Conductive nanocomposite hydrogel and mesenchymal stem cells for the treatment of myocardial infarction and non-invasive monitoring via PET/CT

Introduction: Injectable hydrogels have great promise in the treatment of myocardial infarction (MI); however, the lack of electromechanical coupling of the hydrogel to the host myocardial tissue and the inability to monitor the implantation may compromise a successful treatment. The introduction of conductive biomaterials and mesenchymal stem cells (MSCs) may solve the problem of electromechanical coupling and they have been used to treat MI. We aim to develop an injectable conductive nanocomposite hydrogel (GNR@SN/Gel) to treat MI and monitored the therapeutic effect via ¹⁸F-FDG myocardial PET imaging.

Methods: The injectable conductive nanocomposite hydrogel (GNR@SN/Gel) was fabricated by gold nanorods (GNRs), synthetic silicate nanoplatelets (SNs), and poly(lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA₂₀₀₀-PEG₃₄₀₀-PLGA₂₀₀₀). The left thoracotomy was performed and the left anterior descending coronary artery was permanently ligated at its origin to establish acute myocardial infarction (AMI) models in SD rats. MSCs was isolated from bone marrow of SD rats. MSCs and ⁶⁸Ga⁺³ cations were encapsulated in the GNR@SN/Gel hydrogel and then injected into the margin of the infarcted area 30mins after ligation. ⁶⁸Ga⁺³ loaded hydrogel imaging was performed 1 hour after the establishment of AMI models. ¹⁸F-FDG myocardial viability imaging was performed 1 and 28 days after the establishment of AMI models. Ultrasound and histopathological investigations, including sirius red staining, masson trichrome-staining and immunofluorescence staining, were performed at 28 days after the establishment of AMI models.

Results: Our data showed that SNs can act as a sterically stabilized protective shield for GNRs, and that mixing SNs with GNRs yields uniformly dispersed and stabilized GNR dispersions (GNR@SN) that meet the requirements of conductive nanofillers. The conductivity of GNR@SN/Gel is (6.19 ± 0.07) ×10^-3 S/cm, which is significantly higher than that of SN/Gel, exceeding that of natural myocardial tissue. We successfully constructed a thermosensitive conductive nanocomposite hydrogel by crosslinking GNR@SN with PLGA₂₀₀₀-PEG₃₄₀₀-PLGA₂₀₀₀, where SNs support the proliferation of MSCs; additionally, SNs are also cation exchangers that can adsorb high-valent cations ⁶⁸Ga⁺³, making it possible to monitor the injection site of the hydrogel in vivo. The MSC/GNR@SN/Gel group had a protective effect on myocardial viability both in the early stage and late stage compared with controls, with nonviable myocardium area of 4.61% ± 2.89% and 5.46% ± 2.70% postoperative Day 1 and Day 28, respectively. While the values of GNR@SN/Gel group were 4.75% ± 2.73% and 9.13% ± 4.76%, and MSC/SN/Gel group were 8.12% ± 3.24% and 11.14% ± 3.07%, respectively. Ejection fraction was 83.69% ± 7.13% in the MSCs/GNR@SN/Gel at postoperative Day 28, much higher than that in all treated control groups (p<0.05). The protective effect was further validated by histopathological investigations.

Conclusions: The combination of MSCs and the GNR@SN/Gel conductive nanocomposite hydrogel offers a promising strategy for MI treatment.

This work was supported by the National Natural Science Foundation of China (No. 81873906, 82171985)