Application Progress of Modified Chitosan and Its Composite Biomaterials for Bone Tissue Engineering
Abstract
:1. Introduction
2. Post-Implantation Complications and the Safety of Chitosan
3. Fabrication Strategies
4. Modification Methods of Chitosan for BTE
5. Applications of Chitosan Cross-Linking Modification for BTE
5.1. Physically Cross-Linked Chitosan for BTE
5.2. Chemically Cross-Linked Chitosan for BTE
5.2.1. Aldehyde
5.2.2. Genipin
5.2.3. Tripolyphosphate (TPP)
5.2.4. Other Cross-linkers
5.2.5. Photo-Cross-Linked Chitosan
5.3. Enzymatic Cross-Linked Chitosan for BTE
6. Application of Structure-Modified Chitosan for BTE
6.1. Carboxymethyl Chitosan, CMCS
6.2. Hydroxypropyltrimethyl Ammonium Chloride Chitosan, HACC
6.3. Sulfated Chitosan, SCS
6.4. Glycol Chitosan, GCS
6.5. Guanidinylated Chitosan, GC
7. Application of Chitosan Grafted with Biodegradable Polymers for BTE
Modification | Fabrication | Materials | Effect | Cell/Model | Ref. |
---|---|---|---|---|---|
Physically cross-linked | ice template-assisted freeze-drying | EO-loaded CS/Dex | Exhibit antioxidant, antifungal properties and the inhibition of Candida parapsilosis fungi | - | [129] |
freeze-drying | nanoporous chitin hydrogels | Enhance the strength and Young’s modulus of hydrogel, mBMSC adhesion, and proliferation | mBMSC | [133] | |
direct ink writing (DWI) | CS/PVA | Promote toughness performance | - | [134] | |
double network | CS/PVA/HAp | Increase cell adhesion, proliferation, OCN, ALP, COL I, and osteochondral repair efficacy | Rat bone marrow mesenchymal stem cells (rBMSCs) and L929 cells (Mouse fibroblast cell line)/New Zealand white rabbits with a bone defect (5 mm in diameter and 8 mm deep) in the lateral femoral condyle | [147] | |
Aldehyde-crosslinking | freeze-drying | CS/HA/β-TCP | Promote biological performance, metabolic activity, ALP expression, cell morphology, cell/scaffold interaction, and gene expression | MG63 human osteoblastic-like cells | [153] |
freeze-drying | CS/vanillin hydrogel | Achieve a good balance between self-healing capability and mechanical strength | - | [156] | |
emulsion method | CS/vanillin hydrogel | Provide favorable cell attachment and biocompatibility | MG63 cell/ muscular incision 20 mm long on the backs of SD rats | [157] | |
freeze-drying | vanillin-CS/CS | Exhibit suitable viscosity values and shear thinning behavior for 3D printing applications | - | [158] | |
freeze-drying | Cinnamaldehyde/CS | Show thermal characteristics and stability and synergistic antibacterial activity against Staphylococcus aureus and Escherichia coli bacteria | Staphylococcus aureus or S. aureus (ATCC 25923) and Escherichia coli or E. coli (ATCC 35218) bacteria | [161] | |
Genipin cross-linking | CS and hyaluronic acid solutions PEC+BMP-2 | Control the swelling ratio and degradation of PEC and achieve quite a high loading efficacy, prolonged, and sustained BMP-2 release profile | MC3T3-E1 cells | [165] | |
mixing | gentamycin sulfate (GS)-loaded CMCS hydrogel | Achieve superb inhibition of bacterial growth and biofilm formation of Staphylococcus aureus, enhance the adhesion, proliferation, and differentiation of MC3T3-E1 cells | MC3T3-E1 cells | [168] | |
electrospinning | CS/HA nanofibers | Increase in Young’s modulus and osteoinductive bioactivity | Murine 7F2 osteoblast-like cells | [172] | |
mixing | CS/methylcellulose | Enhance fibroblast, endothelial, and osteoblast proliferation and adhesion | Osteoblasts, fibroblasts, and HUVECs | [173] | |
DWI and freeze-drying | HA/CS composite scaffolds | Friendly environment, increase cell population, levels of viability, and attachment | MG63 human osteoblast-like cells | [274] | |
self-assembly | HA/GO/CS composite hydrogel | Improve the microstructure and mechanical strength. Balance the rigidity and toughness of the composite hydrogel | Rat bone marrow mesenchymal stem cells (rBMSCs) | [275] | |
Tripolyphosphate (TPP) cross-linking | coacervation and lyophilization | nHA/CS/TPP Scaffolds | Exhibit highest ultimate compressive strength and show good osteoblast adhesion and proliferation | OB-6 line cell | [188] |
freeze-drying | CS/Gel/β-TCP scaffolds | Show mechanical improvements, bioactivity, high proliferation rate, high extracellular calcium deposition, excellent cell adhesion, and characteristic osteoblast cell morphology | Human osteoblast cells (CRL-11372) (hOB) | [179] | |
freeze-drying | HA/β-TCP/CS composites | Show good swelling properties, and higher levels of cell proliferation and growth | Human osteoblast-like cells (Saos-2) and mouse fibroblastic-like cells (L929) | [276] | |
Glycerylphytate (G1Phy) | 3d-printing and photopolymerization | GelMA/CS scaffold | Exhibit excellent shape fidelity, resolution, swelling behavior, and mechanical and biological properties; enhance cell adhesion and proliferation | L929 fibroblasts | [191] |
Carbodiimide and citric acid | extruded in a coagulant bath using viscose-type stainless steel spinneret | citrate–CS fibers | Improve the mechanical property, higher stability against enzymatic degradation and hydrophobicity, and superior bio-mineralization | MSCs New Zealand white male rabbits | [193] |
Photo-crosslinking | UV light | MCS/TPVA (Darocur 2959) | Exhibit rapid gelation behavior, improved stiff and compressive strength. Promote L929 cell attachment and proliferation | L929 cell | [200] |
visible blue light with riboflavin | CS-MTT hydrogel | Recruit native cells and promote calvarial healing without the delivery of additional therapeutic agents or stem cells | male CD-1 nude mice | [277] | |
blue light (420–460 nm) | ChI-MA/GO | Showe intermediate platelet aggregation hemolytic tendencies, enhance tissue regeneration | NHOst cells Reconstruction of the distal epiphysis of the femur | [199] | |
Enzymatic-crosslinking | Standard carbodiimide coupling method | HPP-GC + BMP(HRP + H2O2) | Localize osteoprogenitor recruitment and osteogenesis | Col3.6 rat critical sized bilateral calvarial defect model | [278] |
Carboxymethyl chitosan, CMCS | electrospinning | CMCS/HA | Increase the ALP activity and Runx2 expression, promote new bone formation and maturation | mBMSCs circular critical-size Calvarial bone defects (diameter of 5 mm) on both parietal bones of Sprague–Dawley rats | [211] |
electrospinning | PCL/CMCS nanofibrous scaffolds | Adjust the viscosity and charge density and exhibited excellent initial cell attachment and proliferation | human osteoblast cells (MG63) | [214] | |
freeze-drying | NOCC/FD composite hydrogel | Enhance the proliferation, ALP activity, and mineralization of osteoblast cells | L929 mouse fibroblasts and 7F2 osteoblast cell | [279] | |
freeze-drying | SF/CMCS/CNCs/Sr-HAp | Maintain high porosity with a lower swelling ratio, enhanced protein adsorption and ALP activity | bone mesenchymal stem cell (BMSC) | [217] | |
Hydroxypropyltrimethyl ammonium chloride chitosan (HACC) | 3D-printing | PLGA/HA/HACC composite scaffold | Favor cell attachment, proliferation, spreading, and osteogenic differentiation and exhibit good neovascularization and tissue integration | human bone marrow-derived mesenchymal stem cells (hBMSCs) | [219] |
solvent casting-particulate leaching method | silica/HACC/zein scaffold | Exhibit long-lasting antibacterial activity against Escherichia coli and Staphylococcus aureus, and significant early osteogenic differentiation | Rabbit model of critical-sized radius bone defect | [221] | |
PTFE mould | HACC-PMMA | Improve properties, stem cell proliferation, osteogenic differentiation, and osteogenesis-associated gene expression | human mesenchymal stem cells (hMSCs) | [224] | |
Sulfated chitosan (SCS) | - | 2-N,6-O- SCS + BMP-2 | Exhibit a higher cell viability and sprouting ability, secrete more VEGF and NO, and improve the angiogenic potential | Rat bone marrow stromal cells (BMSCs) | [231] |
solution casting | SCS coated on poly(d,l-lactide) (PDLLA) | Increase osteogenic- and angiogenic-related gene and protein expression | Mouse preosteoblast cells (MC3T3-E1s) and human umbilical vein endothelial cells (HUVECs) | [231] | |
- | 2-N,6-O- SCS + BMP-2 | Enhance BMP-2 bioactivity to induce osteoblastic differentiation in vitro and in vivo by promoting the BMP-2 signaling pathway | C2C12 cells | [232] | |
Glycol chitosan (GCS) | solvent cast and evaporation | nHA/GCS composites | No cytotoxicity and promotion of cell ingrowth and osteoconduction | osteoblastic-like (SAOS) and embryonic cell lines (HEK293T) | [238] |
solvent cast and evaporation | CHA/ SF/GCS/DF-PEG self-healing hydrogel + BMP-2 | Promote osteogenic differentiation of mOPCs and promote the proliferation and migration of HUVECs | C57BL/6 suckling rat A 4-mm-deep hole in the femoral condyle of SD rat | [280] | |
electrostatic interaction | GCS-HA NPs + PEGDA+ SrRNPs-H | Increase the level of bone regeneration | Dorsal incision around the lumbar and sacral pine area of male Wistar rats | [240] | |
Guanidinylated chitosan (GC) | sol–gel chemistry and freeze-drying | Sulfonate and carboxylate-containing chitosan/silica hybrid composites | Showed a substantial effect on the mineralization of calcium phosphate and was more efficient to induce heterogeneous nucleation and growth of hydroxyapatite | - | [281] |
- | GC/PANI-containing self-healing semi-conductive waterborne scaffolds | Exhibit excellent shape memory properties and shape recovery ratio, enhanced cell attachment, COL-1, ALP, RUNX2, and OCN expression | Human adipose-derived mesenchymal stem cells (hADSCs) | [282] | |
mixing | LNSs/GC | Show inherent osteogenic properties, a versatile moldable vehicle, facilitating handling and osteogenic potential | Mouse bone marrow stromal cell line (BMSCs, D1 ORL UVA [D1], D1 cell, CRL-12424) | [242] | |
Grafted with PLA | electrospun | CS/PLA/HA | Enhance proliferation of MC3T3-E1 cells used in applications as coating materials on medical devices | MC3T3-E1 cells | [268] |
Grafted with HPMC | coupling reagent-mediated approach | CS/HPMC | Highly water-soluble across a wide pH range, high pH buffering capacity, and a high drug encapsulation efficiency | Metronidazole, methylene blue, tetracycline hydrochloride, and mometasone furoate as drug models | [270] |
Grafted with CMC | Freeze-drying | CS/HPMC/ mesoporous wollastonite | Cyto-friendly nature to human osteoblastic cells, confirmed by calcium deposition and expression of an osteoblast-specific microRNA | MG-63 | [271] |
Grafted with cycle RGD peptide | noncovalent method | CS/cRGD/GO | Provide a multifunctional drug delivery system and can be efficiently loaded with a number of therapeutic agents for biomedical applications | hepatoma cells (Bel-7402, SMMC-7721, HepG2) | [273] |
Grafted with HVP-aldehyde peptide | mixing | CS/HVP | Support the adhesion of osteoblasts, the formation of elongated cell shapes, and increased osteoblast differentiation. | Human (h) osteoblast cells | [283] |
8. Future Directions for Modified CS-Based Bone Scaffolds
9. Challenges and Future Prospects
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Animals/Volunteers (Total) | Incisions/Defects/Cells | Chitosan-Based Form | Effects | Ref. | |
---|---|---|---|---|---|
Preclinical trials | Beagles (n/d) | Open skin wounds on the dorsal side | 20 mg/wound (2 × 2 cm) | Activate immunocytes and inflammatory cells | [53] |
Mail Wistar rats (60) | Bone defects measuring 2 mm in diameter in both tibias | CS/D. ambrosioides spheres | Faster bone regeneration and a controlled release of the extract | [54] | |
New Zealand white rabbits (20) | Undergoing TKA surgery and implanted with titanium rod prostheses | CMCS hydrogel | Reduce the inflammatory response around rabbit knee prostheses, affect the OPG/RANKL/RANK signaling pathway, and promote osteogenesis. | [56] | |
Clinical trials | Patients undergoing abdominal surgery (30) | Wound incisions | CS membrane | An effective antimicrobial and procoagulant and promote wound repair by providing a suitable environment for beneficial microbiota | [57] |
Patients aged 50–70 years old undergoing total or elective hip replacement (n/d) | Human bone marrow stromal cells | CS immobilized glasses | Stimulate fast osteoblast response, displaying rapid cell spreading and cytoskeleton reorganization | [58] |
Cross-linking Method | Strength | Limit |
---|---|---|
Physical cross-linking |
|
|
Chemical cross-linking |
|
|
Enzymatic cross-linking |
|
|
Cross-Linking Agents | Cross-Linking Mechanism |
---|---|
Glutaraldehyde(GA) | |
Vanillin | |
Genipin | |
Tripolyphosphate, TPP | |
Carbodiimide(NHS/EDC) | |
Enzymatic-cross-linking (HRP) | |
Photoinitiators | |
Methylmethacrylate chitosan, ChMA |
CS derivates | Chemical formula |
---|---|
Carboxymethyl chitosan, CMC | |
Hydroxypropyltrimethyl ammonium chloride chitosan, HACC | |
Sulfated chitosan, SCS | |
Glycol chitosan, GCS | |
Guanidinylated chitosan, GC |
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Zhu, Y.; Zhang, Y.; Zhou, Y. Application Progress of Modified Chitosan and Its Composite Biomaterials for Bone Tissue Engineering. Int. J. Mol. Sci. 2022, 23, 6574. https://doi.org/10.3390/ijms23126574
Zhu Y, Zhang Y, Zhou Y. Application Progress of Modified Chitosan and Its Composite Biomaterials for Bone Tissue Engineering. International Journal of Molecular Sciences. 2022; 23(12):6574. https://doi.org/10.3390/ijms23126574
Chicago/Turabian StyleZhu, Yuemeng, Yidi Zhang, and Yanmin Zhou. 2022. "Application Progress of Modified Chitosan and Its Composite Biomaterials for Bone Tissue Engineering" International Journal of Molecular Sciences 23, no. 12: 6574. https://doi.org/10.3390/ijms23126574