PROJECT SUMMARY/ABSTRACT Glaucoma, which is often referred to as the "silent thief of sight," gradually steals vision without early warning signs or pain, and it remains the leading cause of blindness worldwide. Currently, the only known method to slow the progression of glaucoma is to reduce intraocular pressure (IOP), which helps to minimize permanent damage to the optic nerve. However, IOP levels can fluctuate over both daily and seasonal periods, with the greatest peaks often occurring during sleep or in a supine position. In turn, vision loss may occur during sleep, without the patient being aware of it, even if their IOP levels are normal during daytime measurements taken in clinical or home settings. Assessing the 24-hour pattern of IOP on a regular basis, daily, weekly, and monthly can be highly beneficial for patients with glaucoma or those who are at risk of developing the condition, which is however lacking in standard clinical practice. Although wearable ocular tonometers, such as the Triggerfish lens (Sensimed, Inc.), aim to continuously monitor IOP in both clinical and home settings, their long-term use in human eyes is currently limited, particularly during sleep, due to various side effects such as foreign body sensation, eye pain, superficial punctate keratitis, corneal epithelial defects, and conjunctival erythema. To address this unmet need, we propose to develop and optimize a unique class of smart soft contact lenses that build upon existing commercial brands of soft contact lenses, without altering their intrinsic properties, including lens power, biocompatibility, softness, transparency, wettability, oxygen transmissibility, and overnight wearability. We anticipate that the smart soft contact lenses will offer a number of advantages over existing wearable ocular tonometers, including superior safety, user comfort, lens fit, visual field, ease of use, overnight wearability, and measurement accuracy. To this end, we will produce various prototypes of the smart soft contact lenses and then iteratively conduct a comprehensive set of in vitro, ex vivo, and in vivo tests to assess several key features. These include: (1) durability against perpetual cycles of mechanical loads such as flipping, folding, and stretching, chemical treatments such as cleaning and disinfecting, and other possible user mishandling such as dehydration, overheating, or overcooling; (2) in vitro cell viability on human corneal cells; (3) ex vivo sensing performance in enucleated pig eyes; (4) in vivo sensing performance in dogs (without euthanasia); and (5) clinical validity in human eyes, both in-clinic and at-home settings. We will compare the measurement results with those obtained from the in-clinic, portable, and wearable types of current ocular tonometers such as the Goldmann applanation tonometry (GAT), I-Care Home (I-Care, Inc.), and Triggerfish lens (Sensimed, Inc.). We envision the smart soft contact lenses to provide continuous, 24-hour monitori...