Moderate-Intensity Ultrasound-Triggered On-Demand Analgesia Nanoplatforms for Postoperative Pain Management

Abstract

Introduction: The restricted duration is a fundamental drawback of traditional local anesthetics during postoperative pain from a single injection. Therefore, an injectable local anesthetic that produces repeatable on-demand nerve blocks would be ideal.

Methods: We offer ultrasound-triggered on-demand analgesia consisting of dendritic mesoporous silica nanoparticles (DMSN) carried with ultrasound-sensitive perfluoropentane (PFP) and levobupivacaine (DMSN-bupi-PFP) to achieve repeatable and customizable on-demand local anesthetics.

Results: The vaporization of liquid PFP was triggered by ultrasound irradiation to produce a gas environment. Subsequently, the enhanced cavitation effect could improve the release of levobupivacaine to achieve pain relief under a moderate-intensity ultrasound irradiation. DMSN-bupi-PFP demonstrated a controlled-release pattern and showed a reinforced ultrasonic sensitivity compared to levobupivacaine loaded DMSN (DMSN-bupi). The sustained release of levobupivacaine produced continuous analgesia of more than 9 hours in a model of incision pain, approximately 3 times longer than a single free levobupivacaine injection (3 hours). The external ultrasound irradiation can trigger the release of levobupivacaine repeatedly, resulting in on-demand analgesia. In addition, DMSN-bupi-PFP nanoplatforms for ultrasound-enabled analgesia showed low neurotoxicity and good biocompatibility in vitro and in vivo.

Conclusion: This DMSN-bupi-PFP nanoplatform can be used in pain management by providing long-lasting and on-demand pain alleviation with the help of moderate-intensity ultrasound.

Keywords: analgesia; moderate-intensity ultrasound; nanomedicine; phase-transitional.

Figure 1

(A) TEM image of DMSN. The scale bar is 200 nm. (B) TEM image of DMSN-bupi-PFP. The scale bar is 200 nm. (C) Zeta potential of DMSN, DMSN-PFP, and DMSN-bupi-PFP. (D) Size distribution of DMSN, DMSN-PFP, and DMSN-bupi-PFP. (E) N₂ absorption isotherms derived from the BJH pore size distribution curve (F) the absorption branch of DMSN and DMSN-bupi-PFP. (G) Elemental mapping images derived from DMSN-bupi-PFP. The scale bars are 50 nm.

Figure 2

(A) Levobupivacaine release performance of DMSN-bupi-PFP and DMSN-bupi under different treatments. (B) Cell viability of HUVEC cells treated with varying concentrations of DMSN-bupi-PFP. (C) Cell viability of HUVEC cells treated with different concentrations of DMSN-bupi-PFP under ultrasound treatment (0.6 W cm⁻², 1 MHz, 50% duty cycle) (n means no difference between groups).

Figure 3

(A) Light-microscopy images of the ultrasound-responsive DMSN-bupi-PFP at different time points. Scale bar: 50 μm. (B) Ultrasonic image of DMSN-bupi-PFP NPs on B-mode and CEUS-mode imaging at different time points under ultrasound irradiation and (C) corresponding quantitative echo intensity (***p < 0.001 among different times compared to 0 min by one-way ANOVA, n=5). (D) Size distribution of DMSN-bupi-PFP after ultrasound irradiation for 5 min.

Figure 4

(A) Mechanical threshold of mice before and after different treatments in vivo (***p < 0.001 between DMSN-bupi-PFP+US and PBS, compared by one-way ANOVA, n=5). (B) Mechanical threshold of mice treated by DMSN-bupi-PFP + US and DMSN-bupi + US (n means p > 0.05, *p < 0.05, **p < 0.01, ***p < 0.001 between DMSN-bupi-PFP+US and DMSN-bupi+US, compared by t test, n=5). (C) Mechanical threshold of mice treated by PBS, PBS+US and DMSN-PFP (n means p > 0.05 between groups). (D) Thermal latency of mice before and after different treatments (***p < 0.001 between ropivacaine and PBS, compared by one-way ANOVA). (E) Thermal latency of mice treated by DMSN-bupi-PFP + US and DMSN-bupi + US (n means p > 0.05, ***p < 0.001 between DMSN-bupi-PFP+US and DMSN-bupi+US, compared by t test, n=5). (F) Thermal latency of mice treated by PBS, PBS+US and DMSN-PFP. The blue dotted arrows represent ultrasonic irradiation (0.6 W cm⁻², 1 MHz, 2 min) (n means p > 0.05 between groups).

Figure 5

DAPI, c-fos, and TRPV1 co-staining immunofluorescence results of L5 DRG after different treatments followed by ultrasound irradiation. The scale bars are 50 μm.

Figure 6

H&E staining and toluidine blue staining results from the sciatic nerve and surrounding muscle at (A) 3 days and (B) 28 days. The scale bars are 100 μm.

Figure 7

H&E staining results of the major organs (including heart, liver, spleen, lungs, and kidneys). The scale bars are 100 μm.