Additive manufacturing of mitral annuloplasty devices

Mitral valve annuloplasty is a common surgical procedure performed on thousands of patients each year across the world. A less invasive and more successful method of resolving mitral valve regurgitation, repair surgeries now outnumber replacement of the mitral valve in its entirety. As a result, a range of supportive annuloplasty ring devices for maintaining the surgical repair are now available for lifelong implantation. However, these devices underserve some populations leading to replacement surgeries, and rely on assumptions made on the natural, healthy anatomy of the mitral valve. Additive manufacturing (AM) has, for the last few decades, become increasingly adopted into the medical industry. With applications ranging from educational aids to surgical instruments and long-term implantable devices, this field is rapidly expanding and encompassing a greater breadth of medical specialities. In particular, the manufacturing of patient-specific products with reasonable cost and high fidelity is a key area of development for medical applications of additive manufacturing methods. Significant research has already been undertaken in the fields of orthopaedics, regenerative medicine, and pharmaceuticals, producing long-term implantable metal devices, complex polymer scaffolds, and novel drug delivery methods. Personalized annuloplasty rings could lead to greater surgery success rates enabling greater repair longevity, reduced reoperation rates, and reduced risk of future valve replacement. This project aimed to investigate the suitability of the AM technique, selective laser melting (SLM), to create annuloplasty rings tailored to each patient. To achieve this goal, this research focussed first on comparing the existing design assumptions applied to commercial annuloplasty devices against human anatomy using cadaveric dissection and measurement. These studies concluded that whilst the assumed 3:4 ratio applied in annuloplasty design was a good average across a population, the ratio was inconsistent between subjects and could lead to difficulties in sizing devices appropriately for an individual patient. Following this, methods of design and manufacturing were investigated, comparing various tools available in commercial medical-CAD software, Materialise Mimics®. The commonly applied “thresholding” method of isolating structures from patient scan data was found to be insufficient for isolation of soft tissue structures such as the mitral valve annulus from the surrounding cardiac tissue due to the similarity in densities reducing contrast on the scan. A method of single-point design using insertion points of the valve leaflets throughout the scan was shown to be sufficient to reproduce a mitral annular structure, which was then manufactured in the Ti6Al4V alloy, which has been shown to be biocompatible in some orthopaedic applications, using SLM. Post-processing techniques appropriate for the specific application of this device into the cardiovascular system were also investigated. The novel electrolyte jet machining process was employed to moderate surface unevenness caused by inherent properties of the powder bed SLM process, such as stepping or loose powder particles. This process was tested with a range of parameter sets producing varying topographies and therefore applied to different needs of the annuloplasty device. Firstly, the process was applied for reduction of coagulation on the surface of Ti6Al4V alloy samples, and then for amplification of fibroblastic cell growth. The primary parameter sets were found to produce a small reduction in platelet adhesion when compared against as-built SLM surfaces, however failed to reduce the platelet activity to that found on conventionally manufactured Ti6Al4V samples. The secondary parameter sets did not produce any improvement in fibroblastic proliferation in short term studies, however SLM samples were found to be significantly more favourable to fibroblast growth than conventionally manufactured surfaces of the same material grade. Finally, future avenues for work are discussed, including next steps for each of the three areas investigated in this thesis and a view to the future of novel annuloplasty devices as a whole. Recommendations for other applications of electrolyte jet machining are provided, including the potential for anti-biofouling surface processing given the lack of cell survivability found in these studies. Further design recommendations are considered, from computational modelling of the valve through to structured surgical prediction integrated with design of the annuloplasty device

Additive manufacturing of mitral annuloplasty devices

Mitral valve annuloplasty is a common surgical procedure performed on thousands of patients each year across the world. A less invasive and more successful method of resolving mitral valve regurgitation, repair surgeries now outnumber replacement of the mitral valve in its entirety. As a result, a range of supportive annuloplasty ring devices for maintaining the surgical repair are now available for lifelong implantation. However, these devices underserve some populations leading to replacement surgeries, and rely on assumptions made on the natural, healthy anatomy of the mitral valve. Additive manufacturing (AM) has, for the last few decades, become increasingly adopted into the medical industry. With applications ranging from educational aids to surgical instruments and long-term implantable devices, this field is rapidly expanding and encompassing a greater breadth of medical specialities. In particular, the manufacturing of patient-specific products with reasonable cost and high fidelity is a key area of development for medical applications of additive manufacturing methods. Significant research has already been undertaken in the fields of orthopaedics, regenerative medicine, and pharmaceuticals, producing long-term implantable metal devices, complex polymer scaffolds, and novel drug delivery methods. Personalized annuloplasty rings could lead to greater surgery success rates enabling greater repair longevity, reduced reoperation rates, and reduced risk of future valve replacement. This project aimed to investigate the suitability of the AM technique, selective laser melting (SLM), to create annuloplasty rings tailored to each patient. To achieve this goal, this research focussed first on comparing the existing design assumptions applied to commercial annuloplasty devices against human anatomy using cadaveric dissection and measurement. These studies concluded that whilst the assumed 3:4 ratio applied in annuloplasty design was a good average across a population, the ratio was inconsistent between subjects and could lead to difficulties in sizing devices appropriately for an individual patient. Following this, methods of design and manufacturing were investigated, comparing various tools available in commercial medical-CAD software, Materialise Mimics®. The commonly applied “thresholding” method of isolating structures from patient scan data was found to be insufficient for isolation of soft tissue structures such as the mitral valve annulus from the surrounding cardiac tissue due to the similarity in densities reducing contrast on the scan. A method of single-point design using insertion points of the valve leaflets throughout the scan was shown to be sufficient to reproduce a mitral annular structure, which was then manufactured in the Ti6Al4V alloy, which has been shown to be biocompatible in some orthopaedic applications, using SLM. Post-processing techniques appropriate for the specific application of this device into the cardiovascular system were also investigated. The novel electrolyte jet machining process was employed to moderate surface unevenness caused by inherent properties of the powder bed SLM process, such as stepping or loose powder particles. This process was tested with a range of parameter sets producing varying topographies and therefore applied to different needs of the annuloplasty device. Firstly, the process was applied for reduction of coagulation on the surface of Ti6Al4V alloy samples, and then for amplification of fibroblastic cell growth. The primary parameter sets were found to produce a small reduction in platelet adhesion when compared against as-built SLM surfaces, however failed to reduce the platelet activity to that found on conventionally manufactured Ti6Al4V samples. The secondary parameter sets did not produce any improvement in fibroblastic proliferation in short term studies, however SLM samples were found to be significantly more favourable to fibroblast growth than conventionally manufactured surfaces of the same material grade. Finally, future avenues for work are discussed, including next steps for each of the three areas investigated in this thesis and a view to the future of novel annuloplasty devices as a whole. Recommendations for other applications of electrolyte jet machining are provided, including the potential for anti-biofouling surface processing given the lack of cell survivability found in these studies. Further design recommendations are considered, from computational modelling of the valve through to structured surgical prediction integrated with design of the annuloplasty device

Next-generation tissue-engineered heart valves with repair, remodelling and regeneration capacity

Valvular heart disease is a major cause of morbidity and mortality worldwide. Surgical valve repair or replacement has been the standard of care for patients with valvular heart disease for many decades, but transcatheter heart valve therapy has revolutionized the field in the past 15 years. However, despite the tremendous technical evolution of transcatheter heart valves, to date, the clinically available heart valve prostheses for surgical and transcatheter replacement have considerable limitations. The design of next-generation tissue-engineered heart valves (TEHVs) with repair, remodelling and regenerative capacity can address these limitations, and TEHVs could become a promising therapeutic alternative for patients with valvular disease. In this Review, we present a comprehensive overview of current clinically adopted heart valve replacement options, with a focus on transcatheter prostheses. We discuss the various concepts of heart valve tissue engineering underlying the design of next-generation TEHVs, focusing on off-the-shelf technologies. We also summarize the latest preclinical and clinical evidence for the use of these TEHVs and describe the current scientific, regulatory and clinical challenges associated with the safe and broad clinical translation of this technology.</p

Development of an acellular annuloplasty ring for atrioventricular valve repair

Annuloplasty is a common technique used for repair of the mitral valve. It is hypothesised that an acellular biological ring may provide a superior solution by encouraging tissue integration and improved annular dynamics whilst offering similar structure and composition to the native annulus. Human mitral valve annuli (n=3) were characterised using histological methods to reveal the histoarchitecture of the native tissue. The histological features of porcine mitral valve annuli (n=5) were compared to the human annuli, as an alternative source of tissue. Haematoxylin and eosin, alcian blue and Sirius red Miller’s stained sections illustrated the morphology of both species revealing a highly fibrous region at the anterior of the annulus compared to the posterior region. The continuum of the fibrosa layer in the mitral leaflet into the fibrous region around the annulus was also visualised. Differences between species were observed at the trigones where cartilaginous tissue was present in the porcine annuli compared to fibrous tissue in the human tissue. The human mitral valve annuli were heavily calcified and showed signs of ossification, hence porcine annuli were used as the starting material for developing a biological acellular annuloplasty ring. Porcine mitral valve annuli (n = 36) were decellularised using a series of eight iterative protocols. The annuli were successfully decellularised using a protocol comprising two freeze thaw cycles (one cycle in hypotonic buffer), followed by four alternate cycles of washing in hypotonic buffer plus proteinase inhibitors and 0.1% (w/v) sodium dodecyl sulfate in hypotonic buffer plus proteinase inhibitors followed by treatment with nuclease solution, washing in hypertonic buffer and final disinfection wash in 0.1% (v/v) peracetic acid. Histological analysis of the treated tissue revealed removal of nuclei apart from apparent “ghost nuclei” in the trigones. Immunohistochemical analyses revealed loss of collagen IV and laminin associated with the basement membrane but retention of collagens I, II and III responsible for structural integrity. Total DNA content of the processed tissue was less than 50 ng.mg-1 wet weight and in-vitro biocompatibility assays showed decellularised porcine mitral valve annulus tissue was not cytotoxic to BHK and L929 cells. Biomechanical tensile tests using low strain rate to failure of the decellularised porcine mitral annuli showed increased tensile strain and transition strains and stresses compared to the native porcine annuli. A method for functional testing revealed that the acellular rings performed as well as synthetic annuloplasty rings in static tests of regurgitant porcine hearts

Stents for transcatheter aortic valve replacement

Rheumatic heart disease (RHD) is the leading cause of aortic valve disease in the world. Surgery to repair or replace the diseased valves is the only means to save a patient's life once the disease becomes symptomatic. Transcatheter aortic valve replacement (TAVR) has revolutionised the treatment of age-related degenerative aortic valve disease, but is currently not suitable for the majority of RHD sufferers due to the rapid degeneration of flexible leaflet valves in younger patients, contraindications of commercial devices to regurgitant or non-calcific aortic valve disease, and also due to resource or funding limitations. The current research project aimed to develop and test novel compressible balloon-expandable stents suitable for patients with symptomatic rheumatic aortic valve disease, and which would allow for a percutaneous polymeric valve to be manufactured, be crimped onto balloon-based devices, and be expanded into a compliant or non-calcific native aortic valve. Several stent concepts were developed and evaluated using Finite Element Analysis (FEA) and two favoured concepts were selected for more complex FEA, in which the balloon was simulated using an Ogden material model, and rigorous testing. The stent material, a nickel-cobalt-chromium alloy, was modelled as an isotropic elasto-plastic material with isotropic hardening. The novel stent designs incorporated a native leaflet-mimicking crown shape for continuous leaflet attachment and mechanisms to anchor the stented valve within compliant aortic roots. The first of the favoured designs provided tactile location during delivery and anchored using self-expanding arms on a balloon-expandable frame of the same material ("self-locating stents"). The second design anchored using arms that protruded during deployment as a consequence of plastic deformation incurred during crimping ("expanding arm stents"). Prototypes were successfully manufactured through laser cutting and electropolishing and showed good surface quality. In vitro testing included determination of crimping and expansion behaviour and measurement of mechanical properties such as resistance to migration in the anatomy. Valve performance was evaluated through in vitro haemodynamics in a pulse duplicator and durability was tested in a high-cycle fatigue tester. Simulated use testing was performed using cadaveric animal hearts. Finally, valves were also implanted into the aortic valve position of pigs (in acute termination experiments) through a transapical approach in order to verify valve deployment behaviour and function in vivo, and determine the stent's ability to anchor in the native anatomy. Stents could be crimped to diameters below 6mm and deployed using commercial balloons and proprietary non-occlusive deployment devices. FEA simulations of stent crimping and deployment matched experimental behaviour well and provide a tool to optimise stent performance. Peak Von Mises stresses during deployment (1437 MPa and 1633 MPa for self-locating and expanding arm stents, respectively) were comparable to a "zig-zag" stent simulated for control purposes (1650 MPa). Radial strength, evaluated for expanding arm stents, was lower than the Control stent (116 N vs. 347 N). This design, although predicted to be safe under fatigue loading, had a lower fatigue safety factor than the Control stent. Stents resisted migration to forces of at least 22 N, which is four times greater than physiological loading on the valves. Polymeric valves incorporating the stents were constructed and demonstrated good in vitro haemodynamic performance (Effective Orifice Areas ≥2.0cm², ΔP<9 mmHg, regurgitation <6%) and durability of over 400 million cycles. Designs functioned as intended in simulated use tests. Valves constructed using self-locating stents could be successfully deployed without rapid pacing in eight of nine pigs, and valve position was correct in seven of these. Valves of expanding arm stents remained anchored in six of eight attempted implants in pigs. This study has demonstrated proof of concept for a novel balloon-expandable stent for a polymeric transcatheter heart valve that is capable of anchoring in a compliant native aortic valve

The development of a transcatheter mitral valve

Transcatheter heart valve replacements avoid the main risks associated with conventional open heart surgery and so is the preferred replacement technique for high-risk patients with aortic stenosis. Due to technical challenges, adaptation for the mitral position is still in early stages of research. The aim of this project was to develop the novel UCL transcatheter mitral valve (TMV) based on a prior conceptual design. The UCL TMV is designed to treat mitral regurgitation (MR) and is based on the UCL transcatheter aortic valve (TAV) which is retrievable, repositionable and has enhanced anchoring and sealing. The UCL TMV leaflets, which ensure unidirectional blood flow, are novel because they mimic native mitral valve morphology by having two leaflets, being D-shaped and conical. Their optimal design criterion and two key design parameters were identified using a failure mode and effects analysis and numerical simulations were used to select a design with acceptable stress levels and maximum coaptation area. The optimal leaflets were prototyped as a surgical valve to evaluate their performance against available commercial device designs and were then incorporated in TMV prototypes, and assessed for hydrodynamic performance, both of which exceeded international standard requirements. Durability assessment of the TMV is ongoing and very encouraging; currently withstanding > 80 million cardiac cycles. In conclusion, the results presented and ongoing durability assessments for the UCL TMV indicate it could be a new and effective treatment option for severe MR in high-risk patients whom are declined surgical interventions

Atrial Septal Defect

Atrial Septal Defects (ASDs) are relatively common both in children and adults. Recent reports of increase in the prevalence of ASD may be related use of color Doppler echocardiography. The etiology of the ASD is largely unknown. While the majority of the book addresses closure of ASDs, one chapter in particular focuses on creating atrial defects in the fetus with hypoplastic left heart syndrome. This book, I hope, will give the needed knowledge to the physician caring for infants, children, adults and elderly with ASD which may help them provide best possible care for their patients

Clinical and hemodynamic outcomes of trans-apical aortic valve implantation. insights from the i-ta registry

Senile degenerative calcific aortic valve stenosis (AVS) is a progressive disease characterized by a peculiar natural history. When symptoms begin (congestive heart failure and dyspnea, angina, syncope) mortality rate rapidly increase and quality of life dramatically worsen. It has been estimated that the overall survival of patients with severe symptomatic AVS is less than 50% 2 years after the onset of symptoms. The number of patients suffering from AVS worldwide will increase over time as life expectancy progressively extends. The treatment of choice for severe symptomatic AVS is aortic valve replacement (AVR) that is usually performed under general anesthesia, with median sternotomy and cardiopulmonary bypass. AVR is a well-established procedure, with excellent early and long-term results and valve prostheses have now reached optimal hemodynamic performance and duration. During the last few years, the development of sutureless aortic bioprosthesis has made easier the surgical procedure. In fact, aortic valve replacement with sutureless valves (SU-AVR) needs shorter cardiopulmonary bypass and aortic cross clamp times and can be safely performed through a minimally invasive approach. However, a recent survey showed that around 30% of patients with severe symptomatic AVS does not undergo AVR for several reasons: they are not referred for surgery by their family physician or by their cardiologist because of age, they are declined surgery for a high preoperative risk profile; they are inoperable for severe ascending aortic calcification (porcelain aorta). Trans-catheter aortic valve implantation (TAVI) is an alternative therapeutic option in high-risk or inoperable patients. TAVI can be performed through several accesses: trans-femoral (TF-TAVI), trans-apical (TA-TAVI), trans-aortic (TAo-TAVI) and trans-subclavian (TS-TAVI). This thesis will focus on TAVI and in particular on TA-TAVI in terms of, indications, technique and outcomes. We will show the results of the Italian Registry of Trans-Apical Aortic Valve Implantation (I-TA) that includes the great majority of patients who underwent TA-TAVI in Italy since this procedure became commercially available in 2008. Furthermore we will present the results of a propensity-matched study that compared all the three available surgical options for patients with severe symptomatic aortic valve stenosis: surgical aortic valve replacement (SAVR), SU-AVR and TA-TAVI. From the results of these two studies it clearly appears that TA-TAVI is an excellent therapeutic options in patients with aortic valve stenosis. The two main issues that still need to be solved are the incidence of paravalvular leak, and valve durability. Paravalvular leak has been demonstrated to have a significant impact on long term survival while the assessment of valve durability needs a longer observation of these patients in order to reach time points when structural valve deterioration is more likely to occu

Development of a prosthetic heart valve with inbuilt sensing technology, to aid in continuous monitoring of function under various stenotic conditions

In spite of technological advances in the design of prosthetic heart valves, they are still often subject to complications after implantation. One of the common complications is valve stenosis, which involves the obstruction of the valve orifice caused by biological processes. The greatest challenge in diagnosing the development of valve failure and complications is related to the fact that the valve is implanted and isolated. To continuously monitor the state of the valve and its performance would be of great benefit but practically can only be achieved by instrumenting the implanted valve. In this thesis, we explore the development of a prosthetic valve with inbuilt sensing technology to aid in continuous monitoring of valve function under various stenotic conditions. 22mm polyurethane valves were designed via dipcoating. A custom made mock circulatory system was designed and hydrodynamic testing of the polyurethane valves under different flow rates were performed with Effective orifice area (EOA) and Transvalvular Pressure Gradient (TVPG) being the parameters of interest. Valves were subjected to varying levels of obstruction to investigate the effect obstruction has on the pressure gradient across the valves. Similar tests were performed on a Carpentier Edwards SAV 2650 model bioprosthetic valve for comparison. Polyurethane valves were then instrumented with strain gauges to measure peak to peak strain difference, in response to varying levels of obstructions. All the polyurethane valves exhibited good hydrodynamic performance with EOA (>1cm2) under baseline physiological conditions. It was also discovered that pressure difference across the valves was directly proportional to the flow rate. The pressure difference also demonstrated a slow increase during the initial stages of simulated stenosis and a sudden increase as the obstruction became severe. This provides further evidence to support the ideal that stenosis is a slow progressive disease which may not present symptoms until severe. The peak to peak strain differences also tend to decrease as the severity of the obstruction was increased. The peak to peak strain difference is indicative of the pressures within the valve (intravalvular pressure). The results suggest that directly monitoring the pressures within the valve could be a useful diagnostic tool for detecting valve stenosis. Future works involves miniaturisation of the sensors and also the incorporation of telemetry into the sensor design.In spite of technological advances in the design of prosthetic heart valves, they are still often subject to complications after implantation. One of the common complications is valve stenosis, which involves the obstruction of the valve orifice caused by biological processes. The greatest challenge in diagnosing the development of valve failure and complications is related to the fact that the valve is implanted and isolated. To continuously monitor the state of the valve and its performance would be of great benefit but practically can only be achieved by instrumenting the implanted valve. In this thesis, we explore the development of a prosthetic valve with inbuilt sensing technology to aid in continuous monitoring of valve function under various stenotic conditions. 22mm polyurethane valves were designed via dipcoating. A custom made mock circulatory system was designed and hydrodynamic testing of the polyurethane valves under different flow rates were performed with Effective orifice area (EOA) and Transvalvular Pressure Gradient (TVPG) being the parameters of interest. Valves were subjected to varying levels of obstruction to investigate the effect obstruction has on the pressure gradient across the valves. Similar tests were performed on a Carpentier Edwards SAV 2650 model bioprosthetic valve for comparison. Polyurethane valves were then instrumented with strain gauges to measure peak to peak strain difference, in response to varying levels of obstructions. All the polyurethane valves exhibited good hydrodynamic performance with EOA (>1cm2) under baseline physiological conditions. It was also discovered that pressure difference across the valves was directly proportional to the flow rate. The pressure difference also demonstrated a slow increase during the initial stages of simulated stenosis and a sudden increase as the obstruction became severe. This provides further evidence to support the ideal that stenosis is a slow progressive disease which may not present symptoms until severe. The peak to peak strain differences also tend to decrease as the severity of the obstruction was increased. The peak to peak strain difference is indicative of the pressures within the valve (intravalvular pressure). The results suggest that directly monitoring the pressures within the valve could be a useful diagnostic tool for detecting valve stenosis. Future works involves miniaturisation of the sensors and also the incorporation of telemetry into the sensor design