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  1. 1. journal club (22-10-09)<br />topic : autologuschondrocyte implantation<br />
  2. 2. topic : autologuschondrocyte implantation<br />MODERATOR :<br /><ul><li>DR M.BANSAL (M.S. ,D.N.B.)
  3. 3. DR. P .GUPTA (M.S.)</li></ul> SPEAKER :<br /> PRIYANK GUPTA<br />
  4. 4. THE ROLE OF AUTOLOGOUS CHONDROCYTE IMPLANTATION (ACI) IN THE TREATMENT OF ARTICULAR CARTILAGE DEFECTS IN THE KNEE JOINT <br />J. A. L. Hart; and J. Paddle<br />PURPOSE: To define the role of ACI in treatment of cartilagedefects in the knee joint.<br />METHOD: 106 articular cartilage defects in 79 knees of 77 patientswere treated by ACI as described by Brittberg et al, 1994. <br />-43.5%of the lesions involved the patella, <br />-35.2% the femoral condyles,<br />-16.7% the trochlea, and <br />-4.6% the tibial condyles. <br />-20% of kneeshad more than one defect. <br />Associated biomechanical procedureswere carried out in 88.7%.<br />
  5. 5. RESULTS:ASSESSEDARTHROSCOPICALLY 9 MONTHS AFTER IMPLANTATION<br /><ul><li>70 lesions in 58 knees and 56 patients
  6. 6. 4 eligible patientswere not assessed.
  7. 7. The average ICRS repair score (maximum 12)was as follows:</li></ul>-Tibialcondyle 11.5 (4 defects); <br />-Patella 11.3(32 defects); <br />-Femoral condyle 11.0(23 defects) <br />-Trochlea10.7 (11 defects). <br /><ul><li>Synovitis was markedly reduced in all kneeswith well healed defects.
  8. 8. Contraindications to ACI in this serieswere:</li></ul>-Non-contained defects-Bi-polar lesions,-Patients greaterthan 45 years,-Uncorrected biomechanics,-Regional pain syndrometype 1,-Limited joint movement,-Defective subchondral boneplate.<br />CONCLUSION:ACI EFFECTIVELY REPAIRS ARTICULAR CARTILAGE DEFECTSIN THE KNEE JOINT, PROVIDED THAT THE CONTRAINDICATIONS ARE RECOGNISED.Unlike other series, the results for the patella, patellofemoraljoint have matched those for the femoral condyle. This is attributedto the simultaneous biomechanical correction of the patellofemoraljoint. Stabilisation of the articular surface results in resolutionof synovitis.<br />
  9. 9. AUTOLOGOUS CHONDROCYTE GRAFTS: MULTICENTRIC TRIAL WITH 28 KNEE IMPLANTATIONS WITH MORE THAN TWO YEARS FOLLOW-UP<br />Journal of Bone and Joint Surgery - British Volume, Vol 90-B, Issue SUPP_II, 252<br />Purpose of the study: Spontaneous repair of lost deep chondraltissue is minimal in the knee joint. <br />A clinical trial of chondrocyteautografts as described by Brittberg and Peterson was undertakenby the Nantes University Hospital and the French Society ofArthroscopy in 1999.<br />
  10. 10. Material and methods: Twenty-eight patients,<br /> mean age 28 years,underwent surgery in eight centers.<br /> Etiologies were:<br />osteochondritis(n=14), <br />isolated posttraumatic chondorpathy (n=7), <br />chondropathyand full-thickness ACL tear (n=7). <br />All lesions involved thecondyles and were deep (ICRS grds 3 and 4).<br /> Mean surface areainvolved after debridement was 490 mm2 (range 150–1000mm2).<br /> Patients were followed three years after the autologousgrafting to assess functional outcome. <br />An MRI was obtained at2–3 years. <br />Thirteen control arthroscopy procedures wereperformed including<br /> eight with biopsy specimens for histologyand immunohisto-chemistry studies.<br />
  11. 11. RESULTS: Twenty-six patients were reviewed at &gt; 2 yrs<br /><ul><li> There were no general complications,
  12. 12. Three patients presenteda partial avulsion of the graft treated by arthroscopy and oneunderwent arthrolysis at six months.
  13. 13. FUNCTION improved in allpatients except three and pain improved in all.
  14. 14. THE ICRS SCOREimproved from 43 points (range 19–70) to 77 points (range39–84).
  15. 15. Sixteen control MRIs were available and showedthat
  16. 16. the graft was hypertrophic in eleven cases,
  17. 17. on level infour, and insufficient in one.
  18. 18. Marginal integration was goodin 11 cases and partial in five.
  19. 19. Subchondral integration wascomplete in ten cases and mediocre in six.
  20. 20. THE ARTHROSCOPICSCORE was nearly normal (score 8–11) in eight cases andabnormal in five (score 4–7).
  21. 21. THE HISTOLOGICAL CLASS accordingto Knutsen (hyaline richness) was:
  22. 22. one in group 1 (>60%),
  23. 23. three in group 2 (> 40%),
  24. 24. four in group 3 (<40%) and
  25. 25. onein group 4 (bony or fibrous tissue).
  26. 26. Function score (r=0.78and MRI score (r=0.76) were correlated with arthroscopic sores.There was no correlation with the histological results.</li></ul>DISCUSSION:CLINICAL OUTCOME WAS IMPROVED IN MORE THAN 80% OFCASES, SIMILAR TO RESULTS REPORTED FOR HISTOLOGICAL SERIES.The arthroscopic and histological results were equivalent tothose reported by Knutsen but inferior to those reported byBentley or Peterson.<br />
  27. 27. Articular Cartilage<br /><ul><li>Chondrocytes (cartilage cells) </li></ul> embedded in a<br /><ul><li>Highly specialised E.C.M.
  28. 28. Gives elasticity
  29. 29. Provides resistance to tensile,compressive and shear forces
  30. 30. Acts as a smooth , efficient surface for motion. </li></li></ul><li>Hyaline Cartilage Structure􀂋The “stuff” of cartilage:<br /><ul><li>Functions of the Articular Cartilage :</li></ul>– Distribute load<br />– Absorb shock<br />
  31. 31. Chondral Injuries:<br />Commonly these injuries heal by scar tissue formation :<br />
  32. 32. Prevalence and Incidence<br /><ul><li>993 consecutive arthroscopies – 66% articular cartilage pathology, 11% full thickness, localised lesions suitable for repair procedures</li></ul>Aroen A, Loken S, Heir S, et al. Am J Sports Med 2004; 32: 211-15<br /><ul><li>31000 arthroscopic procedures – 63% articular cartilage lesions</li></ul>Curl WW, Krome J, Gordon ES, et al. Arthroscopy 1997; 13: 456-60<br /><ul><li>1000 consecutive arthroscopies – 19% localised chondral/osteochondral lesions</li></ul>Hjelle K et al. Arthroscopy 2002; 18: 730-4<br />
  33. 33. Cartilage Injury Occurs in Many Forms<br /><ul><li>Trauma</li></ul>sports or work related<br /><ul><li>Chronic instability</li></ul>long term effects: ACL and other<br />meniscal deficiency<br /><ul><li>Mal-aligned joint - deformity</li></ul>varus / Valgus<br /><ul><li>OsteochondritisDissecans [OCD]
  34. 34. Genetic pre-disposition / early</li></ul>arthritis<br />
  35. 35. Articular Cartilage Defects :a treatment challenge<br />• Most full-thickness defects are symptomatic<br />– Pain, swelling, locking, catching, grinding<br />• Left untreated,may progress to significant articular defects<br /><ul><li>May lead to debilitating</li></ul>osteoarthritis. <br />
  36. 36. AND, WHAT IS IN OUR BASKET ????<br /><ul><li>Arthroscopic Debridement :
  37. 37. Arthroscopic lavage
  38. 38. Subchondral drilling
  39. 39. MicrofractureMARROW STIMULATION </li></ul> TECHNIQUES<br /><ul><li>Abrasion arthroplasty</li></ul> -to induce the growth of fibrocartilage into the chondral defect.  <br />(This fibrocartilage does not withstand shock or shearing force as well as the original hyaline cartilage, and may deteriorate over time.)<br />
  41. 41. AutologousChondrocyte Implantation (ACI) :BACKGROUND<br /><ul><li>JBJS [Am], 1987 Peterson et al, Gothenburg,– first application of cell engineering in orthopaedics
  42. 42. NEJM, 1994 Brittberget al, Sweden,– successfuly regenerated hyaline-like cartilage in isolated chondral defects.</li></li></ul><li>Identifying a Carticel® Patient<br />Patient Factors:<br /><ul><li>Younger patients –</li></ul> &lt; age 45 - 50 (avg. ~ 35 y.o.)<br /><ul><li>Significant impairment:</li></ul>-Compromised daily living<br />activities. <br />-Refractory to treatment<br /><ul><li>Obesity
  43. 43. Demanding Physical activities
  44. 44. Willing & capable of </li></ul>rehabilitation program<br />
  45. 45. Identifying a Carticel® Patient…….<br />Joint Factors:<br /><ul><li>Symptomatic cartilage defects </li></ul>-Moderate to large (&gt; 2cm2 d.= 1.6)<br /> -On the distal femur (mfc / lfc /trochlea)<br />-Average defect size &gt; 4 cm2<br /> -Either chondral or osteochondral<br /><ul><li>Relatively healthy joint – </li></ul> -No arthritis<br /><ul><li>Co-morbidities(meniscal tear, instability or malalignment) must be corrected prior or concurrent to implantation.</li></li></ul><li>Pre-requisite for surgery :<br /><ul><li>Appropriate biomachenical alignment
  46. 46. Ligamentousstabilty
  47. 47. Range of motion</li></ul>Not recommended for patients who have :<br /><ul><li>an unstable knee
  48. 48. patients sensitive to materials of bovine origins
  49. 49. allergic to the antibiotic gentamicin
  50. 50. in children
  51. 51. yet in any joint other than the knee.</li></li></ul><li>AutologousChondrocyteImplantation (ACI)<br /><ul><li>Strengths:
  52. 52. Can produce hyaline-like cartilage.
  53. 53. Can fill defects regardless of size with functional repair tissue.
  54. 54. Moderate to large defects that have failed previous intervention.
  55. 55. Repair tissue which matures , rather than deteriorates over time.
  56. 56. Expected outcome
  57. 57. Return to previous level of functioning</li></ul>“Biological Joint replacement”<br /><ul><li>Limitations
  58. 58. More invasive
  59. 59. Expense
  60. 60. Longer recovery </li></li></ul><li>ACI – Periosteum (cells under periosteum)<br />ACI – Chondrogide (cells under membrane)<br />MACI – Matrix Induced ACI (cells on membrane)<br /><ul><li>Chondrogide Membrane
  61. 61. Porcine type I/III
  62. 62. Inert Seal
  63. 63. Resorbs in 3-4 months </li></ul>ACI<br />MACI<br />Techniques :<br />
  64. 64. ACI/MACI Generic Method<br />Cells grown on monolayer with patients serum<br />Harvest 200-300mg full thickness cartilage from trochlea (non load bearing)<br />No. cells x 20-30<br />Under inert collagen membrane (ACI)<br />On inert collagen membrane (MACI)<br />
  65. 65. ACI Method<br />
  66. 66. Treatment with CARTICEL <br />Uses your own cartilage cells (chondrocytes) to repair the articular cartilage damage in your knee. When implanted into a cartilage injury, your own cells can form new cartilage; this new cartilage is very similar to your original cartilage. The CARTICEL implantation procedure is called AutologousChondrocyte Implantation or ACI. It is a two-step process. <br />Step 1: Biopsy<br />Knee Cartilage Arthroscopy and Biopsy<br /><ul><li>During an arthroscopic procedure, surgeon assesses the extent of cartilage damage & pt. as a candidate for CARTICEL implantation
  67. 67. “Biopsy” of healthy tissue about the size of a pencil eraser i.e. about 200 -300 mg.
  68. 68. From outer edge of sup. Med. or lat. Femoral condyle or inner edge of lat. Femoral condyle at the intercondylar notch.
  69. 69. This sample is sent to product labs.</li></li></ul><li><ul><li>Biopsy can be stored for up to two years, so you can schedule your surgery at your convenience.
  70. 70. When you are ready, your cells are cultured ; over three to five weeks they increase to approx. 12 million cells in a vial containing 0.3 – 0.4 cc of medium.
  71. 71. Every step of the manufacturing process is monitored to ensure high quality and safety. </li></ul>CARTICEL Manufacturing and Delivery<br />
  72. 72. Step 2: Implantation<br />Cartilage Injury Cleaned<br /><ul><li>During this second stage arthrotomy done to expose knee and any dead or damaged tissue from the injury removed with curette, leaving only healthy tissue.
  73. 73. Biomachenicalallignment procedures if required should be done in conjunction with implantation.</li></li></ul><li>CARTICEL Implantation<br />
  74. 74. Periosteal Patch<br />surgeon takes a small piece of tissue from your shin bone and sews it securely over the injury.<br />CARTICEL Implantation<br /> surgeon injects CARTICEL under the patch.When CARTICEL is surgically implanted into a cartilage injury, it can grow and form new hyaline-like cartilage, with properties similar to those of the original cartilage. <br />Repairing the injury helps to reduce pain and improve movement and function.<br />
  75. 75.
  76. 76.
  77. 77. Aci steps :summarised<br />
  78. 78. MACI Method<br />Cultured chondrocytes seeded in bilayeredtypeI/III collagen membrane<br />Implanted using fibrin glue<br />Matrix remodelled in months, replaced by extracellular matrix regenerate<br />
  79. 79. Complications<br /><ul><li>The overall failure rate is at present quoted as being 10%.
  80. 80. The two most common complications include :
  81. 81. loosening of the transplant tissue,
  82. 82. formation of fibrous tissue at the repair site and adhesions with return of pain and locking.
  83. 83. Neither of these complications usually leaves the patient in a worse condition than his/her pre-transplantation state.
  84. 84. Other adverse events include :
  85. 85. post-op haematoma (big blood clot)
  86. 86. hypertrophic synovitis (angry knee) and superficial wound infection.</li></li></ul><li>ASSESMENT OF TECHNIQUE :<br />Improvements <br />in ClinicalOutcome:<br />: FOLLOW UP results<br />
  87. 87. One Year Assessment<br /><ul><li>Radiographs
  88. 88. Alignment
  89. 89. Bone quality
  90. 90. MRI
  91. 91. Healing cartilage
  92. 92. Graft failure
  93. 93. Arthroscopy + probe
  94. 94. Graft integrity
  95. 95. Pressure
  96. 96. biopsy</li></li></ul><li>FOLLOW UP: Biopsy<br />
  97. 97. FOLLOW UP: MRI<br />
  98. 98. Final appearance of the<br />periosteum sutured over<br />femoral condyle defect. The<br />cartilage cells have been<br />injected under the flap and the<br />final suture placed to close the<br />&quot;cover&quot; and provide a watertight<br />seal.<br />FOLLOW UP: ARTHROSCOPIC<br />Arthroscopic appearance of the<br />same area 12 months after<br />Carticel™ implantation. The<br />defect is no longer visible and<br />there is now hyaline cartilage<br />(biopsy proven) filling the<br />original defect site.<br />
  99. 99. Rehabilitation guidelines<br />Immobilization: first 12-24 hours<br />(CPM): after 12-24 hours, for about 4 weeks<br />Complete joint loading: <br />from about 5th week trochlea/patella<br />from about 8th week condyle<br />Back to sports: Low impact -> within 6 months<br />Repeated impact -> from 8th month<br />High impact -> from 10-12th month<br />
  100. 100. ACI Rehabilitation<br />Weight bearing<br />It is recommended to keep you in non-weight bearing until the second week after surgery (ACI). You can increase the weight bearing gradually and you may be able to sustain your full weight bearing after 6 to 12 weeks from surgery.<br />Range of motion<br />Recovery on your ROM (Range of Motion) is gradually increased with a continuous passive motion (CPM) machine and may be completed to 140 degrees of ROM at 6 weeks to 12 weeks after surgery<br />
  101. 101. ACI Rehabilitation<br />Indoor exercise<br />You can strenghthen your muscles surrounding the knee joint with a four point exercise, as well as isometric, hamstring and squatting exercises, from 4 weeks to 6 weeks after surgery.<br />You may start performing stationary bike activity without resistance and increase the resistance gradually.<br />Outdoor exercise<br />At 13 weeks after surgery you can start walking lightly and at 10 months after surgery you can perform jogging and then you may enjoy intensity exercise like playing tennis or volleyball from 18 months after surgery. <br />Rehabilitation Goals at 12 weeks after ACI<br />Full ROM (Range of Motion) <br />Minimal edema level <br />Minimal occasional pain <br />Pain free tolerance to transitional phase exercise with adequate stability and motor control<br /> <br />
  102. 102. COMPARISON WITH OTHER METHODS OF TREATMENTS :<br />AutologousChondrocyte Implantation <br />Aims to increase the best condition for cartilage defect.<br />Advantages:<br /><ul><li>Hyaline cartilage is formed
  103. 103. Permanent reconstructed cartilage tissue
  104. 104. Most valuable treatment
  105. 105. With Fourth Generation ACI:Use of cell – gel mixture (collagen, hyaluronic acid and fibrin) has fast gelling properties (1 – 5 min) upon transplantation
  106. 106. No membrane or periosteal patch
  107. 107. Minimal surgical exposure and reduced surgery time.
  108. 108. Corrects evenly irregular defect shapes
  109. 109. Applicable to larger defects</li></ul>  <br />
  110. 110. COMPARISON WITH OTHER METHODS OF TREATMENTS……….<br />Abrasion arthroplasty<br />Aims to decrease the inflammation of the joint.<br />Disadvantages:<br /><ul><li>Removes many cartilage fragments from the joint
  111. 111. Symptoms reoccur within one year</li></ul>Drilling and MicrofractureAims to generate a healing response.<br />Disadvantages:<br /><ul><li>The healing response in inadequate
  112. 112. No hyaline cartilage is formed, but rather fibrocartilage
  113. 113. Has a limited lifespan of approximately one year
  114. 114. Rapid deterioration after such procedures can be expected</li></li></ul><li>COMPARISON WITH OTHER METHODS OF TREATMENTS……….<br />Perichondral ResurfacingDisadvantages:<br /><ul><li>Isolated cartilage defects are often too large to be covered byhperichondrum
  115. 115. Long term follow-up of such procedures indicate that the implants undergo endochondral ossification</li></ul>Synthetic Materials (i.e. Carbon Fiber Mesh)<br />Disadvantages:<br /><ul><li> It often results in fibrous tissue formation
  116. 116. Not adequate biomechanically
  117. 117. Often the cause for synovitis in the joints</li></ul>Osteocartiloginous GraftsAims to reconstruct joints.<br />Disadvantages:<br /><ul><li>Unless fresh cartilage is transplanted, the cartilage is dead
  118. 118. Fresh grafts are not commonly used, as they inevitably carry a risk of disease transmission
  119. 119. Cyropreserved grafts can survive for many years, but ultimately deteriorate</li></li></ul><li><ul><li>Results of the Carticel™ procedure have been encouraging although it is not always successful. An analysis was done of the U.S. and Swedish registry of 153 consecutive patients undergoing this procedure with follow-up from 1 week to 94 months. The following results were obtained:
  120. 120. Patients with clinical improvement 85%
  121. 121. Good or Excellent results 42%
  122. 122. Good or Excellent results at 2 years</li></ul>persisting at 5 years post-op 97%<br /><ul><li>Thus, a total of 85% of patients showed some or complete improvement with the</li></ul>implantation technique. The Carticel procedure demonstrated good durability at 5-10 years out.<br />CONCLUSIONS<br />
  123. 123. Conclusions :ACI Vs MACI<br /><ul><li>No current evidence to justify aggressive treatment of asymptomatic lesions with ACI/MACI
  124. 124. Patients with full thickness symptomatic defects do poorly if left untreated
  125. 125. ACI and MACI lead to significant improvement in objective and patient reported clinical outcome scores for up to ten years</li></ul> (even among those with previous failed marrow stimulation techniques)<br /><ul><li>MACI has a superior rate of clinical improvement in comparison to ACI
  126. 126. Repair tissue may remodel and improve in quality with time
  127. 127. ACI and MACI comparable at 6 years</li></li></ul><li>Recent advances:HYAFF 3D matrix<br />HYAFF biomaterials<br />contain high quantities of<br />derivatized HA<br />HA-rich,<br />chondrocyte compatible<br />embryonic-like mileu<br />conductive to regenerative<br />healing patterns<br />
  128. 128. • Non woven felt, 2 mm thick, fiber diameter 10 microns.<br />• Chondrocytes are isolated, and passaged in culture on plastic<br />dishes up to 3 weeks.<br />• Cells are seeded for 2 weeks on HYAFF scaffold at a density of<br />1 x 106 / cm2, resulting in a total of 4 x 106/ cm2 seeded cells per<br />graft.<br />HYAFF-based Scaffold<br />
  129. 129. CHONDRON™<br />Uses a cell – gel mixture (includes collagen, hyaluronic acid and fibrin) that has fast gelling properties (1 – 5 min) upon transplantation.<br />This cell and gel mixture enable even cell distribution three-dimensionally, moldable to fit irregular defect shape and applicable to a larger defect.Thus there is minimal surgical exposure and reduced surgery time.  <br />(three-dimensional reconstruction of a chondron from the growth plate of the murine long bone. the model was generated from multiple sections imaged in an electron microscope. plasma membranes are coloured green and internal organelles are visible within the top cell.)<br />
  130. 130. RECOVERY TO <br />HEALTHY ACTIVE LIFE<br />
  131. 131. THANK YOU<br />