The Feasibility Of Drugs Accelerate/inhibit Spinal Growth As A Two-sided Treatment Method Of Early-onset Scoliosis

Objectives:Current surgical treatments of early onset scoliosis（EOS）require metal internal fixation often caused spontaneous fusion,internal fixation failure,high notch,and infection,which limits the spinal,lung tissue development.Therefore,the aim of this study was to find a chemotherapy for EOS using drugs to regulate the growth of the spine in two ways by interfering with the endochondral osteogenesis of the spinal growth plate,thus creating an treatment that avoids the use of internal fixation for EOS.Based on our previous research,the goal of this study were as follows:1)part I aims to analyze the clinical needs to establish a new chemical treatment option for EOS from the perspective of lung function;2)part II aims to apply Poloxamer gel loaded with aldosterone to different key growth points of the vertebral body of young pigs in different ways and dosages to induce structural scoliosis and to treat scoliosis pig models created by tethering method,3)Growth plates sample were obtained in the previous experiment to explore the key mechanism of chondrocyte apoptosis induced by aldosterone,4)By studying the found key pathway of regulating spinal growth,and further intervention were applied to reverse the growth arrest effect.Meanwhile,the possibility of treating EOS by promoting unilateral spinal growth was explored.Eventually,a two-sided and fixation-free treatment option for EOS was initially constructed.Methods:The pulmonary function tests data of EOS were collected and analyzed retrospectively and were compared with patients suffered from severe spinal deformity.The experiment were mostly carried out in 2-month old pigs.Inhibition effect of Poloxamer loaded with aldosterone on the spine was explored by applying to different key growth points（growth plate,neurocentral synchondrosis（NCS）,growth plate+NCS）,delivering drug according to different methods through intervertebral disc（growth plate broken by hand drill or needle puncture）and applying different aldosterone at various concentrations(10^-3,10^-4,10^-5,10^-6mol/L).To construct and treat the scoliosis model of young pigs by selecting the optimal drug delivery conditions,and the results including radiological findings,histological changes and molecular mechanisms were all examined and analyzed in scoliosis models.Further,according to the results of molecular mechanisms,appropriate aldosterone antagonists were selected,and their antagonistic aldosterone effects were verified both in vitro and in vivo.Results:Cobb angle of EOS patients was significantly lower than patients with severe spinal deformity（P<0.05）,however,there was no significant difference in lung function between the two groups（P>0.05）,and the pulmonary function recovery of severe rigid spinal deformity after surgical correction was limited.Poloxamer loaded with ldosterone can inhibit unilateral spinal growth by interfering with the function of cartilage growth plates,which effectively induced structural scoliosis in normal young pigs.Poloxamer loaded with 10^-4mol/L aldosterone and injected to the unilateral upper and lower spinal growth plates through fine needle puncture was charaterised as the optimal conditions to induce structural scoliosis in this study.Poloxamer loaded with 10^-4mol/L aldosterone were injected to T12-L4,then induced scoliosis of which the mean cobb angle was 15.33±3.09（11-18°）in the first month and improved to 20.33±1.89（19-23°）in the second month after surgery.However,no significant scoliosis was observed at 2 months’follow-up in group that aldosterone injection and contralateral spinal tethering were applied to T12-L4 at the same time.Histological observation of the growth plates obtained from scoliotic pigs showed that aldosterone caused the decrease of growth plate thickness,the decrease of chondrocytes number and the disorder of cell arrangement.RAS/MAPK signaling pathway was confirmed to be involved in this process.Spironolactone and vosoritide were selected as aldosterone antagonists through RAS/MAPK pathway.Both in vitro and in vivo experiments confirmed that the two drugs had significant antagonistic and even reverse effects on aldosterone-induced spinal growth inhibition effect.Moreover,experiment carried out in SD rats by local injection of vosoritide into the tail showed that vosoritide was able to accelerate spinal growth and induce scoliosis.200ul vosoritide（0.2mg/L）was injected into the single vertebral segment of rat tail,and two segments were interfered.At 1 month postoperative,the growth of rat tail was 0.7cm longer than that of normal rat tail,while the same dose of aldosterone injection with 2segment at concentration of 10^-4mol/L caused the growth of rat tail to be 0.7cm slower than normal.Both aldosterone and vosolittide alone showed the ability to promote spinal growth and induce scoliosis.Conclusions:Deformity progress of early onset scoliosis complicated with pulmonary function impairment should be interfered as soon as possible to avoid the aggravation of pulmonary function impairment.In this paper,the innovative way of inhibiting and promoting the growth of the spine by local injection of drugs was established in normal experimental animals,and the ways of promoting and inhibiting the growth could antagonize each other.Local control of asymmetric spinal growth with drugs is a feasible implant-free intervention for early onset scoliosis.