I had the same issue, and after a few stubborn hours of not allowing a machine to outsmart me, I was finally able to get Substance Designer 5,4 to open and work flawlessly in Windows 10. I eventually read two posts that shed enough light on the problem to make sense. I applied both fixes before restating my machine and giving SD a try, so I don't know which fix did the trick or it it was a combination of the two, but as they're both somewhat related, it's not going to hurt if you end up running both. I would attempt the fixes in the following order:
Go here
https://www.microsoft.com/en-us/download/details.aspx?id=40784 and download and run the program that corresponds to your Windows 10 build. It'll restart your system when it's done, but if not, go ahead and restart. When you're rebooted, run SD 5.4 as an administrator, and hopefully you can get back to work. If not...
...go here
https://support.microsoft.com/en-us/kb/929833#bookmark-use%20the%20system%20file%20checker%20tool and follow the directions. Besides scanning for corrupted files, it repairs them as well, so when it's finished, you should hopefully be up and running.
The only other changes that I made to my system that may have helped that you cab try if you're still at a loss, is download and install the latest graphic drivers for your video card(s). If you have the option for a clean install, make sure you check that (It's under Custom Installation). Go back a version of the driver if that didn't help.
And the other thing I did was run a registry cleaning tool. DO THIS AT YOUR OWN RISK IF YOU UNDERSTAND HOW TO MESS WITH THE REGISTRY. MAKE A BACKUP FIRST, AT LEAST.
http://www.wisecleaner.com/wise-registry-cleaner.htmlI didn't have to pay for any upgrades, and I don't own the software. I just did a quick scan under the trial installation, and then I cleaned the files that it recommended once the scan was finished.
