Advances in Growth Factor Delivery for Bone Tissue Engineering

Abstract

Shortcomings related to the treatment of bone diseases and consequent tissue regeneration such as transplants have been addressed to some extent by tissue engineering and regenerative medicine. Tissue engineering has promoted structures that can simulate the extracellular matrix and are capable of guiding natural bone repair using signaling molecules to promote osteoinduction and angiogenesis essential in the formation of new bone tissues. Although recent studies on developing novel growth factor delivery systems for bone repair have attracted great attention, taking into account the complexity of the extracellular matrix, scaffolding and growth factors should not be explored independently. Consequently, systems that combine both concepts have great potential to promote the effectiveness of bone regeneration methods. In this review, recent developments in bone regeneration that simultaneously consider scaffolding and growth factors are covered in detail. The main emphasis in this overview is on delivery strategies that employ polymer-based scaffolds for spatiotemporal-controlled delivery of both single and multiple growth factors in bone-regeneration approaches. From clinical applications to creating alternative structural materials, bone tissue engineering has been advancing constantly, and it is relevant to regularly update related topics.

Keywords: biomaterials; bioscaffold; bone morphogenetic protein; bone regeneration; drug delivery; growth factor; polymer composites; tissue engineering.

Figure 1

The main growth factors that are relevant to the bone-regeneration process: the bone-regeneration process is addressed in four overlapped, different phases of inflammation (phase A), soft callus formation (phase B), mineralization and resorption of the soft callus (phase C), and bone remodeling (phase D) (BMP: bone morphogenetic protein, FGF: fibroblast growth factor, GDF-5: growth/differentiation factor 5, IGF-1: insulin-like growth factor 1, PTH: parathyroid hormone, M-CSF: macrophage colony-stimulating factor, OPG: osteoprotegerin, PDGF: platelet-derived growth factor, PlGF: placental growth factor, RANKL: receptor activator of nuclear factor κB ligand, SDF-1: stromal cell-derived factor 1, TGF-β: transforming growth factor β, TNF-α: tumor necrosis factor α, and VEGF: vascular endothelial growth factor) [18].

Figure 2

Peptides and aptamers are targeting moieties used to deliver drugs to bones through carriers that transit or infiltrate the blood stream and come out after targeting. The delivered drugs are metabolized owing to a pH media variation or via matrix metalloproteinases (MMP) and enzymes [48].

Figure 3

The main biological and structural properties, common compositions, and manufacturing technologies of bone tissue engineering scaffolds [61].

Figure 4

(A) Natural crosslinking of collagen (head-to-tail); (B) the intermolecular crosslink of collagen allowing for the protection of collagen from enzymatic degradation; (C) live/dead cell viability assay of PDLSCs (periodontal ligament stem cells) performed in collagen powder before implantation and 24 h after incubation showing that cells in green are alive; (D) mechanism of reaction to modify a collagen scaffold functionalized with hydroxyapatite and BMP-2, and modified scaffolds; (E) hydroxyapatite scaffold (a) micro-CT pore structure (b), surface morphology (SEM) (c), cross-sectional morphology (SEM) (d), and hydroxyapatite and collagen scaffold (SEM) (e,f); and (F) fluorescent-stained images of a collagen-hydroxyapatite-modified scaffold detecting BMP-2 after 1, 5, and 21 days [75,80,81].

Figure 5

(A) Schematic representation of alginate showing the structure of mannuronate (M) and guluronate (G), and the chair conformation and the sequence of M block and G block arrangement in alginate are shown. (B) Poly (GM)-Ca²⁺ alginate and poly(M)-Ca²⁺ alginate are displayed. (C) The fabrication process for 3D-printed scaffolds from TEMPO-oxidized cellulose nanofibril/sodium alginate hydrogels is shown. (D) Scaffolds printed in different forms and designs from optimal TEMPO-oxidized cellulose nanofibril/sodium alginate hydrogel formulation are shown [92,93,95].

Figure 6

Schematics of delivering systems of growth factors based on the extracellular matrix (ECM) ability to protect growth factors from degradation and to avoid the formation of concentration gradients (a regulatory mechanism): (A) a biomaterial matrix covalently incorporates or co-receives a heparin/heparin-mimetic modified matrix, which binds the growth factors. (B) Receptor (i.e., integrin and growth factor) synergistic signaling through the addition of a fibronectin fragment that has both receptor domains is shown. (C) A growth factor is recombinantly introduced for the factor XIIIa substrate sequence. (D) A growth factor is recombinantly produced for incorporation into the ECM-binding domain that interacts with ECM proteins and/or glycosaminoglycans (GAGs). As a result, the growth factor can bind endogenous ECM or biomaterial matrices constituted of natural ECM proteins such as fibrin and collagen [18].

Figure 7

Different nanocarrier types applicable for the encapsulation and release of growth factors (GFs) (a–f) and a modified scaffold functionalized with nanocarriers for encapsulating GFs (g) [121].

Figure 8

Covalent bond formation between growth factor and carrier: (A) amide group, (B) thioether group, (C) disulfide group, (D) acetyl-hydrazone group, (E) polycyclic group, and (F) click chemistry [155].

Figure 9

Engineered GF gradients: (A) injection of graded biomaterials for bone regeneration; (B) strategies used to create GF gradients within hydrogels: (a) concentration gradient of a single biomolecule (GF1), (b) sequential delivery of three different biomolecules (GF1, GF2, and GF3), and (c) encapsulation of biomolecule(s) in polymeric micro- and nanocarriers; and (C) methods for graded biomaterial fabrication: (a) 3D bioprinting, (b) microfluidics, (c) layer-by-layer scaffolding, and (d) magnetically (electrically) driven distribution of GFs. Created using Biorender.com.