Merely a suggestion, as it is an idea that a game called Risk of Rain uses and think would be fun in Isaac. When you, say, complete the Chest, but you don't exactly want to finish it yet. You could make it so you could go back to the beginning, with the same items, and go through the dungeons/levels again, except they'd be a lot more difficult than the beginning. I think it would work for Isaac, but understand why you wouldn't use it, though. Not exactly original, but I think it would be fun.

it a unique idea but really just boils the game down to people wanting to get more items an become OP :) 

ill play around with it though to see whats doable, if we can raise the difficulty in a way that made scale it might be ok.. wont know till we get to that point though