Living-Engineered Valves for Transcatheter Venous Valve Repair

Abstract

Background: Chronic venous insufficiency (CVI) represents a major global health problem with increasing prevalence and morbidity. CVI is due to an incompetence of the venous valves, which causes venous reflux and distal venous hypertension. Several studies have focused on the replacement of diseased venous valves using xeno-and allogenic transplants, so far with moderate success due to immunologic and thromboembolic complications. Autologous cell-derived tissue-engineered venous valves (TEVVs) based on fully biodegradable scaffolds could overcome these limitations by providing non-immunogenic, non-thrombogenic constructs with remodeling and growth potential. Methods: Tri-and bicuspid venous valves (n = 27) based on polyglycolic acid-poly-4-hydroxybutyrate composite scaffolds, integrated into self-expandable nitinol stents, were engineered from autologous ovine bonemarrow-derived mesenchymal stem cells (BM-MSCs) and endothelialized. After in vitro conditioning in a (flow) pulse duplicator system, the TEVVs were crimped (n = 18) and experimentally delivered (n = 7). The effects of crimping on the tissue-engineered constructs were investigated using histology, immunohistochemistry, scanning electron microscopy, grating interferometry (GI), and planar fluorescence reflectance imaging. Results: The generated TEVVs showed layered tissue formation with increasing collagen and glycosaminoglycan levels dependent on the duration of in vitro conditioning. After crimping no effects were found on the MSC level in scanning electron microscopy analysis, GI, histology, and extracellular matrix analysis. However, substantial endothelial cell loss was detected after the crimping procedure, which could be reduced by increasing the static conditioning phase. Conclusions: Autologous living small-diameter TEVVs can be successfully fabricated from ovine BM-MSCs using a (flow) pulse duplicator conditioning approach. These constructs hold the potential to overcome the limitations of currently used non-autologous replacement materials and may open new therapeutic concepts for the treatment of CVI in the future.

Fibrous scaffolds for building hearts and heart parts

“…These 3D fibrous valve scaffolds support cell culture and matrix remodeling in response to physiologically-relevant flows and pressures when cultured in vitro [240] or in vivo [241]. Implantation of non-endothelialized heart valve constructs into non-human primates resulted in nearly confluent endothelialization after just 4 weeks in vivo [242], suggesting that endothelialization prior to implantation may not be necessary.…”

“…It may also be possible to implant these scaffolds using minimally invasive procedures. For example, Weber et al [240] confirmed that the structure of tissue engineered valves based on a synthetic biodegradable PGA/polyester composite matrix was not affected by crimping, suggesting the feasibility of stented, catheter implantation. Although further study is required to assess the long-term function of these scaffolds in vivo, mounting evidence suggests that cell-free or minimally tissue engineered personalized valve scaffolds can provide immediate functional restoration with the potential for in vivo remodeling and improved host integration.…”

Repair of Saphenofemoral Transition: Reşat Operation for Patients With Venous Reflux

“…13 Similar recommendations are observed in the Clinical Practice Guidelines of the European Society for Vascular Surgery. 14 On the other hand, it is possible to find some innovative interventions in the literature such as the use of cryopreserved vein valves 15 or tissue-engineered valves 16 to solve the problems with the incompetent venous valve. Unfortunately, those studies have reported unsuccessful outcomes.…”

Bioengineered living cardiac and venous valve replacements: current status and future prospects

“…A tissue engineered venous valve solution could overcome these limitations and mainly allow for autologous thromboresistant (endothelialized) implants. In a first experimental in vitro trial, tri-and bicuspid TEVVs have been generated based on the in vitro tissue engineering approach [69]. TEVVs were engineered from autologous bone marrow-derived MSCs and subsequently endothelialized showing layered tissue formation analogous to native valvular tissues [69].…”

“…In a first experimental in vitro trial, tri-and bicuspid TEVVs have been generated based on the in vitro tissue engineering approach [69]. TEVVs were engineered from autologous bone marrow-derived MSCs and subsequently endothelialized showing layered tissue formation analogous to native valvular tissues [69]. The feasibility of using the tissue engineering technique for the generation of future TEVVs for the treatment of CVI has been demonstrated as part of this first study.…”