Japan international Kagawa left Dortmund in 2012 to move to Manchester United, but was unable to nail down a regular starting place under Alex Ferguson or David Moyes.
First-team action proved no easier to come by for the playmaker in the early stages of Louis van Gaal's reign at Old Trafford.
Dortmund completed the re-signing of the 25-year-old at the end of last month, tying him down to a four-year deal after agreeing to pay an undisclosed fee - estimated to be far lower than the amount received for Kagawa two years ago.
Kagawa made 49 Bundesliga appearances for Dortmund during his first spell at the club - from 2010 to 2012 - and could be in line for his 50th league outing this weekend.
The case for a Kagawa start may have been enhanced by Dortmund's somewhat rotten luck during the recent international break.
Germany international Reus was taken off in the second minute of stoppage time in Sunday's Euro 2016 qualifying 2-1 win over Scotland after appearing to injure himself when attempting to pull away from a Charlie Mulgrew challenge.
The attacker was later revealed to have torn ankle ligaments for the second time in four months, with the injury having previously kept him out of Germany's successful World Cup campaign.
Doctors have placed a four-week timescale on his recovery, but coach Klopp is confident of coping without his star man.
"It could have been worse," he told Bild. "I am, of course, very sorry for Marco but four weeks will go quickly.
"We just have to work now and score without him."
As if losing one attacking threat was not enough, Klopp will have been concerned to see striker Ciro Immobile leaving the field on a stretcher in the latter stages of Italy's 2-0 win over Norway on Tuesday.
However, Immobile's hip injury is not thought to be serious and he could be involved on Saturday.
Nuri Sahin remains sidelined after undergoing surgery on his left knee.
Dortmund have won their last eight meetings with Freiburg and have picked up maximum points in the last seven between the sides on home soil.
If the outlook did not already look bleak enough for the visitors, Dortmund have put 17 goals past them on their last four trips to Signal Iduna Park, conceding just one in reply.
Freiburg are looking for their first league win of the season, while Dortmund are aiming to make it back-to-back victories after beginning the season with a 2-0 home defeat to Bayer Leverkusen before bouncing back with a 3-2 win at Augsburg.