Coronary Drug-Coated Balloons as Brief-Contact Drug-Delivery Platforms: Engineering, Tissue Pharmacokinetics, and Angiographic/Imaging Response

1. Introduction

Drug-coated balloon angioplasty differs from drug-eluting stenting because treatment is delivered without a persistent scaffold or polymer reservoir. Whereas DES elute drug over days to months, DCBs must achieve transfer, mural penetration, and tissue retention during a 30–60-second inflation [1]. This narrow window makes the initial device-vessel interaction decisive: coating stability, release kinetics, wall contact, acute transfer, and post-transfer retention all interact with drug pharmacology [1,2,3].

The biological effect of DCBs is determined by drug physicochemistry, excipient microstructure, coating resilience during tracking, balloon expansion and apposition, tissue uptake, and washout. Failure at any step can reduce effective dose and influence late lumen loss, binary restenosis, target-lesion revascularization, and remodeling [1,4,5,6,7,8,9]. Accordingly, nominal drug load and active drug class are incomplete descriptors of performance; the same drug may behave differently when paired with different excipients, coating architectures, carrier systems, or release mechanisms.

1.1. Objective of This Review

This review synthesizes experimental, computational, pharmacological, biomechanical, imaging, and clinical evidence into a mechanistic framework for platform-specific DCB behavior. The emphasis is technological rather than algorithmic: drug chemistry, excipient science, coating engineering, balloon-artery mechanics, tissue pharmacokinetics, imaging correlates, and outcome studies are used to define determinants of DCB success or failure.

2. Scope and Synthesis Approach

This narrative review integrates preclinical, mechanistic, pharmacokinetic, imaging-based, randomized, registry-based, and meta-analytic studies relevant to coronary DCB platform engineering and angiographic/imaging response. Evidence is synthesized qualitatively because bench models, computational methods, device platforms, tissue-retention experiments, imaging endpoints, and trial designs are heterogeneous. Mechanistic observations and clinical outcomes are kept conceptually distinct: bench and computational studies define transfer physics and drug-loss pathways; pharmacokinetic studies define mural exposure; imaging studies characterize remodeling and dissection healing; and clinical trials test angiographic or clinical translation.

This review was designed as a narrative mechanistic synthesis rather than a systematic review. PubMed/MEDLINE and major interventional cardiology trial sources were searched for studies addressing coronary DCB coating technologies, drug-transfer mechanisms, preclinical pharmacokinetics, computational delivery models, intravascular imaging correlates, and randomized or comparative clinical evidence. Priority was given to studies reporting named platforms, device-specific coating or carrier characteristics, quantitative drug-transfer or retention data, and angiographic or imaging endpoints relevant to platform performance.

To preserve a mechanistic rather than broadly clinical focus, quantitative evidence is organized by delivery layer: coating survival, tracking loss, excipient-lesion interaction, tissue-reservoir strategy, imaging-defined remodeling, and lesion-specific translation. This structure emphasizes named-platform behavior and avoids overgeneralization from drug class alone.

3. Mechanistic Foundations of DCB Therapy

3.1. Drug Physicochemistry as a Design Constraint

Drug physicochemistry is central to DCB performance, but it functions as a design constraint rather than as the sole determinant of efficacy. Unlike DES, DCBs must transfer, distribute, and retain drug after brief balloon-artery contact. Lipophilicity, membrane partitioning, intracellular target engagement, tissue binding, particulate or carrier behavior, and washout kinetics influence how much delivery support each platform requires [1,5,10,11,12,13].

Paclitaxel has physicochemical and intracellular properties compatible with brief-contact transfer, including high lipophilicity, tissue partitioning, and microtubule binding [10,11]. These properties may make paclitaxel platforms relatively tolerant of short-contact delivery, but only if sufficient drug reaches relevant mural compartments. The magnitude, distribution, and persistence of tissue effect remain dependent on coating architecture, excipient behavior, lesion preparation, wall contact, and washout. Paclitaxel should therefore not be treated as intrinsically effective independent of platform design.

Limus drugs are potent antiproliferative agents, but their use in DCBs usually requires explicit engineering to support tissue entry and post-contact exposure. Contemporary limus platforms use carrier-mediated uptake, crystalline deposition, phospholipid encapsulation, porous infusion, biodegradable micro-reservoirs, or related persistence-oriented strategies [12,13,14,15,16,17,18,19]. Heterogeneity among sirolimus and other limus balloons likely reflects both engineering diversification and uneven evidence maturity across distinct delivery architectures, not a single limus-class effect.

Direct preclinical comparisons should be interpreted at the platform and model level. In a porcine coronary study comparing MagicTouch sirolimus-coated balloon (SCB), SELUTION SLR SCB, AGENT paclitaxel-coated balloon (PCB), and plain old balloon angioplasty (POBA), all DCBs were associated with minimal neointimal formation in that model, but distal findings differed: embolic material was reported in 15%, 25%, 36%, and 6% of histological sections, respectively, and downstream myocyte necrosis/scarring was observed in 21% of paclitaxel-balloon sections but not in the other groups [13]. These are hypothesis-generating porcine safety and distribution signals; they should not be extrapolated directly to clinical harm.

A platform-level evaluation should distinguish antiproliferative efficacy from vascular-healing and downstream-safety interfaces. Paclitaxel provides favorable short-contact pharmacological features, but particulate transfer, off-target loss, downstream exposure, local cytotoxicity, and delayed healing remain relevant mechanistic considerations [10,13]. Conversely, limus drugs may offer a cytostatic and potentially more healing-compatible biological profile, but only if the platform compensates for less favorable passive tissue retention through engineered delivery or reservoir-based release [14,15,16,17,18]. Local efficacy and vascular response derive from how drug, excipient, carrier, and coating behave during tracking, inflation, tissue entry, retention, and washout [4,6,8,9,20,21,22].

3.2. Tissue Pharmacokinetics and Effective Dose

In balloon-based delivery, nominal drug load is not equivalent to biologically active mural exposure. Loaded dose, coating retained after delivery, drug released at inflation, drug transferred into the vessel wall, drug retained over time, and effective exposure are distinct quantities. Coating may be lost during handling, guide-catheter and guide extension passage, tortuous tracking, lesion crossing, balloon expansion, deflation, withdrawal, or early washout [4,6,8,9,20].

Clinically relevant exposure is best conceptualized as the fraction of drug that reaches and persists in biologically relevant mural compartments long enough to influence restenotic biology. Because inhibitory thresholds are not routinely defined for each named coronary platform, nominal surface dose should not be used as a surrogate for effective local exposure.

Bench and translational data illustrate pre-lesion and off-target variability. In standardized robotic abrasion testing of eight DCBs, visible coating loss ranged from 2.25% to 45.73% in the deflated state and from 1.66% to 40.41% after inflation [20]. These data indicate large between-device differences in mechanical vulnerability, but they are not direct coronary tissue-transfer or pharmacokinetic measurements.

In a combined in vivo, benchtop, and in silico bend-tracking model, passage over a single steep bend produced approximately 30% loss of nominal paclitaxel-coated balloon load, compared with approximately 1% during device insertion alone. Mass-balance analysis estimated that 45.5 ± 11.1% of nominal load was lost to systemic plasma during tracking and that 39 ± 11.1% was available for friction-mediated upstream delivery [6]. Upstream arterial samples contained 1,565.8–10,286.6 ng/g paclitaxel, corresponding to 5.4–46.5% of target-site concentrations, and plasma concentrations peaked immediately after tracking before declining after inflation [6]. These findings show that tracking loss can alter drug destination, but the values are model- and geometry-specific rather than universal coronary constants.

Effective dose should therefore be treated as a post-handling, post-tracking, post-release, and post-transfer variable. The relevant question is how much drug remains available at the treated segment, enters the vessel wall, and persists in biologically active form.

3.3. Transmural Distribution and Lesion Dependence

Drug distribution within the arterial wall is heterogeneous and modified by lesion substrate. Atherosclerotic tissue can alter uptake, wall adhesion, intramural diffusion, binding, and washout in an excipient- and platform-dependent manner [21,22]. Computational models can identify mechanisms and generate hypotheses, whereas imaging and clinical studies test downstream associations.

In an excipient-plaque model, a urea-based formulation simulated higher tracking loss than a butyryl-trihexyl citrate comparator (35.5% vs 8.13%) but higher modeled arterial uptake, while calcified and non-calcified atheroma altered transmural propagation and retentive potential [22]. The conclusion is not that higher tracking loss is desirable; rather, coating preservation and modeled tissue bioavailability can become uncoupled through excipient-lesion interactions.

Clinical and imaging data support the relevance of lesion substrate but should be interpreted as associative unless tested prospectively. In an optical coherence tomography/optical frequency-domain imaging (OCT/OFDI) analysis of 328 de novo DCB-treated lesions, target-lesion failure occurred in 9.5% and was independently associated with haemodialysis, greater maximum calcium arc per 90-degree increment, and absence of post-percutaneous coronary intervention (PCI) medial dissection [23]. These findings link calcific burden and procedural morphology to DCB outcomes, but they do not prove a single pharmacokinetic mechanism. Within the same imaging framework, lower event rates were observed when maximum calcium arc was <180°, although calcium thickness, longitudinal calcium length, circumferential distribution, and the feasibility of plaque modification should also be considered as determinants of expansion, contact uniformity, and drug access [23].

4. Excipient Chemistry and Adhesion Switching

Excipients are functional delivery components, not passive additives. Without a permanent polymer reservoir, they must help preserve coating during delivery, permit rapid or triggered release during inflation, and support local drug availability after deflation [4,8,9,24,25]. In paclitaxel DCBs, excipients influence coating cohesion, shear resistance, dissolution behavior, particle detachment, tissue adhesion, and washout.

Hydrophilic excipients can promote rapid release and acute transfer. Iopromide-based paclitaxel formulations, exemplified by the Paccocath/SeQuent Please lineage, established the benchmark rapid-transfer concept in coronary DCB therapy [1,24]. Bench studies suggest that hydrophilic coating microstructure can alter acute drug transfer during inflation [8], but direct clinical correlates remain indirect. Rapid release is beneficial only if enough coating survives delivery; otherwise, payload may be lost before lesion arrival or dispersed off target [4,6,20].

Urea-based and other hydrophilic systems support local deposition through formulation- and expansion-dependent interactions with the vessel surface [8,25]. Hydrophobic, plasticizer-based, butyryl-tri-hexyl citrate (BTHC)-containing, and resin-based formulations attempt to improve cohesion, reduce premature loss, and preserve drug availability until lesion contact [25]. These approaches should be interpreted as platform-level engineering strategies rather than interchangeable paclitaxel-class properties.

The AGENT platform provides a clinical anchor for the nominal-dose argument, but not direct proof of microstructural mechanism. In AGENT IDE, a 2 µg/mm² paclitaxel-coated balloon reduced 1-year target-lesion failure versus uncoated balloon angioplasty in coronary in-stent restenosis (ISR) (17.9% vs 28.7%), with lower target-lesion revascularization (13.0% vs 24.7%), target-vessel myocardial infarction (5.8% vs 11.1%), and definite/probable stent thrombosis (0% vs 3.2%) [26]. These data show that a lower nominal paclitaxel dose can be clinically effective within a functioning platform, but they do not identify the precise coating-transfer mechanism.

Resin-based systems, including shellac-ammonium matrices, represent another approach to balancing stability and release. Comparative in vitro and in vivo evaluation of a shellac-ammonium paclitaxel-coated balloon versus a benchmark device supports that excipient composition and coating morphology can affect wash-off, acute transfer, and biological response even with the same active drug [27]. These data are translational and should not be converted into claims of clinical superiority without clinical outcome evidence.

Adhesion switching summarizes the central excipient trade-off: a coating must be cohesive during tracking yet releasable during inflation. Fragile coatings may lose drug before lesion arrival, whereas overly stable coatings may release too little during balloon-vessel contact [4,6,9,20,28]. Robotic abrasion and bend-tracking studies provide quantitative evidence that this trade-off can be large, but the values are method-, device-, and geometry-dependent [6,20]. Coating stability should therefore be discussed together with releasability, tissue transfer, retention, and clinical readouts.

5. Coating Morphology and Mechanical Stability

Coating morphology determines how much drug remains available at the lesion and how efficiently it is deposited during inflation. In paclitaxel systems, deposition methods and solvent-excipient combinations generate morphologies ranging from needle-like crystalline structures to smoother amorphous or semi-amorphous coatings, with consequences for cohesion, particulate loss, acute transfer, and tissue deposition [4,8,9,20].

Crystalline paclitaxel coatings may create a high local reservoir and facilitate particulate deposition, but brittle crystalline domains can fragment during handling, advancement, or expansion, leading to premature loss and particle shedding [4,20]. Amorphous or semi-amorphous coatings may improve mechanical integrity and reduce pre-inflation loss, depending on excipient and manufacturing process. Thus, the key variable is not crystallinity alone but the balance between payload preservation and triggered release [4,8,9,20]. At the same time, paclitaxel particulate/crystalline deposition can enhance tissue uptake and prolonged arterial retention after transfer; Granada et al. linked paclitaxel-coated balloon efficacy to tissue uptake, retention, and local particulate/crystalline persistence, supporting crystallinity as a retention-favoring feature when transfer is controlled [29].

For sirolimus balloons, coating or carrier morphology is often essential for delivery success because post-contact exposure must be sustained despite less favorable passive retention. The coating must provide particulate embedding, controlled release, carrier-mediated uptake, or reservoir-like persistence [13,14,15,16,17,18]. In the eight-device robotic abrasion model, three phenotypes were observed: minimal abrasion in both deflated and inflated states, abrasion mainly after balloon expansion, and marked abrasion in both states [20]. This taxonomy distinguishes coatings protected during tracking but releasable after unfolding from coatings vulnerable before inflation.

5.1. Resistance to Shear and Particle Loss

Mechanical stress testing shows that drug loss can occur during sheath passage, guide-catheter manipulation, lesion crossing, tortuous tracking, balloon expansion, and withdrawal. Off-target loss is amplified at bends or high-friction segments, making mechanical stability a determinant of target-lesion dose [6,20]. Lost drug no longer contributes to local antiproliferative effect and may redistribute upstream or systemically.

Tscheuschner et al. demonstrated that upstream arterial samples contained 1,565.8–10,286.6 ng/g paclitaxel, corresponding to 5.4–46.5% of target-site concentrations, while plasma concentrations peaked immediately after tracking and fell roughly 30-fold after inflation [6]. Tracking loss is therefore not simply reduced efficacy; it changes the spatial destination of drug.

5.2. Retention-Oriented Architecture in Sirolimus DCBs

Sirolimus DCB performance depends on whether the platform can generate sufficient tissue entry and sustain local exposure after balloon removal. Because passive brief-contact retention is less favorable for limus drugs than for paclitaxel, contemporary limus platforms rely on crystalline surface depots, nanoparticle encapsulation, phospholipid carriers, biodegradable micro-reservoirs, or porous pressure-driven infusion [13,14,15,16,17,18,19].

These architectures should be interpreted separately. Crystalline sirolimus coatings aim to deposit a temporary mural reservoir; nanoparticle and phospholipid systems aim to improve transit stability, wall deposition, uptake, and delayed release; poly(lactic-co-glycolic acid) (PLGA) micro-reservoir systems distribute drug-loaded biodegradable reservoirs across the vessel surface; and porous pressure-driven systems deliver liquid drug through micropores rather than relying on a conventional external coating [15,17,18,19].

Early clinical signals remain architecture-specific. In SABRE, a porous pressure-driven sirolimus system for coronary ISR enrolled 50 patients and yielded 6-month late lumen loss of 0.31 ± 0.52 mm in the intention-to-treat population and 0.12 ± 0.33 mm per protocol, with binary restenosis 19.1% and 1-year target-lesion failure 12.2% [17]. A microsphere-based sirolimus technology in 56 de novo or restenotic lesions reported 6-month late lumen loss of 0.26 ± 0.45 mm, binary restenosis in 4 of 45 angiographic follow-up cases, and one late target-lesion revascularization (TLR) event [19]. These values should not be pooled as generic sirolimus DCB evidence.

Crystalline sirolimus platforms now have randomized coronary data in both de novo lesions and DES-ISR, but the evidence remains named-platform specific. In a 70-patient randomized de novo coronary trial, SeQuent SCB, a crystalline sirolimus-coated balloon with 4 µg/mm² sirolimus and butylated hydroxytoluene (BHT) excipient, was compared with SeQuent Please NEO, a paclitaxel-coated balloon with 3 µg/mm² paclitaxel. At 6 months, in-segment late lumen loss was 0.04 ± 0.39 mm with PCB and 0.11 ± 0.37 mm with SCB; the mean SCB–PCB difference was 0.07 mm (95% confidence interval (CI) -0.12 to 0.26), meeting the prespecified noninferiority margin of 0.35 mm. Clinical events through 12 months were infrequent and not different, with three TLRs after PCB and two after SCB, and no myocardial infarctions or deaths. This trial supports feasibility and angiographic noninferiority of this crystalline SCB platform in selected de novo lesions after successful lesion preparation, but it was not powered for clinical outcomes and should not be generalized to all sirolimus DCB architectures [30]. Mechanistic OCT data provide a platform-specific imaging correlate: acute transfer and persistence of crystal-like sirolimus deposits have been visualized after SeQuent SCB angioplasty, and the focal, segmental, or circumferential extent of deposits may be associated with more favorable longer-term angiographic response; this should be interpreted as SeQuent SCB-specific crystalline-deposit evidence rather than a general SCB property [31,32].

In DES-ISR, a combined analysis of two parallel randomized trials compared SeQuent SCB with SeQuent Please / SeQuent Please NEO PCB in 101 patients. Six-month in-segment late lumen loss was 0.25 ± 0.57 mm with PCB and 0.26 ± 0.60 mm with SCB; the mean SCB–PCB difference was 0.01 mm (95% CI -0.23 to 0.24), also meeting the prespecified noninferiority margin of 0.35 mm. Twelve-month clinical outcomes did not differ significantly, including TLR (16% vs 10%), major adverse cardiac events (MACE; 18% vs 14%), death (2% vs 2%), myocardial infarction (MI; 0% vs 2%), and stent thrombosis (0% vs 2%) for SCB versus PCB, respectively. These findings support this crystalline sirolimus platform in DES-ISR, but the conclusion should remain restricted to the investigated device because the authors noted variability between regional cohorts and limited transferability to other SCB technologies [33].

5.3. Coating Uniformity and Device-Level Consequences

Coating uniformity improves reproducibility of drug transfer. Homogeneous coatings support predictable balloon-tissue contact and release, whereas heterogeneous or brittle coatings can create focal loss, particulate shedding, and underdosing. Efficacy depends on adequate exposure across the treated segment, not a high average dose with poor spatial consistency [4,8,9,28].

Even within paclitaxel platforms, identical drug class does not guarantee identical angiographic phenotype. In a head-to-head ISR comparison of two paclitaxel balloons with different coating strategies, IN.PACT Falcon showed lower in-segment late lumen loss than DIOR (-0.03 ± 0.43 vs 0.36 ± 0.48 mm; p=0.014), higher distal fractional flow reserve (FFR) at follow-up (0.92 ± 0.07 vs 0.84 ± 0.13), and divergent neointimal-volume trajectories (-16% vs +30%) [24]. This is clinical-translational evidence that coating strategy can modify angiographic and functional response despite the same active drug.

Long-term clinical comparison of Agent PCB and SeQuent Please PCB provides additional device-level evidence within the paclitaxel family. In a 7-year DES-ISR analysis, 262 patients with 323 DES-ISR lesions were treated with either Agent PCB (125 patients, 151 lesions) or SeQuent Please PCB (137 patients, 172 lesions). The 7-year risks of TLR, death, MI, and target-lesion thrombosis did not differ significantly between Agent and SeQuent Please. TLR occurred in 43.2% versus 35.9% (hazard ratio (HR) 1.29, 95% CI 0.87–1.90; p=0.205), death in 26.8% versus 20.2% (HR 1.38, 95% CI 0.82–2.35; p=0.227), MI in 5.9% versus 5.2% (HR 1.10, 95% CI 0.39–3.15; p=0.852), and target-lesion thrombosis in 1.6% versus 0.7% (HR 2.18, 95% CI 0.20–24.10; p=0.523) [34].

These findings should be interpreted cautiously because the SeQuent Please group served as a historical control and procedural differences were present. Vessels and DCB diameters were larger in the Agent group, lesion preparation was more frequent with Agent, and optical coherence tomography (OCT) was used in 23.2% of Agent-treated lesions but in none of the SeQuent Please lesions. The study therefore supports paclitaxel platform heterogeneity while illustrating that comparisons between named devices must consider lesion preparation, imaging use, historical controls, and follow-up strategy [34].

6. Balloon-Vessel Contact Mechanics and Lesion Substrate

DCB efficacy also depends on lesion environment. Calcium burden, plaque composition, neointimal architecture, vessel geometry, lesion length, vessel size, tortuosity, and procedural injury influence apposition, contact-pressure distribution, penetration, tissue disruption, and early retention [1,6,7,21,22,23]. Lesion morphology is therefore an engineering constraint on drug delivery, not merely a clinical descriptor.

ISR provides a scaffolded environment in which acute recoil is constrained, but ISR remains biologically heterogeneous. Bare-metal stent restenosis and DES restenosis differ in neointimal composition, cellularity, lipid content, neoatherosclerosis, calcific change, inflammatory activity, and lesion distribution, all of which may influence transfer and restenosis suppression [1,24,26,33,34]. De novo lesions add recoil control, dissection management, and maintenance of acute luminal gain without a scaffold. Small-vessel disease is particularly sensitive to modest late lumen loss because small absolute reductions in lumen diameter can become clinically relevant restenosis [1,35,36,37,38,39,40].

Calcified lesions are a plausible example of substrate-limited DCB delivery because calcium can impair expansion, contact uniformity, and drug access to the arterial wall. Current coronary evidence is mainly associative and imaging-based. In an OCT/OFDI analysis of 328 de novo DCB-treated lesions, target-lesion failure occurred in 9.5% and was independently associated with haemodialysis, greater maximum calcium arc per 90-degree increment, and absence of post-PCI medial dissection [23]. These findings link calcium burden and procedural morphology to outcome but do not prove a single drug-delivery mechanism.

Plaque-modifying strategies, including scoring balloons, cutting balloons, atherectomy, and intravascular lithotripsy, may improve acute lumen gain, calcium modification, and contact uniformity before DCB delivery [1,41,42]. The evidentiary status varies by lesion subset and study design; these approaches should be presented as lesion-preparation tools that may support DCB delivery rather than as universal requirements.

Bifurcations impose asymmetric wall contact, variable side-branch ostial coverage, altered flow, repeated device manipulation, and heterogeneous injury. DCB-BIF provides randomized evidence for a specific bifurcation setting: simple true bifurcation lesions treated with provisional main-vessel stenting in which the side branch remained severely compromised after main-vessel stenting and first proximal optimization. The trial included Medina 1,1,1; 0,1,1; or 1,0,1 lesions with main-vessel and side-branch reference diameters ≥2.5 mm, side-branch lesion length <10 mm, and ostial side-branch diameter stenosis ≥70% after main-vessel stenting. Patients were randomized to side-branch DCB or noncompliant balloon (NCB) angioplasty, and rescue side-branch stenting was reserved for type C dissection or Thrombolysis in Myocardial Infarction (TIMI) flow <3 [43].

In this setting, DCB-BIF randomized 784 patients to DCB (n=391) or NCB (n=393) treatment of the compromised side branch. The 1-year primary composite endpoint of cardiac death, target-vessel MI, or clinically driven target-lesion revascularization occurred in 7.2% versus 12.5% (HR 0.56, 95% CI 0.35–0.88; p=0.013), driven mainly by fewer myocardial infarctions. Procedural success, crossover to a 2-stent strategy, all-cause death, revascularization, and stent thrombosis did not differ significantly. These data support side-branch DCB angioplasty as a bifurcation-specific strategy, not as broad evidence for all de novo coronary DCB use [43].

Several limitations reinforce this narrow interpretation. Operators were not blinded, complex bifurcations were excluded, sirolimus-coated balloons were not tested, intravascular imaging and physiology were not used systematically, and high rates of periprocedural MI were described as early and of unclear clinical significance [43]. Bifurcation evidence should therefore remain tied to side-branch optimization after provisional main-vessel stenting.

Tortuosity, angulation, long lesions, and ostial segments may also increase coating loss or create spatially inconsistent transfer [6,7,21,22]. DCB performance depends on whether a named platform can deliver and retain sufficient drug within the mechanical and biological environment of the treated segment.

7. Technology Taxonomy of Contemporary Coronary DCB Platforms

A useful classification of coronary DCBs should group devices by the delivery problem they solve. Each platform must preserve drug during delivery, release it during brief inflation, and maintain biologically effective exposure after deflation [1,4,6,8,9]. Table 1 summarizes a platform taxonomy based on delivery architecture rather than drug label alone.

First, benchmark rapid-transfer paclitaxel platforms, represented by the Paccocath/SeQuent Please lineage, address brief-contact therapy through rapid coating dissolution, early tissue transfer, hydrophobic sequestration, and durable antiproliferative effect [1,24,44]. Their angiographic and clinical readouts include low late lumen loss, reduced restenosis, reduced repeat revascularization in ISR, and late lumen enlargement in selected de novo lesions.

Second, modified paclitaxel platforms retain paclitaxel but alter excipient composition, coating architecture, dose density, or surface morphology. Urea-based, hydrophilic, hydrophobic, plasticizer-based, and resin-based strategies test whether handling stability, washout resistance, transfer efficiency, and spatial uniformity can be optimized while preserving paclitaxel pharmacology [9,25,26,27,28,34]. Their readouts should be interpreted as platform-specific rather than proof that all paclitaxel balloons behave similarly. Representative named platforms and their engineering features are summarized in Table 2.

Third, carrier-enabled limus platforms address less favorable passive uptake and shorter effective tissue exposure after brief contact. Phospholipid-based systems, nano-encapsulated sirolimus approaches, and porous-balloon delivery concepts rely on engineered uptake support, carrier-mediated transfer, or pressure-assisted penetration [13,15,16,18]. Fourth, reservoir- or persistence-oriented limus systems, including crystalline coatings, micro-reservoir concepts, PLGA carriers, and related sustained-release technologies, aim to maintain mTOR inhibition by creating a temporary local depot [13,14,15,16,17,18,19].

A porous pressure-driven sirolimus balloon [17], a microsphere- or micro-reservoir-based sirolimus balloon [19], a phospholipid/nanocarrier sirolimus balloon [18,36], and a crystalline sirolimus-coated balloon [30,33] all share a limus payload, but differ in pre-inflation drug location, interface crossing, and post-removal exposure. This taxonomy explains why DCB evaluation must remain device- and platform-specific.

8. Angiographic and Imaging Readouts of Delivery Performance

Angiographic and clinical behavior is the downstream expression of platform engineering and lesion-device interaction. Late lumen loss, binary restenosis, late lumen enlargement, dissection healing, and target-lesion revascularization reflect coating survival, acute transfer, spatial distribution, tissue retention, lesion preparation, and wall response [1,4,6,7,8,9,21,23]. These mechanistic domains and their angiographic/imaging correlates are summarized in Table 3.

8.1. Late Lumen Loss, Binary Restenosis, and Remodeling

Late lumen loss integrates acute luminal gain, neointimal proliferation, recoil, and remodeling. Low or negative late lumen loss is compatible with adequate tissue exposure and durable antiproliferative effect, but it is also influenced by lesion preparation, vessel size, calcium, apposition, coating loss, dissection pattern, tissue retention, and follow-up methodology [6,7,21,22,23]. Binary restenosis represents the threshold consequence of insufficient transfer, inadequate retention, focal underdosing, recoil, negative remodeling, or proliferative rebound.

Late lumen enlargement is a measurable remodeling phenotype in selected paclitaxel DCB cohorts. Kleber et al. reported minimum lumen diameter increase from 1.75 ± 0.55 to 1.91 ± 0.55 mm at 4.1 ± 2.1 months in 58 de novo lesions, with 69% of patients showing net enlargement [45]. Intravascular ultrasound (IVUS) data by Yamamoto et al. identified late lumen enlargement in 74.1% of 54 lesions at 9 months, linked to vessel enlargement and plaque regression; OCT analyses have also characterized late lumen enlargement after paclitaxel-coated balloon treatment, including an OCT/OFDI study that found late lumen enlargement in 40.7% of 108 lesions and associated it with layered plaque and extensive medial dissection [46,47,48]. These imaging observations should be interpreted as remodeling phenotypes and hypothesis-generating mechanistic correlates, not as proof of a single drug-mediated pathway.

Foundational de novo small-vessel trials provide important angiographic context. In BELLO, 182 patients with lesions in small vessels were randomized to paclitaxel drug-eluting balloon or paclitaxel-eluting stent. In-balloon/in-stent late loss was lower with the DCB strategy (0.08 ± 0.38 vs 0.29 ± 0.44 mm; difference -0.21 mm; 95% CI -0.34 to -0.09; p for noninferiority <0.001; p for superiority = 0.001), with restenosis 8.9% vs 14.1%, TLR 4.4% vs 7.6%, and MACE 7.8% vs 13.2% at 6 months [38]. In RESTORE SVD China, 230 patients with de novo small-vessel disease were randomized to Restore DCB or RESOLUTE Integrity DES; the 9-month in-segment percentage diameter stenosis was 29.6 ± 2.0% vs 24.1 ± 2.0%, meeting the prespecified noninferiority criterion, with 1-year TLF 4.4% vs 2.6% [35]. RESTORE SVD China should therefore be cited as de novo small-vessel randomized evidence, not ISR evidence.

Platform-specific remodeling is visible in randomized small-vessel data. In TRANSFORM-I, the MagicTouch sirolimus-coated balloon did not meet noninferiority to SeQuent Please NEO paclitaxel-coated balloon for 6-month angiographic net lumen gain (0.25 ± 0.40 vs 0.48 ± 0.37 mm; absolute difference -0.23 mm, 95% CI -0.37 to -0.09), with higher binary restenosis after SCB (32.8% vs 12.5%) and less frequent late lumen enlargement after SCB than PCB (30.0% vs 53.7%) [36]. In the OCT substudy, lumen volume decreased significantly after SCB (97.35 ± 71.09 to 87.96 ± 61.48 mm³; p=0.03) but not after PCB (69.67 ± 38.24 to 71.64 ± 42.22 mm³; p=0.64) [49]. These findings support the central platform argument: lumen preservation depends not only on drug family, but on whether the named platform creates sufficient and durable tissue exposure in the treated lesion.

A randomized crystalline sirolimus-coated balloon study in de novo lesions further illustrates architecture-dependent limus-platform performance. In a 70-patient randomized trial, SeQuent SCB was noninferior to SeQuent Please NEO for 6-month in-segment late lumen loss (0.11 ± 0.37 vs 0.04 ± 0.39 mm; mean difference 0.07 mm, 95% CI -0.12 to 0.26; noninferiority margin 0.35 mm), with no deaths or myocardial infarctions and few TLR events through 12 months. Together with TRANSFORM-I, this finding reinforces that lumen preservation depends on named-platform performance rather than sirolimus versus paclitaxel alone [30].

8.2. Dissection Biology and Lesion Preparation

Coronary dissection after balloon angioplasty reflects mechanically induced cleavage of the vessel wall, usually along intimal-medial planes. Determinants include balloon sizing and pressure, plaque composition, calcium geometry, lesion eccentricity, vessel compliance, and stress amplification at compliant-rigid interfaces. In DCB angioplasty, controlled non-flow-limiting dissection should not automatically be considered procedural failure, but severe dissection with impaired flow, extensive recoil, vessel closure risk, or instability remains an indication for bailout stenting [1,50].

Lesion preparation is both a mechanical prerequisite and a pharmacokinetic enabler. Adequate preparation improves acute luminal gain, reduces recoil, increases compliance, enhances wall contact, and may create a more homogeneous transfer surface. Scoring and cutting balloons can create controlled plaque modification and intimal micro-incisions; atherectomy or intravascular lithotripsy may improve compliance and expansion in calcified lesions [1,41,42].

The association between medial dissection and favorable remodeling should be interpreted carefully. In late-lumen-enlargement studies, greater dissection index or extensive medial dissection was associated with subsequent lumen enlargement after paclitaxel DCB treatment [47,48], while absence of post-PCI medial dissection predicted higher TLF in an observational de novo DCB PCI cohort [23]. These findings do not justify deliberate creation of deep dissections. Post-DCB medial dissection may mark effective lesion preparation, plaque modification, and compliance gain in selected cohorts, but current evidence is still observational and should not be interpreted as a procedural target.

For clinical practice and trial interpretation, the relevant procedural objective remains adequate lesion preparation with TIMI 3 flow, acceptable residual stenosis and recoil, and no angiographic or imaging evidence of flow-limiting dissection or vessel instability requiring bailout stenting. For limus balloons, whether wall disruption improves tissue exposure likely depends on the platform’s carrier, depot, or retention strategy; direct evidence remains limited and platform-dependent [13,14,15,30,36,49]. Bailout stenting should therefore be discussed as a safety-driven procedural outcome rather than as an intended feature of DCB angioplasty.

8.3. Clinical Outcome Data as Translational Platform Readouts

Clinical outcome data should refine mechanistic interpretation without replacing it. Randomized trials, registries, imaging studies, and meta-analyses occupy different evidentiary layers. Clinical outcomes test whether a treatment strategy improves patient- or lesion-level events; they do not by themselves identify the coating, transfer, retention, or tissue pharmacokinetic mechanism responsible for the result. Conversely, bench, computational, and porcine studies can identify delivery vulnerabilities but do not establish clinical efficacy.

The coronary ISR evidence base supports DCBs as clinically mature in selected settings, particularly for paclitaxel rapid-transfer platforms. Long-term follow-up of the PACCOCATH-ISR I/II trials compared paclitaxel-coated balloon therapy with uncoated balloon angioplasty in 108 patients with ISR. At 5.4 ± 1.2 years, the paclitaxel-coated balloon strategy was associated with lower MACE (27.8% vs 59.3%) and TLR (9.3% vs 38.9%) than control angioplasty [44]. These data provide an important historical coronary anchor for the Paccocath/SeQuent Please lineage.

De novo small-vessel disease has a separate evidence base and should not be judged solely by broad all-comer de novo trials. In BASKET-SMALL 2, 758 patients with de novo lesions in vessels <3 mm were randomized after successful predilatation to DCB or DES. At 12 months, MACE was 7.5% vs 7.3% in the full-analysis population (HR 0.97, 95% CI 0.58–1.64), and noninferiority was met in the per-protocol population [39]. Three-year follow-up showed sustained similarity, with Kaplan-Meier MACE 15% vs 15% and target-vessel revascularization 9% vs 9% [40]. Together with BELLO and RESTORE SVD China, these trials support selected DCB use in de novo small-vessel disease when lesion preparation is adequate [35,38,39,40].

The broader de novo setting is more complex. REC-CAGEFREE I was an open-label, randomized, noninferiority trial at 43 Chinese centers that randomized 2,272 patients with de novo, non-complex coronary lesions after successful predilatation to paclitaxel-coated balloon angioplasty with rescue stenting or intended second-generation thin-strut sirolimus DES. Rescue DES was required in 9.4% of patients in the DCB arm. At 24 months, the device-oriented composite endpoint was higher with the DCB strategy than with intended DES (6.4% vs 3.4%); the absolute risk difference was 3.04%, with an upper one-sided 95% CI boundary of 4.52%, failing the prespecified noninferiority criterion [37]. This trial should be framed narrowly as a negative randomized signal for broad de novo, non-complex coronary use irrespective of vessel diameter, not as a refutation of all de novo DCB strategies, small-vessel DCB use, bifurcation-specific DCB use, or lesion-prepared DCB approaches. In contrast, SELUTION DeNovo provides a named-platform signal in which SELUTION SLR sirolimus-eluting balloon angioplasty with provisional stenting was reported to be noninferior to systematic DES implantation for de novo coronary lesions; this should be interpreted as evidence for a sustained-release sirolimus micro-reservoir platform and treatment strategy rather than as a class-wide reversal of REC-CAGEFREE I [51].

Named-platform comparisons provide more granular evidence that both paclitaxel and limus balloons should be interpreted at the device level. In DES-ISR, long-term comparison of Agent PCB and SeQuent Please PCB showed no statistically significant difference in 7-year TLR, death, MI, or target-lesion thrombosis, despite different paclitaxel doses and coating strategies. TLR occurred in 43.2% versus 35.9% (HR 1.29, 95% CI 0.87–1.90; p=0.205), and target-lesion thrombosis occurred in 1.6% versus 0.7% (HR 2.18, 95% CI 0.20–24.10; p=0.523). However, the historical-control design, lesion-preparation imbalance, and differential OCT use mean that this study should support platform-specific interpretation rather than simple device equivalence [34].

For limus platforms, the combined randomized DES-ISR analysis of SeQuent SCB and SeQuent Please showed noninferior 6-month in-segment late lumen loss (0.26 ± 0.60 vs 0.25 ± 0.57 mm; mean difference 0.01 mm, 95% CI -0.23 to 0.24) and no significant differences in 12-month clinical outcomes, including TLR (16% vs 10%) and MACE (18% vs 14%). These data support the investigated crystalline sirolimus platform in DES-ISR, but should not be generalized to sirolimus-coated balloons with different coating technologies or lower drug loading [33]. This ISR-specific interpretation is also consistent with an ISR-focused head-to-head meta-analysis reporting broadly comparable clinical outcomes between limus- and paclitaxel-coated balloons; the conclusion should remain restricted to ISR and should not be extrapolated to de novo lesions or heterogeneous angiographic surrogates [52].

Pooled paclitaxel-versus-limus comparisons can obscure differences in excipient chemistry, coating morphology, drug dose, carrier design, reservoir strategy, indication, and trial design [30,33,36,53,54]. In Sedhom et al.’s meta-analysis of six randomized trials including 821 patients, clinically driven TLR did not differ significantly between limus and paclitaxel DCBs (10.3% vs 7.8%; risk ratio (RR) 1.32, 95% CI 0.84–2.08). However, limus DCBs had less favorable angiographic surrogates, including binary restenosis RR 1.89 (95% CI 1.14–3.12), late lumen loss mean difference 0.16 mm (95% CI 0.03–0.28), and follow-up minimum lumen diameter mean difference -0.12 mm (95% CI -0.22 to -0.02) [54]. These pooled differences are consistent with delivery and/or retention heterogeneity, but they do not identify the responsible mechanism and should not be reduced to a uniform drug-class hierarchy.

DCB-BIF adds lesion-specific randomized evidence in bifurcation PCI. In simple true bifurcation lesions with a compromised side branch after main-vessel stenting and proximal optimization, side-branch DCB angioplasty reduced the 1-year composite of cardiac death, target-vessel MI, or clinically driven target-lesion revascularization versus NCB angioplasty (7.2% vs 12.5%; HR 0.56, 95% CI 0.35–0.88; p=0.013), with no significant differences in procedural success, crossover to a 2-stent strategy, revascularization, or stent thrombosis. The signal was driven mainly by myocardial infarction, and the authors emphasized that early periprocedural MI was of unclear clinical significance. DCB-BIF therefore supports a bifurcation-specific side-branch strategy during provisional stenting, not broad de novo DCB use [43].

Other comparative syntheses, including Shin 2024, should be interpreted cautiously and at the named-platform level because pooled analyses combine heterogeneous devices, lesion settings, and endpoints [53]. Clinical setting modifies the translational meaning of platform data. ISR constrains recoil and may allow local drug effect to be expressed more directly; de novo small-vessel disease is sensitive to small absolute changes in lumen diameter but has supportive randomized evidence when lesions are selected and prepared; broader de novo use has produced mixed, platform-specific randomized signals, including the negative REC-CAGEFREE I result and the SELUTION DeNovo noninferiority signal for a sustained-release sirolimus micro-reservoir platform; and bifurcation treatment addresses a different mechanical problem related to side-branch optimization and avoidance of additional metal. These settings should not be pooled into a single DCB class narrative.

8.4. Mechanistic Interpretation

The evidence supports a continuum of delivery performance rather than a uniform DCB class effect. Biological response is determined by drug physicochemistry, excipient behavior, coating morphology, resistance to tracking loss, balloon-wall contact, lesion preparation, mural penetration, and retention kinetics [1,4,6,8,9,13,14,15]. Paclitaxel devices demonstrate how favorable brief-contact pharmacology can produce durable results when coating and transfer are adequate. Limus devices demonstrate how carrier, crystalline, phospholipid, porous, or micro-reservoir strategies can adapt drugs requiring sustained exposure, while microgel and hybrid systems remain primarily experimental or future concepts. In both cases, the key question is whether the platform reliably generates sufficient local tissue exposure in the treated lesion.

9. Future Engineering Directions and Evidence Gaps

Future DCB technologies should be developed around coupled mechanical-pharmacokinetic efficacy. The objective is not simply higher balloon drug load, but better payload preservation, triggered release, wall adhesion, reduced off-target loss, temporary tissue-reservoir formation, and lesion-specific exposure [6,7,8,9,21,55]. Paclitaxel development will likely focus on improved coating cohesion, lower particle loss, more homogeneous deposition, reduced downstream dispersion, and efficacy at lower nominal doses. Limus development will likely focus on sustaining exposure through crystalline optimization, nanocarriers, phospholipid systems, porous infusion, PLGA micro-reservoirs, or related depot strategies [13,14,15,16,17,18,19].

Experimental future concepts, including microgel-coated balloons, dual-drug nanoparticle systems, and hybrid architectures, should be presented as preclinical or translational engineering directions rather than contemporary coronary clinical platforms [56,57]. They are relevant to future platform design but should not be grouped with devices supported by randomized coronary evidence.

Computational modeling can support device design and lesion selection by integrating contact pressure, curvature, plaque substrate, binding kinetics, washout, and coating loss [5,6,7,21,22,55]. However, computational results should be treated as mechanistic filters and hypothesis generators, not as clinical outcome evidence. Imaging should be incorporated into platform evaluation because calcium, bifurcations, long lesions, and ISR subtypes impose different constraints on expansion, contact, and drug distribution [1,23,41,42,43].

Several gaps remain despite the growing randomized evidence base. First, head-to-head comparisons between named coronary DCB platforms remain limited, and broad drug-family comparisons obscure differences in excipient chemistry, coating morphology, dose, carrier design, and retention strategy [13,30,33,34,36,53,54]. Recent randomized and comparative studies support specific platforms—such as Agent PCB, SeQuent Please PCB, SeQuent SCB, SELUTION SLR in SELUTION DeNovo, and side-branch DCB use in DCB-BIF—but these results should not be generalized across all paclitaxel or all limus balloons [30,33,34,43,51]. Second, mechanistic endpoints are not standardized. Studies measure visible coating loss, drug mass loss, acute transfer, tissue retention, particle shedding, transmural distribution, and downstream drug effect differently, limiting cross-platform comparison [4,6,8,9,13,20,22,55].

Third, extrapolation across experimental systems is imperfect. Healthy porcine coronaries, bench abrasion models, ex vivo tracking circuits, and in silico simulations isolate important mechanisms but cannot fully reproduce calcified, lipid-rich, restenotic, bifurcating, or tortuous human coronary lesions. Fourth, lesion-stratified data remain sparse. Plaque morphology, calcification, vessel size, bifurcation anatomy, ISR subtype, dissection pattern, and lesion preparation likely influence DCB efficacy but are inconsistently reported [1,7,21,22,23,41,42,43]. Fifth, limus-platform maturity remains uneven; results from one sirolimus architecture should not be generalized to all limus balloons [13,14,15,16,17,18,19,30,36]. Finally, the prognostic value of OCT/IVUS remodeling patterns across DCB platforms remains incompletely defined [23,45,46,47,48,49]. Future studies should link acute lesion preparation, delivery mechanics, follow-up remodeling, and clinical outcome at the named-platform level.

10. Conclusions

Coronary DCB therapy is engineered brief-contact drug delivery. Success depends not on nominal drug load or drug family alone, but on the integrated behavior of drug physicochemistry, excipient function, coating morphology, mechanical stability, adhesion switching, wall contact, lesion preparation, mural penetration, and tissue-retention kinetics.

Paclitaxel platforms illustrate how favorable short-contact pharmacology can support durable coronary results when coating stability, transfer, and lesion preparation are adequate. However, paclitaxel devices also show why particle loss, downstream dispersion, and vascular-healing effects must remain part of platform assessment. Limus platforms illustrate how carrier, crystalline, porous, phospholipid, micro-reservoir, and other depot strategies can adapt drugs that require sustained exposure, but results from one architecture should not be generalized to all limus balloons.

Clinical data reinforce this lesion- and platform-specific framework. Coronary ISR and selected de novo small-vessel disease have supportive randomized evidence, whereas broader de novo use has produced mixed, platform-specific randomized signals, including the negative REC-CAGEFREE I result and the SELUTION DeNovo noninferiority signal for a sustained-release sirolimus micro-reservoir platform [37,51]. Bifurcation, calcified, ISR, and small-vessel lesions pose different mechanical and pharmacokinetic problems and should not be collapsed into a single DCB class effect. Recent randomized data in crystalline sirolimus platforms and bifurcation side-branch treatment further support lesion- and platform-specific interpretation.

The relevant question is whether a named device can reproducibly generate sufficient and durable mural exposure with acceptable spatial consistency, off-target loss, vascular healing, and clinical durability in the lesion context being treated. The next stage of coronary DCB development should move from drug-class comparisons toward measurable platform-performance metrics linking engineering behavior to lesion-level pharmacokinetics, imaging-defined remodeling, and clinical outcomes.