Lessons Learned, Challenges and Opportunities in Translating a Novel Autologous Pulmonary Valve Replacement—An Interim Report and Guidance for Translation

Background: Each year approximately 300,000 babies are born with a congenital heart valve defect worldwide; however, a regenerative and durable solution remains yet to be found.

Methods: To tackle this medical need, a Procedure Pack (PP) has been developed which enables the intra-operative fabrication of an autologous heart valve replacement. The PP consists of a stent, catheter delivery system, crimping tool, crosslinker and mold. Functionality and translatability were shown over 3 design and 1 concept iteration in-vitro as well as in-vivo.

Results: The first 3 design iterations utilized in-house-developed nitinol stents and delivery systems. In sheep, both iteration 1 and 2 did not achieve acceptable results over 12 months due to unfavorable valve design and crosslinking degree, resulting in median regurgitation fraction (RF) of 43% measured by MRI underlined by moderate to severe insufficiency by intracardiac echocardiography (ICE). Adjustments in valve shape and crosslinker in iteration 3 allowed fabrication of fully functional valves with median MRI RF of 8% and trivial to moderate insufficiency by ICE up to 20.5 months. These results were verified in-vitro at certified laboratory AC-Biomed. During all follow-up evaluations, no stenosis was present. Histologically, all valves showed endothelialization and favorable CD163+ macrophage infiltration. Though the third iteration was fully functioning, cost and time to maintain CE certification as per Medical Device Regulation of all five PP components made translation impossible. This urged the need to replace stent, delivery system and crimping tool with commercially available products, limiting the in-house developments to the core intellectual property, which does not yet exist on the market, namely mold and crosslinker. An acute trial in minipigs (n = 3) demonstrated the feasibility of the modification with mild insufficiency and no stenosis, measured by ICE.

Conclusion: The novel autologous pulmonary valve implant performed well up to 20.5 months, with successful adaptation to commercially available medical devices. Also, regulatory and certification costs should be considered early on through risk assessment as per ISO 14971. Prioritizing existing products and minimal in-house development with few suppliers is a possibility to facilitate device translation and certification. Further in-house developments are still being pursued by post-market introduction to enhance medical benefit. This paper provides insight into the development of medical devices from a pediatric cardiology department to overcome forced widespread off-label use of devices.

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Artikel online veröffentlicht:
13. Februar 2024