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Digital isolation is pretty much a must when interfacing to the '''exernal world'. It doesn't have to be an optocoupler, many other types exist. As an example, we had a device where several boards communicate through I2C. Without io buffer, the I2C chips had to be replaced several time a day, adding a buffer solved problem.
As a cheap alternative try a series resistors ~1k range. This will slow down edges to about 100ns, which is ok for serial port.
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If your device you are using SIO or GPIO_OVT pins you can avoid the problem for those many number of pins. A pin configured for hot swap capability is mapped to an SIO or a GPIO Over-Voltage Tolerance (GPIO_OVT) pin that supports hot-swap capability in hardware. Hot swap capability allows the voltage present on the pin to rise above the pin's VDDIO voltage, up to 6.0 V. Hot swap also does not allow a pin with any voltage up to 6.0 V present to leak current into the PSoC device even when the PSoC device is not powered.
I worked before with another device from the PSOC 4 series that sports GPIO_OVT ports, but I'm not sure if the one I am using now has either SIO or GPIO_OVT ports. I'll do my homework and confirm with the specs sheet, but if not, I'll go for port isolation with opto couplers. The advise offered above using buffers is also valuable for cost sensitive applications, but since the real state and cost is about the same for buffers or opto couplers I'll rather play safe and go for the later.