Thermo-induced physically crosslinked polypeptide-based block copolymer hydrogels for biomedical applications

Abstract

Stimuli-responsive synthetic polypeptide-containing block copolymers have received considerable attention in recent years. Especially, unique thermo-induced sol-gel phase transitions were observed for elaborately-designed amphiphilic diblock copolypeptides and a range of poly(ethylene glycol) (PEG)-polypeptide block copolymers. The thermo-induced gelation mechanisms involve the evolution of secondary conformation, enhanced intramolecular interactions, as well as reduced hydration and increased chain entanglement of PEG blocks. The physical parameters, including polymer concentrations, sol-gel transition temperatures and storage moduli, were investigated. The polypeptide hydrogels exhibited good biocompatibility in vitro and in vivo, and displayed biodegradation periods ranging from 1 to 5 weeks. The unique thermo-induced sol-gel phase transitions offer the feasibility of minimal-invasive injection of the precursor aqueous solutions into body, followed by in situ hydrogel formation driven by physiological temperature. These advantages make polypeptide hydrogels interesting candidates for diverse biomedical applications, especially as injectable scaffolds for 3D cell culture and tissue regeneration as well as depots for local drug delivery. This review focuses on recent advances in the design and preparation of injectable, thermo-induced physically crosslinked polypeptide hydrogels. The influence of composition, secondary structure and chirality of polypeptide segments on the physical properties and biodegradation of the hydrogels are emphasized. Moreover, the studies on biomedical applications of the hydrogels are intensively discussed. Finally, the major challenges in the further development of polypeptide hydrogels for practical applications are proposed.

Keywords: immunotherapy; injectable hydrogels; polypeptides; secondary conformation; stimuli responsive; tissue engineering.

Graphical abstract

Figure 1.

Schematic representation, structure and thermoresponsive gelation process for DCH_T. Reproduced with permission from Ref. [17].

Figure 2.

Variation of mPEG-L-PLAla self-assembly with the MW of each block. Reproduced with permission from Ref. [18].

Figure 3.

Two levels of self-assembly behavior of mPEG-b-P(L-EG₂Glu). Reproduced with permission from Ref. [62].

Figure 4.

Schematic illustration of secondary structure transitions, self-assembly and thermo-induced gelation of mPEG-b-P(ELG-co-PLG-g-DEA) or (mPEG-b-P(ELG-co-PLG-g-PD) aqueous solutions at pH 6.5 and a neutral pH, respectively. Reproduced with permission from Ref. [78].

Figure 5.

PEG-b-ODLAG/SWCNT hydrogel for reversible patterning of soft conductive materials. (a) Parallel or antipallel β-sheet conformation of nanofibrils. (b) Reversible conversion of polymeric supramolecular structures in response to stimulus. Reproduced with permission from Ref. [84].

Figure 6.

Schematic illustration for the thermo-induced hydrogel formation at cartilage defect by injection of the BMSC-encapsulated P(LAla-co-LPhe)-b-PEG-b-P(LAla-co-LPhe) hydrogel into the cartilage defect, and the subsequent cartilage repair in vivo. Reproduced with permission from Ref. [98].

Figure 7.

Schematic illustration for the differentiation of TMSCs in blank mPEG-b-PLAla hydrogel, mPEG-b-PLAla/α-CD carbonate inclusion complex hydrogel, or mPEG-b-PLAla/α-CD phosphate inclusion complex hydrogel. Reproduced with permission from Ref. [107].

Figure 8.

Injectable and thermoresponsive DCH_T as vehicles for transplantation of NSCs into CNS. Reproduced with permission from Ref. [101].

Figure 9.

Design of a bioactive 3D scaffold. Reproduced with permission from Ref. [105].

Figure 10.

DOX/CDDP co-Loaded PELG-b-PEG-b-PELG hydrogel for local tumor combination chemotherapy. (a) Chemical structures. (b) Local combination treatment of the nude mouse MDR tumor model. Reproduced with permission from Ref. [126].

Figure 11.

Synergistic immunotherapy of ROS-responsive P(LMet-co-D-1MT)-b-PEG-b-P(LMet-co-D-1MT). (a) Hydrophobicity transition and chemical structure and (b) localized drug delivery for synergistic immunotherapy. Reproduced with permission from Ref. [86].

Scheme 1.

ROP of NCAs via (a) ‘normal amine mechanism’ and (b) ‘activated monomer mechanism’.

Scheme 2.

Schematic illustration for the mechanism of thermo-induced gelation of polypeptide-based block copolymers, and their potential applications for 3D cell culture and controlled cell differentiation, and for local sustained delivery of chemotherapeutics and/or immunostimulating agents.

Scheme 3.

Chemical structures of some representative polypeptide-containing block copolymers. (a) Diblock copolypeptide amphiphiles. (b) (rac-EP²)_m(L_x/EP²_1-x)_n. (c) mPEG-b-PLAla. (d) [PLAla-b-PEG-b-PLAla-EDTA]_m. (e) mPEG-b-P(LAla-co-LPhe). (f) PAla-b-PLX-b-PAla. (g) mPEG-b-P(L-EG₂Glu). (h) mPEG-b-P(L-EEG₂Glu). (i) mPEG-b-P(L-EEG₂Glu). (j) mPEG-b-P(ELG-co-EDG). (k) mPEG-b-PPLG. (l) mPEG-b-P(ELG-co-(PLG-g-TA)). (m) mPEG-b-PLTyr. (n) mPEG-b-ODLAG. (o) mPEG-b-PLMet. (p) mPEG-b-PLVal.