Tissue engineered heart valves: moving towards clinical translation

KEYWORDS:

• Tissue engineered heart valves
• off-the-shelf
• clinical translation
• remodeling
• self-repair capacity

Valvular heart-disease (VHD) represents a major cause of mortality around the globe [1]. In the western societies, VHD is primarily of degenerative origin, while in the developing countries, the major reason is rheumatic [2]. For more than 50 years, surgical heart valve replacement either using mechanical or bio-prosthetic heart valves has been the gold standard to treat VHD with currently approximately 250,000–300,000 replacements globally. Besides conventional open heart surgery, minimally invasive, transcatheter heart valve replacement technologies have proven to be a valid alternative for high-risk candidates not being suitable for surgery [3].

However, despite these technical advancements, the utilized prostheses either being of mechanical or nonliving bioprosthetic origin are still to be considered suboptimal [4]. While mechanical heart valve substitutes require life-long anticoagulation therapy which is well established to come with a significant, and continuously increasing risk of bleeding during a lifetime, in particular, the currently implanted, nonliving bioprosthetic substitutes are well known to have a limited durability due to progressive degeneration and calcification. Importantly, none of the mentioned valve substitutes is capable of mimicking the characteristics of a native heart valve or to provide the unique capacity to continuously adapt to the hemodynamic environment [5]. More than 25 years ago, it was Dr. D. E. Harken a pioneer in heart valve surgery who summarized in his so-called ‘Ten Commandments’ the major characteristics of the ideal heart valve substitute such as durability, absence of thrombogenicity, resistance to infections, lack of antigenicity, and the potential of growth, thereby stating the key features of native living tissues [6].

In this regard, the concept of tissue engineering has been repeatedly proposed as a promising therapy approach. A tissue-engineered heart valve (TEHV) with remodeling, self-repair, and growth capacities would eliminate the problems associated with nonliving prostheses, and thus would be particularly beneficial for congenital applications. More than 20 years ago, Langer and Vacanti [7] introduced the first tissue engineering concept, a so-called in-vitro approach comprising of three main steps: (1) cell harvest and expansion followed by (2) (stem) cell seeding onto a scaffold (which can be of allogenic, xenogenic, or synthetic origin), and completed by (3) a bio-reactor phase prior to in-vivo application [8].

Although the principal in-vivo feasibility of such in-vitro grown TEHVs has been demonstrated [9], from a clinical standpoint, this concept it appears to be technically, logistically, and financially too complex, and thus limiting its broad clinical adoption. One the other hand, this concept has substantially served as a basis for the development of numerous simplified and translational heart valve tissue engineering (HVTE) approaches which are exploring a wide range of different scaffolds technologies.

As one a less complex option, so-called decellularized xenogenic or allogenic heart valves have been repeatedly suggested as a promising starter scaffold for ‘tissue engineering’ of heart valves. Based on numerous preclinical reports, such approaches have been rapidly advanced into a clinical setting demonstrating reasonable mid-term results [10,11] and are currently under further systematic investigation in a big European FP7 initiative, the so-called ESPOIR program (http://cordis.europa.eu/project/rcn/102103_en.html).

However, despite the rapid progress with this concept, several issues remain to be further addressed: first, the use of xenogenic materials is well known to carry a risk of potential immunogenic reactions and zoonotic disease transmission. Second, the access to homografts is very limited to serve all patients in need. Third, and most importantly, the degree of host cell repopulation of such valves remains controversially discussed and needs further clarification in order to ensure their long-term remodeling capacity and durability [12].

In order to circumvent these problems, the use of biodegradable synthetic scaffolds has been repeatedly shown to be a valid and safe option for TEHVs. In a recent preclinical trial, such synthetic scaffolds have been exclusively combined with a so-called ‘in-situ tissue engineering approach’ thereby substantially simplifying the classical in-vitro HVTE approach [13]. Utilizing the body’s intrinsic potential and based on a similar experimental basis described in the setting of tissue engineered vascular grafts [14], in their recent paper, Weber et al. [13] demonstrated the principal feasibility of marrow stromal cell-based, autologous TEHV fabricated and implanted in a single-step intervention in nonhuman primates. Within less than two hours, tri-leaflet TEHVs, generated from biodegradable synthetic-scaffolds, were integrated into self-expanding nitinol-stents, seeded with autologous bone-marrow mononuclear cells, crimped and delivered in a minimally invasive, transapical fashion as pulmonary valve replacements. Its feasibility, safety, and substantial remodeling capacity proven in the pulmonary circulation, the concept was advanced into the high-pressure aortic system and is currently under further investigation [15–17].

However, while this single-step in-situ HVTE approach may represent a substantial step toward clinical relevance, it still requires the utilization of autologous (stem) cell seeding onto the scaffolds. Thus, from the logistical standpoint, such a concept would still require a complex infrastructure for direct cell isolation, preparation, and seeding prior to implantation. Further, it is to mention that besides the principal ongoing debate about the need of cells in the context of in-situ HVTE at all, such concepts also do strongly depend on the cell quality and the intrinsic regenerative potential of each individual donor which may vary according to the underlying health profile.

Therefore, to further simplify HVTE concepts toward clinical translation, a so-called ‘off-the-shelf’ solution would be even more preferable. In this context, an interesting strategy was recently introduced utilizing so-called off-the-shelf human cell-based decellularized tissue-engineered heart valves (dTEHVs) with self-repair and remodeling capacity [18].

Next, in a recent proof-of-concept study using nonhuman primates, such dTEHVs were transapically delivered as pulmonary valve replacements and demonstrated functionality for up to eight weeks. Remarkably, such valves displayed a substantial capacity of extracellular matrix formation and endothelialization being comparable to their native counterparts [19]. In line with these findings, Driessen-Mol and colleagues further underlined the huge potential of such dTEHVs as pulmonary valve replacements in a long-term investigation using an ovine model. In this study, significant recellularization, self-repair capacity, as well as elastic fiber formation could be observed after six months in vivo. On the other hand, the functionality of the implanted dTEHVs worsened over time due to a decline in leaflet co-aptation which was most likely related to a suboptimal valve design [20]. However, the optimization of the valve design was part of a systematic investigation in a recent European Research Initiative (EU FP7 Program ‘LiveValve’, grant no: 242008; http://cordis.europa.eu/result/rcn/55151_en.html) and results from this consortium are expected in the near future.

The huge clinical potential of this off-the-shelf technology was further highlighted by the recent work of Syedain and colleagues evaluating such valves as surgically implanted aortic valve replacements in an ovine model. In addition to an observed appropriate valve function throughout the entire study course, the authors detected a substantial capacity of extracellular matrix formation including elastin, recellularization with interstitial-like cells, and endothelialization and thus considered these findings as unprecedented results for an off-the-shelf tissue-engineered aortic valve [21]. Besides that, another interesting off-the-shelf concept is currently under investigation in an ongoing European FP7 framework program focusing on so-called ‘Intelligent materials for in-situ heart Valve tissue engineering’ (IMAVALVE; http://cordis.europa.eu/project/rcn/110963_fr.html).

However, and despite the current excitement about off-the-shelf solutions that may substantially simplify previous classical HVTE approaches, several key issues need to be addressed [22]. Besides its long-term efficacy proven, in particular, clinical guidelines and safety monitoring protocols need to be defined in order to prevent or allow the early detection of potential failures. This is particularly important given the fact that such off-the-shelf concepts completely rely on the recipients’ individual remodeling and regeneration capacity which may vary substantially between patients [23]. Therefore, the implementation of quality and safety tools (i.e. valve-on-chip strategies) as well as the incorporation of patient-specific solutions (i.e. 3D-printing technologies) is mandatory in order to enhance the clinical safety and quality profile of such valves.

In summary, in the last few years, several important milestones have been achieved in the field of HVTE with a major focus on the significant simplification of current concepts toward clinical translation. In particular, so-called in-situ and off-the-shelf approaches are of particular interest for their clinical potential and are currently under systematic investigation in several multicenter research initiatives. However, despite these advances, several key issues in regard to safety and logistics need to be addressed in order to make HVTE a broad clinical reality in the near future.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.