Functionalized multidimensional biomaterials for bone microenvironment engineering applications: Focus on osteoimmunomodulation

Abstract

As bone biology develops, it is gradually recognized that bone regeneration is a pathophysiological process that requires the simultaneous participation of multiple systems. With the introduction of osteoimmunology, the interplay between the immune system and the musculoskeletal diseases has been the conceptual framework for a thorough understanding of both systems and the advancement of osteoimmunomodulaty biomaterials. Various therapeutic strategies which include intervention of the surface characteristics or the local delivery systems with the incorporation of bioactive molecules have been applied to create an ideal bone microenvironment for bone tissue regeneration. Our review systematically summarized the current research that is being undertaken in the field of osteoimmunomodulaty bone biomaterials on a case-by-case basis, aiming to inspire more extensive research and promote clinical conversion.

Keywords: biomaterials; bone regeneration; bone tissue engineering; drug delivery; osteoimmunomodulation.

FIGURE 1

Macrophages in bone regeneration.(A) Five phases of the process Reproduced from (Schlundt et al., 2021); (B)Metabolic rearrangement in macrophage polarization to proinflammatory or alternatively activated macrophages in vivo; Reproduced from (Wculek et al., 2022); and (C)A switch from M1-to M2-polarized macrophages present in and around the injured side. Reproduced from (Schlundt et al., 2018).

FIGURE 2

(A) An illustration of the surface physicochemical characteristics of biomaterials. Reproduced from (Rahmati et al., 2020); (B) Macrophage polarization using surface chemistry. Reproduced from (Rostam et al., 2020).

FIGURE 3

Structure of the bone and characterization of the osseointegration; (A) Hierarchical structure of bone from the macro-to nanoscale; (B) Hierarchical characterization of osseointegration from the macro-to nanoscale; Similar to bone, the connection at bone−implant interfaces spans several length scales. Reproduced from (Binkley and Grandfield, 2018); (C) Schematic overview of the functionalized multidimensional biomaterials from 0D-4D.

FIGURE 4

Overview of zero-dimensional biomaterials and evidence of their ability to promote bone formation. (A) TEM images of (A1) bare TiO2 nanoparticles, (A2) TiO2-NH2 nanoparticles and (A3) LbL-coated (Q10). The bar represents 100 nm. (B) Thermograms of different LbL-DEX-coated Ti-O-NH2 substrates. Reproduced from (Alotaibi et al., 2019) (C) Schematic illustration of the self-assembled Fe–cat NPs. (D) SEM image and TEM image of the Fe–cat NPs. (E) Representative coronal, axial, and 3D images of rat femurs in the Matrigel group and Matrigel + Fe–cat NP group, provided by micro-CT. Reproduced from (Kong et al., 2022) (F) SEM image of the CS/nHA/CD and CS/nHA scaffolds. (G) TEM image of the CS/nHA/CD and CS/nHA scaffolds. The white arrows show the CD. (H1) Relative expression of osteogenesis-related genes after 7 and 14 days of culture. (H2) Micro-CT 3D reconstruction models of the newly formed bone in the scaffolds. More new bone formation was found in CS/nHA/CD scaffolds at 4 weeks. Reproduced from (Lu et al., 2018).

FIGURE 5

(A) Macroscopic images of clot formation after implantation in vivo; (B) SEM images of the osteocytes-to-implant interface. (C) SEM images of the clot and THE MΦ (purple area) after coculturing; (D) The connection between the TiO₂-tubes, clot and osteoimmunomodulation.

FIGURE 6

(A) Schematic of the sequential fractional electrospinning process; (B) 3D fluorescence images of MC3T3-E1 cells cultured on the inner face of the JGM for 1 day, 4 days, and 7 days; (C) In vivo bone repair evaluation. (C1) Schematic of the operation; (C2) Micro-CT images of the bone; (D) Histological analyses of calvarial defects at 8 weeks. (A) H&E staining images; (E) Schematic of the bone healing mechanism. Reproduced from (Chen et al., 2018).

FIGURE 7

Schematic illustration and regenerative potential of four-dimensional biomaterials (A) 3D printing and characterization of the physical and thermomechanical properties of HA-PELGA composites; 3D μCT images and BMD color maps showing maturing regenerated bone within the defect over time. Reproduced from (Zhang et al., 2019b). (B) Schematic illustration of microfluidic 3D printing responsive scaffolds with biomimetic enrichment channels for bone regeneration. (C) Photothermal responsive performance of the BP-HF scaffolds. Real-time photograph and corresponding thermal images Reproduced from (Wang et al., 2022b) (D) Schematic diagram illustrating that the early and durable enrichment of M2 macrophages above the bone defect mediated by the 4D hierarchically channeled elastomeric membrane contributes to specific shape bone healing. Reproduced from (Liu et al., 2021b).