Enzyme-Triggered Crosslinked Hybrid Hydrogels for Bone Tissue Engineering
Abstract
:1. Introduction
2. Hybrid Hydrogels
3. Various Crosslinking Approaches for Developing Hybrid Hydrogels
3.1. Physically Crosslinked Hydrogels
3.2. Chemically Crosslinked Hydrogels
4. Enzyme Crosslinking Approaches for Bone Tissue Engineering
4.1. Tyrosinase
4.2. Lysozyme
4.3. Horseradish Peroxidase
4.4. Transglutaminase (TG)
4.5. Alkaline Phosphatase (ALP)
5. Conclusions and Future Prospects
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Type of Crosslinking | Mechanism/Response | Advantages | Disadvantages | Ref. |
---|---|---|---|---|
Physical approaches | ||||
Hydrogen bonding | Interaction between electropositive (H) and electronegative (O, N, F) atoms | Safe and less toxic, non-covalent bonds (sacrificial), highly dynamic and reversible character, excellent toughening effect, lowest toxicity, tunable properties, and allows deviations in ion amounts | Weak mechanical characteristics, highly detrimental in aqueous medium, easily dissociate upon heating, low degree of crosslinking | [33,34,35] |
Electrostatic (ionic) interactions | Interaction between positively charged ions (Ca2+, Mg2+, Cu2+, etc.) and negatively charged functional groups or interaction between anionic and cationic molecules or polyelectrolytes under physiological environment | Safe and less toxic, In-situ formation, highly dynamic and reversible character, excellent tunability, stimuli-sensitive behavior | Weak mechanical characteristics, low degree of crosslinking | [36,37] |
Hydrophobic/hydrophilic interactions | Interaction between chemical groups located close to one another | Safe and less toxic, sol-gel transition (i.e., thermal gelation), highly dynamic and reversible character, and tunable properties | Low mechanical properties, hydrophobic/hydrophilic balance is sensitive to polar solvents and temperature, incapability to control the reaction growth, low degree of crosslinking, | [38,39] |
Entanglements of polymeric chains | Complication of intramolecular or intermolecular chains. | Safe and less toxic, enhanced interchain connectivity | Too weak, depends on molecular weight fraction of polymers | [40,41] |
Stereocomplex crystallization | Highly organized form of atoms or molecules/parallel or antiparallel interactions between two independent helices or co-crystallization between polymers with complementary configurations | Safe and less toxic, alternative packing of different polymer chains, and tunable and better mechanical properties | [42,43] | |
Metal coordination | A coordination complex of a central atom/ions (typically metallic) and surrounding arrangement of bound ligands | Safe and less toxic, complexation between ligand-adorned polymers and metal ions | Low degree of crosslinking | [44,45,46] |
Stacking of π–π bonds | Speculative attractive and noncovalent (orbital overlapping) interface between the π bonds in aromatic rings | Strong physical interaction (noncovalent), non-destructive and reversible, can provide hydrophobic domain | Low degree of crosslinking, not very weak interactions, not very directional, generally aromaticity is essential π–π stacking interactions, sensitive to polar solvents, non-negligible cytotoxicity | [47,48,49] |
Chemical approaches | ||||
Enzymatic effect | Enzyme catalyzes the functional groups of the substrate in close proximity | Highly biocompatible, high specificity (chemo-, region-, and stereo-selectivity), high crosslinking density, and minimal requirement | High processing cost, negligible recovery, high sterile condition required, high degree of crosslinking, | [24,50] |
Schiff-base reaction (imine formation) | Shortening of primary amines and active carbonyl groups (aldehyde or ketone) to form imine bonds | Dynamic reversibility, potential pH-sensitive linker, in situ formation of hydrogels | Required washing to remove remaining unreacted substances, high degree of crosslinking | [51,52] |
Michael type addition reaction | Reaction between nucleophile and crosslinked unsaturated carbonyl systems (e.g., olefins, alkynes) to form (-C–C-) bond | In situ formation of hydrogels | Required washing to remove remaining unreacted substances, high degree of crosslinking | [53,54] |
Oxime bond formation | Reaction between an aldehyde or ketone and hydroxylamine | Dynamic covalent character, high efficiency, chemo-selectivity, formation in aqueous solvents and water being the only side-product | Complex synthetic methods, Required washing to remove remaining unreacted substances, high degree of crosslinking | [55,56] |
Diels–Alder “click” reaction | No catalyst needed | Dynamic covalent character, mild and copper-free reaction, facile for in vitro and in vivo applications, | Long gelation time relatively, Required washing to remove remaining unreacted substances, high degree of crosslinking | [57,58] |
Free-radical polymerization | Production of free radicals in monomers using particular initiator and then they form long polymeric chains by joining them together through covalent bonding | Rapid and simple method, no sophisticated and expensive instruments needed | Difficult to control chain propagation, wide particle size distribution, required washing to remove remaining unreacted substances, high degree of crosslinking | [59,60] |
S. No | Enzyme Involved/ Mimicked | Composition | Key Features | Ref. |
---|---|---|---|---|
1. | Tyrosinase | Hyaluronic acid, Chitosan, Dopamine hydrochloride | Multilayer membrane formation, Enhanced cell adhesion, viability, proliferation, and density of immortalized murine calvarial cell line (MC3T3-E1) | [66] |
2. | Tyrosinase | Carboxymethyl–chitosan (CMC), Gelatin, Nano-hydroxyapatite | Assessment of CMC-dependent crosslinking and strength; support in proliferation and differentiation of osteoblast; gel stability in vivo | [67] |
3. | Tyrosinase | Silk fibroin, Gelatin, Calcium chloride | Enhanced the osteogenesis of bone marrow derived progenitor cells (hMSCs); upregulating the gene expression of osteogenic markers (RUNX2, COL I, ALP, OPN, ON); osteocytic markers (DMP 1, PDPN, SOST), and β-catenin, BMP-2, and BMP4; enhancing mineralization processes | [68] |
4. | Tyrosinase | Chitosan, Gelatin, Nanohydroxyapatite | Pore size greater than 150 µm; high swelling ratio; acceptable biodegradability and biocompatibility | [71] |
5. | Tyrosinase | Polycaprolactane, beta-tricalcium phosphate | Enhanced viability and proliferation of osteoblast cells; development of an osteo-mucosal model; stable adhesive strength in wet conditions | [72] |
6. | Lysozyme | Polyethylene Glycol (PEG) | Facile clinical process; good biocompatibility; tight adherence to tissues | [79] |
7. | Horseradish peroxidase (HRP) | Hyaluronic acid, Tyramine | In situ-formed hydrogels; sustained release of BMP-2 in vitro; enhanced gene expressions of osteogenic makers, Alpl, Bglap, and Osx; callus formation in fractured bone in vivo | [84] |
8. | Horseradish peroxidase (HRP) | Calcium-accumulating peptide, Collagen | Induced bone mineralization around the human periodontal ligament stem cells (PDLSCs) loaded in hydrogel; increased osteogenic marker expressions in vitro; formation of bone layer post implantation in vivo | [85] |
9. | Horseradish peroxidase (HRP) | Silk fibroin, Gelatin | Enhanced gelation kinetics; improved mechanical attributes; slow enzymatic degradation; imparted stiffness and β sheet formation; superior morphology and metabolic activity of human mesenchymal stem cells (hMSCs) | [86] |
10. | Horseradish peroxidase (HRP) | Tyramine, Gellan gum | High degree of substitution (~30%); sustained release of betamethasone; high mechanical strength; negligible cytotoxicity and non-significant change in the metabolic activity of chondrogenic primary cells | [87] |
11. | Transglutaminase | Gelatin, Alginate | Cost-effectiveness and adequate safety profile; offered antibacterial properties; effective in reducing implant-related infection; upon treatment in vivo, substantial higher bone volume with intact bony architect was observed | [93] |
12. | Transglutaminase | Gelatin, Hyaluronan, Bacteriological chondroitin, | Enhanced expression of osteocalcin, and osteopontin at gene and protein level in human dental pluripotent stem cells (hDPSCs); effective in accelerated bone regeneration | [94] |
13. | Alkaline phosphatase | Calcium phosphate, Collagen type-1, catechol substituted PEG (cPEG), Fumaric acid/PEG copolymer (OPF) | The effectiveness in mineral formation decreases in the order cPEG > collagen > OPF; highest increment of Young’s modulus in cPEG was demonstrated | [102] |
14. | Alkaline phosphatase | Yeast prion Sup35 with the insertion of peptide segment (GNNQQNY) | Self-assembled nanofibers formation of hydrogelators; cytocompatible upon the insertion of the peptide segment along with enhancement in self-assembly | [104] |
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Sood, A.; Ji, S.M.; Kumar, A.; Han, S.S. Enzyme-Triggered Crosslinked Hybrid Hydrogels for Bone Tissue Engineering. Materials 2022, 15, 6383. https://doi.org/10.3390/ma15186383
Sood A, Ji SM, Kumar A, Han SS. Enzyme-Triggered Crosslinked Hybrid Hydrogels for Bone Tissue Engineering. Materials. 2022; 15(18):6383. https://doi.org/10.3390/ma15186383
Chicago/Turabian StyleSood, Ankur, Seong Min Ji, Anuj Kumar, and Sung Soo Han. 2022. "Enzyme-Triggered Crosslinked Hybrid Hydrogels for Bone Tissue Engineering" Materials 15, no. 18: 6383. https://doi.org/10.3390/ma15186383
APA StyleSood, A., Ji, S. M., Kumar, A., & Han, S. S. (2022). Enzyme-Triggered Crosslinked Hybrid Hydrogels for Bone Tissue Engineering. Materials, 15(18), 6383. https://doi.org/10.3390/ma15186383