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Review
. 2018 May 26;3(4):401-417.
doi: 10.1016/j.bioactmat.2018.05.006. eCollection 2018 Dec.

Bioactive hydrogels for bone regeneration

Xin Bai  1 , Mingzhu Gao  1 , Sahla Syed  2 , Jerry Zhuang  2 , Xiaoyang Xu  2 , Xue-Qing Zhang  1
Affiliations
Review

Bioactive hydrogels for bone regeneration

Xin Bai et al. Bioact Mater. .

Abstract

Bone self-healing is limited and generally requires external intervention to augment bone repair and regeneration. While traditional methods for repairing bone defects such as autografts, allografts, and xenografts have been widely used, they all have corresponding disadvantages, thus limiting their clinical use. Despite the development of a variety of biomaterials, including metal implants, calcium phosphate cements (CPC), hydroxyapatite, etc., the desired therapeutic effect is not fully achieved. Currently, polymeric scaffolds, particularly hydrogels, are of interest and their unique configurations and tunable physicochemical properties have been extensively studied. This review will focus on the applications of various cutting-edge bioactive hydrogels systems in bone regeneration, as well as their advantages and limitations. We will examine the composition and defects of the bone, discuss the current biomaterials for bone regeneration, and classify recently developed polymeric materials for hydrogel synthesis. We will also elaborate on the properties of desirable hydrogels as well as the fabrication techniques and different delivery strategies. Finally, the existing challenges, considerations, and the future prospective of hydrogels in bone regeneration will be outlined.

Keywords: Biomaterials; Bone regeneration; Hydrogel; Tissue engineering.

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Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Schematic illustration of hydrogel-assisted bone regeneration.
Fig. 2
Fig. 2
Method and mechanism to obtain the strong and toughened dual network (DN) hydrogel. (A) The acid SBC was injected into the aqueous solution by using the pipette to form the superstructure. (B) The collagen is quickly injected into the Na2HPO4 solution, and the injection shear creates aligned fibrils (blue). (C) Some twisted collagen molecules produce concentrically oriented fibrils (pink) by fibrillogenesis induced syneresis process. (D) The anisotropic SBC gel was immersed in N, N′- two methacrylamide (DMAAm) solution, and DMAAm was polymerized to obtain collagen based anisotropic DN hydrogel (SBC/PDMAAm). Copyright, Ref. [46], 2017, Elsevier.
Fig. 3
Fig. 3
The effect of poly (vinylphosphonic acid-co-acrylic acid) hydrogels on osteoblast adhesion and proliferation. (A) The Live/Dead human osteoblasts on PVPA-co-AA hydrogels. Live cells stained green, dead cells stained red. (B) The effect of VPA content in PVPA-co-AA hydrogel on the proliferation and metabolic activity of osteoblasts, over 14 days. Copyright, Ref. [52], 2017, Society for Biomaterials.
Fig. 4
Fig. 4
Schematic diagram of the synthesis of small size hydrogel beads by non-equilibrium microfluidic technology. Ethyl acetate absorbs water of droplets containing sodium alginate and the droplet volumes are decreased. The shrunken droplets by gelation produce extremely-small hydrogel beads. Copyright, Ref. [55], 2011, IEEE.
Fig. 5
Fig. 5
Cell-encapsulating microbead implants cultured in osteogenic media (O) or growth media (G). (A–F) Morphology of microbead implants cultured in vitro at day 17, imaged by transmitted light microscopy. (G–L) Viability evaluation of microbead implants cultured in vitro at day 17 via cell staining. (M) Bone volume of microbead implants at 5 weeks. (N) Tissue mineral density (TMD) of microbead implants at 5 weeks. A = acellular; F = freshly isolated BMMC; C = culture-expanded MSC. Scale bar = 200 μm. Copyright, Ref. [60], 2016, Taylor & Francis.
Fig. 6
Fig. 6
Cholesteryl group- and acryloyl group-bearing pullulan nanogel to deliver BMP-2 and FGF-18 for bone tissue engineering. (A) Synthesis and decomposition of CHPOA/hydrogel containing FGF-18 and BMP-2. a) The synthesis of CHPOA/hydrogel block and the chemical structure of CHPOA nanogels and PEGSH. b) The process of releasing FGF-18 and BMP-2 by CHPOA nanogels. (B) Disc-shaped CHPOA/hydrogel for mouse skull defect. a) Disc-shaped CHPOA nanogel/hydrogel. Left, Clear standard CHPOA/hydrogel. Right, Pink rhodamine-labeled CHPOA/hydrogel (CHPOA-Rh/hydrogel). b) Schematic drawing of mouse skull from the top. c) Mouse skull formed round bone defects with a biopsy punch. d) the application of CHPOA-Rh/hydrogel to the circular bone defect. (C) The degree of bone healing after CHPOA/hydrogel releasing FGF-18 and/or BMP-2 in vivo. Disc-shaped CHPOA/hydrogel pellets: group I, PBS; group II, FGF18 (500 ng); group III, BMP-2 (500 ng); group IV, FGF-18 + BMP-2 (500 ng). The percentage of bone healing in 0, 1, 2, 4, 6 and 8 weeks after implantation of CHPOA/hydrogel. Scatter plots show the data of all the samples. Bar represents the average of each stage. Three typical images of the CT are displayed at the bottom of each scatter plot. Copyright, Ref. [64], 2012, Elsevier.
Fig. 7
Fig. 7
Sustained BMP-2 delivery of double interacting nanogels for bone regeneration. (A) The D-NPs have hydrophobic group and ionic interaction group. (B) Compact nanocomposites of D-NP and BMP-2 is formed by the interaction of hydrophobic and ionic interactions. (C) After the injection of BMP-2/D-NP nanocomposites, the nanogel is formed and sustainably release BMP-2 locally. A few weeks later, the new bone is generated and the nanogel is completely degraded. Copyright, Ref. [68], 2015, Elsevier.
Fig. 8
Fig. 8
Operating principle of electrospinning and microfluidic spinning. (A) Electrospinning. (B) Microfluidic spinning. Copyright, Ref. [72], 2017, Elsevier.
Fig. 9
Fig. 9
Core-shell fibrous scaffold for co-deliverling Co and BMP-2. (A) Optical microscopy and SEM images of core-shell hydrogel scaffolds. (B) Microcomputed tomography (μCT) images of new bone formation in rat calvarium defect, treated with fibrous scaffolds. Quantification of (C) new bone volume percentage, (D) bone surface and (E) bone surface density with different combinations of Co and BMP. Copyright, Ref. [78] 2015, Elsevier.
Fig. 10
Fig. 10
GFOGER-functionalized PEG synthetic hydrogel encapsulating BMP-2 for treating murine radial defects. (A) Images of hydrogel formulations with different matches of GFOGER and BMP-2. (B) 3D reconstructed images and mineral density mappings of sagittal sections at the same defect when treated with different hydrogel compositions. (C) New bone volume of different hydrogel compositions at 4 and 8 weeks after surgery. (D) Bridging scores of the defects after 4 weeks of surgery. (E) Maximum torque test of different hydrogel formulations at radial defects 8 weeks post-surgery. Copyright, Ref. [91] 2014, Elsevier.
Fig. 11
Fig. 11
Matrix elasticity modulates the bone regeneration ability of hMSC-encapsulated hydrogels. (A) micro-computed tomographic (μCT) images of bone regeneration in cranial defects in nude rats 12 weeks post-transplantation of different hydrogels (cells alone, standard hydrogel, void-forming hydrogel). (B) Quantitative analysis of new bone volume by μCT within different hydrogels. (C) μCT images of new bone formation in nude rat cranial defects 12 weeks after transplantation of hMSCs-incorporated void-forming hydrogels fixed at various elastic moduli. Evaluation of new bone volume (D) and bone mineral density (E) in nude rat cranial defects 12 weeks post-transplantation of hydrogels with different elastic moduli. (F) Haematoxylin–eosin (H&E) staining images of newly formed bone and remaining polymers. (G) Masson's trichrome staining results showing bone regeneration. Copyright, Ref. [105] 2015, Nature Publishing Group.
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