Feasibility Study Of Photobiomodulation Therapy In Clinical Application Of Acute Spinal Cord Injury

Spinal cord injury(SCI)is a global,high incidence and disability disease,which brings huge economic burden to patients themselves,families and society.The pathological process of spinal cord injury is mainly divided into primary and secondary injuries.The most common cause of primary injuries is acute or chronic compression caused by external forces.Currently,the spinal structure after SCI can be reconstructed by surgical methods.However,secondary immune inflammatory response caused by primary injury continues to progress,resulting in apoptosis of neurons,circulatory disturbance,increase of toxic substances and formation of glial scar,and a series of biological and cytological changes,resulting in the interruption of nerve pathways.Although damaged neurons have the potential to proliferate,the degree of regeneration cannot meet the requirements of motor function recovery.At present,according to the pathophysiological characteristics of spinal cord injury,a variety of treatments have been applied in clinic,such as methylprednisolone,neurotrophic factor,nerve biological scaffolds and stem cell transplantation,but they have not been recognized as effective treatments.Photobiomodulation(PBM)has been extensively studied for its unique photobiological characteristics in the nervous system,such as non-invasive,promoting nerve regeneration,inhibiting the expression of inflammatory cells,inhibiting the formation of glial scars and inhibiting the apoptosis of nerve cells.Particularly,the photosensitive ion channels of nerve cells can be accurately regulated by using some special photosensitizers.The application of photobiomodulation in the treatment of spinal cord injury is a promising method.At present,photobiomodulation has achieved encouraging results in the treatment of central nervous system diseases,especially in brain injury and degenerative diseases.However,the application of photobiomodulation in spinal cord injury is hindered by the serious attenuation of light energy due to the thickness of spinal tissue.for the purpose of application in clinical medicine,we designed a 360° lightemitting fiber embedded in the spinal canal.After decompression and fixation,the patients with acute spinal cord injury were placed above the lamina,directly projecting the light energy onto the surface of the spinal cord,so as to ensure that the least effective light energy with therapeutic effect reached the spinal cord injury.The feasibility and safety of the optical fiber embedding method were tested and the safe parameters of photobiomodulation were screened out.Part I Development of an implantable photobiomodulation instrument in intraspinal canal Objective: Based on 810 nm light source,a fully automatic light source therapeutic instrument in vitro and an embeddable optical fiber in intraspinal canal were designed.Methods: Extracorporeal photobiomodulation instrument was composed of built-in optical fiber,power supply system,microprocessor control system,operation display system,heat dissipation system,laser module and safety alarm system.Medical high transparent silica gel coated optical fibers are joined with developing lines at the same time.The optical fibers are connected with the therapeutic instrument through coupling interfaces in vitro.Results: The photobiomodulation instrument for spinal cord injury treatment was composed of two parts: numerical control laser emitter and optical fiber.The pulse type,time setting,self-detection,temperature detection,refrigeration system and power supply system of the laser were all controlled by microchip and controlled by digital interface.The embedded optical fibers have high flexural and tensile strength,and high transparency medical silica gel ensures its bio-safety.At the same time,the developable material is added into the optical fiber wrapping material.The output power of the optical power meter is basically the same as the actual output power of the optical fiber end.The error is less than 5 mw,which does not affect the curative effect of human body treatment.Conclusion: The stability and safety of photobiomodulation consisting of microchip and digital control system are more guaranteed by a series of optical tests.At the same time,the optical fibers coated with medical silica gel materials do not affect the light permeability and avoid the possibility of leakage of optical fibers.At the same time,the flexibility of silica gel materials also avoids the possible iatrogenic spinal cord compression.Part 2: Feasibility and Safety Validation of 360° optical fiber Implanted in intraspinal canal and Screening of Irradiation Parameters for Spinal Cord Irradiation Objective: Previous studies on spinal cord injury(SCI)have confirmed that percutaneous near-infrared irradiation therapy(NIR-IT)can ameliorate the immunoinflammatory response at the site of injury,promote nerve regeneration,suppress glial scar formation,and promote the subsequent recovery of locomotor function.The current study describes a large-animal model that uses implanted optical fibers to accurately irradiate targeted spinal segments.In addition to demonstrating the method's feasibility,safety and irradiation parameters were determined,and the methodology of irradiating the spinal cord with nearinfrared light was investigated in detail.Methods: A 360° optical fiber was implanted above the T9 vertebrae of Bama miniature pigs and used to transfer near-infrared light(810nm)onto the spinal cord surface.After daily irradiation for 1h at 200,300,500,or 1000 mw for 14 days,both sides of the irradiated area of the spinal cord were assessed for temperature changes,the condition of the spinal cord and vertebral canal was investigated by magnetic resonance imaging,different parameters indicating temperature increase or phototoxicity on the normal spinal cord surface due to near-infrared irradiation(stress response,inflammatory reaction and neuronal apoptosis)were measured,and the animals' lower-limb neurological function and gait during the irradiation process were assessed.Results: The implanted device was stable inside the body of freely moving animals,and the near-infrared light could be directly projected onto the spinal cord surface.Through screening different irradiation parameters,200 mw and 300 mw direct irradiation of spinal cord surface did not cause obvious heating,stress response,inflammatory reaction and neuronal apoptosis.500 mw irradiation could cause mild heating,stress response,immuno-inflammatory reaction and neuronal apoptosis.1000 mw irradiation could cause obvious heating,stress response,immuno-inflammatory reaction and neuronal apoptosis.In the 200 mw,300 mw and 500 mw irradiation groups,there was no structural damage in the histopathological analysis of the spinal cord.There was slight thermal damage in the 1000 mw area,and the axon structure was disordered.However,the neurological function and gait scores of all irradiated groups were normal,and motor evoked potentials and somatosensory evoked potentials were elicited.Compared with the control group,the amplitudes of 200 mw,300 mw and 500 mw irradiated groups were normal,while the amplitudes of 1000 MW irradiated groups decreased slightly,but there was no statistical significance.Conclusion: This study established a safe and responsible approach in-vivo optical fiber implantation that can be used to directly irradiate light onto the spinal cord surface.The safe range of irradiation parameters is 200 mw to 300 mw.providing a new therapeutic approach for clinical application of phototherapy in acute SCI.Part 3: Pre-Clinical Study Of Photobiomodulation In The Treatment of Acute Spinal Cord Injury Objective: This study is an open,non-blind,non-randomized and non-placebo controlled clinical study to observe the feasibility and safety of implantable 360° optical fibers for Photobiological stimulation in spinal cord injury.Methods: According to the inclusion and exclusion criteria,9 patients with acute spinal cord injury requiring surgery were screened and ASAI score was B.After operation,the optical fibers were placed above the vertebral lamina,and the light therapy apparatus was connected to ensure that the light energy projections were on the injured sites.Then the incision was sutured and daily irradiation for 30 min at 300 mw for 7 days.During the irradiation period,the patients were assessed whether the illumination would cause discomfort,whether long-time therapy and optical fibers implantation would cause infection,coagulation function changes and other biochemical indicators.At the same time,after 7 days of irradiation treatment,all patients removed the optical fibers and sent the irradiated parts of in vivo for bacterial culture.Other common adverse events were recorded during photobiomodulation such as respiratory complications,cardiovascular events,deep venous thrombosis/pulmonary embolism,urinary tract infection,etc.EMG,neuropathic pain and neurological function were evaluated at the 7th day and 1th month.Somatosensory evoked potential(SEP)was selected as the evaluation index,and ASIA motor and sensory scores were used to evaluate neurological function.Results: During therapy of irradiation,blood pressure and oxygen saturation fluctuated in the normal range.blood pressure and oxygen saturation fluctuated within the normal range.The fiber itself did not cause the patient's uncomfortable reaction and the inconvenience of turning over,and the entire treatment period the patient's body temperature was normal,and there was no swelling and exudation of the skin at the incision and outlet of the optical fiber,no deep venous thrombosis,no neurological impairment during irradiation,and slightly abnormal blood routine,liver and kidney function,ion series and coagulation function,but no clinical significance.The main consideration was the abnormal changes caused by hand SCI itself.After 7 days of irradiation,all patients removed the optical fibers and sent the irradiated parts to be examined and the bacterial culture was negative.At 1 month,the ASIA sensory and motor function scores of all patients were different improved and three patients changed from ASIA B to C.Conclusion: It is a simple,safe and non-invasive method to treat acute spinal cord injury by embedding 360°optical fibers in the spinal canal.810 nm,daily irradiation for 30 min at 300 mw for 7 days is a safe therapeutic parameter in human acute spinal cord injury.More case studies are needed to verify the effectiveness of PBM in the later period.