1. Nickel defense against the run. Given their struggles against the Jets in this area, the Patriots can expect the Bills to spread them out and attempt to run with Marshawn Lynch, Fred Jackson and C.J. Spiller against the nickel defense. The Patriots have been tough to run against in their base 3-4 defense, but have shown vulnerability against the run in sub packages. Lynch, Jackson and Spiller are tough in space so the Patriots will have to gang tackle.
2. Pass protection on third down. Without running back Kevin Faulk, who is a mainstay in passing situations, the Patriots are likely to call on a combination of players in a pass-protecting role, starting with running back Sammy Morris. The Patriots have been in the shotgun on 56 of their 123 offensive snaps. They might keep quarterback Tom Brady directly under center more often without Faulk to line up next to him in the shotgun.
3. Lee Evans and the big play. The Bills' passing game revolves around Evans and the running backs. With quarterback Ryan Fitzpatrick getting the start, that gives the Bills a better chance at converting the long ball to Evans. Against a young cornerback tandem in Devin McCourty and Darius Butler and/or Kyle Arrington, the Patriots can expect to be tested.
4. Special teams and Roscoe Parrish. The Bills are strong on special teams, with punt returner Roscoe Parrish a potential game-changer. Receiver Matthew Slater, cornerback Kyle Arrington and veteran linebacker Tracy White, three of the Patriots' top special teams players, will be challenged.
5. Stephen Gostkowski bouncing back. Enduring what he's described as a "disaster" of a start to the season, the Patriots kicker is 1 for 4 on field-goal attempts, with misses from 37, 47 and 56 yards. This puts some added pressure on the operation of snapper Jake Ingram, holder Zoltan Mesko and Gostkowski.
6. Better ball distribution from Tom Brady. Last week against the Jets, Brady targeted Randy Moss 10 times with just two completions. On the season, Brady has targeted Moss 18 times, completing just seven passes. While still trying to get Moss involved, Brady must strike the balance of not overlooking his other targets.
7. Florida rookies on defense. Inside linebacker Brandon Spikes is off to a strong start as a starter in the base 3-4 alignment, while outside linebacker Jermaine Cunningham is pushing for more playing time and it wouldn't be a surprise if he starts. The Bills will be looking to establish the run, putting more pressure on the two rookies.
8. Emergence of Julian Edelman. The second-year receiver showed in the preseason opener that he can be a big weapon, but he's been slowed by a foot injury, playing just 10 snaps last week after missing the season opener. The Patriots are looking to find new ways to move the ball without Faulk and Edelman's playing time should increase.
9. Aaron Hernandez and the tight ends. Coming off a six-catch, 101-yard performance, Hernandez is quickly emerging as a big part of the team's offense. Similar to Edelman, his role figures to increase without Faulk in the lineup.
10. Fred Taylor and the running game. A big disappointment in the second half of last week's loss against the Jets, the Patriots' running game will be looking to bounce back. The Patriots are a game-plan offense, meaning they adjust their plan each week based on an opponent's weakness, and the Bills have shown some vulnerability against the run.
Mike Reiss covers the Patriots for ESPNBoston.com. Follow him on Twitter.