1. 1 Resorbable meniscus scaffold for the treatment of partial meniscal tear or meniscal loss P.Djian, P.Beaufils, J Bellemans, P.Colombet, R Cugat, H Laprell, P.Neyret, H Paessler, E.Servien, R.Verdonk, P. Verdonk JOFDOF Martinique les trois ilets 2010

2. 2 No potential financial disclosure Presenters Financial Disclosure

3. 3 Introduction The potential detrimental outcome following partial meniscectomy has been well establish Symposium SFA 1995 : –95 Partial meniscectomies –F.U : 11.5 ± 1.2 Y –45 % arthrosis Symposium SFA 2008 –47 partial meniscectomies –FU : 22.5 Years –100 % arthrosis 3

4. a b c d (a): Intact meniscus (b): partial meniscectomy (c): scaffold implanted knee (d): fully meniscectomized knee Tibial Plateau Load Transmission* *Ovine Model (HSS) 7

5. Current Standard of Care Partial Meniscectomy Mechanical imbalance in the knee joint Addresses symptoms only Biomechanical Cadaver Study 2

6. 3 THE SPORT SURGEONS NEED: A means to replace lost tissue and to reinforce remaining tissue post meniscectomy Ideal Product Requirements: – Biocompatible – Timely biodegradation – Promotes blood vessel and tissue ingrowth – Provides chondroprotection – Easy to insert and suture arthroscopically 3

7. THE ORTEQ SOLUTION The Optimum Material + An Optimized Design Results in: A new vascularized and functional meniscus 4

8. [i] Ghadially FN, Lalonde JM, Wedge JH (1983);136:773-791. [ii] King D. (1936) J Bone Joint Surg 18:1069-1076. THE IRREPARABLE MENISCUS 1

9. 5 The Actifit™ concept Partial meniscectomy Tissue regeneration through vascular ingrowth and cellular infiltration from the synovium and the meniscal rim Regenerated tissue next to meniscal tissue 5

10. Dimensions and shape based on human meniscus 6

11. INDICATION Irreparable medial or lateral partial meniscal tear Intact rim Anterior and posterior horn present Stable knee joint or stabilization procedure within 12 weeks (BMI) < 35 kg/m 2 Axial alignment ICRS classification ≤ 3 Full understanding of importance to adhere to rehabilitation program 8

12. SURGICAL TECHNIQUE: Debride the damage Measure defect Cut the scaffold Insert into defect Suture in place 9 1 2 5 3 4

13. Safety and Efficacy Study 10

14. Study Centers NAME Prof R Verdonk Dr P Beaufils Prof P Neyret Dr H Paessler Dr R Cugat Dr P Colombet Dr H Laprell Dr P Djian Prof J Bellemans AFFILIATION University Hospital Gent Centre Hospitalier de Versailles Centre Livet de Lyon Atos Praxisklinik Heidelberg Hospital Quirón de Barcelona Clinique de Merignac-Bordeaux Lubinus Clinicum of Kiel Institut Nollet Paris University Hospital Pellenberg 11

15. OBJECTIVES – Safety o Adverse event profile (ongoing) o Gross examination at 12 months relook o Device stability and cartilage score on MRI (3, 6, and 12 months) – Performance o Tissue ingrowth Dynamic Contrast Enhanced MRI (3 months) Tissue Biopsy (12 months) – Efficacy o Pain VAS (Baseline, 1 week, 3, 6,12 months) o Functionality IKDC, KOOS, Lysholm (Baseline, 3, 6, 12 months) 12

16. Study Population 13  Enrolment : March 2007- April 2008  Enrolled: 52 subjects (34 M / 18 L)  Withdrawn before 3 month follow-up: 1 post-operative infection  Major protocol violations: 8 subjects (5 M / 3 L) of which 3 withdrawn (2 M / 1 L)

17. Baseline characteristics 14 Medial Lateral N = 34 N = 18 Age (years) Mean ± SD:33.4 ± 9.425.8 ± 8.5 Sex (n) Male:25 (73.5%)14 (77.8%) Female: 9 (26.5%) 4 (22.2%) Longitudinal length (mm) Mean ± SD:48.8 ± 10.443.9 ±8.6

18. Previous surgeries on index knee* No previous surgery on index knee 2 ( 3.8%) One previous surgery on index meniscus 34 (65.4%) Two previous surgeries on index meniscus 12 (23.1%) * Missing data on 4 subjects Baseline characteristics

19. Safety  No Serious Adverse Device Events  Six Serious Adverse Event: Subject numberDescription of SAE 01 ‑ 002*Allograft transplantation / investigational device removal 01 ‑ 005*Medical device removal 01-013Cartilage graft 01 ‑ 023*Knee arthroplasty / investigational device removal 06 ‑ 001Myocardial infarction 07 ‑ 004Post operative infection with investigational device removal * Subjects 01-002, 01-005 and 01-023 did not fulfill the inclusion criteria and were considered protocol violators. 16

20. Safety  AE profile similar to that reported in the literature for meniscal surgery and meniscal implants.  Overall, 29 (55.8%) subjects reported an AE (20 M / 9 L)  Majority of AEs were mild or moderate in intensity.  7 subjects experienced AEs considered probably or possibly related to the device.  22 subjects experienced AEs considered related to the meniscus repair procedure. 17

21. 21 Results Clinical data : –KOOS Score –IKDC Score –VAS –Lysholm score Anatomic control –Relook at one year post-op Biopsie and histological control –MRI 1 week, 3 MO, 6 MO, 12 MO Special interest for vascularization 21

22. Clinical Data : Efficacy  3 Months data available for 51 subjects  6 Months data available for 51 subjects  12 Months data available for 50 subjects  18 Months data available for 30 subjects  Parameters: VAS KOOS IKDC Lysholm score

23. *p=0.007 22.9 point change in mean VAS from baseline* Efficacy at 12 Months -22

24. Efficacy at 12 Months 24.8 point change in mean IKDC from baseline* *p=0.0012

25. 22.4 point change in mean Lysholm from baseline* *p=0.0036 Efficacy at 12 Months

26. KOOS Symptoms *p=0.0371 13.4 point change in mean KOOS Symptoms from baseline* Efficacy at 12 Months

27. *p=0.0117 16.7 point change in mean KOOS Pain from baseline* Efficacy at 12 Months

28. *p=0.0197 16.2 point change in mean KOOS Daily Living from baseline* Efficacy at 12 Months

29. *p=0.0020 30.7 point change in mean KOOS sports from baseline* Efficacy at 12 Months

30. *p=0.0143 21.9 point change in mean KOOS quality of life from baseline* Efficacy at 12 Months

31. 31 Anatomical results Relook at 1 year FU –Biopsie and histological evaluation –27 biopsies samples No signs of necrosis or cells death Biocompatibility Successful tissue ingrowth No loose fragments of scaffold 31

32. Relooks L-M 8001 Photos courtesy of Dr Djian, Paris, France

33. Relooks R-L 1016 Photos courtesy of Professor R Verdonk, Ghent, Belgium

34. Relooks 9003 Photos courtesy of Professor Bellemans, Leuven, Belgium

35. Histology Results Biopsy from center of free inner edge N= 27

36. Histology Results  Fibrous capsule (C)  layer 1: vascular, hyper cellular  layer 2: avascular, transition zone  layer 3: avascular, hypo cellular

37.  Fibrous capsule  layer 1: vascular, hyper cellular  layer 2: avascular, transition zone  layer 3: avascular, hypo cellular Histology Results

38. CD 34 IHC (200x) showing capsule, formation of vessel “sprouts” (arrows) in layer 1 Capsule and Layer 1 Histology Results

39. Sirius Red stain (400x) Layer 2 fibroblasts (short arrow) and fibrochondroblastic-like cells (long arrow) Layer 2

40. Histology Results H&E staining : chondroblast like cells in layer 3 Layer 3

41. Histology Results Immunohistochemistry (400x) with positive cartilage marker S100 Layer 3

42. Imaging Protocol  Anatomic MR imaging at 1 week, 3, 12 and 24 months post-implantation  Dynamic Contrast Enhanced MRI (DCE-MRI) at 3 months  Imaging in first 3 minutes after IV gadolinium injection  Influx of gadolinium causes increase in the signal Intensity (SI) of a tissue  Signal enhancement is primarily determined by vascularization, but also by perfusion rate and capillary permeability [1, 2]  Increase in SI in the first 3 minutes can only be explained by the presence of blood vessels 37

43. Imaging Findings 1 Week  No loosening of sutures or tears of the scaffold were found.  All scaffolds had a normal position of the posterior horn.  Some mild or moderate extrusion of the body of the scaffold was observed. 38

44. Imaging Findings 3 Months  Increased enhancement observed in the peripheral half of the scaffold, and thus evidence of tissue ingrowth into the scaffold in 36/42 (85.7%) subjects with DCE-MRI at 3 months post-implantation. 39

45. Imaging Findings 3 Months  In 32 out of 48 subjects complete filling of the meniscal defect was observed.  17 subjects had slight ( 33%, <66%)) external displacement of the body of the scaffold meniscus. 40

46. Imaging Findings 12 Months  In all subjects tissue gain was achieved with complete fill of the meniscal lesion in 10 out of 33 subjects. Complete filling of the meniscal defect at 12 months in subject with an autologous osteochondral plug transfer to repair a pre-study osteochondral defect overlying the scaffold. 41

47. Imaging Findings 12 Months  3/33 subjects had improved cartilage scores in the index compartment. Filling of cartilage defect in the area overlying the tissue populated scaffold. 42

48. Imaging Findings 12 Months  3/33 subjects had a deteriorated cartilage scores in the index compartment. Of these, two had generalized deterioration of the knee and one had developed a focal defect in an area not in direct contact with the scaffold. Focal defect in area not adjacent to scaffold 43

49. 49 Discussion No comparative data Need to augmente the F.U. Cartilage status 15 years F.U 49

50. 50 Discussion Prospective study Clinical data and safety evaluation Anatomical evaluation with relook and biopsies MRI and vascularization 50

51. Safe – No SADEs – Biocompatible Vital cell populations in all biopsies Promotes ingrowth of meniscus like tissue in 85.7% – Meniscus like morphology in biopsies – Positive staining for chondroblasts Effective – Significant improvements of pain and functionality Easy to use – Sizing, cutting, positioning, suturing – Visible on MRI 44

52. Conclusion Actifit ™ is a safe, novel solution for the treatment of irreparable, partial, meniscal defects 45