Introduction
In 2023, our iGEM team is pioneering a venture into synthetic biology with a clear objective: to enhance the bio-compatibility and mechanical resilience of artificial heart valves, addressing a critical challenge in biomedical engineering. Our inspiration stems from the newly reported protein Titin, known for its unique qualities of providing passive strength, which could be useful for next-generation heart valve constructs.
Heart valve diseases affect millions globally, underscoring the urgency of improving current medical interventions. Conventional heart valves, while life-saving, have significant limitations, including the risk of rejection and the need for replacement. Our project explores the integration of Titin proteins fibers for innovative heart valve material, aiming to mitigate these issues.
Heart Valve Diseases
Heart valve diseases, affecting hundreds of millions worldwide, manifest primarily in three forms: regurgitation, stenosis, and atresia[1]. These conditions disrupt the normal function of the heart's valves - the aortic, mitral, pulmonary, and tricuspid - necessitating medical intervention ranging from repair to complete valve replacement. Regurgitation, for instance, occurs when a valve doesn't close tightly, causing blood to leak backward, while stenosis involves a valve not opening fully, restricting blood flow. Atresia is even more severe, where a valve lacks an opening altogether, blocking blood flow between heart chambers[1].
In the U.S. alone, approximately 2.5% of the population suffers from some form of valvular heart disease, a prevalence that increases with age[2]. According to authority reports from the Committee of the Report on Cardiovascular Health and Diseases in China [3], the prevalence of valvular diseases is 3.8%, affecting about 25 million people in China, of which 1.5 million are patients with severe aortic stenosis. Due to low awareness and limited treatment options, only 1-2% of patients in China undergo surgical intervention.
Over the past decade, the escalating need for valve replacement therapies has been remarkable, with the global heart valves market valued at USD 6.58 billion in 2018, projected to almost triple to USD 15.98 billion by 2026[4]. This surge anticipated rise in aortic valve replacement procedures, expected to reach 850,000 by 2024[4].
Despite the advancements, the cost of valve replacement or repair remains a significant hurdle, ranging from RMB 20,000 to RMB 200,000, and the upper bound cost is equivalent to the total annual income of the top 10 percent workers. The cost imposes a financial strain on patients and healthcare systems alike. This trend highlights an urgent need for more accessible, cost-effective, and long-lasting solutions in the treatment of heart valve diseases.
Challenges with Traditional Heart Valves
Traditional heart valves are primarily classified into two types: biological and mechanical. Each comes with significant drawbacks. Biological valves, often sourced from animal tissues, possess limited durability, leading to potential structural degeneration and necessitating repeated surgeries, especially in younger patients. On the other hand, mechanical valves, while durable, pose a high risk of blood clot formation, requiring patients to undergo lifelong anticoagulation therapy, which significantly impacts their quality of life.
These limitations make the pursuit of an alternative material essential, one that combines both durability and biocompatibility. Our focus is on synthetic biology-derived materials, specifically the Titin protein. Our literature research indicates that Titin's extraordinary mechanical properties surpass those of conventional materials [5, 6], positioning it as a promising candidate for next-generation heart valves. This innovation aims to reduce surgical interventions and improve life quality, particularly for younger patients desiring fewer surgeries and a more active lifestyle.
Experimental Proposal
Our project draws inspiration from innovative research that successfully engineered microbes to synthesize muscle titin polymers, resulting in fibers with exceptional mechanical properties and resilience [5, 6]. Here's our approach:
Protein Synthesis: We'll replicate the production of megadalton titin polymers in a more stable host, E. coli, overcoming challenges associated with synthesizing large proteins.
Segmentation and Connection: Based on prior studies [6, 7, 8], we'll divide the large protein into manageable segments, attaching robust protein connectors to facilitate the later stages of fiber formation.
Wet Spinning Process: We'll explore the wet spinning technique to spin these proteins into long threads, investigating parameters to enhance production efficiency and fiber quality.
The study suggests that these properties derive from unique inter-chain crystallization of folded immunoglobulin-like domains that resist inter-chain slippage while permitting intra-chain unfolding.
Thread Formation and Hardware
Transitioning from protein synthesis to fiber formation presented a unique challenge. Our solution: wet spinning. This technique is essential due to its ability to produce continuous fibers with desirable mechanical properties from a solution of large, complex molecules like proteins. It involves extruding a protein solution through a syringe needle into a coagulation bath, forming stable fibers interconnected by β-sheets, a structure critical for strength and durability.
Our hardware page delves deeper into the intricacies of this process, showcasing our innovative use of stepper motors and ball screw mechanisms for precise control of the extrusion process. It also features our design using the 3D-printer to make customized parts. Head over to our hardware page for a detailed exploration!
From Threads to Therapeutics
Our journey doesn't end at creating threads. We envision these titin-based fibers as the cornerstone of revolutionary heart valve replacements, offering unmatched biocompatibility and mechanical strength. Imagine a future where valve replacements are more durable, safer, and accessible, drastically reducing the need for repeat surgeries and improving patient quality of life.
However, innovations come with ethical considerations. What are the implications of using synthetically engineered materials in the human body? How do we ensure equitable access to these medical advancements? For deep dives into these questions, expert insights, and more, we urge you to explore our Human Practices pages. The future is woven with threads of innovation, ethics, and inclusivity — be part of this vital conversation.
References
[1] "Heart Valve Diseases - Types," NHLBI, NIH, accessed October 2023
[2] "Valvular Heart Disease," CDC, accessed October 2023
[3] Editorial Committee of the China Cardiovascular Health and Disease Report. (2021). Summary of the China Cardiovascular Health and Disease Report 2020. Chinese Circulation Journal, 36(6), 521-545. https://doi.org/10.3969/j.issn.1000-3614.2021.06.001
[4a] Cardiovasc Med, 2021,26(3): 209-218. DOI: 10.3969/j.issn.1007-5410.2021.03.001
[4b]"Heart Valves Market Size, Share, Growth, Trends | Global Report, 2030," Fortune Business Insights, accessed October 2023
[5] Granzier, H., & Labeit, S. (2004). The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circulation research, 94(3), 284-295.
[6] Bowen, C.H., Sargent, C.J., Wang, A. et al. Microbial production of megadalton titin yields fibers with advantageous mechanical properties. Nat Commun 12, 5182 (2021). https://doi.org/10.1038/s41467-021-25360-6
[7]. iGEM 2018 Team, University of British Columbia. Spider Silk Production. Retrieved from http://2018.igem.org/Team:UBC.
[8]. iGEM 2019 Team, Greatbay_SZ. SPIDroin EngineeRing with chroMoprotein And Natural dye. Retrieved from https://2019.igem.org/Team:GreatBay_SZ
