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Novel fusion peptides deliver exosomes to modify injectable thermo-sensitive hydrogels for bone regeneration.

ABSTRACT: Injectable thermo-sensitive hydrogels composed of small intestinal submucosa (SIS) with exosomes derived from bone marrow mesenchymal stem cells (BMSCs) are desired for bone regeneration. However, poor mechanical properties limit the clinical application of SIS hydrogels. Herein, the mechanical properties of SIS hydrogels incorporated with 3-(3,4-dihydroxyphenyl) propionic acid (CA) are assessed. The results show that the mechanical properties of SIS hydrogels are improved. In addition, the retention and stability of exosomes over time at the defect site are also challenges. Fusion peptides are designed by connecting collagen-binding domines (CBDs) of collagen type I/III with exosomal capture peptides CP05 (CRHSQMTVTSRL) directly or via rigid linkers (EAAAK). In vitro experiments demonstrate that fusion peptides are contribute to promoting the positive effect of exosomes on osteogenic differentiation of BMSCs. Meanwhile, the results of hydrogels combining exosomes and fusion peptides in the treatment of rat skull defect models reveal that fusion peptides could enhance the retention and stability of exosomes, thereby strengthen the therapeutic effect for skull defects. Therefore, SIS hydrogels with CA modified by fusion peptides and exosomes appear to be a promising strategy in bone regenerative medicine.

SUBMITTER: Ma S

PROVIDER: S-EPMC8724941 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Novel fusion peptides deliver exosomes to modify injectable thermo-sensitive hydrogels for bone regeneration.

Ma Shiqing S Wu Jinzhe J Hu Han H Mu Yuzhu Y Zhang Lei L Zhao Yifan Y Bian Xiaowei X Jing Wei W Wei Pengfei P Zhao Bo B Deng Jiayin J Liu Zihao Z

Materials today. Bio 20211227

Injectable thermo-sensitive hydrogels composed of small intestinal submucosa (SIS) with exosomes derived from bone marrow mesenchymal stem cells (BMSCs) are desired for bone regeneration. However, poor mechanical properties limit the clinical application of SIS hydrogels. Herein, the mechanical properties of SIS hydrogels incorporated with 3-(3,4-dihydroxyphenyl) propionic acid (CA) are assessed. The results show that the mechanical properties of SIS hydrogels are improved. In addition, the rete ...[more]

PMID: 35024598

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Project description:Injectable therapeutic formulations locally releasing their cargo with tunable kinetics in response to external biochemical/physical cues are gaining interest in the scientific community, with the aim to overcome the cons of traditional administration routes. In this work, we proposed an alternative solution to this challenging goal by combining thermo-sensitive hydrogels based on custom-made amphiphilic poly(ether urethane)s (PEUs) and mesoporous silica nanoparticles coated with a self-immolative polymer sensitive to acid pH (MSN-CS-SIP). By exploiting PEU chemical versatility, Boc-protected amino groups were introduced as PEU building block (PEU-Boc), which were then subjected to a deprotection reaction to expose pendant primary amines along the polymer backbone (PEU-NH2, 3E18 -NH2/gPEU-NH2) with the aim to accelerate system response to external acid pH environment. Then, thermo-sensitive hydrogels were designed (15% w/v) showing fast gelation in physiological conditions (approximately 5 min), while no significant changes in gelation temperature and kinetics were induced by the Boc-deprotection. Conversely, free amines in PEU-NH2 effectively enhanced and accelerated acid pH transfer (pH 5) through hydrogel thickness (PEU-Boc and PEU-NH2 gels covered approximately 42 and 52% of the pH delta between their initial pH and the pH of the surrounding buffer within 30 min incubation, respectively). MSN-CS-SIP carrying a fluorescent cargo as model drug (MSN-CS-SIP-Ru) were then encapsulated within the hydrogels with no significant effects on their thermo-sensitivity. Injectability and in situ gelation at 37°C were demonstrated ex vivo through sub-cutaneous injection in rodents. Moreover, MSN-CS-SIP-Ru-loaded gels turned out to be detectable through the skin by IVIS imaging. Cargo acid pH-triggered delivery from PEU-Boc and PEU-NH2 gels was finally demonstrated through drug release tests in neutral and acid pH environments (in acid pH environment approximately 2-fold higher cargo release). Additionally, acid-triggered payload release from PEU-NH2 gels was significantly higher compared to PEU-Boc systems at 3 and 4 days incubation. The herein designed hybrid injectable formulations could thus represent a significant step forward in the development of multi-stimuli sensitive drug carriers. Indeed, being able to adapt their behavior in response to biochemical cues from the surrounding physio-pathological environment, these formulations can effectively trigger the release of their payload according to therapeutic needs.

Dataset Information

Novel fusion peptides deliver exosomes to modify injectable thermo-sensitive hydrogels for bone regeneration.

Publications

Novel fusion peptides deliver exosomes to modify injectable thermo-sensitive hydrogels for bone regeneration.

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