Biochemical flow cells having sealed inlets and outlets are provided for performing high-volume assays on macromolecules. In one example embodiment, a flow cell with detachable inlet and outlet connectors comprises an inlet manifold, a coverslip, and a substrate disposed below the coverslip to form a reaction chamber, where the substrate is disposed to partially cover the inlet manifold such that a slit is formed along an entire edge of the substrate where fluids can flow from the inlet manifold through the slit, around substantially the entire edge of the substrate, and into the reaction chamber at equalized pressure and without bubbles. In another embodiment, a flow cell comprises an outlet manifold, two or more flow regions each connected to its own loading port via its own flow distribution funnel, each loading port connected to the outlet manifold, and plugs in a wall of the outlet manifold opposite each loading port, such that when a plug is absent from the wall of the outlet manifold, a loading tip may be inserted in its place, passing through the outlet manifold and connecting directly to a loading port.