plasma samples, but also contains many other biomarkers that are unique or at much higher concentration compared to serum and plasma. [5a,8a-f ] Some of the methods for ISF sampling include suction blister, [9] which takes ≈1 h to perform and leaves a lasting wound; reverse iontophoresis [10] and laser microporation of skin followed by ISF collection under vacuum, [11] which require calibration using blood samples and proprietary instrumentation; and microdialysis [12] and open-flow microperfusion, [13] which require minor surgery and significant expertise. In large part because of the limitations of these methods, very few studies have examined ISF, and information on ISF properties and composition (other than glucose concentration) is extremely limited. An alternate approach to collect ISF involves the use of microneedles (MNs), which are solid, tapered structures measuring hundreds of microns in length that painlessly penetrate into tissue, such as skin. MN patches were developed initially for delivery of vaccines and drugs, where they have been shown to be safe and simple to administer. [14a-e] MNs have also been used to puncture the skin and collect microliter quantities of ISF under suction, [8a,15] by passive diffusion through MN bore or built-in sensors, [16a-d] using MNs coated with capture antibodies to collect specific antigens [17a,b] and with MNs made of swellable hydrogel that absorb ISF from the skin. [18a-c] While ISF collection using MNs can be simple, minimally invasive, and well tolerated, most approaches are time consuming, requiring 15-30 min. [19] The goal of this study is to develop a simple and easy-to-use MN patch that can collect ≥2 µL of ISF within 1 min. Results Microneedle Patch DesignThe MN patch was designed as a two-component system comprising a strip of paper (which serves as an ISF reservoir) on the backing of a stainless steel (SS) MN array (which creates micropores in the skin through which ISF can flow to the skin surface) (Figure 1A,B). To collect ISF, the MN patch was repeatedly applied to the skin surface, thereby inducing flow of ISF out of the skin and into the paper reservoirs ( Figure 1C). The MN insertion procedure was well tolerated (Figure 1E,F) with a very mild, transient erythema observed at the insertion site.Interstitial fluid (ISF) that surrounds cells in tissues of the body is a novel source of biomarker that complements conventional sources like blood, urine, and saliva. To overcome difficulties in harvesting ISF, a minimally invasive, rapid, simple-to-use, cost-effective method is developed to collect ISF from the skin involving a microneedle (MN) patch. By pressing 650 µm long MNs at an angle just below the skin surface, blood-free ISF flows through micropores to the skin surface and is absorbed into a thin strip of paper on the MN patch backing for subsequent analysis. An optimized method in rat skin in vivo is well tolerated and able to collect >2 µL of ISF within 1 min. Brief skin pretreatment with MNs followed by a 5 min delay dramatically increas...

Retinal vein cannulation is a technically demanding surgical procedure where therapeutic agents are injected into the retinal veins to treat occlusions. The clinical feasibility of this approach has been largely limited by the technical challenges associated with performing the procedure. Among the challenges to successful vein cannulation are identifying the moment of venous puncture, achieving cannulation of the micro-vessel, and maintaining cannulation throughout drug delivery. Recent advances in medical robotics and sensing of tool-tissue interaction forces have the potential to address each of these challenges as well as to prevent tissue trauma, minimize complications, diminish surgeon effort, and ultimately promote successful retinal vein cannulation. In this paper, we develop an assistive system combining a handheld micromanipulator, called “Micron”, with a force-sensing microneedle. Using this system, we examine two distinct methods of precisely detecting the instant of venous puncture. This is based on measured tool-tissue interaction forces and also the tracked position of the needle tip. In addition to the existing tremor canceling function of Micron, a new control method is implemented to actively compensate unintended movements of the operator, and to keep the cannulation device securely inside the vein following cannulation. To demonstrate the capabilities and performance of our uniquely upgraded system, we present a multi-user artificial phantom study with subjects from three different surgical skill levels. Results show that our puncture detection algorithm, when combined with the active positive holding feature enables sustained cannulation which is most evident in smaller veins. Notable is that the active holding function significantly attenuates tool motion in the vein, thereby reduces the trauma during cannulation.

Glaucoma is the leading cause of irreversible blindness. Current treatments use drugs or surgery to reduce intraocular pressure (IOP). In this study, a drug‐free, nonsurgical method is developed that lowers IOP for 4 months without requiring daily patient adherence. The approach involves expanding the suprachoroidal space (SCS) of the eye with an in situ‐forming hydrogel injected using a microneedle. This study tests the hypothesis that SCS expansion increases the drainage of aqueous humor from the eye via the unconventional pathway, which thereby lowers IOP. SCS injection of a commercial hyaluronic acid (HA) hydrogel reduces the IOP of normotensive rabbits for more than 1 month and an optimized HA hydrogel formulation enables IOP reduction for 4 months. Safety assessment by clinical ophthalmic examinations indicate the treatment is well tolerated. Histopathology shows minor hemorrhage and fibrosis at the site of injection. Further analysis by ultrasound biomicroscopy demonstrates a strong correlation of IOP reduction with SCS expansion. Outflow facility measurements show no difference in pressure‐dependent outflow by the conventional pathway between treated and untreated eyes, supporting the hypothesis. In conclusion, SCS expansion with an in situ‐forming hydrogel can enable extended IOP reduction for treating ocular hypertension and glaucoma without drugs or surgery.

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Measurement of intraocular pressure (IOP) is a standard procedure in ophthalmic research in animals, specifically in glaucomaresearch, and the control of IOP is essential during certain veterinary ophthalmic surgeries. We evaluated the effect of isoflurane on IOP in the clinically healthy laboratory rabbits and tested a way to minimize the alteration of IOP duringisoflurane anesthesia. After measurement of the baseline IOP in each eye of 9 awake New Zealand white rabbits, animals were anesthetized by using either: (1) isoflurane without premedication, (2) a combination of ketamine and xylazine, or (3)isoflurane inhalation after an injection of ketamine–xylazine premedication. Isoflurane led to a sustained increase in IOP ofapproximately 12 mm Hg. In contrast, ketamine and xylazine decreased IOP by nearly 5 mm Hg (all values compared withbaseline measurements in awake, unrestrained animals). The observed decrease in IOP after ketamine–xylazine anesthesiais consistent with anesthetic effects generally seen during anesthesia in other studies. The increased IOP after isofluraneanesthesia in rabbits in this study was an unexpected result that appears to be specific to this combination of anesthetic andanimal species. Premedication with ketamine–xylazine diminished the effect of isoflurane inhalation on IOP. These resultsshould be considered in the design of ophthalmic research studies using rabbits and in intraocular surgery where IOP stabilityis desired.

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