While restenosis rates in percutaneous coronary interventions have been significantly reduced following the use of drug-eluting stents (DES), the permanent implant prevents normal vessel movement and function (expansion, contraction, rotation, vasomotion) due to permanent caging of the vessel [1].

Drug-coated balloons (DCBs) were developed to avoid a permanent implant, but they don’t support the scaffolding of the vessel, particularly to prevent early recoil, and come with a set of challenges such as drug delivery restricted to the time of inflation, and that only 10% of the coating is transferred to the vessel wall [2]. At present, DCBs are predominantly used to treat in-stent restenosis, but also in small vessels [3, 4]. Newer application modalities might be the combination of DCBs with DES to reduce the amount of implanted metal and the subsequent inhibition of vasomotion and the risk of long-term events [5, 6].

Fully bioresorbable scaffolds aim to provide scaffolding to the vessel during the initial healing phase and to be resorbed thereafter, ultimately allowing vascular restoration including lumen enlargement and restoration of vascular physiology and motion [1, 7, 8]. However, they have fallen out of favor through their intrinsic mechanical properties and as outcomes have not been comparable to contemporary DES, in particular in terms of higher restenosis and device thrombosis rates [2, 7], albeit optimized treatment strategies might improve outcomes [7].

The DynamX${}^{\mathrm{\circledR }}$ Bioadaptor (Elixir Medical Corporation, Milpitas, CA, USA) has been developed to overcome these challenges, with the unique feature that allows uncaging of the vessel after in-vivo degradation of the polymer base coat, which occurs over 6 months. The expansion segments also called “uncaging elements” are designed to disengage thus unlocking the artery to allow more normal vessel movement and function as compared to DES in the stented region [9, 10].

The DynamX Mechanistic study was initiated to evaluate the safety and performance of the DynamX Bioadaptor System in patients with de novo coronary artery lesions by assessing both clinical and imaging outcomes. Clinical and imaging outcomes out to two years have been published previously [9, 11], we herein report the final 36-month data.

In addition, two preclinical studies (porcine animal studies) were conducted to obtain further insights into the consequences of the uncaging of the bioadaptor. The first study assessed positive remodelling by optical coherence tomography (OCT) imaging. Another animal study assessed the levels of gene expression of the smooth muscle cells (SMC) in the device implanted neointimal tissue that is indicative of SMC phenotype switching during the arterial injury and subsequent healing upon peripheral coronary intervention [12, 13]. The results are included in this manuscript to provide insights into the biological response seen in the DynamX Mechanistic study.

These are the first 36-month outcomes presented for the novel DynamX Bioadaptor device platform. Only one TLR occurred and no definite or probable device thrombosis were reported.

The DynamX Bioadaptor shares some advanced features with contemporary second-generation DES, i.e., it consists of ultrathin (71 µm) cobalt-chromium struts covered with a biodegradable polymer that elutes novolimus [9]. Its innovative design, however, includes uncaging elements within the bioadaptor pattern that unlock the implant and permit the improvement in vessel movement and function after in-vivo resorption of the bioresorbable polymer coating.

Thus, the DynamX Bioadaptor is the first permanent coronary artery implant designed to improve vessel function and physiology. The ability to improve the vessel function through disengagement of the uncaging elements was demonstrated at 9- to 12-month imaging follow-up [9, 10, 11] through:

(a) Positive arterial remodelling. Unlike DES, where the lumen is expected to decrease over time, the late vessel and bioadaptor expansion, measured by IVUS, compensates for the increase in neointima that occurs with DES implantation and allows for the maintenance of the lumen area that was achieved with the initial deployment (increase in in-device area from 7.39 $\pm$ 1.20 mm${}^2$ at baseline to 7.74 $\pm$ 1.46 mm${}^2$ at 9- to 12-month follow-up, p = 0.0005, increase in vessel area from 14.11 $\pm$ 2.99 mm${}^2$ to 14.54 $\pm$ 3.12 mm${}^2$, p = 0.02, and maintained lumen area with 7.39 $\pm$ 1.20 mm${}^2$ at baseline and 7.36 $\pm$ 1.31 mm${}^2$ at follow-up, p = 0.59).

(b) Improved vessel pulsatility. The vessel pulsatility in the treated segment increased in response to the cardiac cycle (46% improvement in maximum lumen area change at follow-up by IVUS), resulting in a reduction of the segmental mismatch in area compliance between the treated and untreated adjacent segments.

(c) Improved vasomotion. Vasomotion in response to nitroglycerine increased from 0.03 mm${}^2$ post-procedure to 0.17 mm${}^2$ at follow-up.

(d) Restoring angulation. There was a return towards baseline angulation at follow-up (from a mean of 137.6 $\pm$ 16.2° at baseline, over 157.5 $\pm$ 14.5° post-procedure to 149.7 $\pm$ 16.1° at 9- to 12-month follow-up, measured by quantitative coronary angiography).

(e) Reduced stress. The peak stress within the bioadaptor was reduced by 70% after uncaging, evaluated by finite element analysis.

Likewise, in a preclinical animal study with serial OCT assessment at multiple timepoints, the mean device area did only marginally change from post-procedure to 3 months, indicating the absence of acute or subacute vessel recoil. But after uncaging, at 12 and 24 months, the mean device area increased, further demonstrating the ability for positive adaptive remodelling that compensates for the neointimal growth, as seen for the lumen diameter that decreased at three months, but increased again after uncaging.

Another preclinical study showed that the neointimal covering is majorly constituted of SMCs that are not terminally differentiated and may modulate their phenotype in response to local microenvironmental changes such as vascular injury [12, 13]. An initial proliferative and dedifferentiated state of neointimal SMCs is characterized by upregulation of synthetic or activation marker genes, which eventually reverses into a low proliferative and differentiated state characterized by upregulation of contractile genes, e.g., ACTA2, DES, smooth muscle myosin heavy chain (SM-MHC), smooth muscle protein 22-$\alpha$ (SM22$\alpha$), etc. as the healing progresses to finally regain the contractile and physiological properties [16, 17, 18]. Increased expression of contractile genes in the neointima explanted from DynamX vs Xience DES-treated vessel segment at 9 months indicates faster vascular healing with a bioadaptor after uncaging compared to a caged DES [13]. This improvement in vessel function might have contributed to the good outcomes of the DynamX Mechanistic study.

Acknowledging the limitations of the small patient population enrolled in the DynamX Mechanistic study, outcomes are at least comparable to commercially available second-generation DES systems. Twelve-month data have been presented previously and reported low in-device late lumen loss (0.12 $\pm$ 0.18 mm by quantitative coronary angiography analysis), low %volume obstruction (3.39 $\pm$ 4.66% by IVUS analysis) and nearly complete neointimal coverage (98.95 $\pm$ 2.85% covered struts by OCT) [9]. The OCT data also showed sufficient neointimal growth to cover the bioadaptor struts with a thickness that is in the expected range for commercially available DES [19, 20].

At 36 months, only one CD-TLR and no additional CD-TVR occurred. The absence of any non-target lesion CD-TVR is possibly associated with the improvement in segmental compliance mismatch, reducing the irritation at the stent edges. Certainly, the CD-TLR rate of 2.2% at 36 months compares well to other contemporary DES. In the BIONYX trial, the 36-month CD-TLR rate was 4.7% for the zotarolimus-eluting Resolute Onyx stent (Medtronic, Santa Rosa, CA, USA) and 4.6% for the Orsiro sirolimus-eluting DES (Biotronik AG, Buelach, Switzerland) [21]; in the BIOFLOW-V trial, it was 3.2% for Orsiro versus 6.7% for the everolimus-eluting Xience DES (Abbott Vascular, Santa Clara, California) [22]; in the BIO-RESORT trial the 36-month CD-TLR rate ranged from 2.9% to 3.8% for the Orsiro DES, the Resolute Integrity zotarolimus-eluting stent, and the Synergy everolimus-eluting stent (Boston Scientific, Marlborough, Massachusetts) [23]; and in the TALENT trial, it was 5.0% for the Supraflex sirolimus-eluting stent (Sahajanand Medical Technologies, Surat, India) and 5.9% for Xience [24].

Noteworthy, no thrombotic events occurred (0.0% target-vessel myocardial infarction and 0.0% definite or probable device thrombosis), as compared to definite or probable stent thrombosis rates that range from 0.5% to 1.4% in the BIONYX, BIO-RESORT and TALENT trials [21, 23, 24].

In conclusion, the DynamX Bioadaptor demonstrated very good safety and performance outcomes. The 36-month TLF-rate was low with the absence of any target-vessel myocardial infarction, and only one target lesion revascularization. No definite or probable device thrombosis was reported. These outcomes are potentially related to an improved vessel function in the treated segment, as demonstrated through intracoronary imaging and as confirmed in preclinical studies with late lumen enlargement assessed by OCT and an increased expression of contractile genes around 9 months compared to a conventional DES which is indicative for vessel healing. Larger, randomized studies are necessary to corroborate these findings and to compare long-term outcomes against contemporary DES.

CD, clinically-driven; DES, drug-eluting stent; IVUS, intravascular ultrasound; OCT, optical coherence tomography; SMC, smooth muscle cells; TLF, target lesion failure; TLR, target lesion revascularization; TVF, target vessel failure; TV-MI, target-vessel myocardial infarction; TVR, target vessel revascularization.

Data are available from the corresponding author upon reasonable request, but with an embargo of 12 months.

SV, MV, MM, CD, FG, FB, BDB, and AC performed the research. SV and AC were coordinating investigators. RAC, DC, JRC, and AA were responsible for the core laboratory including the core laboratory statistical analyses. SV wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript and agreed to be accountable for all aspects of the work.

The study was approved by the ethics committees of all participating sites and all patients provided written informed consent before any study procedure. Ethics committees were: Institutional Review Board-ZNA/OCMW Antwerpen Lindendreef I, 2020 Antwerpen, Belgium (EC 5001), Comite Medische Ethiek ZOL Schiepse Bos 6, 3600 Genk, Belgium (17/079L), Ethisch Comite OLV Aalst Moorselbaan 164; 9300 Aalst, Belgium (2018/12), Ethische Commissie Onderzoek UZ/KU Leuven Herestraat 49, 3000 Leuven, Belgium (S60976), Il Comitato Etico via Olgettina, 60 - 20132 Milan, Italy (220/2017), Il Comitato Etico Via Morandi, 30 -20097 San Donato Milanese, Milan, Italy (237/2017).

We thank Beatrix Doerr, Consultant Medical Writer, for her help in preparing this manuscript, reimbursed by Elixir Medical Corporation.

This study and the publication charges were funded by Elixir Medical Corporation.

The institutions of SV, MV, MM, FG, FB, CD, BDB, AC received research funding from Elixir Medical to conduct the study, RAC, DC, JRC and AA were involved in the core laboratory. SV reports consultancy fees from Neovasc outside the submitted work and speaker fees from Elixir Medical. BdB reports consulting fees from Abbott Vascular, Boston Scientific, Medyrial, and Xenter paid to his institution. AC reports honoraria for lectures/presentations. The other authors declare no conflict of interest.