Circulating Bubbles in Decompression Sickness: Pathophysiology and Experimental Models.

Decompression sickness (DCS) is a severe condition caused by rapid reductions in ambient pressure during diving, altitude exposure, or aerospace operations, with circulating gas bubbles serving as a central initiating event. Stable nanobubbles on active hydrophobic spots along the vascular lumen can grow under decompression-induced supersaturation, detach, and enter the circulation. Their subsequent behavior is shaped by blood flow, vessel geometry, and coagulation and may lead to thrombosis and microvascular stasis. DCS pathogenesis involves three linked interfaces: the blood-bubble interface activates coagulation and complement; the bubble-endothelium interface causes mechanical injury, endothelial dysfunction, oxidative stress, and cell death; and the endothelium-immune interface, which promotes neutrophil recruitment and NETosis, driving sterile inflammation and microthrombosis. Experimental approaches reproduce different stages of this pathogenic sequence and can be broadly distinguished according to the origin of the bubbles. Whole-animal decompression models and whole-blood decompression systems incorporate pressure reduction or gas supersaturation and can therefore generate bubbles within the experimental system. Many endothelial-cell, vessel-based, and microfluidic platforms use pre-existing or externally generated gas bubbles that are introduced directly into the experimental system. These directly introduced-bubble models do not reproduce decompression-induced bubble genesis; however, they provide precise control over bubble size, flow, vascular geometry, and cellular interactions. They are therefore valuable for dissecting post-formation processes shared by decompression-generated and directly introduced intravascular bubbles, including bubble transport, vascular retention, endothelial injury, thrombosis, and inflammation. Recognizing this distinction in bubble origin is essential for defining the translational relevance and limitations of individual experimental models.