Table 4.

Pre-clinical safety summary for hydrolysis mediated degradable PEG-PLGA-PEG microspheres.

Authors and Year of Publication	Study Model & Duration	Test Material Information.	Ease of Use	Time to Complete Degradation of Test Material	Recanalization	Acute Complications (Vessel Rupture/Perforation)	Local and Systemic Foreign Body Reactions	Embolization Effectiveness.	Device Migration
Maeda et al. (2013)	Porcine Kidney Model. Study duration: 7 days. Control material: gelatin sponge particle (GSP) approx. 1 mm3 9 Minipigs (Mean weight 34.9 kg ± 2.1 kg) Groups comprised two pigs (i.e., four kidneys per group)	PEG-PLGA-PEG 300–500 μm 500–700 μm 700–900 μm Size distributions determined by sieving only. No particle size distribution analysis is provided. 1:2 ratio of saline/contrast for test article with pure contrast for the control article	A 4-F cobra catheter was utilized for the embolization procedures. The mean volume of injected material per kidney was 0.48 mL ± 0.17, 0.24 mL ± 0.11, 0.24 mL ± 0.12 for REM of 300–500 μm, 500–700 μm, and 700–900 μm. Mean volume of control article injected was 1.2 mL ± 0.2 Authors note, “none of the products clogged in the catheter.”	Proposed as 24 h based on tests in PBS. At day 7 the test material was not visible, no fragments of materials were observed in histological slides/analysis. GSP was still present at day 7, though partly degraded. Its presence was associated with foreign body inflammation.	Assessed at 10 min and 7 days using angiography. Large variations due to methodology acknowledged. Assessed at 10 min and 7 days using histological analysis. At day 0 test materials were washed out during processing limiting analysis. Test article showed fully patent vessel lumens after 7 days Recanalization varied based on size of test material: 700–900 μm demonstrated complete recanalization 300–500 μm and 500–700 μm demonstrated partial recanalization.	Numerous patchy arterial lesions, including myointimal proliferation, medial concentric thickening, adventitial fibrosis, and fibrinoid necrosis of the arterial wall, were focally observed. No excessive pain or abnormal behavior reported	Local histological analysis provided. Hematoxylin-eosin-saffron stain used. GSP (control) had eosinophilic or slightly basophilic appearance at day 7 and partly degraded. Presence associated with foreign body inflammation (macrophages, lymphocytes and fibrocytes). Test materials were washed out during histological processing limiting analysis for day 0. At day 7, test material was not visible, no fragments of materials were observed in histological slides/analysis. Fully patent lumen visible on histology.	Recanalization demonstrated on angiography No gross histology to examine presence of long term necrosis	Not addressed.
Verret et al. (2014)	Uterine Artery Sheep Model 6 adult Préalpes Sheep. (Mean weight 54 kg) (Mean age 48 ± 22 months) Study duration: 7 days. Control material: Embosphere 500–700 μm	PEG-PLGA-PEG 500–700 μm Size distributions determined by sieving only. No particle size distribution analysis is provided. 2:1 ration of saline/contrast for test material and 4:5 ratio for control article	Selective embolization of both internal iliac arteries achieved using a 5F “cobra-type” catheter. Superselective embolization of both UAs performed with a 2.7F microcatheter. Mean volume of test material injected per uterine artery was 1.0 mL ± 0.5. Mean volume of control was 1.6 mL ± 0.9 No difference in injectability noted between control and test materials.	Proposed as 24hr based on tests in PBS. At day 7 the test material was not visible, no fragments of materials were observed in histological slides/analysis.	Presence or absence of recanalization assessed based on (i) the presence or absence of vascular lumen with (ii) red blood cells or plasma in the occluded vessel. For test article “complete recanalization rapidly obtained” and fully patent on angiography at 7 days.	Vessel rupture not assessed. None reported.	Local histological analysis provided. Gross examination showed ischemic damage to endometrium and myometrium for test and control uteri. Hematoxylin-eosin-saffron stain used. No test materials or inflammatory response observed at 7 days for test article. Control material showed evidence of recanalization, and was surrounded by macrophages, neutrophils and foreign body giant cells.	Gross examination showed ischemic damage to endometrium and myometrium for test and control uteri. The authors suggest that for the test article, full UA recanalization and absence of parenchymal defects were associated with low endometrial alterations.	Not addressed.