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DISCREET Bioresorbable Drug Coating Technology

A new class of bioresorbable drug coating, DISCREET combines high mechanical integrity and enzyme mediated resorption to promote natural, timely and complete vascular healing.

Polymer technologies were introduced with the first drug-eluting stents to modulate drug to the vessel wall.  Their purpose, as with technologies used today to control drug elution, is straightforward:

  • Maintain mechanical integrity during stent delivery to ensure uniform drug delivery
  • Provide controlled, consistent and full drug elution to the arterial wall
  • Promote, or at least do not interfere with, the normal healing process

Svelte DISCREET drug coating represents an entirely new class of bioresorbable drug coating composed of naturally-occurring amino acids and the well-studied antiproliferative compound sirolimus.  With the toughness and mechanical integrity necessary for direct stenting, DISCREET promotes healing and delivers safe and exceptional long-term clinical outcomes.

A Snapshot of DES Polymer Technologies

First-generation durable polymers lacked consistent mechanical integrity and, more importantly, were associated with chronic inflammation and delayed arterial healing.  This likely caused the increased stent thrombogenicity and adverse events observed beyond 1 year1.

Current generation durable polymers are much improved over their first-generation counterparts, demonstrating improved long-term clinical outcomes.  However room for improvement remains.  Evidence from animal and human studies shows persistent arterial wall inflammation and delayed healing attributed to polymer presence long after drug elution is complete2-3.  This risk is amplified in higher-risk patients with complex lesions where prolonged dual antiplatelet therapy is required to provide safety.

In the search for more biocompatible solutions for drug delivery, development shifted to bioresorbable (non-durable) polymers. Typically composed of PLA (poly-lactic acid), PLLA (poly-L-lactic acid) or PLGA (poly-lactic-co-glycolic acid), these polymers are designed to degrade during and after drug delivery.  This returns the implanted stent to its bare metal state, promoting normalized vascular healing.

Current evidence, however, indicates that the breakdown of PLA / PLLA / PLGA is associated with significant inflammatory response4. During degradation, generated byproducts reduce local pH, creating an acidic environment and inducing inflammation5,6.

Once exposed to blood, bulk degradation of the PLA / PLLA / PLGA polymer begins. Lactic and/or glycolic acid is generated by the non-enzymatic hydrolysis of ester bonds, reducing local pH and creating an acidic microenvironment. This elicits an inflammatory response and activation of the complement cycle, which can be significant and persistent.

PLGA Degradation

Data from a recently published meta-analysis suggest drug-eluting stents utilizing the PLA / PLLA / PLGA class of bioresorbable polymers are associated with similar, or higher, adverse events compared with currently available durable polymer technologies.  Specifically, these bioresorbable polymers demonstrated increased risk for stent thrombosis up to 1 year compared with current durable polymer technology7.

Interestingly, however, trends toward reduced stent thrombosis compared with durable polymers were observed beyond 1 year.

These data may suggest:

  • Current generation durable polymers elicit less of an inflammatory response than PLA / PLLA / PLGA polymers during the first year, though their permanent nature allows for persistent inflammation (and greater risk for adverse events) over the long term;
  • The acidic microenvironment associated with PLA / PLLA / PLGA polymer degradation elicits an inflammatory response which lasts until the polymer is fully resorbed (typically 12 months or less), contributing to increased stent thrombosis risk and adverse clinical events
DISCREET: An Evolution in Drug Coating Technology

In search of a better drug delivery system, Svelte partnered with DSM Biomedical, a global leader in biomaterials science and regenerative medicine. Using DSM’s proprietary polyesteramide (PEA) bioresorbable coating, a new class of drug carrier technology was developed.

The result is DISCREET drug coating, designed to provide high mechanical integrity and optimize healing while delivering desired drug dose to the local tissue in controlled fashion.

DISCREET is composed of two elements:

  • DSM Biomedical’s proprietary, fully bioresorbable drug carrier composed of naturally occurring amino acids (PEA)
  • The well-known anti-proliferative drug sirolimus

Carrier and drug are mixed together and applied to the stent in a single application.

Natural is better

Amino acids naturally occur in the human body and form the building blocks of the highly biocompatible and fully bioresorbable  poly(ester amide) PEA drug carrier incorporated in DISCREET drug coating.  When combined with ester and amide bonds, amino acids form a highly biocompatible PEA carrier matrix ideal for use with drug-eluting stents.

Controlled and complete drug elution

Once delivered to the target lesion, 213 µg/cm2 of sirolimus elutes to the vessel wall over 60 days.  This coincides with peak hyperplastic response following initial stent placement and intimal injury.

DISCREET drug coating with DSM PEA bioresorbable drug carrier. Sirolimus elutes in predictable fashion over approximately 60 days. This is similar to the elution curves observed with other drug-eluting stents utilizing sirolimus or its analogues which have demonstrated suppressed neointimal formation over the long-term. Resorption of the carrier via enzyme mediated degradation continues in consistent fashion over 12 months. Note the molecular weight of the carrier which remains relatively constant through the resportion process, ensuring consistent and complete drug elution.

DISCREET drug coating with DSM PEA bioresorbable drug carrier. Sirolimus elutes in predictable fashion over approximately 60 days. This is similar to the elution curves observed with other drug-eluting stents utilizing sirolimus or its analogues which have demonstrated suppressed neointimal formation over the long-term. Resorption of the carrier via enzyme mediated degradation continues in consistent fashion over 12 months. Note the molecular weight of the carrier which remains relatively constant through the resportion process, ensuring consistent and complete drug elution.

Gradual surface erosion of DISCREET via enzyme mediated resorption occurs over 12 months.  Unlike other bioresorbable drug carriers, the molecular weight of DISCREET remains constant during resorption, ensuring consistent and complete drug elution without bulk degradation or drug burst release.

High mechanical integrity designed for direct stenting

The DSM PEA bioresorbable drug carrier used with DISCREET employs hydrocarbon spacers to provide optimal thermal and mechanical properties.  Low yield strains coupled with high break strains ensure PEA carrier integrity and resiliency when direct stenting and treating complex lesions.

discreet sem imaging thumbnail

The elastomeric properties of DISCREET drug coating provide the mechanical integrity necessary to direct stent and treat challenging lesions without compromise.  This image represents the overlapped area of stents with DISCREET coating after 10 million cycles.

Promote Healing

DISCREET drug coating promotes a natural healing response.  As a class, PEAs are the only drug carrier technology composed of naturally-occurring amino acids which resorb via enzyme mediation.  This provides two important benefits to promote and accelerate healing:

  • Reduced inflammatory response
  • Accelerated and complete endothelial recovery

Reduced Inflammatory Response

By primarily requiring enzymes rather than water to erode, PEA drug carriers generate different byproducts than PLA / PLLA / PLGA carriers during the resorption process.  The enzyme mediated surface erosion occurring with PEAs generate biocompatible materials such as amino acids and aliphatic hydrocarbons which do not affect the pH of the local environment and are naturally assimilated by the body.  Animal testing demonstrates PEA hyperplastic response and inflammation scores similar to uncoated bare metal stents.*

PLA / PLLA / PLGA class of drug carriers, however, generate highly acidic byproducts which reduce pH in the local vascular environment. Change in acidic environment can promote complement activation6, impeding endothelial recovery, delaying healing and causing inflammation, particularly in the short term, which may contribute to adverse events7,8.

Compared with the PLA / PLLA / PLGA class of drug carriers, PEAs reduce secretion of pro-inflammatory cytokines and increase secretion of anti-inflammatory mediators9.

Accelerated Endothelial Recovery

As a class, PEAs are non-hemolytic and do not deplete platelets from the blood; endothelial cells readily adhere, spread and proliferate on them9. Additional in vitro testing demonstrates PEAs are non-cytotoxic and non-inflammatory in vitro, providing strong and consistent endothelial cell adhesion, growth, and monolayer formation10.

histology from animal testing

Animal testing demonstrates endothelial coverage complete at 30 days; minimal fibrin deposition, robust healing at 90 days; sustained healing with no catch-up through 390 days.

Safe and Sustained Outcomes

Early healing and eliminating chronic inflammation lower late-term event rates.  With NO death or stent thrombosis and exceptionally low target revascularization reported through 3-years in Svelte clinical studies, DISCREET demonstrates consistent, safe and durable outcomes.


svelte-des-outcomes

Maintain mechanical integrity during direct stenting and ensure controlled, complete drug elution.
Deliver a natural, bio-friendly platform which promotes healing.

Experience a new class of drug coating technology.  Be DISCREET.

References:

  1. Wilson GJ, Nakazawa G, Schwartz RS, et al. Comparison of inflammatory response after implantation of sirolimus- and paclitaxel-eluting stents in porcine coronary arteries. Circulation 2009;120:141-9, 1-2.
  2. Finn AV, Kolodgie FD, Harnek J, et al. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 2005;112:270-8.
  3.  Joner M, Nakazawa G, Finn AV, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol 2008;52:333-42.
  4. Garg S, Serruys P. Coronary stents: looking forward. J Am Coll Cardiol 2010;56:S43-78.
  5. Ulery B, Nair L, Laurencin C. Biomedical applications of biodegradable polymers. J Polym Sci B Polym Phys 2011;49(12):832-864.
  6. Ceonzo K, Gaynor A, Shaffer L, Kojima K, et al. Polyglycolic acid induced inflammation: Role of hydrolysis and resulting complement activation, Tissue Eng. 2006 February; 12(2): 301-308.
  7. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Clinical outcomes with bioresorbable polymer versus durable polymer-based drug-eluting stents and bare-metal stents: evidence from a comprehensive network meta-analysis. J Am Coll Cardiol 2014;63:299-307.
  8. Patzelt J, Verschoor A, Langer H.  Platelets and the complement cascade in atherosclerosis.  Front. Physiol 6 (2015);49:1-9.
  9. Defife K, Grako K, Cruz-Aranda G, et al.  Poly(ester amide) co-polymers promote blood and tissue compatiblitiy. Journal of Biomaterials Science 20 (2009):1495-1511.
  10. Horwitz J, Shum K, Bodie J, et al.  Biological performance of biodegradable amino acid poly(ester amide)s: endothelial cell adhesion and inflammation in vitro.

 

 DIRECT I clinical study.

 DIRECT II clinical study.

* Data on file at Svelte.

CAUTION: The law restricts SLENDER IDS to sale by or on the order of a physician. Indications, contraindications, warnings and instructions for use can be found in the product labeling supplied with each device. SLENDER IDS is CE approved. DIRECT RX is an investigational device not approved for commercial use. SLENDER IDS and DIRECT RX are not available for sale in the US.