George Kruis will miss the rest of the Six Nations after it was confirmed the England lock will have surgery on a knee ligament injury.
The Saracens second row missed England's opener against France after injuring his knee in training four days before the game.
He will now have an operation on the injury and is expected to be out for between 10 and 12 weeks, meaning he is also unlikely to play again before the British & Irish Lions squad is selected for the summer tour to New Zealand.
Kruis has been removed from England's 32-man training squad for the second fixture in this season's Six Nations against Wales on Saturday, who trained at Pennyhill Park on Sunday evening.
Mako Vunipola has joined the squad and will continue his own rehabilitation from injury.
England coach Eddie Jones told Sky Sports News HQ on Monday: "George has had a tough old time. He's had an ankle clean-out, then a cheekbone clean-out, now he's going to have a knee clean-out.
"He's going to have a pretty clean body by the end of it. He needs to have surgery on that knee - that's the most sure way of making sure he comes back 100 per cent. It's about ensuring he's going to come back...a better player."
The timeline makes it difficult for Kruis to make the cut for the British & Irish Lions tour of New Zealand but Jones is hopeful Warren Gatland might still select him.
"Given he's such a quality player, Warren might gamble on him, but that will be Warren's decision," he said.
England squad to play Wales:
Forwards: Jack Clifford (Harlequins), Dan Cole (Leicester), Charlie Ewels (Bath), Ellis Genge (Leicester), Jamie George (Saracens), Teimana Harrison (Northampton), Dylan Hartley (Northampton), James Haskell (Wasps), Nathan Hughes (Wasps), Maro Itoje (Saracens), Joe Launchbury (Wasps), Courtney Lawes (Northampton), Joe Marler (Harlequins), Matt Mullan (Wasps), Kyle Sinckler (Harlequins), Tommy Taylor (Wasps), Mike Williams (Leicester), Tom Wood (Northampton)
Backs: Mike Brown (Harlequins), Danny Care (Harlequins), Elliot Daly (Wasps), Owen Farrell (Saracens), George Ford (Bath Rugby), Jonathan Joseph (Bath), Alex Lozowski (Saracens), Jonny May (Gloucester), Jack Nowell (Exeter), Henry Slade (Exeter), Ben Te'o (Worcester), Anthony Watson (Bath), Marland Yarde (Harlequins), Ben Youngs (Leicester)