Multi-Scale Simulation On The Physical Mechanism Of Shock-Induced Damage To The Blood-Brain Barrier

Blast-induced traumatic brain injury(bTBI)has been regarded as the "signature injury" of modern warfare,owing to its high fatality and injury rate.Within hours following the bTBI,a number of pathological features such as cerebral edema,intracranial hemorrhage,and intracranial hypertension might be generated.As one of the origins of the above pathological characteristics,the breakdown of the blood-brain barrier(BBB)is the key target for the diagnosis,treatment and prevention of bTBI.As a result,a detailed understanding of the BBB breakdown process is critical in order to develop more effective treatment and preventative strategies.At present,research into the mechanism of BBB breakdown in bTBI is mostly focused on the secondary pathological outcomes of BBB breakdown.However,there is still a lack of understanding of shock-induced physical damage to the BBB,specifically the corresponding mechanism at the molecular scale.In this thesis,multi-scale simulation approaches are used to investigate the physical mechanism of shock-induced damage to the BBB on a molecular level,using the aquaporin model,phospholipid membrane model,and tight junction protein model.The main conclusions of this thesis are as follows:(1)The shock-induced damage threshold value to BBB peroxidized phospholipid membrane,as well as the principal reason for the departure of the threshold from that of normal phospholipid membrane,was identified.The membrane of inflammatory cells is characterized by high peroxidation degrees.Our findings show that peroxidation membranes have a lower shock damage threshold(up,the shock velocity at which the pores in membranes are formed)than normal membranes,and that the threshold drops as the peroxidation degree increases.Furthermore,the distribution of oxidized lipids has a greater impact on the damage threshold than the concentration of peroxidation.The essential reason for this is that the phospholipid membranes with high peroxidation degree exhibit a lower stretching modulus(κs)and bending modulus(κb).This is due to the introduction of polar hydrophobic groups into the tails in peroxidized phospholipids,which strengthens the hydrophilicity of the tails and bends the tail of the phospholipid towards the membrane-water interface,leading to a looser packing of peroxidized phospholipids and reducing the modulus of the membrane.The above conclusions indicate that the inflammatory cells are more susceptible to shock-induced damage,which will be useful for improving the biomedical applications of shock waves.(2)The shock-induced gating mechanism for aquaporin-4(AQP4)was discovered.The results show that the shockwave alone closes the AQP4 channel;however,shock-induced bubble collapse opens it.The jet from bubble collapse forcefully increases the distance between helices and the tilt angles of six helices relative to the membrane vertical direction in a very short time.The average channel size increases about 2.6 times,and the water flux rate is higher by nearly 22 times to normal states.Based on this,a new shock-induced gating mechanism of AQP4 is proposed,in which the overall expansion movement of AQP4 transmembrane helices driven by shock-induced nanojets changes the state of water channels.This may be the potential mechanism of blast-induced brain edema.(3)The significance of the shock-induced tensile effect in the failure of BBB tight junction protein(claudin-5)was revealed.The results indicate that the compression effect from single shockwave does not damage the claudin-5 protein;however,the shock-induced cavitation(or bubble collapse)can cause two types of damage to the claudin-5 protein:one is that the nanojet from shock-induced cavitation acts directly on the claudin-5 protein,which can result in the obvious structural breakdown of TJ proteins(cavitation effect).The other is that the nanojet pushes the relative motion of the two endothelial cell membranes,resulting in a tensile loading to the embedded TJ protein(tensile effect).Further analysis shows that this tensile damage comes from the uneven temporal and spatial distribution of overpressure,which may be a more common origin of physical damage to the BBB.(4)The factors influencing the shock-induced damage threshold of the BBB(BBB structure,BBB composition,and cavitation effect)were investigated,and a mathematical model between the size of cavitation bubbles and the pressure threshold on shock-induced damage to the BBB was established.The results indicate that the BBB’s tight junction structure accounts for the difference in impact damage thresholds between different types of phospholipid membranes.The pore area was decreased by 48.6%when the plasmamembrane of BBB endothelial cells was connected by tight junction proteins.Furthermore,the size of cavitation bubbles also has a significant effect on the shock-induced damage threshold of BBB.The mathematical equation between the critical pressure on BBB disruption and the size of the bubble has been shown,which agrees well with experimental results.This provides a theoretical foundation for larger-scale studies on the BBB damage threshold and has substantial implications for shock-induced damage protection.