Biology subjects

Davalos, R.

Publications and source records attributed to Davalos, R..

3 recordsLinked to original sources

bioRxiv2025

Endoluminal catheter pulsed field ablation for the treatment of atherosclerotic vascular disease

BackgroundAtherosclerotic vascular disease remains a leading cause of morbidity and mortality worldwide. Current treatments such as angioplasty, stenting, and atherectomy are invasive and limited by restenosis, thrombosis, and incomplete long-term efficacy. Pulsed field ablation (PFA), a nonthermal electroporation-based modality, has demonstrated safety in other cardiovascular applications, but it has not been applied for the treatment of endoluminal vascular diseases. We investigated whether pulsed electric fields could be delivered within the coronary artery and if PFA could selectively ablate the cellular components of atherosclerotic plaques. MethodsA bipolar catheter-based PFA probe was fabricated using a balloon catheter with flexible electrodes and evaluated through a combination of ex vivo evaluations. The electrical conductivities of human atherosclerotic plaques were derived from previous impedance measurements for patient-specific multi-tissue and single-cell electroporation modeling. PFA was then evaluated for selective decellularization within an electrical conductivity-matched 3D fibrotic atherosclerosis tissue mimic using high concentrations of human macrophages and aggregated oxidized low-density lipoproteins, encapsulated within a collagen matrix. ResultsEndoluminal bipolar probe evaluation demonstrated probe positioning and high voltage pulsed electric field delivery within the left coronary artery of ex vivo porcine hearts, with maximum ablations (6.99 cm2) and current (13 A) evaluated within live potato tissue. The multi-tissue model then indicated that endoluminal PFA can effectively cover >95% of severe and thick plaques with irreversible electroporation, with single-cell modeling supporting the electroporation of foam cells within the plaque. The 3D atherosclerosis mimic validated the ability of PFA to completely ablate the foam cells with fibrotic tissue at >1000 V/cm. ConclusionsThis study provides the first demonstration of PFA for the treatment of atherosclerotic vascular disease. By combining experimental validation with computational modeling, we establish proof-of-concept that PFA can selectively ablate diseased cells while preserving extracellular architecture, laying the groundwork for future translational development of this therapy.

bioengineering↗

bioRxiv2025

Novel combination of irreversible electroporation and allogenic chimeric antigen receptor (CAR) T-cell therapy synergizes therapeutic outcomes in a preclinical human pancreatic cancer mouse model

Irreversible electroporation (IRE) is a non-thermal ablation modality used clinically for treating unresectable tumors while preserving vital structures through controlled application of pulsed electric fields. Previous data suggest that patient outcomes are enhanced with the induction of an anti-tumor immune response, but current research focuses on using immune checkpoint inhibitors, which function through conventional immune pathways that may be downregulated by cancer or dysregulated by chemo-induced lymphodepletion. Chimeric Antigen Receptor (CAR) T-cells overcome this limitation, as they are engineered with synthetic receptors that redirect lymphocytes to recognize and target cells expressing tumor-specific structures. CARs are engineered to have an increased binding affinity compared to in-situ T-cell binding, amplify internal stimulation cascades, and release pro-inflammatory cytokines that can modulate the endogenous immune system. However, there are still major limitations for adoptive cell therapies in solid tumors, including life-threatening on-target off-tumor cytotoxicity, antigen escape, and failure to infiltrate and persist in solid tumors. Given the substantial evidence that IRE overcomes many of the challenges associated with immune infiltration and persistence in solid tumors, there is a strong premise for using targeted cell therapies following IRE, which would then target residual cancer that could repopulate the lesion. Here, we present the first proof-of-concept combination of IRE with an adoptive cell therapy. We validated that the cell membrane CAR target is not affected in electroporated cells that survive IRE, allowing for subsequent binding and elimination of residual tumor. The research demonstrates the feasibility and synergy of a novel combination of two clinically used techniques.

cancer biology↗

bioRxiv2023

EXTRACELLULAR PERINEXAL SEPARATION IS A PRINCIPAL DETERMINANT OF CARDIAC CONDUCTION

RationaleCardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular volume. Ephaptic theory is premised on the existence of a biphasic relationship between CV and the volume of specialized extracellular clefts within intercalated discs. ObjectiveDetermine the relationship between ventricular CV and structural changes to micro and nano-scale extracellular spaces. MethodsConduction and connexin43 (Cx43) gap junction protein expression were quantified from optically mapped guinea pig whole-heart preparations perfused with albumin, mannitol, dextran 70kDa, or dextran 2MDa. Peak sodium current was quantified from isolated guinea pig ventricular myocytes. Extracellular resistance (Re) was quantified by impedance spectroscopy. Intercellular communication was assessed in a heterologous expression system with fluorescence recovery after photobleaching. Perinexal width was quantified from transmission electron micrographs. ResultsCV was significantly reduced by mannitol, and increased by albumin, dextran 70kDa and 2MDa. The combination of albumin and dextran 70kDa decreased CV relative to albumin alone. Re was reduced by mannitol, not significantly changed by albumin, and increased by both dextran 70kDa and dextran 2MDa. Cx43 gap junction expression and conductance, and peak sodium current were not significantly altered by the osmotic agents. The perinexal width in response to osmotic agents, in order of narrowest to widest, was: albumin with dextran 70kDa, albumin or dextran 2MDa alone, dextran 70kDa or no osmotic agent, and mannitol. When compared in the same order, CV was biphasically related to perinexal width. ConclusionsCardiac conduction does not correlate with bulk tissue impedance, but is biphasically related to perinexal separation, providing evidence that the relationship between CV and extracellular volume in ventricular myocardium is determined by ephaptic mechanisms under conditions of normal gap junctional coupling.

biophysics↗