Dizziness, vertigo, and imbalance are general symptoms of the underlying pathophysiology of vestibular disorders that may vary within individuals. These conditions are possible within all age groups but are highly prominent in human adults aging 65-year-old and above.¹ In relevant conditions, vestibular dysfunction is brought about by hair cells and synaptic ribbon degeneration. These situations may require treatments that require surgical intervention to elicit notable effects. With limited availability of non-invasive treatments, procuring surgery may induce discomfort that further decreases the quality of life of an individual. As such, more efficient and non-invasive ways to treat inner ear anomalies are developed to improve treatment options.

Hair cells located within the inner ear of the cochlea do not have the capacity to regenerate within normal physiological conditions.^2,3 This may signify continuous hearing loss and vestibular disorders that may be obtained through means of physical trauma, age-related deterioration, or further enhanced by ototoxic damage through relevant treatments. Consequential to the administration of antibiotics to alleviate inner ear infections, these can also damage inner hair cells causing functional decline.⁴ Gentamicin, an aminoglycoside, may form reactive oxygen species (ROS) and activate c-Jun N-terminal kinases (JNKs) to initiate cell apoptosis.⁵ Similar mechanisms may be exhibited by systemic exposure to nitrile-based ototoxic compounds that produce relative damage to respective hair cells.^6,7

Focusing on the manifestation of vestibular dysfunction, treatment options relating to improving behavioral function include photobiomodulation (PBM) or low-level laser therapy (LLLT). In this paper, we will provide the basic concepts of LLLT and its regenerative capability within tissues and cells. Furthermore, the following review focuses on the relevant uses of laser therapeutics in the utricle or its structures that may aid in relevant studies.

Light amplification by stimulated emission of radiation (Laser) was introduced during the 1950s, while the first reported medical intervention was reported around 1960s by using ruby laser light for PBM in cardiovascular surgery by McGuff as well as melanoma treatment by Goldman. With the use of PBM, near-infrared light (600-1,000 nm) allows efficient penetration through the skin to produce a non-invasive method targeting procedure.^8,9

One theorized mechanism with laser therapy involve the activation of a photosensitive receptor in the mitochondria of cells. Karu¹⁰ states that cytochrome c responds to laser light due to the reactions of redox metal centers brought about by binuclear Cu_A and Cu_B as well as heme a₃. These components readily absorb near red light around 380 to 880 nm variations which, in turn, increases the electron availability to catalyze dioxygen within cytochrome c oxidases.^11,12 This allows efficient electron transfer and provides sufficient energy generation for cellular proliferation, migration, and repair pathways.

Energy acquisition in the form of adenosine triphosphate (ATP) is crucial in maintaining and elucidating different cellular metabolic activities. In this regard, LLLT is theorized to provide additional ATP reserves through electron excitation from the photoreceptive activators of cytochrome c in the mitochondria.¹³ In a relevant study, ATP signaling activation with the use of LLLT (810 nm) was expressed in P2Y2 and P2Y11 receptors in neural progenitor cells in vitro which allows multiple pathways in the context of mitochondrial activation pathways.^14,15 Together with energy regulation, an increase in proton gradient from Na⁺/H⁺ and Ca²⁺/Na⁺ antiporters and ATP-driven carriers such as Na⁺/K⁺ may show improved cyclic adenosine monophosphate turnover that is essential in cellular communication.¹⁶

Another resultant effect after LLLT exposure include the inhibition of nitric oxide (NO) accumulation which disrupts its binding to cytochrome c oxidases.¹⁷ Furthermore, the maintenance of NO and ROS levels within the system produces a change of redox potential. Such changes in the oxidation-reduction state can induce metabolic synthesis of nucleic acids, proteins, and enzymes, which are essential for cellular regeneration and proliferation.¹⁸ The effects of LLLT/PBM within the hair cell level are summarized in Fig. 1 for better description.

Figure 1. Proposed mechanisms of hair cell regeneration through laser irradiation. Inner ear hair cell damage may manifest in different forms which may be alleviated through laser therapy. The increase of relevant markers for cellular synthesis and cellular pathways may promote proliferative tendencies within functional supporting cells that can rescue inner ear damage through cellular mitosis or hair cell transdifferentiation mechanisms. ATP, adenosine triphosphate.

With the use of an intense beam, speculation of heat generation may occur especially with long exposure times. Interestingly, with the use of LLLT, heat generation was minimally produced during treatments that can affect cellular metabolism. In the provided study, induction of laser within the near-infrared range elicited a temperature change of at least 0.2°C^19,20 was recorded and provided no significant effect on cellular or in vivo studies. The importance of negligible heat generation is likely to eliminate necrotizing effects within the surrounding healthy tissues.²¹ This also prevents damage between the topical surface and the tissue of interest during laser irradiation.

In a relevant study on detecting the effects of LLLT with vestibular regeneration, Zhang et al.¹⁹ reported an increase of antioxidant superoxide dismutase 1 (SOD-1) upregulation by 2-fold within the vestibular sensory epithelium of C57/BL6 mouse. SOD-1 is a relevant marker that shows within age-associated oxidative stress. Limitations of the said study may include the interaction of different cellular responses that were not detected aside from SOD-1. In related works from our group, LLLT (632 nm; 16.2 J/cm²; single dose) was induced on utricle explants from postnatal Sprague Dawley rats (P4) and elicited a protective mechanism to hair cell loss prior to ototoxic damage.²² Such a method allowed retention of hair cells in comparison to gentamicin-induced damage only. A time-dependent study performed by the same group showed better protective capabilities of LLLT after multiple sessions of irradiation for 30 days.²³ Another relevant study showed that LLLT provided beneficial effects with explanted rat utricles with its laser parameters are referenced to acquire regenerative outcome on rat facial nerves.²⁴ As such, the use of a similar wavelength of laser irradiation may provide positive effects that also show similar mechanism of action when it relates to tissue regeneration and repair.

Given the use of laser therapy in different structures, researchers may tackle the use of a pre-existing parameter of laser irradiation and test on a different target tissue which may provide similar regenerative outcomes. The following section provides description of conventional parameters used in LLLT/PBM irradiations. Initially, the source of laser is important to be determined. The laser source may either be continuous wave such as carbon dioxide lasers or pulsed lasers such as erbium:yttrium–aluminium–garnet (Er:YAG), erbium:yttrium–scandium–gallium–garnet (Er:YSGG) and holmium:YAG.²⁵ Provided in their study involves the safety in relevance to total energy distribution and thermal generation with respect to laser irradiation towards the guinea pig cochlea.

Interestingly, the energy density of different lasers varies from the source of irradiation. As stated in Tunér and Hode,²⁶ the energy density (J/cm²), the total calculated amount of energy within a specific area, is important to be described in relevance to wound healing. In relevant cochlear subjects, the energy density may vary in such 162-194 J/cm² provided hair cell recovery after aminoglycoside damage²⁷ to 8 J/cm² to provide tinnitus alleviation.²⁸

Another notable parameter is the application of correct wavelength during irradiation. Avci et al.²⁹ described the use of 390-600 nm is optimal for superficial treatments and a higher wavelength is suitable for targeted tissues that requires further penetration. The use of laser irradiation within 600 nm allows upregulation of cellular protein synthesis, nucleic acid synthesis, and cellular differentiation as to promote growth factor release.³⁰ Limited with providing descriptions of all available parameters in laser therapeutics, it is critical to know the proper declaration of treatment used. Jenkins and Carroll³¹ provided essential information in LLLT/PBM treatment with relevance to device, irradiation, and treatment recording. This provide reproducibility within the area of specialization and provide substantial information that can be adapted to different therapeutic applications.

The use of light therapy has been established in different anatomical structures with the purpose of tissue regeneration to restore its functional effectivity. In this section, we describe similar procedures using LLLT within or near the inner ear structure. A study on LLLT (808 nm; 28.8 J/cm², 14 days) following gentamicin ototoxicity resulted in a regenerative effect 18 days after irradiation.³² The study showed that the LLLT used prior to aminoglycoside ototoxicity elicited a protective response to prevent hair cell damage. In the use of higher wavelengths, 808 nm has also been used in the regeneration and repair of sciatic nerves^33,34 and alveolar nerve crush injury models,³⁵ proving many efficient regenerative capabilities with following the optimization of power, dosage, irradiation duration, and the number of irradiation sessions. However, a recent comparative study from our group shows comparative results of 633 nm and 804 nm lasers on rat facial nerve injury. Corresponding results showed that 633 nm provided better facial nerve recovery by reducing reactive oxygen species in vitro and axonal regeneration as well as Schwann cell recruitment in vivo.³⁶ However, significant studies showed that the use of 808 provided promising results with auditory nerve stimulation as well as functional recovery after hearing loss.³⁷ A relevant study performed by Tamura et al.³⁸ using 808 nm at either 110 or 165 mW/cm² resulted in a protective mechanism against noise-induced hearing loss via inducible nitric oxide synthase (iNOS) inhibition. Regulation of NO is essential to maintain the physiological function of the inner ear and LLLT provided an inhibitory relationship with iNOS and NO production and further inhibits reactive oxygen species accumulation. Such results indicate that with the multitude of parameters for manipulating LLLT, there are numerous combinations that can provide a beneficial effect for tissue regeneration and repair on different structures.

Assuming that LLLT provides a non-invasive mechanism for treatment, certain caveats are to be expected. First, it is not necessarily expected that the full dose within the target structure is readily absorbed. In most cases for animal models such as mouse, light absorption must be strong enough to penetrate 1 mm across the epidermis, connective tissues, and bone before reaching the target organs.¹⁰ In relevance to human representations, such cases can extend to centimeter thickness. Furthermore, the use of high-power intensity lasers may provide a shorter treatment time but may not be highly beneficial all the time. Increasing the power output of the laser to a certain extent may illicit heat generation and further damage surrounding tissues that may cause further deterioration of function and stability of the structure.³⁹ In such cases, the reader should take into consideration the function and effects of the different laser parameters to provide an efficient output of energy within the target structure.

In the following review, we discussed the use of LLLT for inner ear hair cell regeneration and repair. In such regard, the available references for such therapy from different groups are limited with respect to specific targeted areas for laser irradiation. However, the use of laser in different in vitro cell cultures and in vivo has proven the beneficial effects of LLLT. Furthermore, the use of such therapy is widely used in cochlear hair cell regeneration and functional repair but vestibular hair cell regeneration needs further investigation. As mentioned as one of the references in the review, the use of different relevant parameters may produce different treatable outcome within the target tissue. This may be of interest in providing a multitude of treatment possibilities in providing therapeutic effects for vestibular organs. The use of relevant information regarding laser therapy may be deemed useful in providing developments in vestibular organ repair and regeneration in succeeding studies.

None.

No potential conflict of interest relevant to this article was reported.