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Acute in vivo validation of primary biomimetic valve function in juvenile and adult sheep. (A and B) Fabricated prototypes implanted at two polar expansion states (1× and 1.8×) in the native pulmonary valve position of juvenile (n = 4) and adult (n = 4) sheep. Representative plots showing right ventricular (RV) and pulmonary artery (PA) pressures for the (C) 1× and (D) 1.8× valve geometries. Corresponding pulmonary artery flow for the (E) 1× and (F) 1.8× valve geometries. Representative echocardiographic images of implanted valves, demonstrating change in coaptation length (C l ) between the (G) baseline (1×, 14 mm ID) and (H) fully expanded (1.8×, 25 mm ID) geometries.
Source publication
Congenital heart valve disease has life-threatening consequences that warrant early valve replacement; however, the development of a growth-accommodating prosthetic valve has remained elusive. Thousands of children continue to face multiple high-risk open-heart operations to replace valves that they have outgrown. Here, we demonstrate a biomimetic...
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Objective:
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Methods:
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Citations
... One of the most commonly used animal models for such preclinical studies is the domestic sheep (Ovis aries). Use of the sheep model in evaluating novel cardiac devices and their translation to the clinical setting has been widely reported in published literature, especially in evaluating long-term hemodynamic performance and durability, thromboembolic complications, and biocompatibility [16][17][18][19][20][21][22][23][24] . As a result, the sheep has become the standard large animal model for in vivo testing and evaluation of novel cardiac valve replacement devices prior to human use 21 . ...
... Sheep were anesthetized using methods described previously [21][22][23][24] . Briefly, peripheral intravenous access was established with a catheter placed in the external jugular vein, anesthetized with Propofol (1-2 mg/kg) intubated and connected to mechanical ventilation. ...
Preclinical in vivo evaluation is an essential step in the progression of new cardiac devices into patient use, with studies predominantly performed in the domestic sheep model. A growing area of interest in cardiac device development is transcatheter mitral valve replacement (TMVR). Clinically, multimodal imaging, or computed tomography (CT) and echocardiography (echo) are used extensively to preoperatively determine mitral valve morphology prior to an intervention, but there is no description on how these modalities can be implemented to support preclinical studies. The purpose of this study is to apply clinically relevant CT and echo acquisition and assessment techniques to a large group of naive research sheep in order to analyze and report modality-related effects on mitral valve dimensional reference intervals in the sheep model. To this end, fifty-five adult domestic sheep underwent preoperative CT and echo exams and resultant images were analyzed using a landmark-based multiplanar measurement protocol and compiled into a master dataset for statistical analysis. We found moderate agreement between CT and echo-derived measurements of the mitral valve in sheep and propose the first clinically-relevant dimensional indices for the sheep’s naive mitral valve which can be used to guide future studies evaluating novel TMVR devices. This study is the first of its kind in proposing a reproducible method for detailed examination of the mitral valve in the sheep model using clinically-relevant multimodal imaging. As in patients, CT and echo can reveal accurate native mitral valve dimensions in the sheep prior to preclinical TMVR studies.
... These patients will require a cochlear implant, whereby an electronic device containing an array of electrodes and a receiver is surgically implanted into the patient's inner ear to directly stimulate the auditory nerve and recover some of the patient's hearing (Lenarz, 2017;Carlson, 2020;Weltin et al., 2022). Similarly, patients with damaged heart valves will require replacement with artificial valves made of metal or biological material in order to maintain heart function (Singh et al., 2019;Hofferberth et al., 2020;Dreyfus et al., 2022; Figure 1). ...
Stem cells offer new therapeutic avenues for the repair and replacement of damaged tissues and organs owing to their self-renewal and multipotent differentiation capabilities. In this paper, we conduct a systematic review of the characteristics of various types of stem cells and offer insights into their potential applications in both cellular and cell-free therapies. In addition, we provide a comprehensive summary of the technical routes of stem cell therapy and discuss in detail current challenges, including safety issues and differentiation control. Although some issues remain, stem cell therapy demonstrates excellent potential in the field of regenerative medicine and provides novel tactics and methodologies for managing a wider spectrum of illnesses and traumas.
... Scalability and reproducibility are two points of emphasis in the clinical approval process. Although studies have demonstrated satisfactory outcomes for pulmonary and aortic conditions [11,22,23], the number of investigations assessing the hemodynamics of TEHVs in the aortic position remains limited. Most of these studies have primarily concentrated on the mechanical and microscopic properties [10,24]. ...
The application of tissue-engineered heart valves in the high-pressure circulatory system is still challenging. One possible solution is the development of biohybrid scaffolds with textile reinforcement to achieve improved mechanical properties. In this article, we present a manufacturing process of bio-inspired fiber reinforcement for an aortic valve scaffold. The reinforcement structure consists of polyvinylidene difluoride monofilament fibers that are biomimetically arranged by a novel winding process. The fibers were embedded and fixated into electrospun polycarbonate urethane on a cylindrical collector. The scaffold was characterized by biaxial tensile strength, bending stiffness, burst pressure and hemodynamically in a mock circulation system. The produced fiber-reinforced scaffold showed adequate acute mechanical and hemodynamic properties. The transvalvular pressure gradient was 3.02 ± 0.26 mmHg with an effective orifice area of 2.12 ± 0.22 cm2. The valves sustained aortic conditions, fulfilling the ISO-5840 standards. The fiber-reinforced scaffold failed in a circumferential direction at a stress of 461.64 ± 58.87 N/m and a strain of 49.43 ± 7.53%. These values were above the levels of tested native heart valve tissue. Overall, we demonstrated a novel manufacturing approach to develop a fiber-reinforced biomimetic scaffold for aortic heart valve tissue engineering. The characterization showed that this approach is promising for an in situ valve replacement.
... Consequently, recent work has explored strategies to better predict and control the quality of the remodeled valve, whether through optimizing the design and fabrication process, 39,235 or better understanding the underlying cellular processes. 232 39,110,216,239,247 In this review alone, simulations have accurately predicted structural changes due to cellular contraction, 39 compared the expansile capability of various biological valves, 216 and analyzed the mechanical performance of a bileaflet SGHV. 110 In silico studies could readily analyze the functional performance of an expanding prototype without committing excess time to manufacture, thus streamlining the iterative development of growth-accommodating PPVRs. ...
... 232 39,110,216,239,247 In this review alone, simulations have accurately predicted structural changes due to cellular contraction, 39 compared the expansile capability of various biological valves, 216 and analyzed the mechanical performance of a bileaflet SGHV. 110 In silico studies could readily analyze the functional performance of an expanding prototype without committing excess time to manufacture, thus streamlining the iterative development of growth-accommodating PPVRs. As this technology evolves, simulation components may allow the application of artificial intelligence and digital twins, 248,249 wherein the child's growth could be predicted and PPVR expansion modeled with unprecedented patient-specificity. ...
... Such work is integral to developing a comprehensive understanding of the remodeling process; however, the current lack of control over cellular remodeling imposes safety challenges that hinder the clinical translation of TEHVs.238 6.2.3 | Synthetic growth-accommodating heart valvesSGHVs describe purely synthetic polymeric valves that rely on innovative designs to facilitate expansion in lieu of organic remodeling.While some theoretical prototypes have been reported,239 to the best of the authors' knowledge only one SGHVs has been fabricated; a bileaflet valve consisting of ePTFE leaflets on a bare stainless-steel stent, with an expansile capacity of 180%.110 This design was based on computational simulations that demonstrated that bileaflet venous valves could expand up to three times as much as trileaflet semilunar valves while preserving hydrodynamic function.216 ...
Congenital heart diseases (CHDs) frequently impact the right ventricular outflow tract, resulting in a significant incidence of pulmonary valve replacement in the pediatric population. While contemporary pediatric pulmonary valve replacements (PPVRs) allow satisfactory patient survival, their biocompatibility and durability remain suboptimal and repeat operations are commonplace, especially for very young patients. This places enormous physical, financial, and psychological burdens on patients and their parents, highlighting an urgent clinical need for better PPVRs. An important reason for the clinical failure of PPVRs is biofouling, which instigates various adverse biological responses such as thrombosis and infection, promoting research into various antifouling chemistries that may find utility in PPVR materials. Another significant contributor is the inevitability of somatic growth in pediatric patients, causing structural discrepancies between the patient and PPVR, stimulating the development of various growth‐accommodating heart valve prototypes. This review offers an interdisciplinary perspective on these challenges by exploring clinical experiences, physiological understandings, and bioengineering technologies that may contribute to device development. It thus aims to provide an insight into the design requirements of next‐generation PPVRs to advance clinical outcomes and promote patient quality of life.
... Bileaflet valves are typically subjected to high flow rates and relative changes in volume throughout the cardiac cycle. Technical designs of the valves are inspired by profiles of a native valve, which is optimised to resist and adapt to natural variations in vessel diameter, blood volume and oscillations (Hofferberth et al., 2020). ...
Blood-circulating devices such as oxygenators have offered life-saving opportunities for advanced cardiovascular and pulmonary failures. However, such systems are limited in the mimicking of the native vascular environment (architecture, mechanical forces, operating flow rates and scaffold compositions). Complications involving thrombosis considerably reduce their implementation time and require intensive anticoagulant treatment. Variations in the hemodynamic forces and fluid-mediated interactions between the different blood components determine the risk of thrombosis and are generally not taken sufficiently into consideration in the design of new blood-circulating devices. In this Review article, we examine the tools and investigations around hemodynamics employed in the development of artificial vascular devices, and especially with advanced microfluidics techniques. Firstly, the architecture of the human vascular system will be discussed, with regards to achieving physiological functions while maintaining antithrombotic conditions for the blood. The aim is to highlight that blood circulation in native vessels is a finely controlled balance between architecture, rheology and mechanical forces, altogether providing valuable biomimetics concepts. Later, we summarize the current numerical and experimental methodologies to assess the risk of thrombogenicity of flow patterns in blood circulating devices. We show that the leveraging of both local hemodynamic analysis and nature-inspired architectures can greatly contribute to the development of predictive models of device thrombogenicity. When integrated in the early phase of the design, such evaluation would pave the way for optimised blood circulating systems with effective thromboresistance performances, long-term implantation prospects and a reduced burden for patients.
... Bioprostheses and homografts are susceptible to immune responses and structural valve deterioration [3]. Unfortunately, these poor outcomes tend to manifest earlier for younger patients, forcing them to undergo multiple operations throughout their lifetime [4][5][6]. ...
Current heart valve replacements lack durability and sustained performance, especially in paediatric patients. In part, these problems may be attributed to the materials chosen for these constructs, but an important contributing factor is the design of the valve, as this dictates haemodynamic performance and impacts leaflet stresses which may accelerate structural valve deterioration. Most current era bioprosthetic valves adhere to a fundamental design where flat leaflets are supported by stent posts, secured to a sewing ring. This overall design strategy is effective, but functionality and durability may be improved by incorporating features of the native valve geometry. This paper presents a novel workflow for developing and analysing bioinspired valve designs computationally. The leaflet curvature was defined using a mathematical equation that was derived from the 3D model of a native sheep pulmonary valve obtained via micro-computed tomography. Finite Element Analysis was used to screen the various valve designs proposed in this study by assessing the effect of leaflet thickness, Young's modulus, and height/curvature on snap-through, Geometric Orifice Area (GOA) and the stress in the leaflets. This workflow demonstrated benefits for valve designs with leaflet thicknesses between 0.1-0.3 mm, Young's moduli less than 50 MPa, and elongated leaflets with greater curvatures. The proposed workflow brings substantial efficiency gains, minimising manufacturing and animal testing during iterative improvements, and offers a bridge between in vitro and more complex in silico studies in the future.
... Computational modeling can now be used to investigate and optimize valve designs in silico for a more efficient workflow (284,285), through such platforms as finite element analysis (FEA) for structural analysis or full fluid structure interaction (FSI) for hydrodynamic modeling. ...
Current heart valve replacements (HVRs) fail to comprehensively capture the physiological behaviour of native heart valve tissues, allowing the burden of valvular heart disease to persist after surgical intervention. Through extensive research and clinical experience, it has become evident that material selection is central to the success of HVRs. One outstanding candidate material for next-generation HVRs is polyurethane. These polymers exhibit a unique segmented chemical structure that can imitate the mechanical strength and elasticity of soft biological tissues. Consequently, polyurethanes have long been investigated as HVR materials, however, progression to clinical utility has historically been impaired by the material’s susceptibility to biodegradation and calcification. This review presents a concise and critical analysis of past and recent investigations to elucidate the contemporary potential of polyurethane HVRs. Importantly, the overwhelming clinical failure of past prototypes necessitated a detailed examination to validate any further use of polyurethanes in HVR development. Ultimately, chemically modified polyurethanes along with different modifications have been introduced to tackle the shortcoming of the existing polyurethane HVRs and develop biostable biomaterials for next-generation HVRs.
... Multiple efforts are underway to address these issues, from decellularized xenograft tissues specifically for pediatric populations, to "living biomaterials" that alter their properties at multiple length and time scales, such as growthaccommodating implants that expand and grow over time (Patel and Fisher, 2008;Feins et al., 2017;Hofferberth et al., 2020). These new approaches provide an example of technical advances potentially promoting more just research by facilitating inclusion of pediatric populations in the development of biomaterials. ...
Biomaterials--from implanted iron teeth in the second century to intraocular lenses, artificial joints, and stents today--have long been used clinically. Today, biomaterials researchers and biomedical engineers are pushing beyond these inert synthetic alternatives and incorporating complex multifunctional materials to control biological interactions and direct physiological processes. These advances are leading to novel strategies for targeted drug delivery, drug screening, diagnostics and imaging, gene therapy, tissue regeneration, and cell transplantation. While the field has survived ethical transgressions in the past, the rapidly expanding scope of biomaterials science, combined with the accelerating clinical translation of this diverse field calls for urgent attention to the complex and challenging ethical dilemmas these advances pose. This perspective responds to this call, examining the intersection of research ethics -- the sets of rules, principles and norms guiding responsible scientific inquiry -- and ongoing advances in biomaterials. While acknowledging the inherent tensions between certain ethical norms and the pressures of the modern scientific and engineering enterprise, we argue that the biomaterials community needs to proactively address ethical issues in the field by, for example, updating or adding specificity to codes of ethics, modifying training programs to highlight the importance of ethical research practices, and partnering with funding agencies and journals to adopt policies prioritizing the ethical conduct of biomaterials research. Together these actions can strengthen and support biomaterials as its advances are increasingly commercialized and impacting the health care system.
... To circumvent residual pulmonary regurgitation and to accommodate growth with the child in transitional treatments, there are a number of expandable valve conduits being investigated [7][8][9]. A technique of replacing the aortic valve leaflets, which is developed for the adult population [10] and has been performed on the pulmonary valve in adults [11], has recently been described in the paediatric population with isolated congenital aortic valve disorders [12]. ...
Objective:
Residual regurgitation is common after congenital surgery for right ventricular outflow tract malformation. It is accepted as there is no competent valve solution in a growing child. We investigated a new surgical technique of trileaflet semilunar valve reconstruction possessing the potential of remaining sufficient and allow for some growth with the child. In this proof-of-concept study, our aim was to evaluate if it is achievable as a functional pulmonary valve reconstruction in vitro.
Methods:
Explanted pulmonary trunks from porcine hearts were evaluated in a pulsatile flow-loop model. First, the native pulmonary trunk was investigated, after which the native leaflets were explanted. Then, trileaflet semilunar valve reconstruction was performed and investigated. All valves were initially investigated at a flow output of 4 L/min and subsequently at 7 L/min. The characterization was based on hydrodynamic pressure and echocardiographic measurements.
Results:
Eight pulmonary trunks were evaluated. All valves are competent on colour Doppler. There is no difference in mean pulmonary systolic artery pressure gradient at 4 L/min (P = 0.32) and at 7 L/min (P = 0.20). Coaptation length is increased in the neo-valve at 4 L/min (P < 0.001, P < 0.001, P = 0.008) and at 7 L/min (P < 0.001, P = 0.006, P = 0.006). A windmill shape is observed in all neo-valves.
Conclusions:
Trileaflet semilunar valve reconstruction is sufficient and not-stenotic. It resulted in an increased coaptation length and a windmill shape, which is speculated to decrease with growth of the patient, yet remain sufficient as a transitional procedure until a long-term solution is feasible. Further in vivo investigations are warranted.
... Ovine models may also be better suited for modeling of larger pediatric patients and adults given their size. The smallest pediatric heart valve replacements reported in sheep to date were implanted at initial diameters of 12-19 mm (15,16). This is larger than human neonatal valve sizes, which typically range from 7 to 10 mm (17). ...
... Ovine models have traditionally been used as a preferred animal model for pulmonary valve implants due to their similarity in physiology to humans and accelerated calcification response (12, 34). Indeed, several recent studies have shown promising results with pediatric heart valves implanted in sheep (15,16,35). However, pediatric PA tissue was found to be thinner, and more anisotropic compared to ovine PA tissue, and was also significantly stiffer when strained beyond normal physiological conditions (28), although it should be noted that only a single pediatric donor was used. ...
... The measured juvenile porcine diameters roughly align with the range of PV diameters reported for neonates to children a few years of age (5). In addition, our micrometer and caliper measurements of piglet PA wall thickness and PA length were similar to human infants ages 6-8 months (15,28). It should be noted that the research by Zilberman et al. was performed on healthy tissue, and the anatomy of patients with congenital heart defects, who would require valve prosthetics, may differ. ...
Characterization of cardiovascular tissue geometry and mechanical properties of large animal models is essential when developing cardiovascular devices such as heart valve replacements. These datasets are especially critical when designing devices for pediatric patient populations, as there is often limited data for guidance. Here, we present a previously unavailable dataset capturing anatomical measurements and mechanical properties of juvenile Yorkshire (YO) and Yucatan (YU) porcine main pulmonary artery (PA) and pulmonary valve (PV) tissue regions that will inform pediatric heart valve design requirements for preclinical animal studies. In addition, we developed a novel radial balloon catheter-based method to measure tissue stiffness and validated it against a traditional uniaxial tensile testing method. YU piglets, which were significantly lower weight than YO counterparts despite similar age, had smaller PA and PV diameters (7.6–9.9 mm vs. 10.1–12.8 mm). Young’s modulus (stiffness) was measured for the PA and the PV region using both the radial and uniaxial testing methods. There was no significant difference between the two breeds for Young’s modulus measured in the elastic (YU PA 84.7 ± 37.3 kPa, YO PA 79.3 ± 15.7 kPa) and fibrous regimes (YU PA 308.6 ± 59.4 kPa, YO PA 355.7 ± 68.9 kPa) of the stress-strain curves. The two testing techniques also produced similar stiffness measurements for the PA and PV region, although PV data showed greater variation between techniques. Overall, YU and YO piglets had similar PA and PV diameters and tissue stiffness to previously reported infant pediatric patients. These results provide a previously unavailable age-specific juvenile porcine tissue geometry and stiffness dataset critical to the development of pediatric cardiovascular prostheses. Additionally, the data demonstrates the efficacy of a novel balloon catheter-based technique that could be adapted to non-destructively measure tissue stiffness in situ .
