Photobiomodulation:a novel approach to promote trans-differentiation of adipose-derived stem cells into neuronal-like cells

Photobiomodulation,originally used red and near-infrared lasers,can alter cellular metabolism.It has been demonstrated that the visible spectrum at 451-540 nm does not necessarily increase cell proliferation,near-infrared light promotes adipose stem cell proliferation and affects adipose stem cell migration,which is necessary for the cells homing to the site of injury.In this in vitro study,we explored the potential of adipose-derived stem cells to differentiate into neurons for future translational regenerative treatments in neurodegenerative disorders and brain injuries.We investigated the effects of various biological and chemical inducers on trans-differentiation and evaluated the impact of photobiomodulation using 825 nm near-infrared and 525 nm green laser light at 5 J/cm2.As adipose-derived stem cells can be used in autologous grafting and photobiomodulation has been shown to have biostimulatory effects.Our findings reveal that adipose-derived stem cells can indeed trans-differentiate into neuronal cells when exposed to inducers,with pre-induced cells exhibiting higher rates of proliferation and trans-differentiation compared with the control group.Interestingly,green laser light stimulation led to notable morphological changes indicative of enhanced trans-differentiation,while near-infrared photobiomodulation notably increased the expression of neuronal markers.Through biochemical analysis and enzyme-linked immunosorbent assays,we observed marked improvements in viability,proliferation,membrane permeability,and mitochondrial membrane potential,as well as increased protein levels of neuron-specific enolase and ciliary neurotrophic factor.Overall,our results demonstrate the efficacy of photobiomodulation in enhancing the trans-differentiation ability of adipose-derived stem cells,offering promising prospects for their use in regenerative medicine for neurodegenerative disorders and brain injuries.

Photobiomodulation inhibits the expression of chondroitin sulfate proteoglycans after spinal cord injury via the Sox9 pathway

Both glial cells and glia scar greatly affect the development of spinal cord injury and have become hot spots in research on spinal cord injury treatment.The cellular deposition of dense extracellular matrix proteins such as chondroitin sulfate proteoglycans inside and around the glial scar is known to affect axonal growth and be a major obstacle to autogenous repair.These proteins are thus candidate targets for spinal cord injury therapy.Our previous studies demonstrated that 810 nm photo biomodulation inhibited the formation of chondroitin sulfate proteoglycans after spinal cord injury and greatly improved motor function in model animals.However,the specific mechanism and potential targets involved remain to be clarified.In this study,to investigate the therapeutic effect of photo biomodulation,we established a mouse model of spinal cord injury by T9 clamping and irradiated the injury site at a power density of 50 mW/cm~2 for 50 minutes once a day for 7 consecutive days.We found that photobiomodulation greatly restored motor function in mice and down regulated chondroitin sulfate proteoglycan expression in the injured spinal cord.Bioinformatics analysis revealed that photobiomodulation inhibited the expression of proteoglycan-related genes induced by spinal cord injury,and versican,a type of proteoglycan,was one of the most markedly changed molecules.Immunofluorescence staining showed that after spinal cord injury,versican was present in astrocytes in spinal cord tissue.The expression of versican in primary astrocytes cultured in vitro increased after inflammation induction,whereas photobiomodulation inhibited the expression of ve rsican.Furthermore,we found that the increased levels of p-Smad3,p-P38 and p-Erk in inflammatory astrocytes were reduced after photobiomodulation treatment and after delivery of inhibitors including FR 180204,(E)-SIS3,and SB 202190.This suggests that Sma d 3/Sox9 and MAP K/Sox9 pathways may be involved in the effects of photobiomodulation.In summary,our findings show that photobiomodulation modulates the expression of chondroitin sulfate proteoglycans,and versican is one of the key target molecules of photo biomodulation.MAPK/Sox9 and Smad3/Sox9 pathways may play a role in the effects of photo biomodulation on chondroitin sulfate proteoglycan accumulation after spinal cord injury.

Is it possible to anchor a tooth with photobiomodulation?

During orthodontic treatment,we can achieve differential movements by using photobiomodulation(PBM)as an adjuvant before applying force.We can expect a greater bone density that initially resists movement while applying PBM to the other teeth to achieve an accelerating effect.The proposed protocol is to use an 810 nm laser at 0.1W power,applying between 4 and 6J per tooth for 22 s on the vestibular and lingual root surfaces,following the axial axis of the tooth.The energy density depends on the tip selected in the instrument.Normal bone remodeling cannot be avoided by applying high doses of PBM.PBM should be applied before orthodontic force to reduce tooth movement.In addition,PBM can be used during force application to teeth that require acceleration to achieve differential movement in orthodontic treatments.The protocol is the same in both scenarios.

Photobiomodulation provides neuroprotection through regulating mitochondrial fission imbalance in the subacute phase of spinal cord injury

Increasing evidence indicates that mitochonarial lission imbalance plays an important role in derayed neuronal cell death. Our previous study round that photo biomodulation improved the motor function of rats with spinal cord injury.However,the precise mechanism remains unclear.To investigate the effect of photo biomodulation on mitochondrial fission imbalance after spinal cord injury,in this study,we treated rat models of spinal co rd injury with 60-minute photo biomodulation(810 nm,150 mW) every day for 14 consecutive days.Transmission electron microscopy results confirmed the swollen and fragmented alte rations of mitochondrial morphology in neurons in acute(1 day) and subacute(7 and 14 days) phases.Photo biomodulation alleviated mitochondrial fission imbalance in spinal cord tissue in the subacute phase,reduced neuronal cell death,and improved rat posterior limb motor function in a time-dependent manner.These findings suggest that photobiomodulation targets neuronal mitochondria,alleviates mitochondrial fission imbalance-induced neuronal apoptosis,and thereby promotes the motor function recovery of rats with spinal cord injury.

Potential targets and mechanisms of photobiomodulation for spinal cord injury

As a classic noninvasive physiotherapy,photobiomodulation,also known as low-level laser therapy,is widely used for the treatment of many diseases and has anti-inflammatory and tissue repair effects.Photobiomodulation has been shown to promote spinal cord injury repair.In our previous study,we found that 810 nm low-level laser therapy reduced the M1 polarization of macrophages and promoted motor function recovery.However,the mechanism underlying this inhibitory effect is not clear.In recent years,transcriptome sequencing analysis has played a critical role in elucidating the progression of diseases.Therefore,in this study,we performed M1 polarization on induced mouse bone marrow macrophages and applied low-level laser therapy.Our sequencing results showed the differential gene expression profile of photobiomodulation regulating macrophage polarization.We analyzed these genes using gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.Networks of protein-protein interactions and competing RNA endogenous networks were constructed.We found that photobiomodulation inhibited STAT3 expression through increasing the expression of miR-330-5p,and that miR-330-5p binding to STAT3 inhibited STAT3 expression.Inducible nitric oxide synthase showed trends in changes similar to the changes in STAT3 expression.Finally,we treated a mouse model of spinal cord injury using photobiomodulation and confirmed that photobiomodulation reduced inducible nitric oxide synthase and STAT3 expression and promoted motor function recovery in spinal cord injury mice.These findings suggest that STAT3 may be a potential target of photobiomodulation,and the miR-330-5p/STAT3 pathway is a possible mechanism by which photobiomodulation has its biological effects.

Photobiomodulation with Super-Pulsed Laser Shows Efficacy for Stroke and Aphasia: Case Studies

Background: Brain disorders have become more and more common today, due to both the aging population and the ever-expanding sports community. However, a new therapeutic technology called photobiomodulation (PBM) is giving hope to thousands of individuals in need. Traumatic brain injury (TBI), dementia, post traumatic stress (PTSD) and attention deficit (ADD) disorders are in many cases quickly and safely improved by PBM. PBM employs red or near-infrared (NIR) light (600 - 1100 nm) to stimulate healing, protect tissue from dying, increase mitochondrial function, improve blood flow, and tissue oxygenation. PBM can also act to reduce edema, increase antioxidants, decrease inflammation, protect against apoptosis, and modulate the microglial activation state. All these effects can occur when light is delivered to the head, and can be beneficial in both acute and chronic brain conditions. Methods: In this case series, we used a high power, FDA-approved superpulsed laser system applied to the head to treat four chronic stroke patients. Patients received as few as three 6 - 9 minute treatments over a one-week period. The follow up time varied, but in one case was two years. Results: Patients showed significant improvement in their speech and verbal skills. Improvements were also noticed in walking ability, limb movement, less numbness, and better vision. Conclusion: The use of PBM in stroke rehabilitation deserves to be tested in controlled clinical trials, because this common condition has no approved pharmaceutical treatment at present.

Photobiomodulation for the treatment of retinal diseases: a review

Photobiomodulation（PBM）,also known as low level laser therapy,has recently risen to the attention of the ophthalmology community as a promising new approach to treat a variety of retinal conditions including agerelated macular degeneration,retinopathy of prematurity,diabetic retinopathy,Leber’s hereditary optic neuropathy,amblyopia,methanol-induced retinal damage,and possibly others.This review evaluates the existing research pertaining to PBM applications in the retina,with a focus on the mechanisms of action and clinical outcomes.All available literature until April 2015 was reviewed using Pub Med and the following keywords：＂photobiomodulation AND retina＂,＂low level light therapy AND retina＂,＂low level laser therapy AND retina＂,and＂FR/NIR therapy AND retina＂.In addition,the relevant references listed within the papers identified through Pub Med were incorporated.The literature supports the conclusion that the low-cost and noninvasive nature of PBM,coupled with the first promising clinical reports and the numerous preclinical-studies in animal models,make PBM well-poised to become an important player in the treatment of a wide range of retinal disorders.Nevertheless,large-scale clinical trials will be necessary to establish the PBM therapeutic ranges for the various retinal diseases,as well as to gain a deeper understanding of its mechanisms of action.

Current application and future directions of photobiomodulation in central nervous diseases

Photobiomodulation using light in the red or near-infrared region is an innovative treatment strategy for a wide range of neurological and psychological conditions.Photobiomodulation can promote neurogenesis and elicit anti-apoptotic,antiinflammatory and antioxidative responses.Its therapeutic effects have been demonstrated in studies on neurological diseases,peripheral nerve injuries,pain relief and wound healing.We conducted a comprehensive literature review of the application of photobiomodulation in patients with central nervous system diseases in February 2019.The NCBI PubMed database,EMBASE database,Cochrane Library and ScienceDirect database were searched.We reviewed 95 papers and analyzed.Photobiomodulation has wide applicability in the treatment of stroke,traumatic brain injury,Parkinson’s disease,Alzheimer’s disease,major depressive disorder,and other diseases.Our analysis provides preliminary evidence that PBM is an effective therapeutic tool for the treatment of central nervous system diseases.However,additional studies with adequate sample size are needed to optimize treatment parameters.

Comparative study on Photobiomodulation between 630 nm and 810 nm LED in diabetic wound healing both in vitro and in vivo

Photobiomodulation(PBM)promoting wound healing has been demonstrated by many studies.Currently,630 nm and 810 nm light-emitting diodes(LEDs),as light sources,are frequently used in the treatment of diabetic foot ulcers(DFUs)in clinics.However,the dose-effect relationship of LED-mediated PBM is not fully understood.Furthermore,among the 630 nm and 810 nm LEDs,which one gets a better effect on accelerating the wound healing of diabetic ulcers is not clear.The aim of this study is to evaluate and compare the effects of 630 nm and 810 nm LED-mediated PBM in wound healing both in vitro and in vivo.Our results showed that both 630 nm and 810 nm LED irradiation significantly promoted the proliferation of mouse fibroblast cells(L929)at different light irradiances(1,5,and 10 mW/cm^(2)).The cell proliferation rate increased with the extension of irradiation time(100,200,and 500 s),but it decreased when the irradiation time was over 500 s.Both 630 nm and 810nm LED irradiation(5 mW/cm^(2))significantly improved the migration capability of L929 cells.No difference between 630 nm and 810 nm LED-mediated PBM in promoting cell proliferation and migration was detected.In vivo results presented that both 630 nm and 810 nm LED irradiation promoted the wound healing and the expression of the vascular endothelial growth factor(VEGF)and transforming growth factor(TGF)in the wounded skin of type 2 diabetic mice.Overall,these results suggested that LED-mediated PBM promotes wound healing of diabetic mice through promoting fibroblast cell proliferation,migration,and the expression of growth factors in the wounded skin.LEDs(630 nm and 810 nm)have a similar outcome in promoting wound healing of type 2 diabetic mice.

Remote photobiomodulation: an emerging strategy for neuroprotection

Photobiomodulation (PBM)- the irradiation of cells or tissues with low-intensity red to near-infrared light - is emerging as an effective means of enhancing cell and tissue resilience and repair. As reviewed elsewhere (Gordon et al., 2019), the intracellular effects of PBM appear to be primarily mediated by cytochrome C oxidase, a key enzyme in the mitochondrial respiratory chain and a primary photoacceptor of red to near-infrared light. Absorption of light by cytochrome C oxidase alters its redox state, resulting in increased ATP production, the liberation of nitric oxide and a transient burst in reactive oxygen species.

Exploring the use of transcranial photobiomodulation in Parkinson's disease patients

Parkinson＇s disease is a neurological disorder with distinct motor signs of resting tremor,akinesia and/or lead-pipe rigidity,together with non-motor symptoms of impaired smell,cognition and autonomic function.These manifest after a major degeneration of neurones mainly within the brainstem,particularly among the dopaminergic neurones.

Efficacy of Photobiomodulation for Attention Deficit Hyperactivity Disorder (ADHD): Case Studies

Extensive research has now been conducted and published for the treatment of dementia or Alzheimer’s disease, traumatic brain injury (TBI) and other brain disorders using photobiomodulation (PBM), also known as low-level laser therapy (LLLT). However, minimal information is available regarding the use of LLLT for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). We have been using LLLT in our practice for over 15 years addressing chronic pain and injury issues. However, our work with brain injuries is more recent, and we have published three case studies, one describing a serious traumatic brain injury and two describing our success with dementia/Alzheimer’s disease and PTSD. Currently, there is very little published evidence regarding efficacious therapy for ADHD. The case studies presented here, suggest that LLLT can provide alleviation of these symptoms, with some improvement reported after just a single treatment, without any need for pharmaceutical intervention.

Mitochondria are an important target of photobiomodulation in cardiomyocytes

Photobiomodulation(PBM)has been shown to delay the pathological process of heart failure,but the exact mechanism of action is not clear.Mitochondria occupy one-third of the volume of mammalian cardiomyocytes(CMs)and are central transport stations for CM energy metabolism.Therefore,in this study,we explored the regulatory effects of 630 nm light-emitting diodes(LED-Red)on the mitochondria of CMs.The results show that LED-Red-based PBM promotes adenosine triphosphate(ATP)synthesis by upregulating the expression of glycolipid metabolizing enzymes.Correspondingly,there was an improvement in the activity of succinate dehydrogenase(SDH),a key enzyme in the mitochondrial electron transport chain,and the mitochondrial membrane potential.Meanwhile,LED-Red affected the state of mitochondrial oxidative stress and promoted the generation of reactive oxygen species(ROS),but the increased ROS production did not damage the CMs.In addition,mitochondrial division and fusion were also affected by the stimulation of LED-Red.Finally,PBM treatment led to a significant increase in transcript levels of mitochondrial transcription factor A(TFAM),which controls the stability of the mitochondrial genome.Collectively,irradiation with LEDs at 630 nm played a regulatory role in mitochondrial function,suggesting that mitochondria appear to be the recipients of PBM treatment.This study provides more insights into the mechanisms underlying PBM treatment in heart diseases.

PHOTOBIOMODULATION-MEDIATED PATHW AY DIAGNOSTICS

Cellular pathways are ordinarily diagnosed with pathway inhibitors,related gene regulation,or fuorescent protein markers.They are also suggested to be diagnosed with pathway activation modulation of photobiomod ulation(PBM)in this paper.A PBM on a biosystem function depends on whether the biosystem is in its function-specific homeostasis(FSH).An FSH,a negative feedback response for the function to be performed perfectly,is maintained by its FSH-essential subfunctions and its FSH-non-essential subfunctions(FNSs).A function in its FSH or far from its FSH is called a normal or dysfunctional function.A direct PBM may self-adaptatively modulate a dysfunctional function until it is normal so that it can be used to discover the optimum pathways for an FSH to be established.An indirect PBM may self adaptatively modulate a dysfunctional FNS of a normal function until the FNS is normal,and the normal function is then upgraded so that it can be used to discover the redundant pathways for a normal function to be upgraded.

The Growing Evidence for Photobiomodulation as a Promising Treatment for Alzheimer’s Disease

Despite the current belief that there is no effective treatment for Alzheimer’s Disease (AD), one emerging modality may change this belief: Photobiomodulation (PBM). It has credible mechanisms and growing evidence to support its case. Transcranial PBM for AD is a single intervention with multiple pathway mechanisms stemming from delivering low energy near infrared (NIR) light to the mitochondria in brain cells. The mechanisms involve the activation of gene transcription that lead to neuronal recovery, removal of toxic plaques, normalizing network oscillations that can lead to improved cognition and functionality. When PBM is delivered at 810 nm wavelength and pulsed at 40 Hz, early evidence suggests that very significant outcomes are possible. Literature related to PBM and AD has covered in vitro cellular, animal and human case reports, with promising results. They warrant robust randomized trials which are either ongoing or ready to start. The evidence in human studies is manifested in assessment scales such ADAS-cog, MMSE, and ADAS-ADL, and are supported by fMRI imaging and EEG.

Treatment Efficacy of Photobiomodulation for Moderate and Advanced Dementia or Alzheimer’s Disease: Case Studies

Extensive research is ongoing in the use of Photobiomodulation (PBM, often referred to as low-level or cold laser therapy) to treat Alzheimer’s disease as well as other debilitating diseases. The following case studies further confirm that PBM could be a breakthrough approach to limit the progression of insidious diseases. We present four cases, two with mild to moderate dementia and two with more advanced symptoms. Several publications have shown beneficial results, however, several weeks of daily treatments were necessary. The cases described here suggest that moderate and advanced dementia cases can be significantly improved with three or four eight-minute treatments over a 5 - 7-day period when using super-pulsing technology on Monday-Wednesday-Friday schedule (Figure 1). Gives a brief visual explanation of super-pulsing versus continuous wave technology.

Photobiomodulation therapy for osteoarthritis: Mechanisms of action

Photobiomodulation(PBM)is a non-invasive therapeutic modality with demonstrated effects in many fields related to regenerative medicine.In the field of orthopedics,in particular,PBM at various wavelengths has demonstrated the capacity to trigger multiple biological effects associated with protective mechanisms in musculoskeletal tissues.The articles cited in this review show that devices operating close to or within the near infrared range at low intensities can provoke responses which favor the shift in the predominant catabolic microenvironment typically seen in degenerative joint diseases,especially osteoarthritis(OA).These responses include proliferation,differentiation and expression of proteins associated with stable cell cycles.Additionally,PBM can also modulate oxidative stress,inflammation and pain by exerting regulatory effects on immune cells and blocking the transmission of pain through sensory neuron fibers,without adverse events.Collectively,these effects are essential in order to control the progression of OA,which is in part attributed to exacerbated inflammation and degradative enzymatic reactions which gradually contribute to the destruction of joint tissues.PBM may offer medical experts ease of application,financial viability,efficacy and lack of serious adverse events.Therefore,it may prove to be a suitable ally in the management of mild to moderate degrees of OA.This review explores and discusses the principal biological mechanisms of PBM and how the produced effects may contribute to the amelioration of osteoarthritic progression.Literature was reviewed using PubMed and Google Scholar in order to find studies describing the mechanisms of PBM.The investigation included a combination of nomenclature such as:“photobiomodulation”,“phototherapy”,“laser therapy”,“PBM”,“osteoarthritis”,low level light therapy”,“inflammation”and“cartilage”.We considered only articles written in English,with access to the full text.

“Optoanesthesia”: The Application of Transcranial Photobiomodulation to General Anesthesia

General anesthesia relies on pharmacological anesthetics. However, some side effects of anesthetics have been observed. Non-pharmacological transcranial photobiomodulation (tPBM) as an adjuvant treatment may reduce the dosage of pharmacological anesthetics while maintaining anesthetic depth. The inhibitory effects of tPBM in terms of central nervous system depression render it a potential approach for inducing general anesthesia. Alteration of quantum processes of neuronal microtubules, the mechanisms of general anesthesia on consciousness, may occur in response to tPBM treatments. Further, tPBM as an adjuvant treatment may facilitate the distribution of the pharmacological anesthetics in the brain. The analgesic effects of photobiomodulation (PBM) are acknowledged, and PBM has been used for regional analgesia. However, whether tPBM can be used for general anesthesia is unknown. Here, I define “optoanesthesia” as “the use of tPBM for general anesthesia”. I hypothesize that optoanesthesia can act as a means of general anesthesia. Supporting evidence in the form of unconsciousness, amnesia, and immobilization is provided in this paper. In addition, the tPBM-induced frequent yawning (a manifestation of transient arousal-shift during the continuing loss of consciousness during induction of general anesthesia) observed incidentally in my previous study of tPBM preconditioning for seizures also supports the hypothesis. I further discuss the issues with respect to the pharmacokinetics, parameters of optoanesthesia such as wavelength and targeted brain regions, and apparatus design, as well as the compatibility of the optoanesthesia and the Bispectral Index Monitoring System during surgery. Future research is needed to prove this hypothesis.

Development of Photobiomodulation and its Application in Retinal Diseases

Photobiomodulation(PBM)is a therap-eutic approach that utilizes low-energy laser or light to regulate biological tissues.The mechanism is to promote cytochrome C oxidase(CCO)through low energy light,regulate the REDOX of mitochondria,and then regulate the biological functions of tissues and cells.Compared with traditional laser,it has a higher safety.There are a large number of mitochondria in retinal tissue,and studies have shown that PBM has a good protective and regulatory effect on the mitochondrial functions of retina and optic nerve.Therefore,PBM is clinically applied to treat age-related macular degeneration,diabetic retinopathy and retinitis pigmentosa and other retinal diseases.In order to provide a new direction for the treatment of retinal diseases,this paper reviewed the main parameters,mechanisms and the research progress of PBM in the fundus indications.

Photobiomodulation therapy assisted orthodontic tooth movement:potential implications,challenges,and new perspectives

Over the past decade,dramatic progress has been made in dental research areas involving laser therapy.The photobiomodulatory effect of laser light regulates the behavior of periodontal tissues and promotes damaged tissues to heal faster.Additionally,photobiomodulation therapy(PBMT),a non-invasive treatment,when applied in orthodontics,contributes to alleviating pain and reducing inflammation induced by orthodontic forces,along with improving tissue healing processes.Moreover,PBMT is attracting more attention as a possible approach to prevent the incidence of orthodontically induced inflammatory root resorption(OIIRR)during orthodontic treatment(OT)due to its capacity to modulate inflammatory,apoptotic,and anti-antioxidant responses.However,a systematic review revealed that PBMT has only a moderate grade of evidence-based effectiveness during orthodontic tooth movement(OTM)in relation to OIIRR,casting doubt on its beneficial effects.In PBMT-assisted orthodontics,delivering sufficient energy to the tooth root to achieve optimal stimulation is challenging due to the exponential attenuation of light penetration in periodontal tissues.The penetration of light to the root surface is another crucial unknown factor.Both the penetration depth and distribution of light in periodontal tissues are unknown.Thus,advanced approaches specific to orthodontic application of PBMT need to be established to overcome these limitations.This review explores possibilities for improving the application and effectiveness of PBMT during OTM.The aim was to investigate the current evidence related to the underlying mechanisms of action of PBMT on various periodontal tissues and cells,with a special focus on immunomodulatory effects during OTM.