Design And Fabrication Of Dual Controllable Braided Self-reinforced Bioresorbable Cardiovascular Stent And Its Structure-function Relationship Analysis

Congenital vascular stenosis is one of the most common congenital heart diseases,which accounts for 5 %-8 % of all kinds of congenital heart diseases.The incidence rate is 0.02 % to 0.06 %.This leads to the congenital vascular stenosis as a serious issue and threaten the health of infants and young children.The goal of arterial stenosis is to reconstruct the channel of normal blood flow in aorta,recover blood pressure and circulatory function and minimize the pressure gradient around the complication and stenosis.Although vascular stents have not been approved by the FDA for the treatment of congenital vascular stenosis,they have been recommended by pediatric and congenital heart disease research center and the medical community.At present,bioresorbable cardiovascular stents have become potential therapeutic methods for the treatment of congenital vascular stenosis in children due to their good biocompatibility of degradation products.They can maintain mechanical stability during specific time after implantation,support the stenotic vessels and restore normal physiological functions.Moreover,they can be degraded into small molecules after healing process of vascular repair,and excrete by metabolism.Thus,they have the potential to address the problem of long-term restenosis after permanent metal stent implantation.However,the development of bioresorbable cardiovascular stents is mostly focused on the treatment of coronary artery stenosis,which is less than 4 mm in diameter.While,there are few researches in developing those stents for infants with diameter of 6-9 mm.Besides,the insufficient mechanical support of polymeric bioresorbable stents and the mismatch of degradation time to the healing time of vascular repair limit their application to treat pediatric patients.Therefore,it is necessary to design a polymeric bioresorbable cardiovascular stent for patients with congenital vascular stenosis specifically,which has mechanical enhancement properties and suitable degradation properties in order to improve the deficiency of existing polymeric bioresorbable stents and fill the gap in this field.In this paper,we adopted poly(p-dioxanone)(PPDO)monofilaments due to their good mechanical properties and degradation properties.Then three kinds of PPDO braided stents were designed and fabricated by using two-dimensional braiding technology and thermal treatment.The relationship between structure and properties of braided stents were measured by parallel plate test and numerical simulations.Then,PCL multifilament was supplemented into the braided structure and formed dual controllable braided self-reinforced bioresorbable stents,which exhibited the characteristics of controllable mechanical proeprties and degradation perforamce.The in vitro and in vivo experiments were conducted to investigate the efficacy of the dual controllable braided self-reinforced bioresorbable stents.In the second chapter,we firstly chose braiding technology to fabricate polymeric bioresorbable stents based on the clinical requirements.Then the existing two-dimensional tubular braiding technology was analyzed and discussed in order to clarify the buckling role of braiding yarns.Subsequently,PPDO,approved by the FDA,was selected as the raw material.Based on the existed braided technology,braided stents with three kinds of structures were prepared with an inner diameter of 8 mm,and nominated as regular braided stent(RBS),tri-axial braided stents with 4 axial runners(TBS-A),and tri-axial braided stents with 8 axial runners(TBS-B),respectively.In the third chapter,the effect of braided structure and thermally treated temperature on the physical and mechanical properties of fabricated stents was analyzed.We firstly measured the compression properties of three kinds of stents(RBS,TBS-A,and TBS-B)by using parallel plate tester,analyzing the difference in compression force,elastic recovery rate and energy loss rate.The results showed that the compression forces were enhanced by 278.24 % and 225.06 %,respectively,after the introduction of 4 and 8 axial runners in regular braided stents.Besides,the elastic recovery rate and the energy loss rate were also improved,compared with that in RBS.In order to analyze the stress-strain distribution of braided yarns after stents were compressed,the computational simulations were utilized in this study.The parallel plate compression process was simulated by using Abaqus software.The results illustrated that the compression resistance ability of PPDO braided stents was determined by the bending degree of yarns and the number of crossing points,and their interactions.Thus,the resistance ability to deformation can be improved by optimizing the structural parameters.Then,60 °C,80 °C and 100 °C were chosen to thermally treated PPDO braided stents,in order to discuss the effect of thermally treated temperature on the physical and mechanical properties of PPDO braided stents.The results demonstrated that stents could achieve maximum recrystallization after thermally treated by 60 °C.But the internal stress introduced during braiding process was not completely eliminated,leading to unstable structure after treating in this temperature.After thermally treated by 100 °C,better orientation and rearrangement effect of the stents were obtained,and the internal stress generated in the yarn structure was thoroughly eliminated.Thus,the braided structure treated under this condition behaved higher structural stability.At the end of this chapter,the in vitro degradation properties of RBS and TBS-A were measured and the degradation mechanism of PPDO was verified.The results also showed that TBS-A braided stents behaved better mechanical stability and the mechanical integrity can be maintained for more than 4 months.And the compression strength was almost completely lost after degraded for 5 months.The results here were consistent with the healing process of stenotic vascular repair,which suggested that PPDO braided stents could meet the requirements using for cardiovascular stenosis treatment.In the fourth chapter,we optimized the braided structure and prepared a new dual controllable braided self-reinforced bioresorbable stent(Chinese Publication Patent Number: CN108066048A)based on the advantages and disadvantages of the PPDO braided stents mentioned in the second and third chapters.After analyzing the compression resistance of PPDO braided stents,it is clear that the mechanical properties can be improved by limiting the slippage and rotation of the interlacing points.Thus,we firstly designed and fabricated a sheath-core structureal braided yarn with PPDO filament as the core and PCL multifilament as the sheath.Then they were introduced into regular braided structure.After that,PCL layer was softened and bonded at the interlacing points under 90°C for 1h and cooling process.Furthermore,different numbers of sheath-core structureal yarns were selected to form PPDO/PCL self-reinforced braided stents and fabricated two kinds of stents,nominating as c BRS-A(obtained 4 sheath-core structureal yarns)and c BRS-B(obtained 8 sheath-core structureal yarns),respectively.In the fifth and sixth chapters,the effect of structure of the dual controllable braided self-reinforced bioresorbable stent on the mechanical and degradation properties were analyzed.In the fifth chapter,the mechanical properties of PPDO/PCL self-reinforced braided stents were analyzed by using parallel plate tester and finite element method.The experimental results showed that the compression forces were enhanced by 124.06 % and 169.58 % for c BRS-A and c BRS-B,respectively.Besides,the elastic recovery rate of PPDO/PCL self-reinforced braided stents increased to 93.09 ± 1.78% and 94.05 ± 1.60%,compared with 89.89 ± 1.77% of that in control group.The computational results showed that the sheath-core structureal yarns bonded with each other and formed a mechanically reinforced skeleton in the PPDO/PCL self-reinforced braided stent,which limited not only the rotation and slippage of thermally bonded yarns but also the movement of PPDO monofilaments under external force.Besides,the ability to resist external force is stronger with the increase of thermally bonded yarns number.Then,the mechanical change of PPDO/PCL self-reinforced braided stents during the crimping and expanding process was analyzed experimentally and computationally.The results showed that thermally bonded yarns behaved obvious viscoelasticity during crimping and balloon expanding process,while that only happened in balloon expanding process for PPDO filaments.These changes led to the structural and mechanical changes of stents after crimping and expanding process.Besides,part of the mechanical loss can be recovered by the assistant of balloon-dilatation.In the sixth chapter,the in vitro static degradation properties of the dual controllable braided self-reinforced bioresorbable stent were measured.The results showed multi-stage degradation characteristics.Specifically,the PPDO component degraded at the early stage of degradation.Since PCL is more hydrophobic and stable during degradation,the bonded yarns did not degrade during this time and hydrolysis process happened in the later stage.In this case,the concentration of acidic degradation products can be reduced and might have the potential to reduce inflammation.In addition,polymeric scaffolds behaved different degradation characteristics during different mechanically environments.In this research,pulsatile pressure and consistently compressive force were loaded on the PPDO/PCL self-reinforced braided stents.The results illustrated that the degradation products fell from the surface of PPDO filaments and reduced their diameters.Besides,the morphology of PCL components during dynamic loading group did not change obviously,while the structure failure and broke-down of yarns were observed in bonded yarns when only compressive force loaded on the stents.Accordingly,pulsatile pressure changed the degradation mechanism of bioresorbable polymers,while delayed the acceleration rate,which happened in static loading stents.In the seventh chapter,the in vivo animal experiments were conducted by implanting dual controllable braided self-reinforced bioresorbable stent c BRS-A in the iliac artery of pig model,in order to measure the mechanical properties,degradation properties and biocompatibility of stents.Results showed that stented lumen kept open and stents behaved dimensionally stable within 4 months after stent implantation,without displacement and severe vascular damage.Thus,PPDO/PCL self-reinforced braided stent c BRS-A has sufficient mechanical properties.Besides,there was no obvious degradation on the stents during first two month,while it happened in fourth month.Significant degradation happened in PPDO component,while bonded yarns remained stable.This result is consistent with the multi-stage degradation performance exhibited in in vitro static degradation.Moreover,this result is also matched with the healing process(3-6months)of stenotic vessel.Thus,the PPDO/PCL self-reinforced braided stent c BRS-A has suitable degradation properties for cardiovascular stent application.In addition,a large amount of adhesion and growth of endothelial cells occurred in one month after stent implantation,forming a dense endothelial layer.At the fourth month,the endothelial cells were regularly oriented with the direction of blood flow.All these indicated that c BRS-A PPDO/PCL self-reinforced braided stents have good biocompatibility.Our results also showed the severe inflammation in fourth month after stent implantation,suggesting the importance of accurate control the release of gradient degradation products.In summary,based on PPDO monofilaments,we analyzed and discussed the relationship among structure,physical properties,mechanical properties and in vitro degradation properties of two-dimensional tubular braided stents.A novel bioresorbable stent,dual controllable braided self-reinforced bioresorbable stent,was designed and fabricated.The effectiveness of mechanical resistance properties,degradation properties and biocompatibility was analyzed in vitro and in vivo.This new type of bioresorbable stent not only improved the disadvantages of existing polymeric bioresorbable stents for congenital vascular stenosis,but also enriched the property evaluation system of bioresorbable stent.At the same time,this research revealed that it is important and necessary to optimize the design principle of stent structure and material selection,in order to behave more accurate multi-stage degradation performance and reduce the incidence of inflammation reactions.