A tissue penetrating system includes a plurality of cartridges each with a distal port and a proximal port. A plurality of penetrating members are provided, each coupled to a cartridge and having a sharpened distal tip and a shaft portion slidably disposed within the cartridge. A seal is formed by a fracturable material between the penetrating member and the cartridge. The seal is positioned at one or both of a distal port or a proximal port of the cartridge.