Opportunity knocks for Ochocinco: Through two games, the Patriots have run 125 of their 151 offensive snaps (including penalties) with two or more tight ends on the field. That has limited the playing time of Chad Ochocinco, who at this point is No. 3 on the receiver depth chart and has played just 35 snaps in the first two games. But with tight end Aaron Hernandez out with a knee injury and the Patriots potentially entering the game with just one tight end on the 46-man roster, this has the potential to be a game with a lot of three- and four-receiver packages to attack the Bills' vulnerable secondary. That opens the door for more Ochocinco, and possibly the regular-season debut of Taylor Price.
Sub defense vs. spread offense: One of the things that stands out when watching the Bills on offense is that almost every play is out of the spread, with three or four receivers. They both pass and run out of that set, which means this is a game in which the Patriots' sub defense will be tested in both areas (run and pass). This is a good time for the Patriots' defense to brush up on some past problems with sub runs, especially with the NFL's leading rusher, Fred Jackson, on the opposite side this week.
Bills quarterback Ryan Fitzpatrick will take risks -- the Raiders had three solid chances for an interception of Fitzpatrick on the game-winning drive last Sunday -- and so the Patriots' secondary must capitalize when those opportunities present themselves.
Does Spikes even play? Patriots linebacker Brandon Spikes is a niche player at this point, filling a Ted Johnson-type role as a run-stopper against base personnel. The Bills don't use base personnel often -- occasionally they'll have fullback Corey McIntyre in the game as a lead blocker -- so this creates a situation where sub linebackers Gary Guyton, Dane Fletcher and Jeff Tarpinian figure to play more often. Spikes also doesn't regularly contribute on special teams, so it will be interesting to see how often, if at all, he's utilized in the game.
Connolly vs. Williams: Another week, another good test for fill-in Patriots center Dan Connolly. Bills nose tackle Kyle Williams (6-1, 301) doesn't often play head up on the center, but he's an aggressive, hard-nosed player who can be a disruptive penetrator in the middle. With the Patriots potentially calling on more spread formations, the pressure will be on Connolly and Co. to handle the Bills' front seven with little help.
Effectiveness of Haynesworth: Veteran defensive lineman Albert Haynesworth injured his back in practice and didn't participate Thursday and Friday, putting his status for Sunday's game in question. The Patriots need their front seven to make life easier for the secondary against the Bills' spread offense, and a healthy Haynesworth and fellow interior lineman Vince Wilfork could be a matchup edge over a Bills interior line that is without starting right guard Kraig Urbik.
Brady and the three-game NFL record: According to Elias Sports Bureau, quarterback Tom Brady needs 317 yards to tie the NFL record for most passing yardage in a three-game stretch (1,257 yards), which was set by Drew Brees in 2006. Brady has been terrific through the first two games, and if he gets time to throw Sunday he could once again put up big numbers because the Patriots look to have a matchup edge with their pass-catchers against the Bills' defensive backs.
Smith as a wild-card option on offense: The Bills use former New York Jets receiver Brad Smith as a change-up option at quarterback, so that's a wrinkle to monitor. Smith has been held in check through two games (six carries, 20 yards, one incomplete pass) in that role. The Patriots also know how dangerous he can be as a kickoff returner, so the onus is on Stephen Gostkowski to boom touchbacks and take that away from the Bills.
Mesko, punting & the field-position game: With punter Zoltan Mesko having been a question mark all week with an injured left knee, Bill Belichick was still considering a possible emergency option as of Friday. Even if Mesko suits up, there remains the question of how effective he will be. One break for the Patriots is that Bills punt returner Roscoe Parrish is out for the season with an ankle injury.
Mike Reiss covers the Patriots for ESPNBoston.com.