using a three-dimensional (3D) printing technique to enhance an osteoconductive architecture. These scaffolds are further modified with hydroxyapatite (HA), type I collagen (CGI), or chitosan (CS) to impart high osteoinductive potential. In conjunction with cell therapy, these scaffolds may serve as an appealing alternative to bone autografts. This review discusses research gaps in the designing of 3D-printed PCL-based scaffolds from a biomimetic perspective. The article begins with a systematic analysis of biological mineralisation (biomineralisation) and ossification to optimise the scaffold's structural, mechanical, degradation, and surface properties. This scaffold-designing strategy lays the groundwork for developing a research pathway that spans fundamental principles such as molecular dynamics (MD) simulations and fabrication techniques. Ultimately, this paves the way for systematic in vitro and in vivo studies, leading to potential clinical applications.

Keywords: 3D-printed PCL-based scaffold; alveolar bone; biomimetic ossification; biomineralisation; bone tissue engineering; chitosan; collagen; fused filament fabrication; hydroxyapatite.

Figure 2

Scheme of osteocyte–osteoblast–osteoclast interactions enclosed in coupling system. (I) Osteocyte–osteoblast interactions: osteocytes possess the ability to detect mechanical loads on bone. When a bone is loaded, osteocytes convert this load into biochemical signals. Subsequently, osteocytes can release factors, such as prostaglandins and nitric oxide (NO), which modulate osteoblast activity. Through this mechanism, osteocytes promote the activation of osteoblasts to form new bone in response to loading. (II) Osteoblast–osteoclast interactions: osteoblasts produce and release factors such as RANKL (receptor activator of nuclear factor ϰ-B ligand) and M-CSF (macrophage colony-stimulating factor). RANKL binds to the RANK receptor on the surface of osteoclast precursors, leading to their differentiation into fully active osteoclasts. Additionally, osteoblasts produce osteoprotegerin (OPG), which serves as a ‘trap’ for RANKL, inhibiting osteoclast activation. The balance between RANKL and OPG in the bone microenvironment determines whether bone will be resorbed or formed. (III) Osteocyte–osteoclast interactions: osteocytes can also release RANKL, influencing the activation of osteoclasts. Furthermore, osteocytes can secrete factors that inhibit osteoclast activity in response to mechanical loading [6,55,56,57].

Figure 6

Division of bone grafts according to their origin. An autograft is a tissue transferred from the same individual. It has been considered to be the standard of bone graft replacements. An allograft is a tissue transplanted within the same species, e.g., from one person to another. A xenograft is a tissue or organ that is derived from a species that is different from the recipient of the specimen. An alloplastic graft consists of synthetic biopolymers. It is synthetically derived or made from natural materials [116].

Figure 1

Scheme incorporating the most critical properties and parameters in the fabrication of 3D-printed PCL-based scaffolds.

Figure 3

Diagram of the stages of bone ossifications. Endochondral ossification: (I) the formation of model cartilage (scaffold) rich in chondrocytes; osteoblasts migrate inside the cartilage scaffold; (II) inside the cartilage scaffold, osteoblasts produce primary bone in the form of bone trabeculae; (III) simultaneous loss of model cartilage and growth of bone tissue (chondrocytes undergo apoptosis and the cartilage matrix is degraded). Intramembranous ossification: (I) the formation of a tissue membrane rich in fibroblasts; fibroblasts differentiate into osteoblasts; (II) based on membrane tissue, osteoblasts produce primary bone in the form of bone trabeculae, which are connected to form a network; (III) a bone tissue grows in the space. For both of them: (IV) a bone is constantly transformed and adapted to the body’s needs; osteoblasts, osteoclasts, and osteocytes control remodelling.

Figure 4

The formation of HA crystals in and out of the matrix vesicles.

Figure 5

Scheme of the behaviour of Ca and P_i depending on pH in the matrix vesicle.

Figure 7

Chemical formula of PCL.

Figure 8

Chemical formula of HA.

Figure 9

Tertiary structure of CGI. Longitudinal (a) and transverse (b) view.

Figure 10

The modification pathways from chitin (CN), through chitosan (CS) to carboxymethyl chitosan (CCS) and chitosan sulphate (CSS).

Figure 11

Diagrams of the relationship between mechanical stress (MS), biochemical signals (BS), and ossification process (OP). Several models explaining the relationship between MS and BS in OP may be considered. In the parallel model (a), MS and BS are presumed to function independently, yet they concurrently influence OP without mechanotransduction. In the series model (b), it is suggested that MS initiates BS, which then triggers OP, indicating the presence of mechanotransduction. Finally, the series-parallel model (c) proposes that MS and BS interact with each other through a coupled mechanism, affecting OP, which is characteristic of mechanotransduction. Option (a) is a theoretical concept and is regarded as the least likely, while option (c), although more complex, is considered the most plausible.

Figure 12

Diagram presenting the pathways from fundamental principles to clinical applications. Each phase of the methodology is predicated on a structured analytical procedure, which entails the decomposition of multifaceted issues into more manageable constituent elements. This is followed by a synthesis procedure, which involves a methodical progression from elementary subjects and phenomena to those of greater complexity. Finally, an enumeration procedure is employed, necessitating a thorough and systematic review to ascertain that all facets of the problem under investigation have been duly considered.