How Did María Isabel Díaz Lose Weight

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Most therapies for the treatment of sensorineural hearing loss are challenged by delivery through multiple tissue barriers to a difficult-to-access anatomic location of the inner ear. In this review, we will provide a recent update on various drug therapy, gene therapy, and cell therapy approaches used in clinical and preclinical studies for sensorineural hearing loss and approaches taken to overcome drug delivery barriers in the ear. Small molecule drugs for pharmacotherapy can be delivered by systemic or local delivery, where the blood-base barrier prevents the former and tissue barriers including the tympanic membrane, round window membrane, and/or oval window prevent the latter. Meanwhile, gene and cell therapies often require targeted delivery to the cochlea, which is currently achieved through intra-cochlear or intra-labyrinthine injection. To improve the stability of bioactive molecules during treatment, e.g. For RNAs, DNAs, proteins, additional packaging vehicles are often required. To address the various biological barriers to drug delivery into the inner ear, each type of therapy and intended therapeutic payloads will be discussed in this review, commonly used delivery routes, delivery vehicles if needed (e.g. viral and non-viral nanocarriers), and drug penetration and persistence. Other strategies to improve release (eg, hydrogel, nanocarriers, permeability enhancers, and microfluidic systems). Overall, this review aims to capture important advances and key steps in the development of inner ear therapies and delivery strategies over the past two decades for the treatment and prevention of sensorineural hearing loss.

How Did María Isabel Díaz Lose Weight

How Did María Isabel Díaz Lose Weight

Hearing loss is the fourth leading cause of disability worldwide (Vos et al., 2017). An estimated 466 million people, more than 5% of the world’s population, live with hearing loss, which is defined as the inability to detect sound through vibration-mechanical energy or convert it into electrochemical nerve signals. According to the latest 2021 estimate by the World Health Organization, the global economic burden of this disease is $980 billion (World Health Organization, 2021). Furthermore, hearing loss causes immeasurable obstacles to the patient’s quality of life, as it hinders the development of speech, causes difficulties in social activities or increases the risk of unemployment (Council, 2005; Cunningham et al., 2017) . .

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The anatomy of the ear can be divided into the outer ear, middle ear, and inner ear (Figure 1A). The outer ear and middle ear are separated by the tympanic membrane (TM). The middle ear has three membranes responsible for sound transmission. The inner ear (also called the labyrinth) contains the cochlea, vestibule, and semicircular canals. The cochlea is the auditory sensory organ, while the vestibule and semicircular canals form the vestibular system responsible for balance and spatial orientation. Based on ear anatomy, hearing loss can be divided into two categories: (i) conductive hearing loss, which refers to hearing loss caused by injuries to the outer and middle ear, and (ii) sensorineural hearing loss (SNHL), which refers to hearing loss. Deafness caused by injuries to the inner ear and auditory nerve pathway (Figure 1A) requires drug delivery to the inner ear (Cunningham et al., 2017). SNHL accounts for nearly 90% of all cases of hearing loss (Nyberg et al., 2019). It is the most common sensory disorder in developed countries (Smith et al., 2005). Here we focus our discussion on SNHL and the inner ear drug delivery approaches developed to address this disorder. We refer readers to a more detailed discussion of conductive hearing loss (Johnsen et al., 2012; Dougherty and Kesser, 2015; Hill-Feldham et al., 2020).

Figure 1. (A) A schematic of an ear structure; Sensorineural hearing loss (SNHL) is caused by injuries to the inner ear or neurons along the vestibular auditory nerve from the cochlea to the brain. (B) Cross-sectional plan of the cochlea showing three scales and associated anatomical structures. (C) A schematic of a sensory hair cell. (B, C) Reprinted with permission from Willems and Epstein (2000).

Sensorineural hearing loss is characterized by degeneration of two types of cells: cochlear hair cells, which are the primary mechanoreceptors for sound, and/or auditory nerve neurons, which transmit signals from the cochlea to the cochlear nucleus in the brainstem. . auditory processing (Møller, 2011; Cunningham et al., 2017). SNHL can have both non-genetic and genetic causes. Non-genetic factors include noise exposure (Daniel, 2007), viral infections (e.g., Zika, cytomegalovirus) (Cohen et al., 2014), chronic middle ear infection (English et al., 1973), ototoxic chemicals (e.g. .chemotherapeutic). agents) the drug cisplatin, an aminoglycoside antibiotic) (Bisht and Bisht, 2011), autoimmune disease (Mijovic et al., 2013) and aging (Gordon-Salent, 2005). There are also cases of idiopathic SNHL without an identifiable cause, which is termed sudden-onset SNHL (SSNHL) and is defined by the onset of hearing loss of 30 dB or more within a 72-hour (h) window (Kuhn et al., 2011). 70% of genetic SNHLs are non-syndromic, during which hearing loss is the only pathology. Non-syndromic hearing loss can be classified based on genetic location as autosomal dominant (DFNA), autosomal recessive (DFNB) and X-linked recessive (DFN), which is less common than the other two (Williams and Epstein, 2000). Conversely, syndromic hearing loss is accompanied by various additional clinical features. For example, Usher syndrome (USH1B/1F/1G/2A/3A) results in symptoms of hearing loss and loss of balance and vision.

Current treatment options approved by the United States Food and Drug Administration (US FDA) for SNHL primarily consist of hearing aids and cochlear implants. Hearing aids are sound amplifiers that are worn in the outer ear and are typically prescribed to patients with mild to moderate hearing loss (Food and Drug Administration, 2018a). Cochlear implants are surgically approved for use in patients with severe hearing loss; They bypass the weakened ear structures and transmit sound-induced currents directly to the auditory nerve via an electrode placed in the cochlea (Food and Drug Administration, 2018b). Cochlear implants, when combined with intensive speech therapy, can help linguistically deaf children develop normal language skills (Clarke, 2004). Although greater differences in patient outcomes have been reported for cochlear implants, this may be due to inadequate simulation of natural hearing and the need for post-operative cognitive rehabilitation (Zeng, 2016).

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In clinical practice, corticosteroids such as prednisone, prednisolone, and dexamethasone are recommended as first-line therapy in US otolaryngology to manage SSNHL (Chandrasekhar et al., 2019), although they are not yet FDA approved. . Recognized symptoms. Oral corticosteroids are prescribed within 2 weeks of onset of symptoms and intra-tympanic corticosteroids are prescribed if there is no improvement after 2-6 weeks. There is considerable variability in the efficacy of corticosteroid therapy versus placebo. Furthermore, they are only effective within a short period of time before permanent sensory damage occurs, and even if treated within this window, patients may not gain usable hearing from this treatment. These defects have prompted exciting preclinical research focusing on regenerative therapies to replenish the population of hair cells and neurons in the cochlea and restore their functions. For genetic SNHLs untreatable by traditional pharmacological therapy, gene therapies are being developed and tested in mouse models (Table 1); They seek to select missing genes or repair defective genes to restore normal cochlear development and hearing function.

In this review, we will discuss three categories of treatment options (divided based on the treatment modalities offered): pharmacologic therapy, gene therapy, and cell therapy (Table 2). In each class, the discussion is further organized based on the delivery vehicles and delivery route used. To achieve efficacy, all three treatment classes must overcome one or more types of biological barriers in the ear. Below, we first review the structure of the inner ear in the context of SNHL, and point out the target anatomical locations for drug delivery. Building from this, a brief overview of potential barriers and common delivery approaches used to date to overcome these barriers will be provided at the end of this section.

The auditory sense organ, the cochlea, is spiral-shaped and consists of three chambers: scala vestibuli (vestibular tube), scala media (cochlear tube) and scala tympani (tympanic tube) (Figures 1A, B; Raphael and Altsüler, 2003 ). The scala media is filled with endolymph fluid. , the other two volumes are filled with perilymph fluid (Raphael and Altsüler, 2003). These fluids are held in specific ionic compositions to facilitate mechanical electrical conduction of sound through hair cells (Park, 2015).

How Did María Isabel Díaz Lose Weight

The basilar membrane separating the scala media from the scala tympani is the organ of Corti (Fig. 1b)—a sensory epithelium containing one row of inner hair cells (IHCs), three rows of outer hair cells (OHCs), and more. Rows of subsidiary cells. Each hair cell contains a mechanosensitive organ called stereocilia (Figure 1c)—consisting of bundles of actin filaments—that respond to sound-induced shear.

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