Resorbable particles: Are they the future?

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1 Resorbable particles: Are they the future? Jafar Golzarian Professor of Radiology & Surgery Director, Division of Interventional Radiology University of Minnesota

2 Why Resorbable? Common sense: Trend Patient preference Material not needed after the results No long-term foreign material persists in the body Vessels restoration Repeat interventions

3 Why is the resorption important? - All Embolization materials provoke foreign body reaction to some extent - Reveals a biomaterial intolerance - With the current embolic materials the inflammatory reactions can be long term Kwak et al, Radiology 2005,236:151-8

4 Intolerance Embolization : Vessel occlusion + Thrombus + Ischemia + Biomaterials Acute PMN infiltration Chemo-attraction of monocytes macrophages Adherent Macrophages activation and fusion, T-cells recruitement Tissue remodeling : thin fibrous capsule Biomaterials surface passivated Immuno-inflammatory cells apoptosis Antigen-mediated activation Immunostimulation, hypersensitivity : T and B-cells proliferation Macrophages fusion : Giant cells High tissue remodeling : necrosis, fibrosis, thick fibrous capsule Biomaterial degradation Persistence of inflammatory cells Resolution Chronic inflammation Good tolerance Poor tolerance

5 Non Spherical PVA PVA TGMS MP, GC, L Infl GC PVA fragments PVA Fib TGMS

6 Recanalization Vs Revascularization Recanalization is not revascularization Angio: vessels may recanalize by resorption of the thrombosis, partial PMN, MP and GC or particle exclusion however the vessels most often is damaged (arteritis) based on histological analysis Verret et al.biomaterials 2001;32:

7 Resorption Blood flow occlusion Ideal biomaterial resorption : MS Complete revascularization Inflammatory cells Bad biomaterial resorption : Collagen Incomplete revascularization Slow resorption : fragmentation High inflammatory response Artery wall remodeling Chronic inflammation Stenosis Fibrosis

8 Recanalization and particle exclusion after embolization of uterine arteries in sheep: a long-term study Laurent et al, Fertil Steril2009;91:884-92

9 Repeat Embolization in Tumor Vessel patency post TACE: 81% with Gelfoam and 74% with PVA Geschwind et al, CVIR 2003;26:111-7

10 Drug Release Inflammatory response has a significant impact on a local drug pharmacokinetics : (Blanco E, JBMR, 2004 : Doxorubicinloaded PLGA milli-rod implanted in radiofrequency ablated rat liver or control rat liver. The wound healing zone acted like a barrier for the drug diffusion) Continuous drug release over time with permanent drug loadable particles Increased risk of biliary toxicity (Biloma, ) Guiu et al, Journal of Hepatology 2012;56:

11 Resorbable Gelfoam is the original resorbable material used for embolization Results are excellent in areas such as trauma, UFE, and any area that particulate materials are used Issue is that the material is irregular, provoke inflammation and unpredictable resorption

12 Marketed Material Ref Nature Resorption time Starch Gelatin sponge PLGA-collagen In development Embocept Gelfoam TM, Gelitaspon Occlusin 500, Imbiotechnologies Material Ref Nature Resorption time Gelatin MS Ohta, 2007 Natural Nat & Synth Natural Hours Weeks Months Weeks Chitosan Kwak, 2005 Natural Months Chitosan-Cellulose Weng, 2011 Natural Weeks/ Months PMA - PLGA Verret 2012 Synthetic Hours/Days Only small Not calibrated Slow resorption Small sizes Slow resorption - Slow resorption 2 Examples Soluble PVA Shomura, 2011 Synthetic Hours to weeks

13 A Porous Gelatin Sponge, GELPART (Nippon-Kayaku, inc.)

14 Degradable Starch Microspheres (DSM) - TACE EmboCept S parameters cross-linked, partially hydrolyzed starch polymere matrix median diameter: 50 / um (lodge in precapillary vessel area) half-time: appr min. degadation by -amylase fragments: Dalton (water-soluble)

15 Degradable Starch Microspheres (DSM) - TACE Different Chemo-agents mixed with DSM Higher tumoral dose Potential for increased response rate and survival in patients who failed systemic chemo Resorption before expression of VEGF and allowing multiple treatment without vascular occlusion or damage Vogl T et al. J Cancer Res Clin Oncol 2006, 132:

16 RESMIC Calibrated =>Targeting Resorption within days in vitro and in vivo ANGIO RECANALIZATION D7 +++ Degradation products Low size < 50 kda Non-cytotoxic biocompatible Post-embolisation 1 week

17 Absorbance at 490nm Cellulose-Chitosan Human Umbilical Vein Endothelial Cells (HUVEC) BRMS Control Control OCMC/CCN-I OCMC/CCN-II OCMC/CCN-III Day 0 Day 1 Day 3 Time (day) Cytotoxicity assay, inserts used

18 Degradation In lysozyme Day 0 Day 3 Degradation time adjustable: Day 9 14 days,1 month, 2 months, etc. Day 14 Day 0 Day 16

19 Day 0 H&E Day 6 H&E 73 days-rabbit kidney-total occlusion * Day 6 PAS Day 7 PAS Day 7 Elastin Day 30 Day 73 PAS *

20 Before embolization Post embolization Day 14 Before embolization Post embolization Day 21 Before embolization Post embolization Day 30

21 Ideal Embolization Particles Visible under fluoroscopy Easy to use/injectability Shapeable Controlled compressibility No Chronic Inflammation Loadable Resorbable Controlled-resorption