Advanced Sensoring Technologies for Evaluation and Management of Lower Urinary Tract Symptoms

Nowadays, urination dysfunction caused by lower urinary tract symptoms (LUTS) has been a nonnegligible issue owing to its influences on patients’ physical and mental health, and in particular, the detection of the urination process and analysis of the urine samples of the patients have been the priority for diagnosis and treatment of LUTS. In this article, the existing perception of LUTS, such as the etiologies of LUTS and current approaches for LUTS evaluation in the clinic, is systematically summarized. Furthermore, several novels lower urinary tract (LUT) status‐sensing systems used for monitoring physiological indexes, including intravesical pressure, urine flow rate, residue urine volume, bladder volume, and biomarkers in urine, are introduced. It is believed that this presentation will make a contribution to deepening the comprehension of LUTS and promote the development of rapid, accurate, and convenient LUT testing techniques.


Introduction
Urination is a basic physiological function for humans and animals to excrete metabolic waste and maintain body fluid balance. [1] The storage and periodic voiding of urine mainly depend on the synergetic action of two functional units in the lower urinary tract: 1) the bladder (as the container) and 2) the outlet (composed of the bladder neck, urethral sphincter, and DOI: 10.1002/adsr.202300037 urethra), [2] and the synergy between these organs is regulated by the complex neural system such as brain, spinal cord, peripheral nerves, etc. [3] Once the control system or the functional units get damaged or diseased, a series of lower urinary tract symptoms (LUTS) will inevitably appear.
LUTS refers to various abnormal manifestations (including storage, voiding and post micturition symptoms) in the urination cycle caused by changes in the structure and function of the lower urinary tract, [4] and symptoms such as urination hesitancy, frequency, postmicturition dribble, urination incontinence, and others can often be seen in clinic. [5] Nowadays, LUTS has been a common problem that affects a large number of people of all ages, and it is estimated that population affected by LUTS will be over 2.3 billion by 2018. [6] Aging is one main reason accounting for LUTS because of the structural and functional changes in lower urinary tracts of the elderly. [7] What is more, LUTS caused by some chronic diseases including obesity, metabolic syndrome, diabetes, obstructive sleep apnea, etc., is quite prevalent in children and young adults, [8] and some people with congenital neurological diseases or bladder dysfunction may even suffer from this issue in their lifetime. [7] Because of the troublesome symptoms like urinary incontinence, urinary frequency, urgency, nocturia, bladder pain, and so on, the quality of life of the LUTS patients will be greatly influenced. [9] On top of this, LUTS is one reason of hospitalization, and treatment of LUTS has posed significant economic and public health burdens. [10] By analyzing the symptoms, the etiologies of LUTS include infections and inflammation, neurogenic bladder, bladder outlet obstruction, non-neurogenic bladder dysfunction, congenital abnormalities, endocrinopathies, and drugs, [11] which can be seen that LUTS is affected by numerous factors. In view of the complex etiologies of LUTS, its high prevalence worldwide and high economic loss it brings, [12] it is of an urgent need for effective diagnosis and treatment. At present, there are several methods for diagnosis and treatment of LUTS, including urodynamic studies, video urodynamic studies (VUDS), and laboratory examinations. [13] For example, although urodynamic studies may not be able to cure the LUTS, it is useful to assess the symptoms; [14] laboratory tests such as urinalysis, blood tests can be used to diagnose the infection and inflammation of urinary tract or cystitis precisely; [15] and VUDS is of great use in www.advancedsciencenews.com www.advsensorres.com analyzing the etiologies and providing scientific instructions for the treatment effectively. [16] In this review, we summarize the pathological causes and current diagnosis and treatment methods for LUTS, aiming to analyze the symptoms more deeply, and then equipment and electronic sensors for clinical use will be introduced. First, etiologies of LUTS are elaborated for better understanding of the complaints. Afterward, current diagnosis and treatment methods for LUTS are demonstrated. Finally, we describe commonly used and novel monitoring methods for the LUTS diagnosis and treatment in detail.

Introduction of LUTS
LUTS was first proposed by Adams [17] in 1994 for better evaluation and more precise description of prostatism, and the definition of LUTS was finally standardized by the International Continence Society (ICS) in 2002. [18] According to the diseases or changes in patients' condition, [19] LUTS can be categorized as: i) Voiding symptoms, which is mainly caused by enlarged gland, increased mechanical obstruction (the static factors) and changes of smooth muscle tension in the prostatic interstitial (the dynamic factors), [5] leading to symptoms including urinary hesitancy, dysuria, urinary stuttering, acraturesis, weak urinary stream, urinary bifurcation, drippling of urine, and uroschesis; ii) Storage symptoms, which is also named as irritative symptoms, [20] referring to the natural or stimulated detrusor contraction when the patients attempt to suppress urination because of the sensation of bladder filling, which is generally caused by overactive or underactive bladder, [21] and frequency, nocturia, hydrouria, urgency, abnormal sensation of bladder filling (increase, decrease, loss), and urinary incontinence are the main symptoms; iii) Postmicturition symptoms refer to abnormalities or discomfort after urination, and patients usually suffer from incomplete emptying, post-micturition dribble urgency, and other symptoms. [15a] The pathology of LUTS is quite complicated and has not been fully elucidated. It involves the neural network regulating the prostate, urethra, bladder, pelvic nerve, and vascular network supporting the structure of the lower urinary tract. Existing research suggests that possible mechanisms causing LUTS contain: i) Changes in signaling pathways, ① decrease of nitric oxide (NO)/cGMP. Because generally NO has an inhibitory effect on smooth muscle tone of the lower urinary tract, NO deficiency is considered to be one of the causes of LUTS. [22] ② Increased Rho kinase activity, up-regulation of this pathway will lead to abnormal urethral tone and bladder contraction. [23] ii) Changes in hormones and their receptors, ① changes in sex hormones and their receptors. Androgen is one important reason for the prostatic hyperplasia that leads to LUTS. [24] Moreover, the interaction between androgen and estrogen may cause changes in the bladder outlet structure, which attributes to LUTS. [25] ② Changes of hypothalamic-pituitary-adrenal axis (HPA) hormones and their receptors. Psychological factors are closely related to LUTS, and the corticotropin-releasing hormone (CRF) secreted by the hypothalamus can regulate the physical response mediated by stress response, such as pelvic hyper-pain. Stress response-induced mood swings can activate the CRF pathway, thereby affecting bladder function. [26] iii) Nervous system disorders, sympathetic nerve overactivity is associated with bladder outlet obstruction (BOO) and enhanced afferent nerve activity is also related to LUTS. [27] iv) Other mechanisms, including Lower urinary tract atherosclerosis and ischemia, inflammation, and central nervous system lesions. [28]

Etiologies of LUTS
LUTS is caused by a variety of complaints that affect the function of bladder and its outlet, [16a] and both physical damage and chronic diseases may lead to LUTS. In this part, multiple causes including infections and inflammation, neurogenic bladder, nonneurogenic bladder, bladder outlet obstruction, congenital abnormalities, endocrinopathies, and drugs [11] are described in detail (Figure 1).

Infections and Inflammation
It has been reported that various complaints caused by bacterial and viral infections or lesions in lower urinary tract are associated with LUTS, including urethritis, prostatitis, cystitis, etc. [29] Urethritis is defined as inflammation of the urethra and categorized as gonococcal urethritis (GU) and non-gonococcal urethritis (NGU). [30] GU is caused by Neisseria gonorrhoeae infection resulting from patients' unsafe sex, with purulent inflammation of the urinary system mucosa as the main symptom. [31] NGU is the most common type of urethritis at present, main pathogens including Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis, Herpes simplex virus, and Haemophilus parainfluenzae. [32] As a common urinary tract syndrome, prostatitis has a broad effect on men's health in the context that nearly half of the males get disturbed by this condition currently. [33] According to the pathological causes and current clinical research status, prostatitis can be divided into four categories by the National Institutes of Health (NIH), containing: i) acute bacterial prostatitis (ABP), which is caused by systemic infection and usually manifests as severe prostatic symptoms, possibly resulting in acute bacterial urinary tract infection (UTI), ii) chronic bacterial prostatitis (CBP) resulting from chronic bacterial infection, the symptoms are not always obvious, but the patients may experience recurrent UTIs caused by the same type of bacteria, iii) chronic prostatitis, also named as chronic pelvic pain syndrome, characterized by pelvic pain and voiding symptoms without bacterial infections, generally caused by hypo-immunity or bad living habits, iv) asymptomatic inflammatory prostatitis (AIP). Patients with AIP usually do not feel discomfortable, but sometimes leukocytosis appears and may develop into symptomatic prostatitis. [34] Although prostatitis generally does not threaten patients' life safety, it may seriously affect their quality of life (QoL) and mental health as the results of various voiding abnormalities. [35] Cystitis is an inflammatory complaint caused by bacterial infection (Escherichia coli, Proteusbacillus vulgaris, etc.) and other non-bacterial infection factors (such as drug factors, urinary stones, foreign bodies, radiotherapy, etc.) [36] According to the course of disease and symptoms, cystitis can be divided into acute cystitis and chronic cystitis, resulting in patients with lower urinary tract symptoms such as frequency, urgency, and dysuria. [37] In addition to the diseases mentioned above, there are also other infectious and inflammatory factors attributing to LUTS, such as balanitis caused by chemicals, allergies and infections, and sexually transmitted diseases (gonorrhea, syphilis, herpes, etc.). [38]

Neurogenic and Non-Neurogenic Bladder
Bladder disorders can occur for many reasons, such as diabetes, spinal injuries, detrusor under/overactivity, and so on. According to the pathogenesis of the conditions, bladder disorders can be classified as either neurogenic or non-neurogenic. [39] a) Neurogenic bladder: Neurogenic bladder dysfunction, which is also referred as neurogenic lower urinary tract dysfunction, [40] refers to a variety of lower urinary tract dysfunction due to disturbances in neural control mechanisms, manifesting as a series storage or voiding problems. [41] Multiple factors including central lesion, peripheral nervous system injuries, infectious and immune diseases, iatrogenic factors, congenital diseases, and psychological states [42] may lead to neurogenic bladder disorders and influence the normal function of the patients' lower urinary tracts. Neurogenic bladder is a dynamic and chronic disease, patients need long-term hospitalization, which not only reduces their quality of life, but also causes heavy economic burden to the patients and society due to high medical costs. [43] b) Non-neurogenic bladder: Non-neurogenic bladder, also known as Hinman syndrome, [44] is a urinary dysfunction that is usually caused by bad urination habits, unstable psychological, or mental state other non-neuropathic factors, accompanied by urinary retention, dysuria, and other clinical symptoms. In 1977, Allen et al. [45] reported 21 cases with similar symptoms, which supported Hinman's findings, and he indicated that although no specific pathogenesis was identified, urodynamic examination showed that the patients had detrusor and urethral disorders.
The main feature of non-neurogenic bladder is that neuropathic defects or lesions cannot be detected by modern examination methods, but the clinical symptoms and morphological changes of the bladder are similar to those of the neurogenic bladder. [46] According to the etiology of non-neurogenic bladder, changing poor urination habits and psychological intervention have been the main therapeutic means. [47] Compared with neurogenic bladder, non-neurogenic bladder has no neurological damage, so many patients recover more quickly and do not require long-term follow-up. Nevertheless, how to diagnose and identify neurogenic bladder and non-neurogenic bladder is still difficult in clinical treatment. [48]

Bladder Outlet Obstruction
Bladder outlet obstruction (BOO) is a pathological condition characterized by difficulty in urinating due to increased resistance to urine outflow caused by various bladder neck or urethral lesions, [49] including urethral stricture disease, primary bladder neck obstruction (PBNO), benign prostatic hypertrophy (BPH), prostate cancer, etc. [50] Because BOO is one main reason for bladder contraction dysfunction and bladder compliance changes, different degrees of lower urinary tract symptoms will show up. [51] Urethral stricture is mainly caused by inflammation, tumor, urinary stones, or trauma, and then urethral cavity gradually shrinks and causes the discomfort of urination. The main clinical manifestations contain decreased urine flow, frequency, urinary pain, dribbling, and so on. Patients also have symptoms such as urinary retention and recurrent urinary tract infections. [52] Primary bladder neck obstruction (PBNO) is also a cause of LUTS, but its etiology has not been fully elucidated. Possible causes include structural changes of bladder neck, morphological abnormalities of bladder detrusor, abnormalities of transverse urethral sphincter, and sympathetic hyperactivity. Clinical manifestations included voiding symptoms (dysuria, hesitancy, decreased urine flow, incomplete emptying, etc.), storage symptoms (frequency, urgency, urinary incontinence, nocturia, etc.), or both. [53] BPH is a special histopathological disease characterized by proliferation of stromal and epithelial cells. [54] Clinically, it often presents lower urinary tract symptoms including frequent urination, urgent urination, nocturia, endless urination, and so on. These symptoms will gradually get worse with age, and BPH with lower urinary tract symptoms has become a common disorder in men over 50. [55] The pathophysiological manifestations of BPH are bladder outlet obstruction, and the causes can be divided into static factors (mechanical obstruction, caused by the pressure against the urethra from prostatic hyperplasia) and dynamic factors (caused by the activation of 2 adrenergic receptors in the bladder neck, prostate capsule, and glandular smooth muscle, resulting in smooth muscle contraction and increased muscle tone). [56] Since the prostate is the gland surrounding the urethra at the exit of the bladder, when prostate cancer appears, the enlarged gland of the prostate will compress the urethra, resulting in obstruction of the urinary tract and related LUTS. [57] www.advancedsciencenews.com www.advsensorres.com

Congenital Abnormalities of the Kidneys and Urinary Tracts (CAKUT)
CAKUT refers to a series of conditions consisting of anatomical abnormalities of the urinary system. The malformations are caused by abnormal development of the urinary system during the embryonic period, and congenital malformations are developmental defects caused by genetic or environmental factors, including congenital malformations of the kidney, ureter, bladder, and urethra, [58] which may lead to frequency, dysuria, urinary incontinence, urinary tract infection, and other LUTS.

Endocrinopathies
Current studies have shown that endocrine diseases are also one of the causes of LUTS, such as diabetes. [61] Generally, diabetes is thought to occur due to a variety of causes and in the case of dysfunction of human organs.
Type I diabetes is now based on genetic causes, in addition to the induction of other infectious agents. It is a disease of the immune system in which insulin is not adequately secreted due to damage to B cells. [62] Compared with type I diabetes, there are many other causes of type II diabetes: ① Insomnia, it can cause the inability to secrete enough insulin or reduce the sensitivity of tissues to insulin, leading to the occurrence of diabetes. ② Obesity and age are also predisposing factors of diabetes. ③ Human immune factors, in the physical examination of patients with type I diabetes, it is usually found that cell surface antibodies and islet cell antibodies coexist with other human immune diseases. ④ Mental factors, patients with mental stress often have symptoms such as irritability and insomnia, which makes the organs unable to balance and coordinate, resulting in metabolic disorders in many systems, damage to islet function, and then suffer from diabetes. [63] The clinical lower urinary tract symptoms of diabetes are mainly characterized by decreased bladder sensitivity, increased maximum bladder capacity, impaired bladder contraction, and increased residual urine volume, sometimes accompanied by urgency, urinary incontinence, and recurrent urinary tract infection. Diabetic bladder is not a life-threatening disease, but it significantly reduces the quality of life of patients. [64] Moreover, researchers found that there are also other endocrinopathies or endocrines associated with LUTS. For instance, by assessing the thyroid function of the female patients from March 2017 to September 2020, Zargham et al. [65] found that the severity of stress urinary incontinence and storage symptoms might be related to hypothyroidism. In addition, Nicolson et al. [66] discovered the possible relationship between estrogens and LUTS in males. By using endocrine disruptors, Bisphenol-A and estradiol-17 in animal trials, they found that adult male mice developed urination dysfunction, indicating the potential risks of environmental estrogens on urologic health in men.

Drugs
In clinical practice, drugs used to treat non-urinary system diseases sometimes cause many adverse reactions of the urinary system. These adverse effects may be due to local effects or be the result of a systemic reaction of the autonomic nervous system or a disorder of centrally controlled bladder emptying caused by the drugs. [67] The adverse effects include: i) Hemorrhagic cystitis, hemorrhagic cystitis caused by drugs is considered to be the cause of hematuria, dysuria, and frequency, and includes a variety of antineoplastic agents (cyclophosphamide), antibiotics (penicillin), and others (nonsteroidal anti-inflammatory drugs, etc.) [68] ii) Uroschesis, urination is a complicated physiological process. In the beginning of urination, the nerve impulse to the adrenal receptor at the neck of the bladder is weak, while the parasympathetic nerve, which maintains the tension of the detrusor muscle, will be excited, so that the urine can be discharged completely. [69] Adverse reactions to drugs can affect this mechanism, resulting in retention of urine, such as anti-muscarinic drugs (reducing bladder contractions), anesthetics, and analgesics. [70] iii) Urinary incontinence, due to the adverse reactions of some drugs, the inhibitory effects on the nervous system and smooth muscle during medication will appear, resulting in a large amount of urine production in a short period of time and urinary incontinence, [71] including long-acting sedatives (slowing down patients' response to urination), diuretics (production of a large amount of urine in a short period of time), anti-parasympathetic drugs (reducing urethral sphincter contractions), anti-sympathetic drugs (resulting in urethral sphincter relaxation), and calcium channel blockers (relaxing smooth muscle and weakening bladder contractions). [72] In addition to the factors above, some drugs may induce the formation of tumors and urinary stones, leading to LUTS. [73]

Diagnosis and Evaluation of LUTS
Diagnosis is a crucial means to determine the disease according to the patients' manifestations, combined with etiologies, pathogenesis, and pathological process, so as to help patients recover. In this part, three methods commonly utilized in evaluation and diagnosis of LUTS are introduced, and key contents are summarized in Figure 2.

Urodynamic Studies
Urodynamics is a branch of urology surgery, which is mainly based on the principles and methods of hydrodynamics and electrophysiology, through the detection of pressure of various parts  of the urinary tract, flow rate, and bioelectrical activity, so as to explore the function and mechanism of urination, as well as the pathophysiological changes of urinary dysfunction diseases, so as to provide accurate objective basis for clinical diagnosis and treatment. Comprehensive urodynamic examination is an ideal method to intuitively and quantitatively reflect urinary tract function. [74] In clinical practice, commonly used urodynamic tests include: i) Urinary flow rate measurement, urinary flow rate measurement is a non-invasive urodynamic test method. The equipment required is simple and inexpensive. It can help medical staff understand the symptoms of urine storage and urination in patients, and it is an essential screening program for most patients with LUTS. [75] ii) Filling cystometry, this measurement can be used to assess detrusor and sphincter function during bladder filling and urination, including bladder sensation, detrusor activity and compliance, bladder safety volume, and internal and external sphincter function. It can be used to guide the frequency and time of intermittent catheterization, drinking water plan, bladder function training and treatment, reduce the occurrence of bladder infection, and improve patients' ability to control urination. [76] iii) Pressure-flow rate measurement, measurement of urethral resistance is the only basis for urodynamic diagnosis of bladder outlet obstruction, but it is difficult to measure it directly with existing methods. Because the relationship between bladder pressure, flow rate, and urethra resistance basically follow Ohm's law, that is, pressure is proportional to flow rate and inversely proportional to resistance. Based on this relationship, the pressure-flow rate measurement can be indirectly used to calculate urethral resistance by measuring bladder pressure and urine flow rate, thus contributing to the diagnosis of obstruction. [77] Pressure-flow rate measurement provides objective evidence for BOO and is currently the 'gold standard' recommended by ICS for diagnosing BOO. [78] iv) Pelvic floor electromyography. Pelvic floor electromyography is used to evaluate the innervation of pelvic floor muscles and to record the electromyographic activity of the puborectal external sphincter with needle electrode, cylindrical membrane electrode, or filamentous electrode. Pelvic floor electromyography contributes to monitoring the functional status and innervation of pelvic floor mus-cles, determining whether myogenic or neurogenic diseases occur, and guiding the diagnosis of LUTS. [79]

Video Urodynamics Studies
On the basis of conventional urodynamic measurement of bladder pressure and urodynamic parameters, VUDS shows the morphological changes of the bladder and urethra at the same time, which provides a basis for clinical diagnosis and treatment. For diseases such as complex bladder and urethral dysfunction, lower urinary tract obstruction and stress urinary incontinence, video urodynamic examination can more accurately reflect the potential pathophysiological changes of the lower urinary tract, [80] which has great diagnostic value for lower urinary tract voiding dysfunction and has become an important evaluation method. Clinically, VUDS can be used to diagnose female bladder outlet obstruction, female stress urinary incontinence, male voiding dysfunction after prostate surgery, vesicoureteral reflux, neurogenic bladder, and other symptoms. [81] Chiang et al. [82] reported the application of VUDS in monitoring the urination of patients with chronic brain diseases (Parkinson's disease, cerebrovascular accident, and early dementia), finding that there was a high incidence of detrusor overactivity, abnormal bladder contraction, BOO, which is of great significance in accurate management of LUTS. Through retrospective analysis of VUDS results, Jiang et al. [83] discovered that bladder dysfunction usually occurred in male patients over 70 years old rather than BOO, which indicates the effect of VUDS in precise diagnosis and treatment of LUTS. Tosaka et al. [84] obtained clear detection results of urethral and pelvic floor abnormalities in LUTS patients by transrectal ultrasonography, proving the effectiveness of VUDS in clinic use. In addition to the above, VUDS is also an important means to improve the skills of the clinicians, [85] playing an important role in this digital era.

Laboratory Examinations
Laboratory examinations are important for the diagnosis and prognosis of kidney, urinary tract diseases, and other systemic diseases, mainly including urinalysis, serum prostate specific antigen (PSA) detection, and renal function detection. [86] Urinalysis mainly consists of: i) pH value, [87] the urinary pH value reflects the acid-base balance in the body and the regulatory function of the kidney. The decrease of pH value is commonly caused by diabetes, gout, acidosis, chronic glomerulonephritis, etc., while the increase is often caused by vomiting, urinary tract infection, taking bicarbonate drugs, alkalosis, etc. ii) Urinary specific gravity (SG), [88] SG is the ratio of the weight of urine to the same volume of pure water at 4°C. Under normal circumstances, to maintain the balance of fluids and electrolytes, human body needs to excrete water and various substances through the kidneys. The value of urinary specific gravity depends on the concentration and dilution function of renal tubules and is proportional to the concentration of solute (salt, organic matter) contained in urine, and inversely proportional to urine volume. Acute glomerulonephritis, diabetes mellitus, chronic nephritis, glomerular interstitial disease, chronic renal failure, and diabetes insipidus all lead to changes in urinary specific gravity. iii) Urinary protein (PRO), [89] urinary protein is caused by protein in the urine exceeding the reabsorption capacity of renal tubules. It is commonly seen in glomerulonephritis, nephrotic syndrome, renal insufficiency, and drug intake (e.g., quinine). iv) Urinary glucose (GLU), [90] the presence of glucose in the urine depends on the blood glucose level, the filtration rate of glucose in the glomerulus, the reabsorption rate of glucose in the proximal tubules and urine flow. Glycosuria occurs when the glucose threshold exceeds the renal threshold or when the renal threshold is lowered, and it is an important indicator for diagnosing diabetes and other endocrine diseases. v) Urinary bilirubin (BIL), [91] Bilirubin, a degradation product of hemoglobin, is an important indicator to diagnose hepatocyte injury and to identify jaundice, which is of great significance in clinical diagnosis and prognosis. vi) Ketone body (KET), [92] during starvation, glucose metabolism disorders, increased lipolysis, and diabetic ketoacidosis, ketonemia occurs because the production rate of ketone bodies is greater than the consumption rate in human body, followed by ketonuria. vii) Nitrite (NIT), [93] when the urinary system gets infected, the test result will be positive because bacteria reduce nitrate to produce nitrite. It is commonly seen in urinary tract infections caused by Escherichia coli. viii) Urine occult blood (BLD), [94] urine occult blood reflects hemoglobin (Hb) in urine. When intravascular hemolysis occurs, red blood cells will be destroyed, and a large amount of Hb enters the blood. If the amount exceeds the binding capacity of haptoglobin, Hb will be excreted with the urine, leading to hemoglobinuria.
Prostate specific antigen (PSA) is a single-chain glycoprotein secreted by the prostate gland and has prostate tissue specificity. Serum total prostate specific antigen is currently the biological index of prostate cancer, and when prostate specific antigen increases, there is the possibility of prostate cancer. [95] Many kidney diseases are difficult to be detected in the early stage, so the renal function detection is necessary. [96] Commonly seen diseases such as acute and chronic nephritis, acute and chronic renal failure, nephrotic syndrome, diabetic nephropathy, hypertensive nephropathy, and so on can be detected by this method, which is significant in disease diagnosis and treatment, and serum urea, creatinine, 2-microglobulin, and uric acid are commonly used in renal function detection. [97]

Sensors for Intravesical Pressure Measurement
Intravesical pressure is measured by filling the bladder manually to detect the relationship between bladder capacity and pressure changes during urine storage and bladder pressure changes in urination. The primary objective is to test detrusor function during urine storage and voiding, which plays an important role in the diagnosis and etiological analysis of bladder dysfunction, as well as guiding the selection of the best treatment plan and evaluation of the treatment effect. [98] At present, intravesical pressure measurement is often used in conventional urodynamics to assess bladder function, including bladder sensation, detrusor stability, bladder compliance, etc. [99] However, there are some factors influencing the results, such as the influence of patients' psychological factors, saline perfusion, and catheterization. [100] Therefore, novel techniques with higher efficiency and more precise detection capabilities will be in urgent need in the future.
Soebadi et al. [101] also developed a wireless and real-time intravesical pressure sensor, Bladder Pill, for repeated and longterm measurement of bladder behavior ( Figure 3A). This device consists of a pressure microsensor and a 3D inductively coupled coil that provides energy, and it was evaluated in vivo by implantation into the bladders of the minipigs. By comparing the measuring results of the Bladder Pill with that of the current transurethral catheter method, the Bladder Pill performed better when monitoring multiple voids and conducting long-term measurement, on top of this, the Bladder Pill was able to record the patients' bladder pressure during the daytime without impacting their daily life, which was of great potential for better study of human bladder behavior. Ge et al. [102] reported an improved transurethral catheter method in clinically monitoring intravesical pressure ( Figure 3B). In order to reduce the inspection time and injuries to the patients, they developed a portable monitoring device that comprised a catheter, a pressure sensor, and a control unit. Through Bluetooth, the real-time intravesical pressure could be sent to a mobile phone. In addition, the control unit was able to set a threshold alarm and open or close the catheter clip, and they also demonstrated that the duration of the urodynamic studies could be reduced from 3 h to 10 min, which was efficient and brought less pain to the patients. To avoid psychological burdens and potential infection risks to the patients brought by the conventional catheterization in the intravesical pressure measurement, Zhong et al. [103] designed a portable implantable sensor that was wireless, battery less, and capable of monitoring the intravesical pressure in real-time. In this system, the data could be transmitted to the receiver by Bluetooth Low Energy (BLE), and the implanted sensor could be powered by wireless power transmission system with a maximum distance of 7 cm (Figure 4). Though in vivo and in vitro experiments, they also proved the accuracy, feasibility, and consistency of this system in intravesical pressure measurement. At present, traditional bladder pressure measurement can be only done in hospital by the equipment that is of poor movability, high expenses, and low efficiency, which is inconvenient for the patients. To solve these issues, Liu et al. [104] reported a portable dynamic bladder pressure monitor equipment and verified its feasibility in clinic by comparison with conventional approach (Figure 5). The whole Figure 3. Intravesical pressure detectors. a) From left to right are schematic diagram of Bladder Pill in vivo, waistband-shaped device for in vivo test, and rectangular frame (ensuring continuous and accurate tests of intravesical pressure in awake pigs). Reproduced with permission. [101] Copyright 2019, Public Library of Science. b) Schematic diagram and pictures of the bladder pressure monitoring system, containing: saline for perfusion, the injection system, the three-way stopcock of the injection system and the control unit. Reproduced with permission. [102] Copyright 2022, Elsevier. . a-f) The schematic diagram of the intravesical pressure monitoring system, appearance of the sensor, system modules of the pressure monitor system, maximum working distance test, and application of the system in animal trials. Reproduced with permission. [103] Copyright 2019, IEEE.
system composes of monitoring software and hardware with a total of seven parts, which are easy to operate and convenient for the operators to observe the status of the patients. The testing results showed that there was no obvious difference between this device and traditional method, proving its accuracy and reliability in measuring bladder pressure. In addition, due to its portability and cheap price, patients can use it either in hospital or at home without high economic burdens, which is of great benefit. Figure 5. Modules of the portable dynamic bladder pressure monitoring device (bladder piezometric tube, rectal balloon piezometric tube, connecting pipe, externally biased pressure sensor) and the monitoring software. Reproduced with permission. [104] Copyright 2016, John Wiley and Sons.

Sensors for Urine Flow Rate Measurement
Patients with LUTS usually have symptoms such as urgency, frequency, nocturia, etc., and because these symptoms are rarely accompanied by obvious urinary tract infections or inflammatory lesions in the early stage, the lack of high-quality diagnosis and intervention treatment to aggravate the condition inevitably increase the pain of patients and the difficulty of treatment. Therefore, these symptoms must be fully assessed in order to better guide treatment. [105] Urinary flow rate measurement has been an important clinical assessment since the 1960s and is by far the most widely used assessment of urine flow mechanics, mainly due to its advantages of non-invasive, practical simplicity, and low cost. [106] Although urinary flow rate measurement alone cannot accurately diagnose the causes of bladder dysfunction, as one of the most convenient means of preliminary screening, it has a very high sensitivity to determine whether patients are able to urinate normally.
Goldman et al. [107] evaluated the ability of a novel electronic urine output measuring device, the RenalSense Clarity RMS Sensor Kit, by comparing its hourly urine output in real time with that of the manual method in current clinic (Figure 6). The device is based on a custom-designed sensor that is designed in accordance with the principle of heat conduction and is integrated into a standard sterile catheter to monitor the flow of urine as it passes through the catheter in real time. Data are then transmitted to the console via cable to achieve the effect of real-time monitoring and to meet the data collection and analysis objectives of the study. And the results showed that the real-time urinary flow rate recorded by the device was more accurate and reliable than the manual method, and the continuous graphic monitoring of urinary flow rate could effectively help the medical stuff diagnose the bladder status of patients, prevent and treat various complications. In the study by Brotfain et al., [108] a sensor that is capable of monitoring minute-to-minute urine flow rate was utilized to record the hemodynamic status of the critically ill multiple trauma patients. During the treatment, Foley catheters connected to the device URINFO 2000 TM were inserted into patients' bladders. And this novel urine collection and flow measurement system with an optical drip detector could measure and calculate the urine output at different flow rates and osmotic pressures every 3 min accurately, which provides important guidance in monitoring the hemodynamic status of the patients with critically ill multiple traumas. To evaluate the urine flow rate precisely, sanitarily, and continuously, Qi et al. [109] developed a proof-of-concept detector on the basis of a millimeter-wave FMCW (frequencymodulated continuous wave) radar (Figure 7). In the experiment, they used a squeezable dummy bladder to simulate the urination and recorded the whole process with the radar, and then the result was compared with that of the traditional indirect weight measurement. Their work verified that the radar could not only measure the instantaneous flow rate, but also sense tiny streams of liquid accurately and sensitively, which was of great potential in LUTS diagnosis.

Sensors for Residual Urine Volume and Bladder Volume Measurement
In treatment of LUTS, it is necessary to monitor patients' urination and residual urine volume so as to develop new bladder care plans. The technique of bladder scanning residual urine volume measurement is to measure the residual urine volume in the bladder by scanning and showing the liquid dark area in the bladder. The feasibility of routine use in clinical rehabilitation and the accuracy of measurement have been confirmed in many reports. [110] Similarly, in diagnosis and treatment of urological dysfunction, it is essential for the medical staff to monitor the bladder volume of the patients to evaluate the function. [111] Given the significance of these two physiological indexes, some monitoring approaches are discussed in this part.
Park et al. [112] reported post-void residual volume measurement by using a portable real-time pre-scan imaging bladder scanner (BioCon-500) and compared its results with those of a conventional bladder scanner (BVI-3000). To obtain true post-void residual volume, the catheterization was conducted promptly after scanning, and the results showed that measured values of both devices were close to the true value, indicating the feasibility of the portable bladder scanner in monitoring postvoid residual volume (Figure 8). Choe et al. [113] also reported the application of a novel portable ultrasound scanner, the Biocon-700 in monitoring residual urine volume, and the catheterization was performed immediately after scanning as well to assess the accuracy of the scanner. The results showed the Person's correlation coefficient between the scanner and the catheter was 0.872 (R 2 = 0.76), and the mean difference was 23.59 ± 37.32 mL, demonstrating that the scanner was able to precisely evaluate the residual urine volume. To better understand and monitor bladder function and status, McAdams et al. [114] designed a catheterless fluid volume estimating system for studying chronic neurophysiology of the lower urinary tract. This portable device was implanted into a feline's bladder without affecting its function or causing injuries, and the benchtop test showed that this system was able to evaluate the intravesical fluid volume from 0 to 50 mL, with a root-mean-square error of 11.32%, offering a translatable technology platform for clinical use. Owing to common mechanical mismatch between traditional electronic devices and body tissues, stretchable electronics have aroused wide concern for their potential in medical use. Stauffer et al. [115] reported a chipless wireless strain sensor on the basis of a soft conductor (Au-TiO 2 NW) to monitor the bladder volume in real-time for a long term (Figure 9). The system enables several centimeters of wireless strain sensing at up to 50% strain, and through a proofof-principle measurement, the results showed the feasibility of the system for continuous monitoring of bladder volume in vivo.

Sensors for Urinalysis
Urinalysis is one of the most important tests in clinical practice, which is of great importance for the detection of human urinary system because urine contains abundant physiological information, [116] and in recent years, an increasing number of studies have been conducted to quantify the urinary biomarkers   . a-e) A schematic diagram of the monitoring system, circuit diagram of the system, readout system and its coil, the implantable RLC sensor with a stretchable capacitor and side view scanning electron microscope image of a cut through the capacitor. Reproduced with permission. [115] Copyright 2018, John Wiley and Sons. Figure 10. Schematic diagrams of the urinalysis sensors system. ① Suction nozzle, ② electrode tube, ③ connector containing three connective strips, ④ and ⑤ Pt cables for connecting the electrodes and the potentiostat, ⑥ and ⑦ suction nozzle and cannula of the pipette, ⑧ sleeve for fixing the cables. Reproduced with permission. [119] Copyright 2021, Elsevier.
for the diagnosis and treatment of cancer, metabolic abnormalities, and bacterial infections. [117] At present, urine analyzers based on preclinical medicine and photoelectric technology can detect the components in urine quickly and accurately, which has been main auxiliary tools for doctors in diagnosis. [118] However, the urine analyzers used in hospital are generally expensive and large in size, which is not suitable for community hospital, small clinics, or family use. In this part, several novel portable analyzers and their effects in measurement are introduced.
Liu et al. [119] reported a hand-held electrochemical sensor for urinalysis. In their studies, a novel point-of-care testing (POCT) device for analyzing the components of urine is developed by integrating an electronic sensor with a pipettor (Figure 10). This system enables the measurement of urinary pH, uric acid (UA), Figure 11. a-f) Schematic diagrams of the device, circuit diagram, and operating principle of the system, photos of the device, the operation app on the smartphone, test results of a bladder cancer patient and a healthy individual. Reproduced with permission. [120] Copyright 2022, John Wiley and Sons. and urea though one working electrode and allows semiautomatic operation with one hand, including sapling, measurement and cleaning, which greatly simplified manual work. In addition, this portable device possesses the advantage of being costeffective and easy to be produced, which contributes to the development of sensors for urinalysis. To conduct non-invasive early diagnosis of bladder cancer, Yang et al. [120] developed a urinalysis sensor by integrating a control panel, indium gallium zinc oxide filed-effect transistor (IGZO FET) biosensor arrays, and an internet terminal for the detection of the proteins related to bladder cancer (Figure 11). The high sensitivity of this sensor enables the identification of bladder cancer with an accuracy of 95% in 197 patients and 75 healthy individuals, the differentiation of cancer stages with an accuracy of 90% and assessment of bladder cancer recurrence after surgeries. Due to the advantages of low cost, portability, being non-invasive and easy to operate, this device has the potential to translate into clinical use for bladder cancer diagnosis and prognosis. In the diagnosis and treatment for chronic kidney diseases, urinary protein is an important biomarker. Thus, Vermesh et al. [121] introduced a method for measuring urinary protein concentration by using a miniaturized optoelectronic sensor through a fluorescence assay that is on the basis of the protein-induced fluorescence enhancement (PIFE) phenomenon, achieving sensor response to protein concentration changes in real-time This portable device consists of a vertical cavity surface emitting laser (VCSEL), photodetector, and other customized electronics (Figure 12). And by comparing the results of the sensor measurements with those of Figure 12. a-c) Photo-isomerization of cyanine dyes between a photoactive trans isomer and a cis isomer, the photoisomerization of the photoactive trans isomer fluoresces on excitation and protein measurement process by the photodetector. Reproduced with permission. [121] Copyright 2021, Elsevier. Figure 13. a-e) The schematic of the device and the monitoring process by attaching the sensor into a diaper, test operation on the sensor, the flow chart of the app recognition pattern, and the interfaces of the app. Reproduced with permission. [122] Copyright 2018, Royal Society of Chemistry. Figure 14. a-c) Schematic diagram of the capacitive touch screen sensor, predicted results from the touch screen algorithm and the schematic diagram of the touch screen structure. Reproduced under the terms of the CC BY license. [123] Copyright 2014, The Authors, published by MDPI.
the gold-standard clinical laboratory measurements, they verified that the sensor was highly accurate in detecting urinary protein concentration. In monitoring infections in lower urinary tract, Zhou et al. [122] designed a novel wearable and cost-effective sensor to detect the biomarkers including glucose, leukocytes, nitrite, blood, and proteins in urine. By combining this sensor with a diaper, the whole process of measurements can be finished in 10 min, and the results can be obtained by an app on the smartphone, which is user-friendly (Figure 13). Through linear dis-criminant analysis, the levels of the biomarkers in the urine samples can be accurately calculated, proving this device a potential tool for diseases diagnosis. Honrado et al. [123] also reported a capacitive touch screen sensor (CTSS) for urinary tract infection detection (Figure 14). In this study, they found a measurable capacitance change when the amount of E. coli or ions in the detected liquids changed, demonstrating that urinary tract infections can be monitored by detecting the components of the urine samples, which can be used to design a portable device for clinical use.

Conclusion and Outlook
In this review, we focus on the LUTS analysis and detection of related physiological indexes in order to obtain better understanding of LUTS and guide the development of the diagnosis and treatment technologies. First, the background of LUTS, including its definition, current status, and risks, is introduced. Afterward, several factors leading to LUTS (infections and inflammation, neurogenic and non-neurogenic bladder, bladder outlet obstruction, congenital abnormalities, endocrinopathies, and drugs) and the consequences caused by them are described in detail. Then, current diagnosis and treatment approaches for LUTS, including urodynamics, video-urodynamics, and laboratory examinations are discussed for following introduction of the monitoring systems. At last, we introduced several novel and innovative detectors that can be used to conveniently and accurately monitor the status of the LUT and analyze the biomarkers of the urine samples.
In the decades since LUTS was first proposed, great progress has been made in the understanding and treatment of LUTS with the development of theoretical research and technologies, but improvement is still in urgent need now. On the one hand, there are bound to be more factors leading to LUTS in modern society, so theoretical research of LUTS is still necessary, and on the other, existing studies have demonstrated that information technology will be the key to developing new techniques for accurate, rapid, and convenient detection of LUT status.