Progress and prospects of nanocomposite hydrogels in bone tissue engineering

Figures & data

Figure 1. Chemical structures of nanoclay platelets currently used for various biomedical engineering applications. Nanoclays are basically ultrathin (≈1 nm thick) platelets with a dual charge that makes it easy to dissolve and incorporate into almost any existing hydrogel matrix. Reproduced with permission [56]. Copyright, John Wiley and Sons.

Figure 2. Schematic representation of the design strategy for the development of multifunctional nanocomposite hydrogels. DNA—nSi injectable hydrogels are formed viaa two-step gelation method. The first step consists of an intermediate weak gel (pregel) formation by heating and subsequent cooling of double-stranded DNA. The denaturation of doublestranded DNA followed by rehybridization in a random fashion facilitates the development of interconnections between adjacent DNA strands (type A network points) via complementary base pairing. Introduction of nSi in the second step of the gelation process increases the number of network points (type B) viaelectrostatic interaction with the DNA backbone, resulting in a shear-thinning injectable hydrogel. Reprinted with permission from Basu et al. (2018) [70].

Figure 3. Engineering of an osteon-like, cell-laden hydrogel as discussed in Section 2.1.2 a) Schematic representation of the formation of hydroxyapatite nanoparticles in GelMA. b) Schematic representation of the UV-microfabrication procedure employed in the generation of the osteon-like microstructures. c) Bright-field and fluorescence imaging of the resulting biomimetic osteon construct. c) Reprinted with permission from Shi et al. (2016) [90] Copyright 2015, American Chemical Society.

Figure 4. Synthesis of MNP-reinforced nanocomposite hydrogels. (a) Nanocomposite hydrogels were synthesized by combining PEG-dopamine-MNPs with GelMA and exposing it to UV radiation in the presence of a photoinitiator to obtain covalently crosslinked network. (b) Crosslinking of the prepolymer solution was monitor using UV rheology. After the UV radiation was turned on, a significant increase in the modulus of the prepolymer solution was observed, indicating the formation of a crosslinked network. (c) The presence of MNPs within nanocomposite network was determined from XPS. (d) TEM images of nanocomposite show uniform distribution of MNPs within GelMA matrix. Inset show the electron diffraction pattern. (e) SEM micrographs of the nanocomposites indicate the formation of highly porous and interconnected networks. Reprinted with permission from Jaiswal et al. (2016) [115].

Figure 5. Illustration of modulating cell − matrix interactions and mechanosensing of hMSCs by using a MNP-borne soft hydrogel substrate under a directional magneticfield. (A, B) Upward/downward magnetic attraction induces the EXPOSED/HIDDEN presentation of MNPs grafted with cell adhesive ligand on the hydrogel surface to trigger the activation/inactivation of cell mechanotransduction signaling, respectively. (C) Detailed chemical structures in a gray dashed square from (A). Reprinted with permission from Wong et al. (2020) [116].

Figure 6. (a) Schematic description of gelatin methacrylate (GelMA) coated onto a carbon nanotube (CNT). (b) High resolution TEM image of CNT-GelMA. (c) Stress-strain curves of CNTGelMA hydrogels with various concentrations of CNTs. (d) Tensile moduli of CNT-GelMA hydrogels. (e) 3T3 fibroblasts cultured on GelMA hydrogel (A) and CNT-GelMA hydrogel (B).(Scale bar: 100 μm) Reprinted with permission from Shin et al. (2012) [131]. Copyright 2011 American Chemical Society.

Figure 7. (A). SMH/GO hydrogels as an artificial bone substitute for bone regeneration in a rat calvarial defect model via regulating BMSCs migration and osteogenesis differentiation.

Characterizations of SMH/GO hydrogels. (B) Preparation of SMH/GO hydrogels via UV light at 365 nm. (C) FTIR spectra of SMH/GO hydrogels. (D) Mechanical properties of SMH/GO hydrogels. (E) Degradation profiles of SMH/GO hydrogels in PBS (pH7.4, 37 oC). (F) Scanning electron micrographs of SMH (left), SMH/GO-1 (middle) and SMH/GO-2 (right). Scale Bars, 500μm (upper panel) and 10μm (lower panel). Red arrowheads indicate graphene oxide. Reprinted with permission from Qi et al. (2020) [144].

Table 1. The properties of nanocomposite hydrogels.

Strategy	composition	Specific properties of NC hydrogels for tissue engineering related applications	Ref
Clay-based nanocomposite hydrogel	Nano Silicate + Gelatin Methacrylate (GelMA)	Mechanical properties: a 4-fold increase in compressive modulus and a 10-fold increase in peak tensile stress Biological activity: a 3-fold increase in alkaline phosphatase activity and 4-fold increase in mineralized matrix formation.	[55]
Clay-based nanocomposite hydrogel	Laponite XLG ([Mg5.34Li0.66Si8O20(OH)4] Na0.66 +Poly(N-isopropylacrylamide) (PNIPA)	Mechanical properties: The tensile modulus, elongation, and tensile strength are up to 453 kPa, 1,000%, and 1.1 MPa, respectively, and the breaking energy is not less than 1,000 times that of the classical PNIPAAM hydrogel.	[75]
Clay-based nanocomposite hydrogel	Laponite RD and XLG + poly (ethylene glycol) diacrylate (PEGDA), gelatin, alginate	Mechanical properties: The Young's modulus of PEGDA-Laponite composite was increased by 1.9 times, the Young's modulus of gelatin-Laponite composite was increased by 3.3 times, and the alginate-Laponite was increased by 7.4 times. 3D printing properties: It has shear thinning properties (thixotropic response time ≈ 0.08s). The printed product can support itself Biocompatibility: It does not cause any cytotoxic effect, the degradation rate is more stable in 7 days, suitable for cell growth	[153]
Clay-based nanocomposite hydrogel	Laponite + Alginate + Methylcellulose	Mechanical properties: From day 1 to day 21, Young's modulus decreased significantly: 76 ± 8.9 kPa to 28.6 ± 9.3 kPa (porous) and 226 ± 28.8 kPa to 54 ± 32.3 kPa (solid); Compressive strength: 40.8 ± 4.7 kPa to 1.6 ± 0.4 kPa (porous) and 53.8 ± 11.4 kPa to 8.4 ± 3.0 kPa (solid). 3D printing properties: The rheological properties are better, and the nanocomposite hydrogel is more viscous at constant shear rate; stable 3 D structures can be drawn; the drawn 3 D structures do not swell significantly in cell culture media (20% swelling after 21 days.) Biocompatibility: The cell viability after 3 D printing is about 70-75% Drug Loading and Release Performance: The drawn three-dimensional scaffold can sustainably release VEGF (no difference in absolute release), and the cumulative release curve is almost linear.	[154]
Clay-based nanocomposite hydrogel	Silicate Nanoparticles + GelMA(three different concentrations) + VEGF + HUVEC cells	Mechanical properties: The compressive modulus of the outermost nanosilicate composite hydrogel is 6.5 ± 1.0 kPa 3 D printing properties: The printed tubular scaffold is divided into three layers, the innermost layer degrades after 12 days to form 500 μm channels (to promote blood vessel ingrowth); the outermost layer is loaded with mesenchymal stem cells to promote osteogenesis. Biocompatibility: After 7 days of culture, HUVECs and hMSCs survived at 94% and 77% and maintained proliferation in the printed scaffolds. Drug Loading and Release Performance: The composite scaffolds released almost four times the amount of VEGF that physically mixed GelMA + VEGF	[155]
Clay-based nanocomposite hydrogel	Silicate Nanoparticles+ Gelatin + DNA	Injectable properties：Their shear-thinning properties are maintained after drug loading, confirming their potential as injectable drug delivery systems. Mechanical properties: Self-supporting structure can be formed after injection, yield stress increases from 29.45 ± 3.75 to 73.98 ± 9.42 Pa Drug Loading and Release Performance: Gelatin hydrogels released approximately 80% of the loaded drug within 2 days, and nanocomposite hydrogels released 50% of the loaded drug within 5.5 days Biocompatibility: After 72 h in vitro, all hydrogel-treated groups showed more than 85% cell viability	[70]
Ceramic-based nanocomposite hydrogel	Calcium phosphate Nanoparticles + collagen + dexamethasone	Mechanical properties: It has a porous structure similar to that of pure collagen hydrogel scaffolds, but Young's modulus of BCP/collagen composite scaffolds is at least 2.5 times higher than that of collagen scaffolds Porous structure: The diameter of the spherical large hole is 405 mm∼450mm, and the diameter of the small hole is 65.3 mm ± 23.5 mm Biocompatibility: MSCs were able to adhere and proliferate better in BCP scaffolds, with more osteogenic mineralization after 14 days of culture. In vivo experiments verify that BCP stents can form more blood vessels	[95]
Ceramic-based nanocomposite hydrogel	β-Tricalcium Phosphate (β-TCP) Nanoparticles+ PNT hydrogels+ TGF-β	Mechanical properties: Tensile strength 53–410 kPa, strain at break 245–860%, Young’s modulus 20–43 kPa. 3D printing properties: It has rapid thermal reversibility and shear thinning properties. It exhibits rapid recovery when subjected to oscillatory shear strain. Characteristics of the printed scaffolds: pore size of 700 ± 35µm, porosity of 68.3 ± 2.3%, compressive strength of 6.05 ± 0.45 MPa, and compressive modulus of 115Kpa. Biocompatibility: MSCs can adhere and proliferate, and grow faster than the hydrogel scaffold group Biological activity: The cartilage-related markers (Aggrecan, collagen type II) and osteogenesis-related markers (ALP, collagen type I, OCN, RUNX2) of the scaffolds in the β-TCP group were more expressed	[156]
Ceramic-based nanocomposite hydrogel	NanoHA+ alginate-based hydrogels	Biocompatibility: Cells can adhere and grow Biological activity: Expression of Sp7, Col1a1 and BGLAP was increased to levels similar to osteogenic induction cultures. In vivo experiments: verified that this composite hydrogel can form more trabecular bone and form thicker trabecular bone	[157]
Ceramic-based nanocomposite hydrogel	Three-phase ceramic nanomaterials (MSM: composed of Mg2SiO4, MgO and Si3Sr5) + silk fibroin hydrogel	Injectable properties：The composite hydrogel was able to pass through 18 g, 21 g and 23 g injection needles. The average maximum force required to inject at 50 mm/min using a 10 ml syringe ranges from: 18 g: 20 ∼ 37 N, 21 g: 54 ∼ 91 N, 23 g: 126 ∼ 138 N Mechanical properties: The average compressive strength of the composite hydrogel was 10.0 ± 2.0 kPa, and the compressive modulus was 51.4 ± 6.3 kPa. All hydrogels showed weight loss after soaking in PBS solution for 63 days, the highest weight loss is 20.5 ± 5.4% Porous structure: Freeze-dried hydrogels: sponge-like network morphology with an average pore size of 50–100 μm Biological activity: Nanocomposite hydrogel can promote more collagen type I, osteopontin(OPN) and BMP-2 expression; After 3 months of implantation, the composite hydrogel group exhibited more blood vessel formation compared with the silk fibroin hydrogel.	[158]
Ceramic-based nanocomposite hydrogel	Bioglass Nanoparticles (BGN)+ GelMA Hydrogel	Mechanical properties: As the concentration of BGN increased, the Young's modulus of the composite hydrogel also increased from 84.67 ± 16.17 to 178 ± 47.70 kPa, its expansion ratio dropped from 8.30 to 6.37. Porous structure: There was no difference in the mean pore area between groups (1.5 × 10^5 μm^2) Biocompatibility: The percentage of MSCs seeding efficiency decreased with increasing BGN (minimum 30%). All groups showed more than 90% cell viability. Biological activity: The BGN nanocomposite hydrogel group showed increased expression of bone-related genes: osteocalcin increased 7.84 (1.5% BGN) and 13.13 (2.5% BGN) fold, and collagen type I increased 13.56 (1.5% BGN) and 29.92 (2.5%) BGN) times, Runx2 increased 6.47 (1.5% BGN) and 12.83 (2.5% BGN) times. In vivo: Bone volume/total volume (BV/TV) was 3.89 times higher in the BGN group than in the control group	[159]
Iron oxide-based nanocomposite hydrogel	Iron oxide nanoparticles+ Chitosan Hydrogel	Mechanical properties: The compressive strength of the composite hydrogel increased from 41.6 ± 0.8 kPa to 88.6 ± 4.9 kPa. Its yield strength increased by 416% (from 95.1 ± 7.6 kPa to 490.9 ± 24.2 kPa) and its elastic modulus increased by 265% (from 0.46 ± 0.09 MPa to 1.68 ± 0.06 MPa). Drug Loading and Release Performance: The cumulative release and partial release of the drug from the nanocomposite hydrogels were enhanced by 67.2% and 31.9%, respectively. Biocompatibility: MTT results and cell morphology indicated that the nanocomposite hydrogel has good biocompatibility.	[28]
Iron oxide-based nanocomposite hydrogel	Magnetic Nanoparticles (MNPs)+ Polyethylene glycol (PEG) based hydrogels	Biocompatibility: Enhanced cell activity under the action of an external static magnetic field (SMF) Biological activity: Alkaline phosphatase (ALP) activity, expression of osteogenic markers (Runx2, collagen type I, Osterix), and mineralized matrix deposition were enhanced in the nanocomposite hydrogel group compared with the control group Responsiveness: Enrichment of endothelial, pericyte, and CD31-positive cell populations increased upon magnetic stimulation	[33]
Iron oxide-based nanocomposite hydrogel	Magnetic Nanoparticles (MNPs)+ Carboxymethyl Chitosan Hydrogel	Drug Loading and Release Performance: The introduction of magnetic nanoparticles led to the reduction of the swelling capacity of the composite hydrogel from 16.4 g/g to 10 g/g; Responsiveness: Increased drug release from composite hydrogels under external alternating magnetic field (AMF) strengths of 150 and 300 G, the maximum cumulative drug release of the composite hydrogel was about 82%	[160]
Iron oxide-based nanocomposite hydrogel	Magnetic Nanoparticles (MNPs)+ Gelatin Hydrogel+ SDF-1 and BMP2	Mechanical properties: After repeated magnetic field stimulation, the compressive modulus of the nanocomposite hydrogel scaffold did not change significantly (20 ∼ 25KPa), its Young's modulus does not change(4 ∼ 5KPa). Biocompatibility: Cells can adhere and grow on scaffolds Responsiveness: Electromagnetic trigger BMP-2 release. The release time of the BMP-2 can be controlled remotely, from immediate release to a delay of up to 11 days. Porous structure: It has a highly porous and interconnected structure with pore diameters ranging from 100-500μm	[161]
Iron oxide-based nanocomposite hydrogel	Magnetic Nanoparticles (MNPs)+ Gelatin Hydrogel	Mechanical properties: The compressive modulus of the magnetic hydrogel is 2.79 MPa and that of the ordinary hydrogel is 2.25 MPa. The compressive modulus of normal human cartilage is generally between 0.08 MPa and 50 MPa Biocompatibility: The surface of the composite hydrogel has micropores and inhomogeneity, which is favorable for cell adhesion and growth Responsiveness: Composite hydrogels exhibit good superparamagnetic properties (100 mT constant static magnetic field) Biological activity: In vivo experiment: Nanocomposite hydrogel group: More than 80% of the defects were repaired in 8 weeks, and completely repaired in 12 weeks. Control: 50% repair at 8 weeks, 70% repair at 12 weeks.	[162]
Black phosphorus (BP)-based nanocomposite hydrogel	polydopamine modified black phosphorus (pBP) nanosheet+ poly (vinyl alcohol) (PVA) hydrogel	Mechanical properties: The elongation at break of the pure PVA hydrogel is about 310% and the tensile strength is 1.23 MPa, while the elongation at break of the PVA/0.4BP hydrogel is 400% and the tensile strength is 2.71 MPa. Both compressive strength and modulus increased with increasing pBP content. The maximum compressive strength and modulus (PVA/0.8pBP hydrogel with 0.8 wt% pBP) are increased by 192% and 160%, respectively Responsiveness: After 5 min of NIR irradiation, the temperature of PVA/0.2BP increased from 23 °C to 74 °C, while under the same conditions, the temperature of PVA/0.4BP increased from 23 °C to 86 °C. The 808 nm NIR thermal conversion efficiency (Z) of PVA/pBP hydrogel is 31.5% Biocompatibility: 3T3 fibroblasts can span adjacent pores and exhibit well-expanded attachment and spreading Porous structure: Compared with pure PVA hydrogels, composite hydrogels can form more interconnected pore structures with higher porosity Drug Loading and Release Performance: The loading level (LL) of the PVA/pBP hydrogel gradually increased with the increase of the pBP content, and the maximum LL of the PVA/0.8pBP hydrogel was as high as B95% (the LL of the hydrogel group was 80%).	[163]
Black phosphorus (BP)-based nanocomposite hydrogel	Black phosphorus nanosheets+ SrCl2+ Polylactic-glycolic acid (PLGA) hydrogel	Mechanical properties: In the PVA/BP composite hydrogel, the addition of 0.02, 0.05 and 0.1 w/v % BP resulted in an increase in modulus to 4.4 ± 0.8, 5.3 ± 1.0 and 7.3 ± 1.4 kPa, respectively. Biocompatibility: More than 95.0% of cells in all groups were still alive in vitro. Drug Loading and Release Performance: During the first cycle of NIR radiation, about 40% of the drug can be released from the PVA/0.4 bp hydrogel, while only about 15% of the drug is released from the pure PVA hydrogel. After four periodic near-infrared irradiations, the CR release process of PVA/0.4pBP is close to equilibrium, and the total release amount reaches about 78%, which is about twice that of pure PVA hydrogel. Porous structure: The average size of PLGA microspheres is 38.1 ± 9.8 µm, and the sizes of SrCl2/PLGA and BP SrCl2/PLGA microspheres are 49.6 ± 10.5 and 45.4 ± 12.9 µm, respectively	[129]
Carbon-based nanocomposite hydrogel	photo-crosslinked sericin methacryloyl (SerMA)+ Graphene oxide (GO)	Mechanical properties: The compressive modulus of the sericin methacryloyl (SerMA) hydrogel (SMH) is 17KPa, which can be improved by the incorporation of graphene: SMH/GO-0.02% (34 kPa) and SMH/GO-0.04% (43 kPa). The degradation rate of these hydrogels was negatively correlated with the GO content. Degradation rate measured at 45 days: 73% for SMH, 43% for SMH/GO-1, and 39% for SMH/GO-2. Biological activity: The area of new bone regeneration in skull defect: 94.7% for SMH/GO-2, 70.3% for SMH, 56.5% % for untreated Biocompatibility: The proliferation rate of BMSCs adhered to the hydrogel was similar to that of cells cultured in medium containing 10% fetal bovine serum (FBS)	[144]
Carbon-based nanocomposite hydrogel	Graphene oxide+ Regenerated cellulose/polyvinyl alcohol（RCE/PVA）	Mechanical properties: With the addition of 1.0 wt% GO, the tensile strength of the composite hydrogel increased from 0.52 MPa to 0.73 MPa, and the elongation at break increased from 103% to 238%, an increase of 40.4% Responsiveness: The swelling ratio of GO-RCE/PVA hydrogels increased with increasing pH. With the addition of 1.0 wt% GO, the swelling ratio of the GO-RCE/PVA hydrogel in acidic solution was 195%, and the swelling ratio in alkaline solution was 400%, an increase of about 105%. With the addition of 1.5 wt% GO, the final swelling ratio of the hydrogel was increased to 450%.	[145]
Carbon-based nanocomposite hydrogel	Graphene oxide+ alginate	3D printing properties: Addition of GO significantly increases the viscosity, shear thinning properties and shear recovery of alg/GO hydrogels. The shear moduli of alg/GO-0.5 and alg/GO-1.0 at frequency 1 Hz were 1.19 and 1.23 times higher than that of alg/GO-0. Dimensional change of scaffolds when cultured in vitro: alg/GO-0 increased by 143.9 ± 1.7%, alg/GO-0.05 by 134 ± 1.4%, alg/GO-0.25 by 137 ± 0.5%, alg/GO-0.5 increased by 128 ± 0.1% and alg/GO-1.0 by 132 ± 3.8% Biocompatibility: Cells can adhere and proliferate in scaffolds Biological activity: When differentiation was induced for 1 week, the amount of calcium deposition in the group with GO scaffold was slightly higher than that in the group without GO scaffold (alg/GO-0: 16.26 ± 1.8 mg dL^-1, alg/GO-1.0: 21.38 ± 2.1 mg dL^-1). The ALP activity of alg/GO hydrogel was 2.5 times higher than that of the control group.	[142]
Carbon-based nanocomposite hydrogel	Graphene oxide (GO)+ Ti scaffolds + gelatin microspheres (GelMS)	Mechanical properties:The fixation rate of GO/Ti scaffold was 60%, which was higher than that of pure Ti scaffold (30%) Porous structure: a 3 D interconnected porous structure with a pore size of 100 to 200 µm Drug Loading and Release Performance: GelMS GO/Ti scaffolds exhibit sustained-release and dual-release properties. On the GelMS GO/Ti scaffold, vancomycin exhibited sustained release, with 63.4 ± 3.4% of Van being released after 21 days. The stents in the control group released 76.9 ± 3.5% of vancomycin within 5 days. Biocompatibility: Cells can adhere and proliferate in scaffolds. Biological activity: Better osteogenesis on GelMS GO/Ti scaffolds. In vivo experiments showed no bone tissue deposition in the control scaffold, and 25% bone deposition in the GelMS GO/Ti scaffold.	[141]

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