Santana, who won the American League Cy Young Award in 2004 and '06, missed the '11 season following surgery on the shoulder and now faces a steep climb toward another comeback. He will be 35 at the start of next season.
"It's very difficult. If anybody can do it, it would be Johan," Mets pitching coach Dan Warthen told The Associated Press. "We wish him luck and we feel sick about what's happened."
The previous surgery came on Sept. 14, 2010. Santana made his return last season and went 6-9 with a 4.85 ERA in 21 starts. He had a 2.38 ERA after throwing the first no-hitter in Mets history last June 1 against the Cardinals, an outing that required 134 pitches.
Santana posted an 8.27 ERA the rest of the way and was shut down in mid-August as he fought problems with his ankle, back and shoulder.
"I've known Johan long enough to know that I don't think that he'd want to go out like that," third baseman David Wright told the AP. "He's going to probably work just as hard, if not -- if it's possible -- work harder, to come back from this. I wouldn't be surprised at all if I see him pitch again."
The Mets were looking forward to a healthy 2013 from Santana when he reported to camp in mid-February, but he soon began dealing with left shoulder weakness and never made it into a Grapefruit League game.
Nonetheless, Warthen told the AP that Santana's injury isn't "a byproduct of the no-hitter."
General manager Sandy Alderson has said the final year of Santana's contract is not insured, which will force the Mets to pay his full $25.5 million salary this year, plus another $5.5 million if they want to buy out his $25 million team option for 2014.
If Santana does not pitch again for the Mets, he will conclude his tenure with a 46-34 record and 3.18 ERA over 109 starts. He led the Majors with a 2.53 ERA and finished third in the National League Cy Young Award voting in 2008 after being traded by the Twins to New York.
But the injury bug bit Santana after that, and he hasn't reached 30 starts in a season since.
The Venezuela native is 139-78 with a 3.20 ERA over 12 big league seasons and sits 12 strikeouts away from the 2,000 mark.