Smart, Soft Contact Lens For Wireless Immunosensing of Cortisol


Despite various approaches to immunoassay and chromatography for monitoring cortisol concentrations, conventional methods require bulky external equipment, which limits their use as mobile health care systems. Here, we describe a human pilot trial of a soft, smart contact lens for real-time detection of the cortisol concentration in tears using a smartphone. A cortisol sensor formed using a graphene field-effect transistor can measure cortisol concentration with a detection limit of 10 pg/ml, which is low enough to detect the cortisol concentration in human tears. In addition, this soft contact lens only requires the integration of this cortisol sensor with transparent antennas and wireless communication circuits to make a smartphone the only device needed to operate the lens remotely without obstructing the wearer’s view. Furthermore, in vivo tests using live rabbits and the human pilot experiment confirmed the good biocompatibility and reliability of this lens as a noninvasive, mobile health care solution.


The steroid hormone, cortisol, which is known as a stress hormone, is secreted by the adrenal gland when people are stressed psychologically or physically (1). This secretion occurs when the adrenal gland is stimulated by adrenocorticotropic hormone, which is secreted by the pituitary gland when it is stimulated by the corticotropin-releasing hormone secreted by the hypothalamus. This serial cortisol secretion system is referred to as a hypothalamus–pituitary gland–adrenal gland axis, which is affected by chronic stress, resulting in abnormal secretion of cortisol (23). The accumulation of cortisol caused by the abnormal secretion of cortisol increases the concentrations of fat and amino acid, which can result in diverse severe diseases (e.g., Cushing’s disease, autoimmune disease, cardiovascular complications, and type 2 diabetes) and neurological disorders (such as depression and anxiety disorders) (27). In contrast, abnormally low cortisol levels can lead to Addison’s disease, which results in hypercholesterolemia, weight loss, and chronic fatigue (8). In addition, it was recently reported that plasma cortisol can be correlated to the prognosis of traumatic brain injury (9). Furthermore, the extent of cortisol secretion varies from person to person, and it changes continuously (1011). Thus, developing health care systems for real-time monitoring of the cortisol level has been explored extensively over the past decade as the key to the quantitative analysis of stress levels. Although various efforts have led to the development of cortisol sensors that can measure the concentration of cortisol in blood, saliva, sweat, hair, urine, and interstitial fluid (1217), the accurate measurement of cortisol concentrations has been limited because of the difficulties associated with the transportation and storage of cortisol as well as the instability of the biologically active cortisol in these body fluids at room temperature. In addition, these conventional sensing methods require bulky equipment for the extraction and analysis of these body fluids, which is not suitable for mobile health care systems (1218). Therefore, the development of noninvasive and wearable sensors that can monitor cortisol concentration accurately is highly desirable for a smart health care solution. For example, the immunoassay method, which uses an antigen-antibody binding reaction, has been used extensively for electrochemical cortisol immunosensors using saliva and interstitial fluid, except tears (121419). However, these immunosensors still require the use of bulky impedance analyzers for the analysis of the Nyquist plot from electrochemical impedance spectroscopy. Although the cyclic voltammetry (CV) technique can be used as an alternative approach for sensing cortisol, additional bulky electrochemical instruments still are necessary for analyzing the CV curves (131419). Recently, wearable forms of cortisol sensors that use sweat were developed (15), but they still required bulky measurement equipment (1516). Therefore, portable and smart sensors that can monitor the accurate concentration of cortisol in real time are highly desirable for use in mobile health care.

Among the various body fluids, tears, in particular, contain important biomarkers, including cortisol (2021). Thus, the integration of biosensors with contact lenses is a potentially attractive candidate for the noninvasive and real-time monitoring of these biomarkers from tears (2225). However, an approach for fabricating a smart contact lens for sensing the cortisol in tears has not been demonstrated previously. Thus, here, we present an extraordinary approach for the formation of a smart, soft contact lens that enables remote, real-time monitoring of the cortisol level in the wearer’s tears using mobile phones. This smart, soft contact lens is composed of a cortisol sensor, a wireless antenna, capacitors, resistors, and integrated circuit chips that use stretchable interconnects without obstructing the wearer’s view. The components of this device (except the antenna) were protected from mechanical deformations by locating each of the components on discrete, rigid islands and by embedding these islands inside an elastic layer. A graphene field-effect transistor (FET; with the binding of monoclonal antibody) was used as this cortisol immunosensor, which exhibited a sufficiently low detection limit, i.e., 10 pg/ml, for its sensing of cortisol in human tears in which the cortisol concentration ranges from 1 to 40 ng/ml (26). This sensor was integrated with a near-field communication (NFC) chip and antenna inside the soft contact lens for the real-time wireless transmission of the data to the user’s mobile device (e.g., a smart phone or a smart watch). The antenna occupies a relatively large area of this soft lens, so it requires its high stretchability, good transparency, and low resistance for operating a standard NFC chip at 13.56 MHz. In our approach, the hybrid random networks of ultralong silver nanofibers (AgNFs) and fine silver nanowires (AgNWs) enabled high transparency and good stretchability of this antenna and its low sheet resistance for reliable standard NFCs (at 13.56 MHz) inside this smart contact lens. Thus, the fully integrated system of this smart contact lens provided wireless and battery-free operation for the simultaneous detection and transmission of the cortisol concentration from tears to a mobile phone using standard NFC. In addition, a human pilot trial and in vivo tests conducted using live rabbits demonstrated the biocompatibility of this lens, and its safety against inflammation and thermal/electromagnetic field radiation suggests its substantial usability as a noninvasive, mobile health care solution.


Cortisol immunosensor

A graphene FET sensor was fabricated by binding the cortisol monoclonal antibody (C-Mab) to the surface of graphene for the immunosensing of cortisol. Here, graphene acts as a transducer that converts the interaction between cortisol and C-Mab into electrical signals. Figure 1A shows the immobilization process of C-Mab to graphene. Immobilization proceeds through amide bonding of the C-Mab onto the carboxyl group of the graphene surface via the EDC [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride]/NHS (N-hydroxysulfosuccinimide) coupling reaction. A chemical vapor deposition–synthesized graphene layer was transferred onto a desired substrate and exposed to ultraviolet ozone (UVO) to activate the surface of the graphene with the carboxylate group. Figure S1 shows the contact angle between this surface of the graphene and a droplet of deionized (DI) water. Longer exposure time to UVO can decrease the hydrophobicity of graphene with decreasing the contact angle. Table S1 shows the increase in the electrical resistance of graphene that resulted from this UVO treatment. In our experiment, 2 min of exposure time to UVO decreased the contact angle from 70° to 38° without increasing the resistance of the graphene notably. UVO exposure times longer than this threshold time degraded the resistance of the graphene excessively, so the time of exposure of our samples to UVO was limited to 2 min. Figure S2A illustrates the process of immobilizing C-Mab through the EDC/NHS coupling reaction. This two-step coupling reaction of EDC and NHS can mediate the amide bonding between the carboxylate group of the UVO-exposed graphene and the amine group of the protein (12172728). Here, EDC forms reactive O-acylisourea ester, thereby making the surface unstable. This O-acylisourea ester reacts with the NHS to form amine-reactive NHS ester with the surface still remaining semistable. Then, C-Mab with the amine group reacts with the amine-reactive NHS ester, thereby forming stable amide bonding that can immobilize C-Mab to the NHS on the surface of the graphene. Figure S2B shows the Fourier transform infrared (FTIR) spectroscopy spectra of the DI water after the cortisol sensor had been immersed for 24 hours. The spectra of the DI water in which the sensor was immersed were not significantly different from those of the pristine DI water. However, the C-Mab solution that had a concentration of 1 μg/ml had a significant peak intensity in the range of 3000 to 2800 cm−1, representing the N-H bonding in the C-Mab. These results indicated that C-Mab formed stable bonding on the carboxylated graphene and was negligibly detached by exposure to water.


Estrogen receptor α plays an important role in Cushing’s syndrome during pregnancy


Cushing’s syndrome (CS) during pregnancy is very rare with a few cases reported in the literature.

Of great interest, some cases of CS during pregnancy spontaneously resolve after delivery. Most studies suggest that aberrant luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR) seems to play a critical role in the pathogenesis of CS during pregnancy.

However, not all women during pregnancy are observed cortisol hypersecretion. Moreover, some cases of adrenal tumors or macronodular hyperplasia with LHCGR expressed, have no response to hCG or LH.

Therefore, alternative pathogenic mechanisms are indicated. It has been recently reported that estrogen binding to estrogen receptor α (ERα) could enhance the adrenocortical adenocarcinoma (ACC) cell proliferation.

Herein, we hypothesize that ERα is probably involved in CS development during pregnancy.

Better understanding of the possible mechanism of ERα on cortisol production and adrenocortical tumorigenesis will contribute to the diagnosis and treatment of CS during pregnancy.

Read the entire article here:

Cortisol Levels Predict Remission in Cushing’s Patients Undergoing Transsphenoidal Surgery

In patients with Cushing’s disease, removing the pituitary tumor via an endoscopic transsphenoidal surgery (TSS) leads to better remission rates than microscopic TSS, according to new research.

But regardless of surgical approach, plasma cortisol levels one day after surgery are predictive of remission, researchers found.

The study, “Management of Cushing’s disease: Changing trend from microscopic to endoscopic surgery,” was published in the journal World Neurosurgery.

Because it improves visualization and accessibility, endoscopic TSS has been gaining popularity over microscopic TSS to remove pituitary tumors in Cushing’s disease patients. Yet, although this surgery has been associated with high remission rates, whether it outperforms microscopic surgery and determining the factors affecting long-term outcomes may further ease disease recurrence after TSS.

A team with the All India Institute of Medical Sciences addressed this topic in 104 patients who underwent surgery from January 2009 to June 2017. Among these patients, 47 underwent microscopic surgery and 55 endoscopic surgery. At presentation, their ages ranged from 9 to 55 (mean age of 28). Also, patients had been experiencing Cushing’s symptoms over a mean duration of 24 months.

Eighty-seven patients showed weight gain. Hypertension (high blood pressure) and diabetes mellitus were among the most common co-morbidities, found in 76 and 33 patients, respectively. Nineteen patients had osteoporosis and 12 osteopenia, which refers to lower-than-normal bone mineral density.

As assessed with magnetic resonance imaging, 68 patients had a microadenoma (a tumor diameter smaller than one centimeter) and 27 had a macroadenoma (a tumor one centimeter or larger). Only two patients had an invasive pituitary adenoma.

Two patients with larger tumors were operated on transcranially (through the skull). The surgery resulted in total tumor removal in 90 cases (86.5%). A blood loss greater than 100 milliliter was more common with endoscopic than with microscopic TSS.

Ten patients developed transient diabetes inspidus, two experienced seizures after surgery, and six of nine patients with macroadenoma and visual deterioration experienced vision improvements after TSS.

The incidence of intraoperative leak of cerebrospinal fluid — the liquid surrounding the brain and spinal cord — was 23.2%, while that of post-operative leak was 7.7% and was more common in microadenoma than macroadenoma surgery (9.8% vs. 5.0%).

Seventeen patients were lost to follow-up and two died due to metabolic complications and infections. The average follow-up was shorter for endoscopic than with microscopic surgery (18 months vs. 35 months).

Among the remaining 85 cases, 65 (76.5%) experienced remission, as defined by a morning cortisol level under 5.0 μg/dL, restored circadian rhythm (the body’s internal clock, typically impaired in Cushing’s patients), and suppression of serum cortisol to below 2 μg/dl after overnight dexamethasone suppression test.

The remission rate was 54.5% in pediatric patients and was higher with endoscopic than with microscopic TSS (88.2% vs. 56.6%). Also, patients with microadenoma showed a trend toward more frequent remission than those with macroadenoma (73.2% vs. 64.3%).

Ten of the remaining 20 patients experienced disease recurrence up to 28 months after surgery. Sixteen cases revealed signs of hypopituitarism, or pituitary insufficiency, which were managed with replacement therapy.

A subsequent analysis found that morning cortisol level on day one after surgery was the only significant predictor of remission. Specifically, a one-unit increase in cortisol lowered the likelihood of remission by 7%. A cortisol level lower than 10.7 μgm/dl was calculated as predicting remission.

Overall, the study showed that “postoperative plasma cortisol level is a strong independent predictor of remission,” the researchers wrote, and that “remission provided by endoscopy is significantly better than microscopic approach.”


Why It’s Safer Than Ever To Remove Pituitary Tumors

Removing a pituitary tumor by surgery can be tricky. The gland is surrounded by carotid arteries, optic nerves, and lots of important brain matter. Nor is it easy to access or visualize. But with the help of revolutionary technology and modern expertise, surgeons are now able to remove pituitary tumors in a safe and minimally invasive way. / Image courtesy of Mayfield Brain & Spine

There are three basic things you should know about your pituitary gland: it’s buried away at the base of your brain; it’s very important; and, alas, it has a habit of growing tumors.

Did your pulse quicken a tiny bit at mention of “tumors?” If so, it’s because your thyroid told it to, on instructions from your pituitary gland. But now it’s normal again, right? For that you can thank cortisol, which your pituitary gland told your adrenal glands to make in response to stress.

That’s just the tip of the iceberg, according to Yair Gozal, MD, neurosurgeon at Mayfield Brain & Spine.

“The pituitary gland is also known as the master gland,” he explains. “It regulates the release of hormones from other glands, controlling blood pressure, urine output, body temperature, growth, metabolism, lactation, ovulation, testosterone, stress response, and more.”

That of course means when something is wrong with your pituitary gland—say, a tumor—the symptoms can vary. Perhaps the tumor grows from the part of the pituitary gland that produces prolactin, which regulates sexual function. In that case, a prolactinoma will result in halted menstruation or erectile disfunction (among other things.) Alternatively, suppose the tumor grows from the part of the pituitary gland that produces growth hormone. These tumors cause gigantism in children and acromegaly in adults (again, among other things.)

So it follows, the part of the pituitary gland where the tumor grows will determine its symptoms. But these only account for “functioning” tumors—that is, tumors that secrete too much or too little of a particular hormone. Other tumors, termed “non-functioning,” do not secrete hormones at all. These buggers just take up space until they begin pressing on adjacent parts of the brain that would rather not be pressed on. Symptoms include headache, vision loss, nausea, vomiting, or fatigue. Non-functioning tumors can also pinch the pituitary gland itself, resulting in a broad-based loss of pituitary function.

Pituitary tumors are unusually common. Fifteen percent of adults have one. Most do not cause symptoms or require treatment. If you have one that does, your treatment may involve medication, radiation, and surgery.

Removing a pituitary tumor by surgery can be tricky. The gland is surrounded by carotid arteries, optic nerves, and lots of important brain matter. Nor is it easy to access or visualize. But with the help of revolutionary technology and modern expertise, surgeons are now able to remove pituitary tumors in a safe and minimally invasive way.

For the vast majority of cases, surgeons opt for a transsphenoidal approach. Here, the surgeon inserts an endoscope through the nostril to reach the pituitary gland. The endoscope’s camera relays video to a monitor, which allows the surgeon to visualize the tumor and be precise while removing it. Nowadays the surgeon is further aided by computer image guidance. The computer system gives the surgeon a real-time, three-dimensional model of his or her instruments in the operating space, adding extra degrees of precision—and safety—to the procedure.

“Technology has really moved ahead in this field,” says Gozal. “You get such good visualization. It’s made the operation relatively straightforward.”

Straightforward, that is, for a multidisciplinary team of neurosurgeons, ENT surgeons, and endocrinologists equipped with all that technology and all their training.

“I wouldn’t go anywhere that didn’t have a team for this,” says Gozal. “It’s all about developing expertise. That’s the key. It’s the expertise that has made this safer to do.”

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Internationally recognized as a leader in neurological surgery, Mayfield has forged a rich and lasting heritage through technical innovation, research, and a commitment to patient care. Mayfield physicians are continuously recognized among the Best Doctors in America and Top Doctors in Greater Cincinnati.

Mayfield Brain & Spine has four convenient locations in Greater Cincinnati: Rookwood Exchange (3825 Edwards Road, Suite 300, Cincinnati, 45209); Green Township (6130 Harrison Ave., 45247); West Chester (9075 Centre Point Drive, 45069); and Northern Kentucky (350 Thomas More Parkway, Suite 160, Crestview Hills, 41017).



Bilateral Adrenocortical Adenomas Causing Adrenocorticotropic Hormone-Independent Cushing’s Syndrome

Adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome (CS) is mostly due to unilateral tumors, with bilateral tumors rarely reported. Its common causes include primary pigmented nodular adrenocortical disease, ACTH-independent macronodular adrenal hyperplasia, and bilateral adrenocortical adenomas (BAAs) or carcinomas. BAAs causing ACTH-independent CS are rare; up to now, fewer than 40 BAA cases have been reported. The accurate diagnosis and evaluation of BAAs are critical for determining optimal treatment options. Adrenal vein sampling (AVS) is a good way to diagnose ACTH-independent CS.

A 31-year-old woman had a typical appearance of CS. The oral glucose tolerance test showed impaired glucose tolerance and obviously increased insulin and C-peptide levels. Her baseline serum cortisol and urine free cortisol were elevated and did not show either a circadian rhythm or suppression with dexamethasone administration. The peripheral 1-deamino-8-D-arginine-vasopressin (DDVAP) stimulation test showed a delay of the peak level, which was 1.05 times as high as the baseline level. Bilateral AVS results suggested the possibility of BAAs. Abdominal computed tomography showed bilateral adrenal adenomas with atrophic adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). Magnetic resonance imaging of the pituitary gland demonstrated normal findings. A left adenomectomy by retroperitoneoscopy was performed first, followed by resection of the right-side adrenal mass 3 mo later. Biopsy results of both adenomas showed cortical tumors. Evaluations of ACTH and cortisol showed a significant decrease after left adenomectomy but could still not be suppressed, and the circadian rhythm was absent. Following bilateral adenomectomy, this patient has been administered with prednisone until now, all of her symptoms were alleviated, and she had normal blood pressure without edema in either of her lower extremities.

BAAs causing ACTH-independent CS are rare. AVS is of great significance for obtaining information on the functional state of BAAs before surgery.

World journal of clinical cases. 2019 Apr 26 [Epub]

Yu-Lin Gu, Wei-Jun Gu, Jing-Tao Dou, Zhao-Hui Lv, Jie Li, Sai-Chun Zhang, Guo-Qing Yang, Qing-Hua Guo, Jian-Ming Ba, Li Zang, Nan Jin, Jin Du, Yu Pei, Yi-Ming Mu

Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China., Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China., Department of Pathology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China.


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