Chondrotransplant DISC

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Chondrotransplant DISC

  1. 1. Content In vitro characterization – of co.don chondrotransplant ® DISC Animal trial - feasibility Indications Background Manufacturing of co.don chondrotransplant ® DISC Application of co.don chondrotransplant ® DISC Autologous Disc-derived chondrocyte Transplantation (ADCT)
  2. 2. Background Degenerative disc disease (DDD) <ul><li>Early stage </li></ul><ul><li>Loss of disc tissue due to disc </li></ul><ul><li>herniation </li></ul><ul><li> Progression of degeneration </li></ul><ul><li>Development of chronic back </li></ul><ul><li>pain </li></ul><ul><li> Significant recurrence rate </li></ul><ul><li>Late stage </li></ul><ul><li>Fusion </li></ul><ul><li>Loss of mobility </li></ul><ul><li>Artificial disc </li></ul><ul><li>Persistent back pain </li></ul><ul><li>Therapy failure </li></ul>
  3. 3. Background Degenerative disc disease (DDD) Early stage  Loss of disc tissue due to sequestrectomy  Progression of degeneration  Development of chronic back pain  Significant recurrence rate <ul><li>Late stage </li></ul><ul><li>Loss of mobility </li></ul><ul><li>Artificial disc </li></ul><ul><li>Persistent back pain </li></ul><ul><li>Therapy failure </li></ul>? Transplantation of autologous disc-derived cells (ADCT) ?
  4. 4. Indication <ul><li>Indications </li></ul><ul><li> stage after sequestrectomy </li></ul><ul><li>progressive degeneration of the Nucleus pulposus </li></ul><ul><li>stage after decompression </li></ul><ul><li>expansion of indication for discogenic pain and dark disc </li></ul><ul><li>adults up to approx. 55 years of age </li></ul>Transplantation of autologous disc-derived cells For  biological repair of disc tissue  functional and structural regeneration  prevention/delay progressive degeneration  avoiding spinal fusion
  5. 5. Content In vitro characterization – of co.don chondrotransplant ® DISC Animal trial - feasibility Indications Background Manufacturing of co.don chondrotransplant ® DISC Application of co.don chondrotransplant ® DISC Autologous Disc-derived chondrocyte Transplantation (ADCT)
  6. 6. In vitro processing of disc-derived chondrocytes Sequester tissue Isolation of disc chondrocytes Expansion of disc chondrocytes Disc cells in monolayer Cell cultures Sequestrectomy
  7. 7. In vitro characterization of co.don chondrotransplant ® DISC low cell density high cell density Fig.: Proliferation curve. Proliferation of disc-derived cells
  8. 8. Phenotype of disc chondrocytes Anulus fibrosus (AF), Nucleus pulposus (NP) and Co-culture (CC) cultures:  constant expression of biglycan , decorin , aggrecan , CEP68 , collagen types I and III  decreasing expression of S100 in higher passages  no expression of collagen type II Fig.: Decorin mRNA Expression in CC ML cultures. In vitro characterization of co.don chondrotransplant ® DISC M P1 P2 P3 P4 P5 P6 P7
  9. 9. <ul><li>adhesion of cultured disc derived chondrocytes to </li></ul><ul><li>native tissue </li></ul><ul><li>cell migration into tissue fissures </li></ul><ul><li>filling of fissures by de novo synthesized matrix </li></ul>Adhesion and Integration of cultured disc chondrocytes disc-derived cells native disc tissue In vitro characterization
  10. 10. <ul><li>Improved differentiation of disc derived chondrocytes in co- </li></ul><ul><li>cultures </li></ul><ul><li>disc specific markers expressed and secreted by co-cultures </li></ul>Regenerative Capability of human disc chondrocytes  contribution to regenerative processes following disc-derived chondrocyte transplantation In vitro characterization of co.don chondrotransplant ® DISC
  11. 11. Experimental Model Animal trial Pressure measurement fluoroscopic control <ul><li>12 months follow up </li></ul><ul><ul><ul><ul><ul><li>15 mixed-bred dogs </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>lateral vertebral plate debridement </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>use of nucleus and lateral anulus tissue </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>autologous disc cells with own serum </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>no addition of antibiotics/fungistatics </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>L1-L2 damaged & no cell transplantation </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>L2-L3 control disc </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>L3-L4 damaged & disc cell transplantation ( ADCT ) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>after pressure measurement and </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>under fluoroscopic control </li></ul></ul></ul></ul></ul>Animals: Disc damage: Cell transplants: Experimental groups:
  12. 12. Progressive disc healing induced by ADCT <ul><li>Damaged discs: </li></ul><ul><li>dense scar tissue, </li></ul><ul><li>marrow fibrosis & edema </li></ul><ul><li>ADCT-treated discs: </li></ul><ul><li>reduced marrow blanching, </li></ul><ul><li>lucent matrix appearance, </li></ul><ul><li>less scarred, </li></ul><ul><li>reestablishment of vertebral margin </li></ul>L3-L4 ADCT L1-L2 damaged Animal trial <ul><li>Disc height differences after 1year: </li></ul><ul><li>dam./control & dam./ADCT significant </li></ul><ul><li>control/ADCT not significant </li></ul>
  13. 13. Structural restoration of intervertebral disc induced by ADCT <ul><li>homogenous cell distribution </li></ul><ul><li>complete fibrous reconstruction </li></ul><ul><li>regenerate with disc-specific </li></ul><ul><li>composition </li></ul><ul><li>homogenous tissue structure </li></ul><ul><li>no signs of vascularization and necrosis </li></ul>12 months, damaged disc. 12 months, damaged & ADCT treated disc. intact disc . Animal trial
  14. 14. Positive BrdU-stained cell nuclei within ADCT-treated disc levels. Identification of transplanted BrdU-labeled disc derived cultured chondrocytes Animal trial
  15. 15. Damaged disc: ADCT-treated disc:  Pericellular positive SafraninO staining for transplanted chondrocytes  Loss of SafraninO staining within defect area.  No pericellular staining. Intact disc: Compositional restoration of the intervertebral disc <ul><li>SafraninO staining </li></ul><ul><li>of disc interior </li></ul>x25 x100 x25 x200 x25 Animal trial
  16. 16. x200 x100 Strong staining for collagen type II.  Intercellular and p ericellular positive collagen type II staining  Low expression of collagen type I Compositional restoration of the intervertebral disc ADCT-treated disc: Intact disc: Low staining for collagen type I. x25 x25 Animal trial x25 x25
  17. 17. <ul><li>Feasibility: </li></ul><ul><li>human nucleus and anulus cells can be propagated in vitro </li></ul><ul><li>freezing/thawing does not affect cell viability </li></ul><ul><li>transplantation is technically feasible </li></ul><ul><ul><li>pressure validation </li></ul></ul><ul><ul><li>minimally invasive </li></ul></ul><ul><li>Outcome: </li></ul><ul><li>no progressive disc degeneration </li></ul><ul><li>maintenance of disc height </li></ul><ul><li>de novo matrix generation through transplanted cells </li></ul><ul><li>well integrated de novo synthesized matrix </li></ul><ul><li>complete fibrous reconstruction </li></ul><ul><li>maintenance of segmental mobility </li></ul><ul><li>contribution of transplanted cells to observed clinical success of pilot </li></ul><ul><li>trials </li></ul>Ganey et al., 2004, Spine Induction of intervertebral disc regeneration by ADCT Conclusion Animal trial
  18. 18. Content In vitro characterization – of co.don chondrotransplant ® DISC Animal trial - feasibility Indications Background Manufacturing of co.don chondrotransplant ® DISC Application of co.don chondrotransplant ® DISC Autologous Disc-derived chondrocyte Transplantation (ADCT)
  19. 19. co.don chondrotransplantDISC ® <ul><li>Autologous manufacturing using the Integrated Isolator Technology (IIT) </li></ul><ul><li>Regulated as a biological therapeutic: </li></ul><ul><ul><li>Manufacturing permission according </li></ul></ul><ul><ul><li>to the German drug law §13 since 1997 </li></ul></ul><ul><ul><li>Quality-Management-System DIN EN ISO </li></ul></ul><ul><ul><li>9001:1994/2000 guideline 91/356/EWG </li></ul></ul><ul><ul><li>Good Manufacturing Practices (GMP) for </li></ul></ul><ul><ul><li>pharmaceutical products WHO 1993 </li></ul></ul><ul><ul><li>Guidelines for pharmaceutical Companies in </li></ul></ul><ul><ul><li>Germany </li></ul></ul><ul><ul><li>ISO 14644-1 for the clean room </li></ul></ul><ul><ul><li>PIC/S-guideline (Pharmaceutical Inspection- </li></ul></ul><ul><ul><li>Convention) </li></ul></ul>Integrated Isolator Technology (IIT) Regulation of human TE products in Germany
  20. 20. Manufacturing of co.don chondrotransplant ® DISC Doc. Doc. Doc. Agreement co.don ® AG Biopsy and Blood obtaining Xmedika Biopsy kit Surgeon Biopsy kit Xmedika new Biopsy kit Shipment via courier, within 48h to co.don® AG
  21. 21. Isolation of disc-chondrocytes by enzymatical digestion, monolayer culture, In-Process control Lock in of Biopsy and Serum into the isolator Quality control Manufacturing of co.don chondrotransplant ® DISC Doc. Doc. Doc. Doc. Doc. co.don ® AG Production IIT (Integrated Isolator Technology) Preparation of Biopsy and Serum Receiving control
  22. 22. Expansion of disc-chondrocytes in monolayer Manufacturing of co.don chondrotransplant ® DISC Doc. Doc. Doc. Doc. Expansion of disc- chondrocyte transplants If necessary freezing of monolayer cells & recultivation Arrangement of the transplantation appointment between co.don ® AG, Xmedika and surgeon
  23. 23. Completion of the product including packing and labeling Quality control Final inspection & Product release Shipment of co.don chondrotransplant ® DISC and under LHO condition u sing an courier organized by co.don ® AG, Xmedika Durability : 43h Manufacturing of co.don chondrotransplant ® DISC Doc. Doc. Doc. Doc. Doc. Doc. Xmedika / Surgeon Transplantation
  24. 24. Biopsy Kit Biopsy Kit <ul><li>Evaluated and standardized shipment conditions </li></ul><ul><li>Standardized packaging </li></ul><ul><li>Qualified supplier for raw materials </li></ul>
  25. 25. <ul><li>Disc biopsy obtaining </li></ul><ul><li>- Discectomy </li></ul><ul><li>- Discectomy combined by nucleotomy </li></ul><ul><li>Endoscopy (e.g. endoscopic alligator forceps d=1.3mm) </li></ul><ul><li>Decompression (e.g. using a decompressor, avoiding heating and only by short application) </li></ul>Manufacturing of co.don chondrotransplant ® DISC
  26. 26. Transplant Kit Transplant Kit <ul><li>Evaluated & standardized shipment conditions </li></ul><ul><li>Standardized packaging </li></ul><ul><li>In time delivery (limited durability) </li></ul><ul><li>theoretical and practical training of surgeons </li></ul>
  27. 27. Placement of the needle for application of chondrotransplant DISC. under fluoroscopic control; application of chondrotransplant DISC without fluoroscopic control <ul><li>Transplantation (ADCT) </li></ul><ul><ul><li>under local anesthesia </li></ul></ul><ul><ul><li>placing injection needle under into nucleus area under fluoroscopic control </li></ul></ul><ul><ul><li>percutaneous injection of chondrotransplant ® DISC contralateral to the site of disc herniation </li></ul></ul>Application of co.don chondrotransplant ® DISC Vial with co.don c hondrotransplant ® DISC co.don chondrotransplant ® DISC shipment under LHO conditions .
  28. 28. Application of co.don chondrotransplant ® DISC Injection needle <ul><li>puncture needle = injection needle: e.g. 21G </li></ul><ul><li>or </li></ul><ul><li>-use of puncture needle (e.g. 19G) and injection needle (22G) </li></ul>
  29. 29. <ul><li>1 ml tube containing cell transplant storage on ice till injection needle was placed </li></ul><ul><li>Re-suspending cell solution by gentle shaking </li></ul><ul><li>Transferring into a e.g. 1ml syringe using a cannula (> 22G) </li></ul>Application of co.don chondrotransplant ® DISC Transplantation
  30. 30. Indication – Contraindication <ul><li>Indications </li></ul><ul><li> stage after sequestrectomy </li></ul><ul><li>progressive degeneration of the </li></ul><ul><li>Nucleus pulposus </li></ul><ul><li>stage after decompression </li></ul><ul><li>expansion of indication for </li></ul><ul><li>discogenic pain and dark disc </li></ul><ul><li>adults up to approx. 55 years of </li></ul><ul><li>age </li></ul><ul><li>Contraindications </li></ul><ul><li>chronic inflammations or chronic </li></ul><ul><li>degenerative spine diseases </li></ul><ul><li>(i.e. spondylarthrosis) </li></ul><ul><li>previous chemo- and thermonucleolysis </li></ul><ul><li>of the affected intervertebral disc </li></ul><ul><li>uncontained anulus fibrosus </li></ul><ul><li>Modic Changes >2 </li></ul><ul><li>pregnancy </li></ul><ul><li>infectious diseases (Hep C,HIV I+II ) </li></ul>

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