A Novel Thermosensitive Gel For Protecting Surrounding Organs During Liver Thermal Ablation

Background and Objectives:Percutaneous thermal ablation has been widely used for treating tumors involving the liver,kidneys and bones.However,collateral thermal damage to surrounding tissuesis one of the most common complications,which limited itsapplications in clinical practice.To insulate and protect the surrounding tissues effectively and reduce thermal injury,0.9% normal saline has beengenerally suggested.However,the most important limitation when using normal salineis that fluid can quikly move away and stay for a short time.So it may result in unsatisfactory results.This study aimed to prepare novel thermosensitive gel(Poloxamer 407,P407)and evaluate its effectiveness and safety in reducing thermal injury to the surrounding organs during liver thermal ablation.Methods: 1.Preparation of novel thermosensitive gel.Serial dilutions ranging from 15-30 w/w%Poloxamer 407(P407)in deionized water were prepared and their gelation temperatures were determined using a rotor.The gelation times were obtained at different temperatures.Its viscosity was tested with a Brookfield R/S+rheometer.Taken together,the formula and preparing process of novel thermosensitive gel was eventuallyoptimized which could gel at lower temperature in shorter time.2.Insulation effect ex vivo The above novel thermosensitive gel was positioned between the liver pieces,which is defined as 3mm,5mm and 10 mm.Microwaves were applied at 30 w for 180 s.The temperatures were recorded on both sides of the gel.3.Insulation effect in vivo study of thermosensitive gel during percutaneous microwave ablation of liver adjacent to the diaphragm.3.1 Effectiveness of the gel in vivo Twenty-four male and female adult New Zealand white rabbits were randomlydivided into three groups in this study.Hydrodissection with 5ml novel thermosensitive solutionor 0.9% normal saline was injected between the liver and diaphragm in the experimental groups.No barriers were applied to the controls.After microwave ablations at 30 w for 180 s,the rabbits were sacrificed and dissected immediately.The frequency,size,and degree of thermal injury to the diaphragm were compared histologically among the three groups.3.2 Safety of the gel in vivo Subsequently,other eight rabbits were injected with 5ml novelthermosensitive solution and microwave ablations were performed at microwave output power of 30 w for 180 s.Using 2 ml of ear vein blood,the levels of atanine aminotransferase(ALT),aspartate aminotransferase(AST),blood urea nitrogen(BUN),and serum creatinine(SCr)in serum were tested 1 day before microwave ablation and 3 and 7 days after the procedures 3.3 Measurement of absorption/degradabilityof the gel Twelve NIH-NU/NU mice were included for exploring the absorption or degradability of the novel thermosensitive gel.A dose of 0.5 m L of the solution was subcutaneously injected into the right back of nude mice.The nude mice were sacrificed and dissected 15 min,1h,3h and 6 h after administration of the agent.The size of thegelwas observed and photographed.Results: 1.Preparation of novel thermosensitive gel Various formulas were screened based on gelation temperature and time.At last,22.5 %P407 gel was considered to be the optimal formula which satisfying clnical practice.The prepared thermosensitive gel had a gelation temperature at 22.3 °C and a gelation time of 90 sat 37 °C.In addition,its viscosity increased as temperature rised.It exhibited fluid below 18°C and then transformed to a semi-solid above 22.3 °C.2.Insulation effect of the gel ex vivo Temperature testing demonstrated that the maximum temperature differences of 20.0±0.6 °C,26.4±0.5 °C and 30.9±2.2 °C were observed on both sides of the gel with a thickness of 3mm,5 mm and 10 mm after MW ablation at 30 w for180s.Whenthe mean temperature of one side of the gel reached 60 °C,the temperatures of the other side of the gel were52.2±1.0 °C,41.9±1.1 °C and 29.1±2.4 °C.Based on the results above,5mm novel thermosensitive gel could protect the surrounding structures.3.Insulation effect in vivo study of thermosensitive gel during percutaneous microwave ablation of liver adjacent to the diaphragm..3.1 Effectiveness of the gel in vivo The effects of ablations extended into the surrounding diaphragm in none of the gel-protected animals,five of the saline-protected animals and all(eight)of the control animals.Thermal damage to the diaphragm differed significantly in size among the three groups(P = 0.001-0.011).We graded the degree of diaphragm thermal injury according to a four-point scoring system(none,0;mild,1;moderate,2;severe,3).Thermal injury degreeto the diaphragm was in turnin the control,saline,gel group(P = 0.001-0.04).However,there was no significant difference in the volume of ablation zone among the three groups(P>0.05).3.2 Safety of the gel in vivo The levels of ALT,AST,BUN,and SCr in serum were assayed before and after microwave ablation as indicators of liver and renal functions.Our statistical analysis showed that there was no significant difference among the groups pre-and postoperatively(P>0.05).3.3 Measurement of absorption/degradability of the gel Our results indicate that the novel thermosensitive hydrogel gelled well at the injection site.The size of the gel kept diminishing until it had almost disappeared after 6 h.Conclusions: 1.The novel thermosensitive gel was prepared-22.5% P407 hydrogel,which gelled at 22.3 °C and took very short time(90s)to gel at 37 °C.2.Ex vivo experimental study demonstrated that 5mm novel thermosensitive gel could protect the surrounding structures.3.In vivo experimental study demonstrated that 5mm novel thermosensitive gel could be an effective choice for hydrodissection on protecting the diaphragm during microwave ablation of liver adjacent to the diaphragm.4.The novel thermosensitive gel did not impact on liver and renal functions.5.The novel thermosensitive gel could be absorbed or degradable after 6 h.