Development of a flexible, multi-technology bio-fabrication robotic platform: a focus on tissue-engineered heart valves (TEHV)

Valvular heart disease (VHD) is a growing global health concern affecting over 41 million people worldwide, with a 45.1% increase in prevalence in the last three decades (Figure 1). This prevalence is expected to triple by 2050 due to longer life expectancies. VHD affects all age groups, including pediatric patients, such as those with congenital heart disease (CHD), which impacts approximately 20,000 children annually in the US.Current treatments for VHD mainly involve valve repair or replacement. While there have been significant advancements in heart valve replacement techniques, long-term outcomes have not improved substantially. Mechanical valves, known for their durability, require lifelong anticoagulant therapy and come with complications like bleeding and thrombosis. Bioprosthetic valves, offering better hemodynamics and no need for anticoagulation, often require re-intervention within 10 to 15 years, posing risks, especially for the elderly. They are also unsuitable for pediatric patients and hinder natural growth. Moreover, existing clinical heart valve prostheses are often unsuitable for pediatric patients which may require multiple re-interventions, affecting both quality of life and healthcare system finances.This concerning economical trend has implications not only for patient health but also on the healthcare system costs. The projected tripling of age-related degenerative valve diseases by 2050 predicts a tough scenario for the close future. In response to these challenges, tissue engineering has emerged as a promising solution to address the challenges of heart valve replacement. The goal is to replicate native organs and tissues to provide organ alternatives. Tissue-engineered heart valve (TEHV) scaffolds are designed as off-the-shelf alternatives, eliminating the need for organ donors and promoting native tissue regeneration while reducing the risk of prosthesis rejection. This approach aims to mitigate complications associated with foreign materials used in traditional heart valve prostheses, such as metal or porcine/ovine decellularized tissues, which can lead to issues like bleeding, thrombogenicity, and calcification.The process begins with a thorough study and characterization of native organs and tissues to faithfully emulate their micro and macro structures, achieving equivalent biomechanical functionality through biomimicry strategies.Despite significant progress in the clinical translation of TEHV, several challenges remain. These include the need for comprehensive preclinical evaluations and large-scale clinical trials to establish TEHV as standard therapeutic devices. A promising approach should involve the development of a single heart valve scaffold device with biostable elastic leaflets that faithfully replicate native biomechanical and hemodynamic properties. However, existing techniques and technology platforms fall short in addressing four key design factors simultaneously: macroscopic morphology and size, in-plane mechanics, out-of-plane mechanics, and microstructure.To address these limitations, this work introduces a novel technique using electrospinning to replicate the native structure and function of heart valves at both the macro and meso-scale. Additionally, in line with the trend of enhancing the automation of scaffold fabrication processes for precision and repeatability, a multi-axis robotic platform for melt-electrowriting is introduced. This platform shows promise in producing support structures on complex collectors with overhangs and concavities, such as heart valve collectors and bifurcating vessels. The integration of robotics into the bio-fabrication process holds great potential for tissue engineering, promising more consistent and precise scaffolds and ultimately improving the effectiveness and durability of heart valve replacement therapies.In summary, the combination of electrospinning and Melt-Electrowriting can form a multi-technology platform for next-generation scaffold fabrication, addressing key design factors in heart valve engineering.