Design and Discovery of Resorbable Polymers for Coronary Stents Presented at Polymers in Medicine and Biology 2013 Joachim Kohn Director New Jersey Center for Biomaterials Rutgers University Piscataway, New Jersey
Overview This lecture covers the early history of stent development up to the first deployable prototype, focusing on polymer design principles The following lecture by Dr Zeltinger focuses on the clinical experience and recent data Disclosure: Joachim Kohn is a consultant for REVA and has a financial interest in REVA
Percutaneous Transluminal Coronary Angioplasty (PTCA)
Resorbable or permanent? The very early thoughts about preventing restenosis after angioplasty indicated that a temporary support device was needed to keep the injured blood vessel open The Kohn Lab submits a research proposal on developing new polymers for resorbable stents in 1988 (and doesn t get funded) For lack of any other options, the first clinically used stents were permanently implanted metal stents.
Progression of Stent Development Metal stents 93 Palmaz-Schatz stent FDA approved for coronary use Antiplatelet or anticoagulant coated metal stents 00 Phosphorylcholine coated and heparin coated stents FDA approved Resorbable polymeric stents 00 Tamai et al. first to implant resorbable PLLA coronary stents in humans using a heated balloon technique Anti-restenosis drug-eluting, coated stents 03 CYPHER Sirolimus-eluting coronary stent FDA approved 2006 Abbott introduces Absorb, a drug eluting bioresorbable vascular scaffold (BVS) made of PLLA 2007 REVA Medical announces trials of its resorbable, radioopaque, drug eluting vascular scaffold made of a new X-ray visible polycarbonate
Early Resorbable stents - Examples Stack et al. 88 Poly(L-lactic acid) stent Yoklavich et al. 96 PLA/TMC stent by J&J Cordis molded by Tesco Assoc. Tamai et al. 00 Zigzag helical coil Poly(L-lactic acid) Deployed in humans Biosensors and Guidant Prototype Self-Expanding Stent
Why is it so difficult to design a polymer stent that matches the performance of metal stents Polymer Properties Not usually radio-opaque Low strength & stiffness Poor flexibility Difficult to deform rapidly without damage Tends to creep under continuous load Physical aging and crystallization during storage Metal Properties Radio-opaque High strength and stiffness High flexibility Easily deformable Creep resistant Storage stability
Why is it so difficult to design a polymer stent that matches the performance of metal stents Polymer Properties Not usually radio-opaque Low strength & stiffness Poor flexibility Difficult to deform rapidly without damage Tends to creep under continuous load Physical aging and crystallization during storage Target Polymer Properties Incorporate iodine Poly(BPA carbonate) Redesign the stent Redesign the stent High Tg, strong interchain interactions Amorphous, high Tg
Tyrosine-derived monomers are building blocks for resorbable biomaterials CH 3 HO C OH CH 3 Bisphenol A (BPA) HO I CH 2 CH 2 O C NH CH CH 2 OH I C O O Non-toxic monomer system Polymer libraries of polyarylates, triblock copolymers, polycarbonates Tyrosine-derived polymers degrade exclusively into metabolites, nutrients and components that are classified as GRAS by the FDA R
Increasing the design flexibility The original REVA stent polymers were terpolymers of iodinated DTR, DT, and PEG
Unprecedented freedom in the design of an optimized stent material Pendant Chain E,B,H, O etc Carboxylate (DT) Iodination PEG Cell Adhesion Resorption Visibility Stiffness Stiffness Stiffness Stiffness Cell Adhesion Tyrosine-derived polycarbonates allow for the efficient modification of polymer properties
The problem of design complexity Poly(glycolic acid) Design parameters: molecular weight molecular weight distribution annealing/crystallinity A simple design of about 20 experiments is sufficient to explore the design space of poly(glycolic acid) Poly(x%DTR-co-y%DT-co-z %PEG MW carbonate) Design parameters: overall polymer composition random vs block architecture PEG molecular weight DTR pendent chain A library of over 10,000 discreet compositions, each one with potentially useful, individual properties It is no longer possible to synthesize all potential compositions explore all potential composition
Combinatorial-Computational Approach Kohn, J., W.J. Welsh, and D. Knight., Biomaterials, 2007. 28(29): p. 4171-7"
We can make hundreds of polymers Automated Parallel Synthesis Station up to 192 parallel reactions substantial flexibility in the design of workflows shared user facility is open to potential collaborators
Rapid Screening Immuno-Fluorescence-Assay to detect adsorbed fibrinogen as a screen for thrombogenicity Procedure Coat microwells with polymers Incubate with a single protein solution Detect adsorbed protein with fluorescently labeled antibody Compare the fluorescence signals for multiple polymers within one plate 384- well plate
Screening for fibrinogen adsorption fluorescence signal (% of control) 300 250 200 150 100 50 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 Polymer The screening of 44 polymers with at least 16 repetitive measurements per polymer (704 data points) can be conveniently achieved in two plates and required only about 2 hours of technician work time.!
Gene Expression of Pro-Inflammatory Cytokines as a screening test for inflammation 10.50 10.00 9.50 9.00 8.50 8.00 7.50 7.00 6.50 6.00 5.50 IL-1 beta expression polymer Variation in IL-1beta expression in peritoneal rat macrophages in contact with 72 different polymer surfaces
Effect of PEG on protein adsorption and cell attachment (fibroblasts) 0.45 100 Adsorbed FN (µg/cm?) 0.40 0.35 0.30 0.25 0.20 0.15 Data Linear Fit R 2 = 0.9616 Cell Attachment (%) 80 60 40 * 0.10 0.05 20 * * 0.00 0 2 4 6 8 10 PEG Content (%) 0 0 2 4 6 8 10 PEG Content (%) Protein adsorption (Fibronectin) on surfaces of poly(dte-co-peg carbonate) is reduced by inclusion of PEG Total cell number decreases significantly when the amount of PEG in the polymer reaches 6 Mol%.
Artificial Neural Network (ANN) Input Input Input Input Input Input Input Input Input Any measured parameter or observation Hidden Layer A set of weighed linear regressions or other functions Output Prediction of the model The ANN needs a training set of data to determine the optimum value of the weighing functions in the hidden layer that lead to the closest match between an experimentally determined outcome and the prediction of the model. Thereafter the ANN can make empirical predictions of the outcome when presented with similar data sets.
Computational Models to Predict Protein Adsorption and Cell Growth 48 polymer" were prepared" 24 polymers" were explored" 24 polymers" were never tested" Experimental data were used to train" the computer models" These data were used as inputs to predict protein adsorption and cell growth"
Prediction of the Glass Transition 120.00 100.00 80.00 Tg (deg C) 60.00 40.00 measured predicted 20.00 0.00 0 10 20 30 40 50 60 70 polymer number (arbitrary)
Prediction of Fibrinogen Adsorption 220 170 120 70 measured predicted 20 0 10 20 30 40 50 Polymer (arbitrary number)
Prediction of Normalized Metabolic Activity (NMA) for rat lung fibroblasts 120 100 80 60 40 measured predicted 20 0 10 20 30 40 50 Polymer (arbitrary number)
Combinatorial-computational method Advantages Relatively simple Relatively cheap Relatively effective for exploring a limited range of properties Disadvantages Requires a training set, e.g., polymers still have to be synthesized and experimental data must be collected Accuracy of the predictions depends on the quality of the experimental data Predictions are only made for specific polymers classes and are not generalizable to other polymer structures
Summary: Acceleration of the pace of development The process started with the identification of desirable polymer properties by the customer, a stent company Searching within a library space of over 10,000 possible compositions, a polymer with suitable properties relating to DEGRADATION, MECHANICAL STENGTH, HEMOCOMPATIBILITY, and X RAY VISIBILITY was found, synthesized and tested within about 1 year The combinatorially designed material performed as predicted. A fully deployable stent could be fabricated upon first trial Visibility by fluoroscopy of the polymer stent (top) and a market leading steel stent (bottom) Hemocompatibility in the pig coronary model: 3 weeks post implantation, there was no evidence for necrosis, inflammation, thrombosis or restenosis.
The initial stent prototype could be deployed (*) Note: This is a historic image, dating back to 2002. This is not representative of the current REVA stent design.
Why is the development of a degradable polymer stent a significant challenge? Polymers lack strength compared to metals, requiring significant optimization of composition and processing Many common polymer properties are incompatible with stent requirements, requiring device design work-arounds : Rapid deformation Device flexibility Extremely thin struts Radio-opacity Vascular tissue compatibility and very benign degradation products to minimize inflammation-mediated restenosis Processibility
Thank you!