10.1007/s40204-022-00185-8

Injectable hydrogels for bone and cartilage tissue engineering: a review

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  • Nafiseh Olov1,
  • Shadab Bagheri-Khoulenjani1,
  • Hamid Mirzadeh*1,
  1. Polymer and Colour Engineering Department, Amirkabir University of Technology, Tehran, 15875-4413, IR

Published in Issue 2022-04-14

How to Cite

Olov, N., Bagheri-Khoulenjani, S., & Mirzadeh, H. (2022). Injectable hydrogels for bone and cartilage tissue engineering: a review. Progress in Biomaterials, 11(2 (June 2022). https://doi.org/10.1007/s40204-022-00185-8
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Abstract

Abstract Tissue engineering, using a combination of living cells, bioactive molecules, and three-dimensional porous scaffolds, is a promising alternative to traditional treatments such as the use of autografts and allografts for bone and cartilage tissue regeneration. Scaffolds, in this combination, can be applied either through surgery by implantation of cell-seeded pre-fabricated scaffolds, or through injection of a solidifying precursor and cell mixture, or as an injectable cell-seeded pre-fabricated scaffold. In situ forming and pre-fabricated injectable scaffolds can be injected directly into the defect site with complex shape and critical size in a minimally invasive manner. Proper and homogeneous distribution of cells, biological factors, and molecular signals in these injectable scaffolds is another advantage over pre-fabricated scaffolds. Due to the importance of injectable scaffolds in tissue engineering, here different types of injectable scaffolds, their design challenges, and applications in bone and cartilage tissue regeneration are reviewed.

Keywords

  • In situ injectable hydrogels,
  • Injectable microparticles,
  • Injectable shape memory scaffolds,
  • Bone tissue engineering,
  • Cartilage tissue engineering

References

  1. Aalaie and Vasheghani-Farahani (2012) Swelling behavior of sulfonated polyacrylamide nanocomposite hydrogels in electrolyte solutions: comparison of theoretical and experimental results 21(3) (pp. 175-183) https://doi.org/10.1007/s13726-012-0016-3
  2. Aalaie et al. (2008) Effect of montmorillonite on gelation and swelling behavior of sulfonated polyacrylamide nanocomposite hydrogels in electrolyte solutions 44(7) (pp. 2024-2031) https://doi.org/10.1016/j.eurpolymj.2008.04.031
  3. Abdollahi Boraei et al. (2021) Enhanced osteogenesis of gelatin–halloysite nanocomposite scaffold mediated by loading strontium ranelate 70(6) (pp. 392-402) https://doi.org/10.1080/00914037.2020.1725754
  4. Ahmadian et al. (2019) The effect of hyaluronic acid hydrogels on dental pulp stem cells behavior (pp. 245-254) https://doi.org/10.1016/j.ijbiomac.2019.08.119
  5. Amsden (2015) Biodegradable injectable in situ forming drug delivery systems (pp. 9-28) https://doi.org/10.1016/S0168-3659(02)00008-1
  6. Appel et al. (2010) Supramolecular cross-linked networks via host-guest complexation with cucurbit[8]uril 132(40) (pp. 14251-14260) https://doi.org/10.1021/ja106362w
  7. Bagheri Khoulenjani S, Etrati-Khosroshahi M, Mirzadeh H (2010) Fabrication and characterization of a natural injectable nanocomposite for bone tissue engineering applications. Amirkabir University of Technology
  8. Bagheri-khoulenjani et al. (2012) A novel injectable bio-nanocomposite for bone tissue engineering applications 35(8)
  9. Bagheri-Khoulenjani et al. (2013) Particle size modeling and morphology study of chitosan/gelatin/nanohydroxyapatite nanocomposite microspheres for bone tissue engineering 101(6) (pp. 1758-1767) https://doi.org/10.1002/jbm.a.34481
  10. Bai et al. (2016) Self-reinforcing injectable hydrogel with both high water content and mechanical strength for bone repair (pp. 546-556) https://doi.org/10.1016/j.cej.2015.12.021
  11. Bai et al. (2017) Dual crosslinked chondroitin sulfate injectable hydrogel formed via continuous diels-alder (DA) click chemistry for bone repair (pp. 123-130) https://doi.org/10.1016/j.carbpol.2017.02.062
  12. Baker et al. (2013) Shape memory poly(ε-caprolactone)-co-poly(ethylene glycol) foams with body temperature triggering and two-way actuation 1(38) https://doi.org/10.1039/c3tb20810a
  13. Bakhshi et al. (2006) The effect of additives on naltrexone hydrochloride release and solvent removal rate from an injectable in situ forming PLGA implant 17(5) (pp. 354-359) https://doi.org/10.1002/pat.717
  14. Baruch and Machluf (2006) Alginate–chitosan complex coacervation for cell encapsulation: effect on mechanical properties and on long-term viability 82(6) (pp. 570-579) https://doi.org/10.1002/bip.20509
  15. Basu et al. (2020) Self-healing DNA-based injectable hydrogels with reversible covalent linkages for controlled drug delivery (pp. 159-169) https://doi.org/10.1016/j.actbio.2020.01.021
  16. Behtouei et al. (2022) Bead-free and tough electrospun PCL/gelatin/PGS ternary nanofibrous scaffolds for tissue engineering application 139(2) (pp. 12-14) https://doi.org/10.1002/app.51471
  17. Bencherif et al. (2012) Injectable preformed scaffolds with shape-memory properties 109(48) (pp. 19590-19595) https://doi.org/10.1073/pnas.1211516109
  18. Bhatia et al. (2005) Polyelectrolytes for cell encapsulation 10(1) (pp. 45-51) https://doi.org/10.1016/j.cocis.2005.05.004
  19. Bulmus (2011) RAFT polymerization mediated bioconjugation strategies 2(7) (pp. 1463-1472) https://doi.org/10.1039/C1PY00039J
  20. Bush et al. (2016) Xylan hemicellulose improves chitosan hydrogel for bone tissue regeneration 27(8) (pp. 1050-1055) https://doi.org/10.1002/pat.3767
  21. Chang et al. (2017) Injectable scaffolds: preparation and application in dental and craniofacial regeneration (pp. 1-26) https://doi.org/10.1016/j.mser.2016.11.001
  22. Chatani et al. (2013) Relative reactivity and selectivity of vinyl sulfones and acrylates towards the thiol-michael addition reaction and polymerization 4(4) (pp. 1048-1055) https://doi.org/10.1039/C2PY20826A
  23. Chen et al. (2018) Injectable self-crosslinking HA-SH/Col I blend hydrogels for in vitro construction of engineered cartilage (pp. 57-66) https://doi.org/10.1016/j.carbpol.2018.02.057
  24. Cheng et al. (2017) Injectable shape-memorizing three-dimensional hyaluronic acid cryogels for skin sculpting and soft tissue reconstruction 23(5–6) (pp. 243-251) https://doi.org/10.1089/ten.tea.2016.0263
  25. Chia et al. (2002) Multi-layered microcapsules for cell encapsulation 23(3) (pp. 849-856) https://doi.org/10.1016/S0142-9612(01)00191-0
  26. Chuang et al. (2018) Hydrogels for the application of articular cartilage tissue engineering: a review of hydrogels https://doi.org/10.1155/2018/4368910
  27. Chung and Park (2007) Surface engineered and drug releasing pre-fabricated scaffolds for tissue engineering 59(4) (pp. 249-262) https://doi.org/10.1016/j.addr.2007.03.015
  28. Chung et al. (2008) Highly open porous biodegradable microcarriers: in vitro cultivation of chondrocytes for injectable delivery 14(5) (pp. 607-615) https://doi.org/10.1089/tea.2007.0263
  29. Cleutjens and Creemers (2002) Integration of concepts: cardiac extracellular matrix remodeling after myocardial infarction 8(6) (pp. S344-348) https://doi.org/10.1054/jcaf.2002.129261
  30. Cui et al. (2010) Self-assembly of peptide amphiphiles: from molecules to nanostructures to biomaterials 94(1) (pp. 1-18) https://doi.org/10.1002/bip.21328
  31. Dehsorkhi et al. (2014) Self-assembling amphiphilic peptides 20(7) (pp. 453-467) https://doi.org/10.1002/psc.2633
  32. Divband et al. (2021) Bioactive chitosan biguanidine-based injectable hydrogels as a novel BMP-2 and VEGF carrier for osteogenesis of dental pulp stem cells https://doi.org/10.1016/j.carbpol.2021.118589
  33. Donati et al. (2009) Experimental evidence of counterion affinity in alginates: the case of nongelling ion Mg2+ 113(39) (pp. 12877-12886) https://doi.org/10.1021/jp902912m
  34. Dyondi et al. (2012) A nanoparticulate injectable hydrogel as a tissue engineering scaffold for multiple growth factor delivery for bone regeneration https://doi.org/10.2147/IJN.S37953
  35. Eftekhari et al. (2020) The use of nanomaterials in tissue engineering for cartilage regeneration; current approaches and future perspectives 21(2) https://doi.org/10.3390/ijms21020536
  36. Elisseeff et al. (2000) Photoencapsulation of chondrocytes in poly(ethylene oxide)-based semi-interpenetrating networks 51(2) https://doi.org/10.1002/(sici)1097-4636(200008)51:2<164::aid-jbm4>3.3.co;2-n
  37. Emami et al. (2021) Modified hydroxyapatite nanoparticles reinforced nanocomposite hydrogels based on gelatin/oxidized alginate via schiff base reaction https://doi.org/10.1016/j.carpta.2021.100056
  38. Eshghi Esfahani et al. (2021) 5-Fluorouracil-loaded poly(vinyl alcohol)/chitosan blend nanofibers: morphology, drug release and cell culture studies 30(2) (pp. 167-177) https://doi.org/10.1007/s13726-020-00882-w
  39. Fang et al. (2014) Poly(l-glutamic acid)/chitosan polyelectrolyte complex porous microspheres as cell microcarriers for cartilage regeneration 10(1) (pp. 276-288) https://doi.org/10.1016/j.actbio.2013.09.002
  40. Feng et al. (2017) Corrigendum to ‘mechanically resilient, injectable, and bioadhesive supramolecular gelatin hydrogels crosslinked by weak host–guest interactions assist cell infiltration and in situ tissue regeneration’ [Biomaterials 101C (2016) 217–228] (pp. 346-347) https://doi.org/10.1016/j.biomaterials.2016.09.012
  41. Gao et al. (2017) Sr-HA-graft-poly(γ-benzyl-l-glutamate) nanocomposite microcarriers: controllable Sr2+ release for accelerating osteogenenisis and bony nonunion repair 18(11) (pp. 3742-3752) https://doi.org/10.1021/acs.biomac.7b01101
  42. Gao et al. (2018) Fabrication and characterization of collagen-based injectable and self-crosslinkable hydrogels for cell encapsulation (pp. 448-456) https://doi.org/10.1016/j.colsurfb.2018.04.009
  43. Gao et al. (2018) Injectable and self-crosslinkable hydrogels based on collagen type II and activated chondroitin sulfate for cell delivery 118(2018) (pp. 2014-2020) https://doi.org/10.1016/j.ijbiomac.2018.07.079
  44. Ghaeini-Hesaroeiye et al. (2020) Dual responsive chondroitin sulfate based nanogel for antimicrobial peptide delivery (pp. 297-304) https://doi.org/10.1016/j.ijbiomac.2019.12.026
  45. Ghanbari et al. (2021) Thermosensitive alginate-gelatin-nitrogen-doped carbon dots scaffolds as potential injectable hydrogels for cartilage tissue engineering applications 11(30) (pp. 18423-18431) https://doi.org/10.1039/d1ra01496j
  46. Ghanian et al. (2018) In situ forming, cytocompatible, and self-recoverable tough hydrogels based on dual ionic and click cross-linked alginate 19(5) (pp. 1646-1662) https://doi.org/10.1021/acs.biomac.8b00140
  47. Gilarska et al. (2020) Bioactive yet antimicrobial structurally stable collagen/chitosan/lysine functionalized hyaluronic acid-based injectable hydrogels for potential bone tissue engineering applications (pp. 938-950) https://doi.org/10.1016/j.ijbiomac.2019.11.052
  48. Gohil and Kumar (2017) An injectable and biomimetic multi-phase nanocomposite for non-invasive bone tissue engineering: fabrication and mechanistic evaluation 28(11) (pp. 1453-1463) https://doi.org/10.1002/pat.4022
  49. Goodarzi et al. (2020) Injectable drug loaded gelatin based scaffolds as minimally invasive approach for drug delivery system: CNC/PAMAM nanoparticles https://doi.org/10.1016/J.EURPOLYMJ.2020.109992
  50. Gopinathan and Noh (2018) Click chemistry-based injectable hydrogels and bioprinting inks for tissue engineering applications 15(5) (pp. 531-546) https://doi.org/10.1007/s13770-018-0152-8
  51. Hadi Derakhshan et al. (2015) In situ forming hydrogel based on chondroitin sulfate-hydroxyapatite for bone tissue engineering 64(17) (pp. 919-926) https://doi.org/10.1080/00914037.2015.1030662
  52. Hashemi Doulabi et al. (2008) Synthesis and preparation of biodegradable and visible light crosslinkable unsaturated fumarate-based networks for biomedical applications 19(9) (pp. 1199-1208) https://doi.org/10.1002/pat.1112
  53. Hashemi Doulabi et al. (2015) Potential application of a visible light-induced photocured hydrogel film as a wound dressing material (pp. 1-10) https://doi.org/10.1155/2015/867928
  54. Hou et al. (2004) Injectable scaffolds for tissue regeneration 14(13) (pp. 1915-1923) https://doi.org/10.1039/b401791a
  55. Hunt and Grover (2010) Cell encapsulation using biopolymer gels for regenerative medicine 32(6) (pp. 733-742) https://doi.org/10.1007/s10529-010-0221-0
  56. Jeong et al. (2020) Supramolecular injectable hyaluronate hydrogels for cartilage tissue regeneration 3(8) (pp. 5040-5047) https://doi.org/10.1021/acsabm.0c00537
  57. Jiang et al. (2014) Click hydrogels, microgels and nanogels: emerging platforms for drug delivery and tissue engineering 35(18) (pp. 4969-4985) https://doi.org/10.1016/j.biomaterials.2014.03.001
  58. Jin et al. (2007) Enzyme-mediated fast in situ formation of hydrogels from dextran–tyramine conjugates 28(18) (pp. 2791-2800) https://doi.org/10.1016/j.biomaterials.2007.02.032
  59. Jin et al. (2009) Injectable chitosan-based hydrogels for cartilage tissue engineering 30(13) (pp. 2544-2551) https://doi.org/10.1016/j.biomaterials.2009.01.020
  60. Jin et al. (2010) Synthesis and characterization of hyaluronic acid-poly(ethylene glycol) hydrogels via michael addition: an injectable biomaterial for cartilage repair 6(6) (pp. 1968-1977) https://doi.org/10.1016/j.actbio.2009.12.024
  61. Jin et al. (2011) Chondrogenesis in injectable enzymatically crosslinked heparin/dextran hydrogels 152(1) (pp. 186-195) https://doi.org/10.1016/j.jconrel.2011.01.031
  62. Jonidi Shariatzadeh et al. (2021) Injectable and reversible preformed cryogels based on chemically crosslinked gelatin methacrylate (GelMA) and physically crosslinked hyaluronic acid (HA) for soft tissue engineering https://doi.org/10.1016/j.colsurfb.2021.111725
  63. Kazemi-Aghdam et al. (2021) Injectable chitosan hydrogel embedding modified halloysite nanotubes for bone tissue engineering https://doi.org/10.1016/j.carbpol.2021.118311
  64. Khan et al. (2015) Fabrication of polymeric biomaterials: a strategy for tissue engineering and medical devices (pp. 8224-8249) https://doi.org/10.1039/C5TB01370D
  65. Khan et al. (2020) Synthesis of physically cross-linked gum arabic-based polymer hydrogels with enhanced mechanical, load bearing and shape memory behavior 29(4) (pp. 351-360) https://doi.org/10.1007/s13726-020-00801-z
  66. Kim et al. (2005) Microsphere of apatite-gelatin nanocomposite as bone regenerative filler 16(12) (pp. 1105-1109) https://doi.org/10.1007/s10856-005-4714-7
  67. Kim et al. (2007) Bone regeneration using hyaluronic acid-based hydrogel with bone morphogenic protein-2 and human mesenchymal stem cells 28(10) (pp. 1830-1837) https://doi.org/10.1016/j.biomaterials.2006.11.050
  68. Kim et al. (2008) Injectable in situ–forming PH/thermo-sensitive hydrogel for bone tissue engineering 15(4) (pp. 923-933) https://doi.org/10.1089/ten.tea.2007.0407
  69. Kim et al. (2010) Heparin-based hydrogel as a matrix for encapsulation and cultivation of primary hepatocytes 31(13) (pp. 3596-3603) https://doi.org/10.1016/j.biomaterials.2010.01.068
  70. Kim et al. (2018) Enzyme-mediated tissue adhesive hydrogels for meniscus repair (pp. 479-487) https://doi.org/10.1016/j.ijbiomac.2017.12.053
  71. Kim et al. (2020) Injectable hydrogels based on MPEG-PCL-RGD and BMSCs for bone tissue engineering 8(15) (pp. 4334-4345) https://doi.org/10.1039/d0bm00588f
  72. Kiran et al. (2020) Synthesis, characterization of β-CD based novel hydrogels with dual objectives of drug release and dye removal 29(7) (pp. 615-623) https://doi.org/10.1007/s13726-020-00826-4
  73. Kocak et al. (2020) In-situ forming ph and thermosensitive injectable hydrogels to stimulate angiogenesis: potential candidates for fast bone regeneration applications https://doi.org/10.3390/ijms21051633
  74. Kondiah PJ, Choonara YE, Kondiah PPD, Marimuthu T, Kumar P, Du Toit LC, Pillay V (2016) A review of injectable polymeric hydrogel systems for application in bone tissue engineering. Molecules 21(11)
  75. Kondiah et al. (2017) Development of an injectable pseudo-bone thermo-gel for application in small bone fractures 520(1–2) (pp. 39-48) https://doi.org/10.1016/j.ijpharm.2017.01.039
  76. Koshy et al. (2014) Injectable, porous, and cell-responsive gelatin cryogels 35(8) (pp. 2477-2487) https://doi.org/10.1016/j.biomaterials.2013.11.044
  77. Koshy et al. (2016) Click-crosslinked injectable gelatin hydrogels 5(5) (pp. 541-547) https://doi.org/10.1002/adhm.201500757
  78. Kretlow and Klouda (2007) Injectable matrices and scaffolds for drug delivery in tissue engineering 59(4) (pp. 263-273) https://doi.org/10.1016/j.addr.2007.03.013
  79. Krishnamachari et al. (2008) Self-assembly of cell–microparticle hybrids 20(5) (pp. 989-993) https://doi.org/10.1002/adma.200701689
  80. Kumar Meena et al. (2019) Polymeric microgels for bone tissue engineering applications—a review https://doi.org/10.1080/00914037.2019.1570512
  81. Kunkit et al. (2019) Physical hydrogels prepared from cationically modified pectin with tunable sol-gel phase transition behaviors https://doi.org/10.1080/00914037.2019.1695208
  82. Kwon et al. (2014) In vivo osteogenic differentiation of human turbinate mesenchymal stem cells in an injectable in situ-forming hydrogel 35(20) (pp. 5337-5346) https://doi.org/10.1016/j.biomaterials.2014.03.045
  83. Langer and Vacanti (1999) Tissue engineering: the challenges ahead (pp. 86-89) https://doi.org/10.1038/scientificamerican0499-86
  84. Laughlin et al. (2008) In vivo imaging of membrane-associated glycans in developing zebrafish 320(5876) (pp. 664-667) https://doi.org/10.1126/science.1155106
  85. Lee and Tae (2007) Formulation and in vitro characterization of an in situ gelable, photo-polymerizable pluronic hydrogel suitable for injection 119(3) (pp. 313-319) https://doi.org/10.1016/j.jconrel.2007.03.007
  86. Lee et al. (2001) Degradable and injectable poly(aldehyde guluronate) hydrogels for bone tissue engineering 56(2) (pp. 228-233) https://doi.org/10.1002/1097-4636(200108)56:2<228::AID-JBM1089>3.0.CO;2-9
  87. Lendlein and Langer (2002) Biodegradable, elastic shape-memory polymers for potential biomedical applications 296(5573) (pp. 1673-1676) https://doi.org/10.1126/science.1066102
  88. Li (2010) Self-assembled supramolecular hydrogels based on polymer–cyclodextrin inclusion complexes for drug delivery (pp. 112-118) https://doi.org/10.1038/asiamat.2010.84
  89. Li et al. (2010) Investigation into thiol-(meth)acrylate michael addition reactions using amine and phosphine catalysts 1(8) (pp. 1196-1204) https://doi.org/10.1039/C0PY00100G
  90. Li et al. (2017) Accelerated bony defect healing based on chitosan thermosensitive hydrogel scaffolds embedded with chitosan nanoparticles for the delivery of BMP2 plasmid DNA 105(1) (pp. 265-273) https://doi.org/10.1002/jbm.a.35900
  91. Li et al. (2018) Self-crosslinking and injectable chondroitin sulfate/pullulan hydrogel for cartilage tissue engineering (pp. 173-183) https://doi.org/10.1016/j.apmt.2017.12.002
  92. Li et al. (2020) Injectable hydrogels based on gellan gum promotes in situ mineralization and potential osteogenesis https://doi.org/10.1016/j.eurpolymj.2020.110091
  93. Lin et al. (2013) Thermoresponsive hydrogels from phosphorylated ABA triblock copolymers: a potential scaffold for bone tissue engineering 14(7) (pp. 2206-2214) https://doi.org/10.1021/bm4003442
  94. Liu et al. (2007) Review of progress in shape-memory polymers 17(16) https://doi.org/10.1039/b615954k
  95. Liu et al. (2009) Gradient collagen/nanohydroxyapatite composite scaffold: development and characterization 5(2) (pp. 661-669) https://doi.org/10.1016/j.actbio.2008.09.022
  96. Liu et al. (2011) Nanofibrous hollow microspheres self-assembled from star-shaped polymers as injectable cell carriers for knee repair 10(5) (pp. 398-406) https://doi.org/10.1038/nmat2999
  97. Liu et al. (2016) Poly(ε-caprolactone) dendrimer cross-linked via metal-free click chemistry: injectable hydrophobic platform for tissue engineering 5(11) (pp. 1261-1265) https://doi.org/10.1021/acsmacrolett.6b00736
  98. Liu et al. (2020) Injectable electrical conductive and phosphate releasing gel with two-dimensional black phosphorus and carbon nanotubes for bone tissue engineering 6(8) (pp. 4653-4665) https://doi.org/10.1021/acsbiomaterials.0c00612
  99. Ma et al. (2010) Injectable hydrogels based on chitosan derivative/polyethylene glycol dimethacrylate/n, n-dimethylacrylamide as bone tissue engineering matrix 79(3) (pp. 620-627) https://doi.org/10.1016/j.carbpol.2009.09.015
  100. Makvandi et al. (2020) Hyaluronic acid/corn silk extract based injectable nanocomposite: a biomimetic antibacterial scaffold for bone tissue regeneration https://doi.org/10.1016/j.msec.2019.110195
  101. Makvandi et al. (2021) Correction to: injectable hyaluronic acid-based antibacterial hydrogel adorned with biogenically synthesized AgNPs-decorated multi-walled carbon nanotubes 10(4) (pp. 321-322) https://doi.org/10.1007/s40204-021-00170-7
  102. Mather et al. (2006) Michael addition reactions in macromolecular design for emerging technologies 31(5) (pp. 487-531) https://doi.org/10.1016/j.progpolymsci.2006.03.001
  103. Matsuno et al. (2008) Preparation of injectable 3D-formed beta-tricalcium phosphate bead/alginate composite for bone tissue engineering 27(6) (pp. 827-834) https://doi.org/10.4012/dmj.27.827
  104. Mi et al. (2017) Injectable nanoparticles/hydrogels composite as sustained release system with stromal cell-derived factor-1α for calvarial bone regeneration https://doi.org/10.1016/j.ijbiomac.2017.03.098
  105. Mohamadnia et al. (2009) Investigation of drug release and 1H-NMR analysis of the in situ forming systems based on poly(lactide-co-glycolide) 20(1) (pp. 48-57) https://doi.org/10.1002/pat.1279
  106. Montgomery et al. (2017) Flexible shape-memory scaffold for minimally invasive delivery of functional tissues 16(10) (pp. 1038-1046) https://doi.org/10.1038/nmat4956
  107. Motlaq et al. (2019) Differences in self-assembly features of thermoresponsive anionic triblock copolymers synthesized via one-pot or two-pot by atom transfer radical polymerization 57(9) (pp. 524-534) https://doi.org/10.1002/polb.24808
  108. Nair and Laurencin (2007) Biodegradable polymers as biomaterials 32(8) (pp. 762-798) https://doi.org/10.1016/j.progpolymsci.2007.05.017
  109. Nemati Hayati et al. (2012) Characterization of poly(3-hydroxybutyrate)/nano-hydroxyapatite composite scaffolds fabricated without the use of organic solvents for bone tissue engineering applications 32(3) (pp. 416-422) https://doi.org/10.1016/j.msec.2011.11.013
  110. Neuss et al. (2009) The use of a shape-memory poly(e{lunate}-caprolactone)dimethacrylate network as a tissue engineering scaffold 30(9) (pp. 1697-1705) https://doi.org/10.1016/j.biomaterials.2008.12.027
  111. Nguyen and West (2002) Photopolymerizable hydrogels for tissue engineering applications 23(22) (pp. 4307-4314) https://doi.org/10.1016/S0142-9612(02)00175-8
  112. Ni et al. (2014) Injectable thermosensitive PEG-PCL-PEG hydrogel/acellular bone matrix composite for bone regeneration in cranial defects 35(1) (pp. 236-248) https://doi.org/10.1016/j.biomaterials.2013.10.016
  113. Nikpour et al. (2021) Biological and bioactivity assessment of dextran nanocomposite hydrogel for bone regeneration 10(4) (pp. 271-280) https://doi.org/10.1007/s40204-021-00171-6
  114. Nimmo et al. (2011) Diels-alder click cross-linked hyaluronic acid hydrogels for tissue engineering 12(3) (pp. 824-830) https://doi.org/10.1021/bm101446k
  115. Niranjan et al. (2013) A novel injectable temperature-sensitive zinc doped chitosan/β-glycerophosphate hydrogel for bone tissue engineering 54(1) (pp. 24-29) https://doi.org/10.1016/j.ijbiomac.2012.11.026
  116. Orive et al. (2003) Cell encapsulation: promise and progress 9(1) (pp. 104-107) https://doi.org/10.1038/nm0103-104
  117. Ossipov et al. (2007) Formation of the first injectable poly(vinyl alcohol) hydrogel by mixing of functional PVA precursors 106(1) (pp. 60-70) https://doi.org/10.1002/app.26455
  118. Park et al. (2019) An injectable, click-crosslinked, cytomodulin-modified hyaluronic acid hydrogel for cartilage tissue engineering 11(1) (pp. 1-16) https://doi.org/10.1038/s41427-019-0130-1
  119. Perez et al. (2014) Utilizing core-shell fibrous collagen-alginate hydrogel cell delivery system for bone tissue engineering 20(1–2) (pp. 103-114) https://doi.org/10.1089/ten.TEA.2013.0198
  120. Pourjavadi et al. (2019) Injectable chitosan/κ-carrageenan hydrogel designed with au nanoparticles: a conductive scaffold for tissue engineering demands (pp. 310-317) https://doi.org/10.1016/j.ijbiomac.2018.11.256
  121. Ren et al. (2018) Injectable polysaccharide hydrogel embedded with hydroxyapatite and calcium carbonate for drug delivery and bone tissue engineering (pp. 1257-1266) https://doi.org/10.1016/j.ijbiomac.2018.06.200
  122. Ressler et al. (2018) Injectable chitosan-hydroxyapatite hydrogels promote the osteogenic differentiation of mesenchymal stem cells (pp. 469-477) https://doi.org/10.1016/j.carbpol.2018.06.029
  123. Ressler et al. (2021) Ionic substituted hydroxyapatite for bone regeneration applications: a review (pp. 1-16) https://doi.org/10.1016/j.oceram.2021.100122
  124. Rottensteiner et al. (2014) In vitro and in vivo biocompatibility of alginate dialdehyde/gelatin hydrogels with and without nanoscaled bioactive glass for bone tissue engineering applications 7(3) (pp. 1957-1974) https://doi.org/10.3390/ma7031957
  125. Salem et al. (2003) Porous polymer and cell composites that self-assemble in situ 15(3) (pp. 210-213) https://doi.org/10.1002/adma.200390047
  126. Sanmartín-Masiá et al. (2017) Extracellular matrix-inspired gelatin/hyaluronic acid injectable hydrogels 66(6) (pp. 280-288) https://doi.org/10.1080/00914037.2016.1201828
  127. Seo et al. (2017) Tuning physical properties and BMP-2 release rates of injectable hydrogel systems for an optimal bone regeneration effect (pp. 91-104) https://doi.org/10.1016/j.biomaterials.2017.01.016
  128. Shapiro (2008) Bone development and its relation to fracture repair. The role of mesenchymal osteoblasts and surface osteoblasts (pp. 53-76) https://doi.org/10.22203/eCM.v015a05
  129. Sharifi S, Mirzadeh H, Imani M, Atai M, Ziaee F (2007) Photopolymerization and shrinkage kinetics of in situ crosslinkable n-vinyl-pyrrolidone/poly(e-caprolactone fumarate ) networks.
  130. https://doi.org/10.1002/jbm.a
  131. Sharifi et al. (2008) Synthesis, photocrosslinking characteristics, and biocompatibility evaluation of n-vinyl pyrrolidone/polycaprolactone fumarate biomaterials using a new proton scavenger 19(6) (pp. 1828-1838) https://doi.org/10.1002/pat.1134
  132. Sharifi et al. (2009) Synthesis, characterization, and biocompatibility of novel injectable, biodegradable, and in situ crosslinkable polycarbonate-based macromers 90A(3) (pp. 830-843) https://doi.org/10.1002/jbm.a.32138
  133. Sharifi et al. (2009) Injectable in situ forming drug delivery system based on poly(e-caprolactone fumarate) for tamoxifen citrate delivery: gelation characteristics, in vitro drug release and anti-cancer evaluation 5(6) (pp. 1966-1978) https://doi.org/10.1016/j.actbio.2009.02.004
  134. Sharifi et al. (2011) Hydroxyapatite scaffolds infiltrated with thermally crosslinked polycaprolactone fumarate and polycaprolactone itaconate 98A(2) (pp. 257-267) https://doi.org/10.1002/jbm.a.33108
  135. Shavandi et al. (2016) Injectable gel from squid pen chitosan for bone tissue engineering applications 77(3) (pp. 675-687) https://doi.org/10.1007/s10971-015-3899-6
  136. Shi et al. (2006) Injectable nanocomposites of single-walled carbon nanotubes and biodegradable polymers for bone tissue engineering 7(7) (pp. 2237-2242) https://doi.org/10.1021/bm060391v
  137. Shi et al. (2020) Nano-silicate-reinforced and SDF-1α-loaded gelatin-methacryloyl hydrogel for bone tissue engineering (pp. 9337-9353) https://doi.org/10.2147/IJN.S270681
  138. Shih and Lin (2012) Cross-linking and degradation of step-growth hydrogels formed by thiol–ene photoclick chemistry 13(7) (pp. 2003-2012) https://doi.org/10.1021/bm300752j
  139. Shin et al. (2003) In vivo bone and soft tissue response to injectable, biodegradable oligo(poly(ethylene glycol) fumarate) hydrogels 24(19) (pp. 3201-3211) https://doi.org/10.1016/S0142-9612(03)00168-6
  140. Singh et al. (2018) Injectable hydrogels: a new paradigm for osteochondral tissue engineering 6(35) (pp. 5499-5529) https://doi.org/10.1039/c8tb01430b
  141. Sivashanmugam et al. (2015) An overview of injectable polymeric hydrogels for tissue engineering (pp. 543-565) https://doi.org/10.1016/j.eurpolymj.2015.05.014
  142. Śmiga-Matuszowicz et al. (2017) Novel crosslinkable polyester resin-based composites as injectable bioactive scaffolds 66(1) (pp. 1-11) https://doi.org/10.1080/00914037.2016.1180614
  143. Solouk et al. (2014) Injectable scaffold as minimally invasive technique for cartilage tissue engineering: in vitro and in vivo preliminary study 3(2–4) (pp. 143-151) https://doi.org/10.1007/s40204-014-0031-x
  144. Sun and Huang (2010) Mechanisms of the multi-shape memory effect and temperature memory effect in shape memorypolymers 6(18) (pp. 4403-4406) https://doi.org/10.1039/C0SM00236D
  145. Sun et al. (2012) Highly stretchable and tough hydrogels 489(7414) (pp. 133-136) https://doi.org/10.1038/nature11409
  146. Sun et al. (2012) Stimulus-responsive shape memory materials: a review 33(1) (pp. 577-640) https://doi.org/10.1016/j.matdes.2011.04.065
  147. Temenoff and Mikos (2000) Injectable biodegradable materials for orthopedic tissue engineering 21(23) (pp. 2405-2412) https://doi.org/10.1016/S0142-9612(00)00108-3
  148. Thakur et al. (2016) Photocrosslinkable and elastomeric hydrogels for bone regeneration 104(4) (pp. 879-888) https://doi.org/10.1002/jbm.a.35621
  149. Thornton et al. (2004) Shape retaining injectable hydrogels for minimally invasive bulking 172(2) (pp. 763-768) https://doi.org/10.1097/01.ju.0000130466.84214.f7
  150. Tommasi et al. (2016) An injectable hydrogel as bone graft material with added antimicrobial properties 22(11–12) (pp. 862-872) https://doi.org/10.1089/ten.tea.2016.0014
  151. Tong et al. (2014) Smart chemistry in polymeric nanomedicine (pp. 6982-7012) https://doi.org/10.1039/c4cs00133h
  152. Toniato et al. (2019) Hybrid chitosan/amniotic membrane-based hydrogels for articular cartilage tissue engineering application https://doi.org/10.1080/00914037.2019.1636249
  153. Townsend et al. (2017) Colloidal gels with extracellular matrix particles and growth factors for bone regeneration in critical size rat calvarial defects 19(3) (pp. 703-711) https://doi.org/10.1208/s12248-017-0045-0
  154. Tzouanas et al. (2014) Mesenchymal stem cell and gelatin microparticle encapsulation in thermally and chemically gelling injectable hydrogels for tissue engineering 102(5) (pp. 1222-1230) https://doi.org/10.1002/jbm.a.35093
  155. van de Manakker et al. (2008) Self-assembling hydrogels based on β-cyclodextrin/cholesterol inclusion complexes 41(5) (pp. 1766-1773) https://doi.org/10.1021/ma702607r
  156. Van Tomme et al. (2005) Mobility of model proteins in hydrogels composed of oppositely charged dextran microspheres studied by protein release and fluorescence recovery after photobleaching 110(1) (pp. 67-78) https://doi.org/10.1016/j.jconrel.2005.09.005
  157. Van Tomme et al. (2005) Self-gelling hydrogels based on oppositely charged dextran microspheres 26(14) (pp. 2129-2135) https://doi.org/10.1016/j.biomaterials.2004.05.035
  158. Van Tomme et al. (2006) Degradation behavior of dextran hydrogels composed of positively and negatively charged microspheres 27(22) (pp. 4141-4148) https://doi.org/10.1016/j.biomaterials.2006.03.023
  159. Van Tomme et al. (2008) Macroscopic hydrogels by self-assembly of oligolactate-grafted dextran microspheres 9(1) (pp. 158-165) https://doi.org/10.1021/bm700931q
  160. Van Tomme et al. (2008) Effect of particle size and charge on the network properties of microsphere-based hydrogels 70(2) (pp. 522-530) https://doi.org/10.1016/j.ejpb.2008.05.013
  161. Varshosaz et al. (2021) Effect of bassorin (derived from gum tragacanth) and halloysite nanotubes on physicochemical properties and the osteoconductivity of methylcellulose-based injectable hydrogels 192(June) (pp. 869-882) https://doi.org/10.1016/j.ijbiomac.2021.10.009
  162. Vo et al. (2015) In vitro and in vivo evaluation of self-mineralization and biocompatibility of injectable, dual-gelling hydrogels for bone tissue engineering (pp. 25-34) https://doi.org/10.1016/j.jconrel.2014.11.028
  163. Vo et al. (2017) Acellular mineral deposition within injectable, dual-gelling hydrogels for bone tissue engineering 105(1) (pp. 110-117) https://doi.org/10.1002/jbm.a.35875
  164. Wang et al. (2003) Collagen-hydroxyapatite microspheres as carriers for bone morphogenic protein-4 27(2) (pp. 162-168) https://doi.org/10.1046/j.1525-1594.2003.06953.x
  165. Wang et al. (2018) Fabrication of nanofibrous microcarriers mimicking extracellular matrix for functional microtissue formation and cartilage regeneration (pp. 118-132) https://doi.org/10.1016/j.biomaterials.2018.04.033
  166. Wasupalli and Verma (2020) Injectable and thermosensitive nanofibrous hydrogel for bone tissue engineering https://doi.org/10.1016/j.msec.2019.110343
  167. Watson et al. (2014) Synthesis and characterization of injectable, biodegradable, phosphate-containing, chemically cross-linkable, thermoresponsive macromers for bone tissue engineering 15(5) (pp. 1788-1796) https://doi.org/10.1021/bm500175e
  168. Watson et al. (2015) Biodegradable, phosphate-containing, dual-gelling macromers for cellular delivery in bone tissue engineering (pp. 286-296) https://doi.org/10.1016/j.biomaterials.2015.07.016
  169. Wei et al. (2009) Thermosensitive hydrogels synthesized by fast diels–alder reaction in water 50(13) (pp. 2836-2840) https://doi.org/10.1016/j.polymer.2009.04.032
  170. Wu et al. (2020) Effect of poly(ethylene glycol)-derived crosslinkers on the properties of thermosensitive hydrogels 29(8) (pp. 679-691) https://doi.org/10.1007/s13726-020-00831-7
  171. Xavier et al. (2015) Bioactive nanoengineered hydrogels for bone tissue engineering: a growth-factor-free approach 9(3) (pp. 3109-3118) https://doi.org/10.1021/nn507488s
  172. Xie et al. (2015) Strong electroactive biodegradable shape memory polymer networks based on star-shaped polylactide and aniline trimer for bone tissue engineering 7(12) (pp. 6772-6781) https://doi.org/10.1021/acsami.5b00191
  173. Xu et al. (2013) Injectable hyaluronic acid-tyramine hydrogels incorporating interferon-Α2a for liver cancer therapy 166(3) (pp. 203-210) https://doi.org/10.1016/j.jconrel.2013.01.008
  174. Yan et al. (2015) Controlled release of simvastatin-loaded thermo-sensitive PLGA-PEG-PLGA hydrogel for bone tissue regeneration: in vitro and in vivo characteristics 103(11) (pp. 3580-3589) https://doi.org/10.1002/jbm.a.35499
  175. Yan et al. (2016) Injectable alginate/hydroxyapatite gel scaffold combined with gelatin microspheres for drug delivery and bone tissue engineering (pp. 274-284) https://doi.org/10.1016/j.msec.2016.02.071
  176. Yan et al. (2016) Injectable in situ forming poly(l-glutamic acid) hydrogels for cartilage tissue engineering 4(5) (pp. 947-961) https://doi.org/10.1039/C5TB01488C
  177. Yan et al. (2018) Nanocomposite porous microcarriers based on strontium-substituted HA-g-poly(γ-benzyl-l-glutamate) for bone tissue engineering 10(19) (pp. 16270-16281) https://doi.org/10.1021/acsami.8b02448
  178. Yang et al. (2014) In situ-forming injectable hydrogels for regenerative medicine 39(12) (pp. 1973-1986) https://doi.org/10.1016/j.progpolymsci.2014.07.006
  179. Yeh et al. (2006) Micromolding of shape-controlled, harvestable cell-laden hydrogels 27(31) (pp. 5391-5398) https://doi.org/10.1016/j.biomaterials.2006.06.005
  180. Zajforoushan Moghaddam et al. (2017) Thermo-responsive diblock and triblock cationic copolymers at the silica/aqueous interface: a QCM-D and AFM study (pp. 546-555) https://doi.org/10.1016/j.jcis.2017.06.044
  181. Zhang et al. (2014) A bioactive ‘self-fitting’ shape memory polymer scaffold with potential to treat cranio-maxillo facial bone defects 10(11) (pp. 4597-4605) https://doi.org/10.1016/j.actbio.2014.07.020
  182. Zhang et al. (2015) Injectable peptide decorated functional nanofibrous hollow microspheres to direct stem cell differentiation and tissue regeneration 25(3) (pp. 350-360) https://doi.org/10.1002/adfm.201402618
  183. Zhang et al. (2019) Thermosensitive hydrogels as scaffolds for cartilage tissue engineering 20(4) (pp. 1478-1492) https://doi.org/10.1021/acs.biomac.9b00043
  184. Zheng Shu et al. (2004) In situ crosslinkable hyaluronan hydrogels for tissue engineering 25(7) (pp. 1339-1348) https://doi.org/10.1016/j.biomaterials.2003.08.014
  185. Zhou et al. (2021) Polymer-based porous microcarriers as cell delivery systems for applications in bone and cartilage tissue engineering 66(2) (pp. 77-113) https://doi.org/10.1080/09506608.2020.1724705
  186. Ziadlou et al. (2021) Optimization of hyaluronic acid-tyramine/silk-fibroin composite hydrogels for cartilage tissue engineering and delivery of anti-inflammatory and anabolic drugs https://doi.org/10.1016/j.msec.2020.111701