Sabella, whose team secured their place in next year's World Cup in Brazil last month, will use the last two matches to try fringe players as he looks to settle on a final squad of 23.
"Messi's absence is always impossible to disguise," Sabella told Argentina's Radio 9.
"It's a different story, not just for us but also our rivals. It's a psychological blow when Leo's not on the pitch and it's a challenge to find a solution to the problem."
Captain Messi is Argentina's match-winner and top scorer with 10 in qualifying, a tally he shares with Uruguay's Luis Suarez, and rarely do the team fail to win when he finds the net.
"The team's heart will be missing," said Sabella of the additional absences of Mascherano and Gago before adding that he now has the chance to test Lucas Biglia and Ever Banega together in central midfield.
"On the one hand, I'd prefer to field the same team to run it in more, but I also can't help thinking this is a good chance to try out players and bed them in."
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- Javier Mascherano
- Fernando Gago
- Gonzalo Higuain