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The Gunners’ playmaker was sorely missed in midfield during the bulk of last season.
Cazorla has not featured for Arsenal since limping off in the 6-0 win over Ludogorets last October.
An Achilles problem has led to multiple operations and the midfielder’s continued absence, despite initial optimism he would return swiftly.
Arsenal expected the 32-year-old to be back fit three weeks after the Champions League tie.
But Express Sport understands Cazorla now faces the prospect of being sidelined for almost two full seasons in succession.
The news will come as a big blow to Gunners supporters, with the skilful Spaniard having become a fan favourite during his five years at the Emirates.
Cazorla played a pivotal role in the team during his first three seasons in north London, but long-term injuries have plagued him since late 2015.
Arsenal still opted to renew his contract last term until the summer of 2018.
However, it is understood Cazorla’s best hope of returning to action will potentially be for Arsenal’s Under-23s, no earlier than April.
Should the former Villarreal man suffer no more setbacks, he has an outside chance of bidding farewell in the first team at the end of the campaign.
On his difficult journey over the past year, Cazorla said in May: “[Arsenal] were very good to me, they renewed me before my operation, the manager talked to me and gave me peace of mind.
“It’s been a difficult season, since I have not played since November. I’ve been through surgery eight times.
“I had the last one yesterday, and hopefully everything will go well.
“Since November I have had complications. There was bacteria in the operating room and I suffered an infection in a bone. The scar did not close and I had a skin graft.”