Centre Tatyana Heard makes her first England appearance in three years in an experimental side for Saturday's World Cup warm-up against the United States.
Claudia MacDonald, who thought her career had been ended by a neck injury in 2021, starts on the wing.
Cath O'Donnell also returns from injury to fight for a place in the second row.
England's World Cup campaign in New Zealand begins against Fiji on 8 October, with Middleton due to name a 32-player squad on 20 September.
Number eight Poppy Cleall, fly-half Zoe Harrison, captain Emily Scarratt, wing Jess Breach and flanker Zoe Aldcroft keep their places after beating France in April.
Ellie Kildunne steps in for Helena Rowland at full-back, while Natasha Hunt is at scrum-half with Leanne Infante on the bench.
Hannah Botterman, Amy Cockayne and Bryony Cleall form an all-new front row as Rosie Galligan starts alongside O'Donnell at lock.
Aldcroft is in the back row with Poppy Cleall and 20-year-old Sadia Kabeya, who starts in place of Six Nations star Marlie Packer.
O'Donnell's Loughborough team-mate Morwenna Talling, 20, will be looking to make an impact off the bench in a competitive back five.
England will play Wales in their second warm-up game in Bristol on 14 September.
'Limited opportunities' for squad selection
Having beaten New Zealand comfortably twice in November and France in April, England are favourites to win the World Cup and have had an unprecedented two months of preparation in camp.
Middleton says he is "edgy" ahead of their meeting with a United States side that beat Scotland 21-17 at the end of August.
Given England beat the United States 89-0 last time the sides met in November 2021, the individual battles for World Cup positions may be more intriguing than the match as a whole.
Middleton must reduce his 39-player squad to 32 and says there will be "50-50 calls" to be made based on Saturday's performances.
Heard - who was out for over a year after sustaining a second major knee injury in the summer of 2019 - is one such call, up against Amber Reed, Holly Aitchison and Rowland for the 12 shirt.
"Tats [Heard] gives us a bit of a different dimension," Middleton said
"She's come back in brilliant form. She gives us great go-forward, direct running and she's a great stopper in defence.
"Sometimes in sport, opportunities are limited and, with just the two matches before the tournament in New Zealand, this is one of those occasions."
England: Kildunne; Breach, Scarratt (capt), Heard, MacDonald; Harrison, Hunt; Botterman, Cockayne, B Cleall, Galligan, O'Donnell, Aldcroft, Kabeya, P Cleall.
Replacements: Powell, Muir, Brown, Talling, Fleetwood, Infante, Rowland, Aitchison.