Preheat the oven to 375°F (190°C) and line a rimmed baking sheet with parchment paper.
In a large mixing bowl, combine the ground beef, breadcrumbs, egg, milk, garlic powder, onion powder, oregano, salt, and pepper until just incorporated.
Divide the meat mixture into two equal portions.
Shape the first portion into a rectangle approximately 1-inch thick on the prepared baking sheet.
Place the mozzarella block in the center of the meat rectangle, leaving a 1-inch border on all sides.
Shape the second portion of meat over the cheese, pressing the edges together firmly to seal the cheese inside completely.
In a small bowl, whisk together the ketchup, brown sugar, and balsamic vinegar.
Brush half of the glaze over the top and sides of the meatloaf.
Bake for 45 minutes, then apply the remaining glaze and bake for an additional 15 minutes or until the internal temperature reaches 160°F (71°C).
Allow the meatloaf to rest for 10 minutes before slicing to stabilize the cheese core.