Periodic Reporting for period 2 - BIOMITRAL (Engineering the mitral valve: bioinspired control of structure and function for enhanced in vivo performance)
Reporting period: 2023-03-01 to 2024-08-31
The prevalence of heart valve disease among the US population is 2.5%, with aortic and mitral regurgitation (MR) being the most common pathologies. More specifically, the EURObservational Research Programme, initiated by the European Society of Cardiology, estimates that MR (both primary and functional) alone affects 21.3% of patients. Tissue-engineered heart valves (TEHVs) have demonstrated the potential to restore function, regenerate native-like tissue, for the pulmonary and aortic valve applications in large animal models. However, this concept has never been extended to atrioventricular valves, and in particular to the mitral valve (MV), despite its related pathologies affects a considerable fraction of valve disease patients.
This project introduces a bio-inspired design methodology and bioprocessing technology to engineer a polymeric, stent-less MV capable of constructive remodeling, replicating native structure-function relationships, and incorporating the chordal apparatus (BIOMITRAL). Incorporating engineered chordae tendineae allows to restore the mechanical continuum: ventricle – papillary muscle - chordae tendineae – valve leaflets that characterize native atrioventricular valves. This feature, represents a major element of technological and conceptual innovation that may lead to better treatments for MV functional regurgitation. Assessment of the technology will be carried out in vitro and on pre-clinical models.
This project introduces a bio-inspired design methodology and bioprocessing technology to engineer a polymeric, stent-less MV capable of constructive remodeling, replicating native structure-function relationships, and incorporating the chordal apparatus (BIOMITRAL). Incorporating engineered chordae tendineae allows to restore the mechanical continuum: ventricle – papillary muscle - chordae tendineae – valve leaflets that characterize native atrioventricular valves. This feature, represents a major element of technological and conceptual innovation that may lead to better treatments for MV functional regurgitation. Assessment of the technology will be carried out in vitro and on pre-clinical models.
During the reporting period (months 1 to 30), the research efforts have been focused on: A) experimental characterization of human native valves; B) in silico modelling of the BIOMITRAL prototypes; C) perfecting our biofabrication approaches for mitral valve and chordal apparatus engineering.
Aiming to establish a database of structural and mechanical properties of fresh human valvular tissue we are currently working in collaboration with the Division of Cardiac Surgery of Istituto Mediterraneo per i Trapianti (ISMETT) hospital which is part of University of Pittsburgh Medical Center Italy. Unlike our study, the current state of the art is limited being strictly based on cadaveric samples or functional data acquired in vivo by medical imaging. Methods adopted include gross examination, morphometric measurements, histological assessment, multiphoton imaging of collagen and elastin fibers, scanning electron microscopy and biomechanical testing.
Based on the collected data as well as the data available in the literature, we built finite-element method (FEM) models replicating shape and function of the MV and CT apparatus. These models allowed us to assess organ level function and distribution of stresses within the valve so that the optimal configuration of chordae tendineae in terms of number and anchoring points could be identified.
A key factor of innovation for BIOMITRAL fabrication process was the use of our patented double-component deposition technique (US20220039946A1) that allows for a controlled deposition of polymeric micro-fibers on intricate geometries by altering the collecting target surface conductivity. In order to advance this method, we coupled it with COMSOL Multiphysics modeling aiming to optimize the geometry of the collectors. We also established a multi-phase fabrication process, characterizing processing conditions for each of the phases to achieve desired thickness, microstructure, and mechanical properties. This paves the road to the integration of robotic with this processing methods. Similarly, the bioengineered chordae tendineae were fabricated using a mandrel-less deposition technique (US11680341B2), solvent welding strategies to connect valve leaflets with the chordae were evaluated during this reporting period.
Aiming to establish a database of structural and mechanical properties of fresh human valvular tissue we are currently working in collaboration with the Division of Cardiac Surgery of Istituto Mediterraneo per i Trapianti (ISMETT) hospital which is part of University of Pittsburgh Medical Center Italy. Unlike our study, the current state of the art is limited being strictly based on cadaveric samples or functional data acquired in vivo by medical imaging. Methods adopted include gross examination, morphometric measurements, histological assessment, multiphoton imaging of collagen and elastin fibers, scanning electron microscopy and biomechanical testing.
Based on the collected data as well as the data available in the literature, we built finite-element method (FEM) models replicating shape and function of the MV and CT apparatus. These models allowed us to assess organ level function and distribution of stresses within the valve so that the optimal configuration of chordae tendineae in terms of number and anchoring points could be identified.
A key factor of innovation for BIOMITRAL fabrication process was the use of our patented double-component deposition technique (US20220039946A1) that allows for a controlled deposition of polymeric micro-fibers on intricate geometries by altering the collecting target surface conductivity. In order to advance this method, we coupled it with COMSOL Multiphysics modeling aiming to optimize the geometry of the collectors. We also established a multi-phase fabrication process, characterizing processing conditions for each of the phases to achieve desired thickness, microstructure, and mechanical properties. This paves the road to the integration of robotic with this processing methods. Similarly, the bioengineered chordae tendineae were fabricated using a mandrel-less deposition technique (US11680341B2), solvent welding strategies to connect valve leaflets with the chordae were evaluated during this reporting period.
Fresh human valve tissue characterization would substantially advance the field once supported by a larger data sample, we currently completed the analysis of 18 hearts, we are aiming for 30 subjects to complete the study.
The notion of double-component deposition was already considered disruptive for the field as proven by the extramural funds we received, by the successful creation of our start-up, and the positive outcomes in multiple patent submissions (e.g. issued in US - US20220039946A1, EU - EP3261584A4 and Japan - JP2023171956A). The technique was further enhanced by multiphysics simulation that allowed to predict material deposition on complex-shaped collectors and enabled a better-informed design of these collecting targets.
When completed we expect that the BIOMITRAL project and its derived BIOCORD (ERC-PoC) project will demonstrate feasibility on a clinically relevant model for a surgical MV prostheses able to better address functional regurgitation. Additional goals include: establishing fresh human heart valve functional and structural data base, advancing polymer processing technologies for anatomy inspired implantable medical devices.
The notion of double-component deposition was already considered disruptive for the field as proven by the extramural funds we received, by the successful creation of our start-up, and the positive outcomes in multiple patent submissions (e.g. issued in US - US20220039946A1, EU - EP3261584A4 and Japan - JP2023171956A). The technique was further enhanced by multiphysics simulation that allowed to predict material deposition on complex-shaped collectors and enabled a better-informed design of these collecting targets.
When completed we expect that the BIOMITRAL project and its derived BIOCORD (ERC-PoC) project will demonstrate feasibility on a clinically relevant model for a surgical MV prostheses able to better address functional regurgitation. Additional goals include: establishing fresh human heart valve functional and structural data base, advancing polymer processing technologies for anatomy inspired implantable medical devices.