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Table 1 The injectable hydrogel systems and their crosslinking reactions/interactions and applications

From: Injectable hydrogels delivering therapeutic agents for disease treatment and tissue engineering

Injectable Hydrogel Systems

Crosslinking Reactions/Interactions

Applications (therapeutic agents)

Notes

References

Agar

    

 Agar/MBP

PC, HB/

Delivery of TD (DOX), chemotherapy for colon cancer, photothermal treatment by MBP

Temperature-sensitive release, temperature changed by MBP (a photoabsorbent)

[37]

Alginate

    

 Alginate-Ca

PC, EI/

Delivery of TD (MX) and TPs (SDF-1α and pDNA), breast cancer therapy

Self-healing, the release and therapeutic efficacy regulated by pulsatile ultrasound

[38]

 OAlg/CMCS with GMs-TH

CC, SBR/

Bacterial infection therapy

Antibacterial and biodegradable properties

[52]

Chitosan

    

 Chitosan/gelatin/polydopamine

PC, EI/ MR, SBR,

Parkinson’s disease therapy, TD delivery (MT)

Mechanical strength improved via EI

[20]

 Chitosan/gelatin/NDs

PC, EI, HB, VDWF/HB, DDI, HP

Scaffold for TE (embedded cell: VEGF)

Thermosensitive gelation, mechanical features improved by NDs, sustained release

[30]

 Chitosan-polyaniline/oxidized dextran

CC, SBR/

Delivery of TDs (Amoxicillin and ibuprofen)

pH- and electric field- responsive, antibacterial activity

[33]

 CEC/OSA

CC, MR/

TAD

Self-assembling, self-healing

[49]

 GC/poly(EO-co-Gly)-CHO

CC, SBR/

Scaffold for TE (embedded cell: chondrocyte), cartilage repair

Mechanical properties and morphology controlled by poly(EO-co-Gly)-CHO

[51]

Chondroitin Sulfate (ChS)

    

 Pluronic F127-ChS/PEG

CC, DACR/

Scaffold for TE (embedded cell: BMP-4), bone defect repair

Gelation of Pluronic F127-ChS at 37 oC, dual crosslinked Pluronic F127-ChS/PEG hydrogels

[44]

Collagen

    

 Collagen/Au

PC, EI/

PTT, PDT, TAD (TMPyP), breast cancer therapy

Shear-thinning, self-healing, antitumor efficacy affected by light irradiation

[21]

 Collagen

PC, EI/

Scaffold for TE (embedded cell: osteoblast (OB)), bone repair

Successful bone tissue regeneration by OB and LIPUS

[39]

Dextrin

    

 CD/PEG-phospholipid/Fe3O4

PC, HI/

Hyperthermia cancer therapy, chemotherapy for preventing breast cancer recurrence, delivery of TDs (PTX, DOX)

PTX and DOX Released by ACMF induced heat

[34]

Gelatin

    

 Gelatin MPs

PC, EI/

Scaffold for TE (embedded TPs: VEGF and BMP2)

Release controlled by hydrogel degradation induced by CLSPA collagenase

[40]

 Gelatin-tetrazine fg/Gelatin- norbornene fg

CC, DACR/

Scaffold for TE

Cell-compatible and enzymatically degradable properties

[43]

Hyaluronic acid (HA)

    

 HA-CD/ HA-AD, and HA-CD-MA/HA-AD-MA

PC, HGI, CC/

Delivery of TP (EPC), vascular regeneration

Shear-thinning, self-healing

[28]

 HA-HMDA-cytosine/HA-HMDA-guanosine

PC, HB/

Delivery of TP (BSA), scaffold for TE

pH-sensitive and self-healing, gelation only at pH 6-8

[32]

 HAMC

PC, EI, HB/

Delivery of TPs (RSCs, NSCs), retina and brain tissue therapy, scaffold for TE

Biodegradable and light-sensitive, HAMC-CD44 interaction

[35]

 HA-Heparin (HA-HP)

CC, PIC/

Delivery of TP (AFS), wound healing

Crosslinking by UV light

[56]

 HA-Tyr

CC, EMCR, OCR/

Scaffold for TE (embedded cell: hESC)

Highest hESC proliferation at HA-Tyr hydrogels with modulus of 350 Pa

[59]

Peptide/protein

    

 P1

PC, PI, HP/

Delivery of TDs (vitamin B12 and vancomycin, an antibiotic)

Thixotropic behavior at physiological condition

[23]

FGd/Ag

PC, PI/

Antimicrobial treatment with Ag

Mechanical stability for six months, high antimicrobial activity

[24]

 PA

PC, HI, HB, EI/

Chemotherapy, delivery of TD (DOX)

PA concentration-dependent release behavior

[25]

 Peptide/catalase/glucose oxidase

PC, EI/

Diabetic therapy, delivery of TP (insulin)

pH- and glucose-sensitive, self-assembling

[31]

 Multi-domain peptides (MDPs) nanofiber/liposome NPs

PS, HB, HI/

Delivery of TPs (EGF, PlGF-1, MCP-1), Scaffold for TE

Release regulated via the hydrogel degradation by enzyme-mediation and the physical gelation by self-assembly

[41]

 Protein and Protein-GOX-CAT (PGT)

CC, EMCR/

Scaffold for TE

Reversible self-healing, enzyme (glucose) mediated crosslinking by dynamic covalent interaction, 100% recovery PGT

[58]

PCL

    

 PEG-PCL-PEG

PC, HI/

Chemotherapy including diabetic treatment, delivery of TP (insulin)

Sol-gel transition at 37 oC, lower viscosity than Pluronic®, Fickian release

[26]

PEG

    

 Polyamine-PEG-polyamine

PC, CC, EI, HB, PI/

Delivery of TPs (insulin, BSA, glucose, avidin, neutravidin, or IL-12)

Self-assembling at 30 oC

[19]

 PLga-PEG-PLga -chol fg/ PLga-CD fg

PC, HGI/

Scaffold for TE

Self-healing, self-assembling, properties regulated by the ratio of CD/Chol, high storage modulus

[27]

 PCLA-PEG-PCLA/heparin

PC, HI, CC, MR/EI

Delivery of TP (lysozyme), immunotherapy

Thermosensitive gelation at BT, sustained release

[29]

 PEG- aryl thiol fg/PEG-maleimide fg (or heparin-maleimide fg)

CC, MR/RLI

Delivery of TPs (FGF-2, cytokines, and immunomodulatory agents)

Light-and reducing environment- sensitive release

[36]

 PEG/TMVCyss and PEG/wt-TMV

CC, MR and PC/

Scaffold for TE

TMV with multi-functionality, storage moduli improved by adding TMVCyss. No effect of wt-TMV on storage moduli

[48]

 PEG/PPLL

CC, SBR/

Delivery of TDs (ME and 5FC), colon cancer therapy

Degradation and release controlled by pHs

[53]

Polyoxamine

    

 Polyoxamine-maleimide fg/ Polyoxamine-furyl fg

PC, CC, HI, DACR/

Delivery of TP (bevacizumab, an antibody), colon, lung, and breast cancer therapy

Physical and chemical crosslinking, triphasic release controlled by two polyoxamines

[45]

PVA

    

 PVA-Tyr and PVA-Tyr-sericin-gelatin (PVA-SG)

CC, PIC/

Scaffold for TE (embedded TP: Schwann)

Crosslinking by visible light, PVA-Tyr: no cell adhesion, PVA-SG: cell adhesion

[55]

PNIPAAm

    

 PNIPAAm/CNC

PC, VDWF, HB/

Delivery of TD (MT), wound dressing

Volume transition at 36-39 oC, Mechanical strength increased by CNC

[22]

  1. Abbreviations: ACMF Alternating current magnetic field, AD Adamantine, AFS Amniotic fluid-derived stem, BMP2 bone morphogenetic protein 2, BMP-4 Bone morphogenetic protein 4, BSA Bovine serum albumin, BT Body temperature, CAT Catalase, CC Chemical crosslinking, CD Cyclodextrin, CEC N-Carboxyethyl chitosan, Chol Cholesterol, CLSPA collagenase Chromatographically purified collagenase, CMCS carboxymethyl chitosan, CNC Cellulose nanocrystal, DACR Diels Alder click reaction, DDI dipole-dipole interaction, pDNA plasmid DNA, Dox doxorubicin, EGF Epidermal growth factor, EI Electrostatic interaction, EMCR Enzyme-mediated crosslinking reaction, EPC Endothelial progenitor cell, FGF-2 Fibroblast growth factor, fg functional group, 5FU 5-fluorouracil, GC glycol chitosan, FGd 20-deoxy-20-fluoroguanosine, GMs Gelatin microspheres, GOX Glucose oxidase, HA Hyaluronic acid, HAMC Hyaluronic acid-methylcellulose, HB Hydrogen bonding, hESCs Human embryonic stem cells, HGI Host-gest interactions, HI Hydrophobic interaction, HMDA Hexamethylenediamine, IL-12 Interleukin-12, LIPUS Low-intensity pulsed and ultrasound, MA Methyl acrylate, MBP MoS2/Bi2S3-PEG, MCP-1 monocyte chemoattractant protein-1, ME Metformin, MGH Magnetic gellan gum hydrogel, MPs microparticles, MR Michael reaction, MT Metronidazole, MX Mitoxantrone, NDs Nanodiamonds, NPs Nanoparticles, NSCs Neural stem and progenitor cells, OAlg Oxidized alginate, OCR Oxidative coupling reaction, OSA Oxidized sodium alginate, P1 boc-AUDA-Phe-COOH (AUDA 11-aminoundecanoic acid, Phe L-phenylalanine), PA Peptide amphiphile, PC Physical crosslinking, PCL Polycaprolactone, PCLA Poly-(ε-caprolactone-co-lactide), PDT Photodynamic therapy, PEG Polyethylene glycol, PI π-Interaction, PIC Photo-initiated crosslinking, PLga Poly(L-glutamic acid), PlGF-1 Placental growth factor-1, PNIPAAm Poly(N-isopropylacrylamide), PPLL PEG-b-poly(L-lysine), Poly(EO-co-Gly)-CHO Poly(ethylene oxide-co-glycidol)-CHO, PTT Photothermal therapy, PTX Paclitaxel, PVA Poly(vinyl alcohol), PVA-SG PVA-tyramine-sericin-gelatin, RLI Receptor–ligand interaction, RSCs Retinal stem cells, SBR Schiff base reaction, SDF-1α stromal cell-derived factor 1α, TAD Therapeutic agent delivery, TDs Therapeutic drugs, TE Tissue engineering, TH Tetracycline hydrochloride, TPs Therapeutic proteins, TMPyP meso-tetra(N-methyl-4-pyridyl) porphine tetrachloride (a photosensitive drug), TMV Tobacco mosaic virus, wt-TMV Wildtype TMV, TMVCyss Cysteine-containing TMV mutants, Tyr Tyramine, VDWF van der Waals force, and VEGF Vascular endothelial growth factors