Okay, here are my thoughts.
First off: Whatever you do, ensure that it stays fair. If the players are forced to go on adventuring despite persistent injuries/penalties, account for them.
I've seen or heard about interesting "drawback" mechanics that give the player a benefit whenever the flaw comes into play, but otherwise is "cost-neutral" (you can't take drawbacks just to pay for other cool abilities - we all know that leads to min-maxing and munchkining...
Handling Injuries "fairly":
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Try to give penalties that can at least be roughly translated to other mechanical effects that are traditionally worth a game resource. For example, if having a severe injury causes a -2 penalty to all physical rolls (attacks, physical skills) and reduces your speed by 2 squares, this is a bit as if you were (in 4E terms) constantly marked. Any encounter in which your injury is part of grants therefore worth some extra XP equal to a monster of a level (maybe only a minion monster...). If the DM tries to figure out the difficulty of an encounter, he can use this XP cost to get a more precise value.
(Note that the XP is not reserved for the injured player character. It's group XP, like anything else. If the fighter suddenly becomes less effective, the whole team has to work harder...)
An alternative might be to just reward action points for this. Could be cool, too, but it's a little more difficult since the granularity is lower, so you need injury penalties that have similar effective cost.
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Okay, with that part out of the way, you might come up with actual mechanics for getting injuries.
Getting Injured
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If a character is first bloodied in combat, he might take a persistent injury. Reroll the attack that caused the character to be bloodied. If it hits the victims Fortitude Defense, it suffers one wound.
If a character is first dropped to 0 hp or less, he can take a persistent injury. Reroll the attack that caused the character to drop. If it hits the victims Fortitude Defense, the character suffers a wound.
Alternative: Instead of rerolling attack, just roll a save.
Optional: As long as a character has action points or healing surges remaining, he can take a free (or immediate action for more "grit") to spend it and negate the injury the moment it happens. If an action point is spent, the point spent counts only in so far against your per encounter limit in as you can now no longer spend an action point for anything else but to avoid an injury.
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Wounds (Abstract Method):
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For each wound a character has, he regains one healing surge less per day. This represents your bodies effort to heal yourself.
The first wound is "free". It doesn't cause any further penalties. Your pure awesomeness means you're fine though you shouldn't be.
The second wound causes a -2 injury penalty to all checks.
The third wound adds a -2 penalty to all defenses and movement. (Minimum 1 square of movement)
The fourth wound increases the check penalty to -5.
The fifth wound drops checks, defense and movement by 5.
The sixth wound is simply to much. You're unconcious, until healed.
Healing a wound requires 1 day per number of wound you currently have. So if you have 5 wounds, you need 5 days to recover from it. After that, you need another 4 days to recover from the next. And so on.
A Healing spell triggering a Healing Surge heals a single wound.
Optional (Reduced Cleric Dependency) A Heal check that triggers a Healing Surge has the same effect, but it can be only applied either as first aid (within the same encounter / 5 minutes after the injury) or as long-term aid (6 hours of extended rest).
Alternative: Roll a save each day to see if you make progress at all. 20 removes a wound, 10+ means you make progress, less means you don't.
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Wounds (Complex Method):
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Determine the hit zone to determine which body part is injured:
Roll 1d6:
6: Head (1d6: 1-3: Jaw; 4-6: upper head)
4-5: Torso (1d6: 1-3 Chest, 4-6: waist)
3-4: Arm (1d6: 1-2: Left Arm; 3-4: Right Arm, 5: Left Hand, 6: Right Hand)
1-2: Leg (1d6: 1-2: Left Leg; 3-4 Right Leg; 5: Left Foot, 6: Right Foot)
Each part can take only 4 wounds.
The first wound is for free. Your badassitude allows you to compensate.
The second wound means you take a -2 penalty to all checks or movement related to that body part. The third wound means you take a -5 penalty to all checks or movement related to that body part.
Only apply the highest penalty. Torso wounds apply to all strength, Dexterity or constitution based checks, as well as Reflex and Fortitude Defense. Head wounds apply to all Dex, Wisdom, Intelligence or Charisma Based checks, and Will Defense.
A fourth wound can fully "destroy" the body part. Roll also a Save. If the save fails, the body part is severed or crushed, and requires powerful restorative magic (Regeneration) to be repaired. If a body part is part of a larger part (like the jaw is a part of a head), roll one save for each part. Only if each save fails, the part is destroyed.
If the save succeeds, the part is unusable until further medical attention arrives. (Anyhting that triggers a healing surge can make the part functional again, removing the third wound).
A nonfunctional head means you're unconcious, a nonfunctional torso means your paralyzed and can't move or attack and can perform any purely mental actions. Destroyed head or torso mean you're dead. Sorry.
Wounds take one day to heal. You can heal only one wound per day by spending one of your next days healing surges. Roll a Save. If it succeeds, your wound heals.
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Please Note: Despite both variants using wounds, the wounds function different. In the second "simulationist" variant, a lot more wounds can persist.
Both systems are complex enough to create a lot of variations of the rules to "fine-tune" it to your hearts desire. Neither rule claims to be perfect, complete or "realistic".
