McGinnis, R. | Search bioRxiv

bioRxiv2026

Histotripsy-induced vascular remodeling in the tumor microenvironment enhances local and off-target intratumoral drug delivery

Solid tumors are known to be refractory to treatment due to a poorly perfused microenvironment that blocks immune cell infiltration and effective drug delivery. Histotripsy is a non-invasive focused ultrasound modality that generates cavitation microbubbles to mechanically disrupt solid tumors, resulting in decreased hypoxia and stimulation of tumor-targeted adaptive immune responses. In this study, we aim to investigate whether post-histotripsy hypoxia reduction and cytotoxic immune cell infiltration are associated with normalization of tumor vasculature and enhanced perfusion. Structural analysis of both treated and contralateral off-target tumors following partial histotripsy revealed significant vascular remodeling, enhanced vascular integrity, and decreased vascular leakage indicative of vascular normalization in multiple in vivo models of melanoma, hepatocellular carcinoma, and pancreatic adenocarcinoma. These effects appeared antigen-specific, as no remodeling was observed in contralateral off-target tumors of discordant pathology. Mechanistically, CXCR3+CD8+ T cells played a role in mediating these vascular changes, as genetic knockout of CD8 and pharmacological antagonism of CXCR3 impaired both remodeling and normalization. Additionally, significant changes in endothelial CXCR4 and Angiopoietin-1 and -2 expressions were observed following histotripsy, indicating their potential involvement in promoting vascular normalization and remodeling. Significant vascular remodeling was accompanied by enhanced tumor perfusion and intratumoral delivery of chemotherapeutic agents and therapeutic monoclonal antibodies. These findings suggest that histotripsy not only creates a more favorable microenvironment for immunotherapy, but also optimizes drug delivery into solid tumors. Combinatorial approaches using histotripsy with chemotherapy or immunotherapy may be a novel therapeutic strategy to overcome current limitations of conventional solid tumor therapies.

immunology↗

bioRxiv2021

Wearables-Only Analysis of Muscle and Joint Mechanics: An EMG-Driven Approach

Complex sensor arrays prohibit practical deployment of existing wearables-based algorithms for free-living analysis of muscle and joint mechanics. Machine learning techniques have been proposed as a potential solution, however, they are less interpretable and generalizable when compared to physics-based techniques. Herein, we propose a hybrid method utilizing inertial sensor- and electromyography (EMG)-driven simulation of muscle contraction to characterize knee joint and muscle mechanics during walking gait. Machine learning is used only to map a subset of measured muscle excitations to a full set thereby reducing the number of required sensors. We demonstrate the utility of the approach for estimating net knee flexion moment (KFM) as well as individual muscle moment and work during the stance phase of gait across nine unimpaired subjects. Across all subjects, KFM was estimated with 0.91 %BW*H RMSE and strong correlations (r = 0.87) compared to ground truth inverse dynamics analysis. Estimates of individual muscle moments were strongly correlated (r = 0.81-0.99) with a reference EMG-driven technique using optical motion capture and a full set of electrodes as were estimates of muscle work (r = 0.88-0.99). Implementation of the proposed technique in the current work included instrumenting only three muscles with surface electrodes (lateral and medial gastrocnemius and vastus medialis) and both the thigh and shank segments with inertial sensors. These sensor locations permit instrumentation of a knee brace/sleeve facilitating a practically deployable mechanism for monitoring muscle and joint mechanics with performance comparable to the current state-of-the-art.

bioengineering↗