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A neuroprosthesis to restore the vagal-cardiac closed-loop connection after heart transplantation

Periodic Reporting for period 2 - NeuHeart (A neuroprosthesis to restore the vagal-cardiac closed-loop connection after heart transplantation)

Reporting period: 2020-01-01 to 2021-06-30

With 3500 annual surgeries worldwide, heart transplantation is the last resort for an increasing number of patients affected by end-stage heart failure (HF). Heart transplant (HTx) can significantly increase life expectancy of HF patients but unfortunately exercise capacity and health-related quality of life of HTx recipients are still limited, due to the increased frequency of late complications mainly owing to chronotropic incompetence because of cardiac denervation. Orthotopic heart transplantation (OHT) is the most common approach of HTx, involving the complete explantation of the native heart, making surgical denervation inevitable. Therefore, the modulation of rate- and load-contractility relationship of the donor heart is significantly altered after transplantation even if using different surgical techniques. Addressing this fundamental clinical problem is the main goal of NeuHeart, that is being furthered by specifically investigating the physiology of denervated heart and developing a bioelectronic solution based on the closed-loop neuromodulation of the vagus nerve (VN), using a regenerative neural interface (for VN stimulation) and implanted artificial sensors (to record sensory information and close the loop). This integrated cardiac smart neuroprosthesis will be tested in a pre-clinical model of OHT to demonstrate the feasibility of artificially re-establising vagal control in a denervated heart, by re-enabling the cardiac-vagal connection: we expect that the overall research output of the project will deliver multiple impacts, remarkably contributing to heart transplant science (fundamental research), help in the constitution of a new treatment paradigm for heart failure (clinics and society), and reach into the emerging industry of bioelectronic medicine (technology market), guaranteeing Europe a preminent technological position into this field.
Three different designs for implantable regenerative autonomic interfaces have been produced, based on thin film technology, microchannels, and microwires. Biocompatible polymers electrospinned Neural Guidance Conduits have been produced in 3 different inner diameters, ready for testing. Further biocompatible materials and process methods are being tested for advanced Neural Guidance Conduits, as well as neural regeneration-compliant hydrogel fillers.

Implantable electronics and packaging solutions to control NeuHeart hardware are being developed by: (i)Preliminary design and tapeout of a modular 16-channel stimulator in CMOS technology; (ii) Implantable sensor readout reviews; (iii) Preliminary system level design of an implantable readout system.
A non-mechanical stiffness sensor has been developed through (i) Literature review of electrical impedance spectroscopy (EIS) towards heart stiffens monitoring; (ii) EIS system development; (iii) Preliminary design of an integrated version of the new EIS method.

Five conceptual approaches for heart activity sensors have been developed, with three approaches for epicardial implantation, and two concepts designed for implantation into the ventricular wall.

The EM modeling effort for the first year focused on (i) establishing the required technologies for modelling EM-neuron interactions in detailed, microscopy- and histology-based multifascicular nerve models, (ii) construction and exploration of initial models of vagus nerve stimulation, and (iii) performing first sensitivity analysis and uncertainty quantification work. In addition, theoretical ground work towards (iv) stimulation optimization and (v) validation has been performed.

A baseline model that reproduces cardiac dynamics in heart-failure patients was developed which forms the foundation for modelling hemodynamic changes and impairment of autonomic control in early heart transplant recipients.The baseline model was modified and extended to simulate hemodynamic changes and impairment of autonomic cardiac control that can be observed in early heart transplant recipients.The result is an integrated model, composed of the cardiovascular system, intrinsic heart rate control and autonomic regulation.

Activities aimed at full mapping of the VN, led to the establishment and implementation of a multimodal imaging pipeline combining classical histology techniques with anti-Stokes Raman scattering (CARS), optical coherence tomography (OCT), contrast enhanced micro-CT (μCT) and high-resolution episcopic microscopy (HREM). A bank of biological samples has been fully established from 4 different models.

We reviewed the most relevant literature and the prominent legislation to identify and analyse the ethical and legal issues of potential relevance for the project.In particular, attention has been devoted to ethical concerns, legal constraints and applicable regimes, regulatory gaps, economic barriers and implications for healthcare systems and barriers/business opportunities for the European medical devices industry. Research has been conducted to identify the Cardiovascular devices and Global heart transplant market and stakeholders at the EU/extra EU level to strategically target the dissemination and communication activities.
The goals of neuHeart are being furthered by pursuing the following specific objectives (SOs):
SO1: development of a fully implantable cardiac regenerative autonomic interface able to effectively stimulate the VN and promote its reconnection with the cardiac muscle, restoring the vagal-cardiac loop.
SO2: development of a new bio-mechatronic sensor to be physically interfaced with the cardiac muscle to record in real time physiological information related to heart activity.
SO3: development of implantable miniaturized electronics to: (1) provide focused, highly selective and power-efficient stimulation via the regenerative autonomic electrode; (2) acquire and process the information from the bio-mechatronic sensor; (3) harvest energy to power the implantable circuits and provide wireless communication with the external electronics.
SO4: study of the VN functional units and development of advanced (hybrid neural) multiscale electromagnetic and neuronal dynamics simulation models for the optimization of the design of the regenerative autonomic interface, assessment and optimization of stimulation selectivity and for the closed-loop control algorithms.
SO5: development of advanced models of the cardiovascular system to define the optimal stimulation strategies according to all the sensory information recorded and to the specific characteristics of the regenerative autonomic interface.
SO6: Full system integration testing in a preclinical model of denervated hearts and orthotopic heart transplantation under monitoring of cardiac function and responsiveness to adrenergic, pacing and preload stimulation.
SO7: investigation about the regulatory and ethical, legal, societal, and economic (“ELSE”) impacts related to its final goals. A revision of relevant pieces of legislation (i.e. the European regulatory scheme for implanted medical devices) will be performed in order to verify whether they address the specificities of the smart cardiac neuroprosthesis.
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