FUNCTIONAL AND RADIOLOGICAL EVALUATION OF AUTOLOGOUS CHONDROCYTE IMPLANTATION USING A TYPE I/III COLLAGEN MEMBRANE: FROM SINGLE DEFECT TREATMENT TO EARLY OSTEOARTHRITIS. William Brett Robertson (MSc., MAAESS AEP) Volume I A thesis submitted to the School of Surgery and Pathology (Orthopaedics) and the School of Human Movement and Exercise Science at the University of Western Australia as requirement for the degree of Doctor of Philosophy. October, 2006
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FUNCTIONAL AND RADIOLOGICAL EVALUATION OF AUTOLOGOUS CHONDROCYTE IMPLANTATION USING A TYPE I/III COLLAGEN
MEMBRANE: FROM SINGLE DEFECT TREATMENT TO EARLY OSTEOARTHRITIS.
William Brett Robertson (MSc., MAAESS AEP)
Volume I
A thesis submitted to the School of Surgery and Pathology (Orthopaedics) and the School of Human Movement and Exercise Science at the University of Western
Australia as requirement for the degree of Doctor of Philosophy.
October, 2006
ACKNOWLEDGEMENTS
The author wishes to express his sincere appreciation to the following people for their
significant contributions over the course of his PhD canditure. This research thesis
would not have been possible without their involvement:
To my Supervisors. Firstly, Professor David Wood, for providing the initial impetus for
this study and for all of his support and assistance. Secondly, Professor Timothy
Ackland, for all of his time, patience and valuable counsel. I could not have asked for
better supervisors. It has been an honour and a privilege.
To Dr Daniel Fick and Dr James Linklater for their invaluable help with the
development of the MRI scoring system and for all of the countless hours they sent
scoring MRI scans. You are both true gentlemen.
To all of my subjects for their time, patience and shear hard work over the course of this
study.
Finally to my parents, Eric and LeAnne for their love, counsel and support for which I
consider myself truly blessed.
ii
To Anitra, my Wife, with all my Love
Every obstacle yields to stern resolve.
Leonardo da Vinci
iii
CONTENTS
Page
VOLUME ONE
Chapter One – The Problem 1
Introduction 1
Significance of the study 2
Requisite Research 3
Issues with Rehabilitation 5
Justification of the study 5
Thesis structure 7
Definition of terms 11
Chapter Two – Review of literature 13
Chapter Three – Standard Practice Exercise Rehabilitation Protocol 33
Rehabilitation Program Aims and Rationale 42
Pre surgery program (8 weeks) 47
Post surgery program (1 year) 51
- phase 1 (0 to 3 weeks) 56
- phase 2 (4 to 6 weeks) 57
- phase 3 (7 to 12 weeks) 57
- phase 4 (3 to 6 months) 59
- phase 5 (6 to 9 months) 60
- phase 6 (9 to 12 months) 60
Exercise Progression Summary 62
iv
Frequently Asked Questions 63
Return to Elite Level Competition 66
References 67
Appendices to Chapter 3 70
VOLUME TWO Chapter Four – MRI and Clinical Evaluation of Collagen-Covered Autologous
Chondrocyte Implantation (CACI) at Two Years 114
Abstract 116
Introduction 117
Materials and Methods 118
Results 127
Discussion 131
Acknowledgements 136
References 137
Chapter Five – MRI and Clinical Evaluation of Matrix-Induced Autologous
Chondrocyte Implantation (MACI) at Two Years 148
Abstract 150
Introduction 151
Materials and Methods 153
Results 159
Discussion 163
Conclusion 167
Acknowledgements 169
References 169
v
Chapter Six – Combined High Tibial Osteotomy and Matrix-Induced
Autologous Chondrocyte Implantation (MACI) for early
Osteoarthritis of the Knee 179
Abstract 181
Introduction 182
Methods 185
Results 190
Discussion 193
Conclusion 196
Acknowledgements 196
References 197
Chapter Seven – Summary, Recommendations and Conclusion 205
Summary 205
Recommendations for Future Research 208
Conclusions 211
Appendix One – Combined Anteromedialisation Tibial Tubercle Osteotomy
and Autologous Chondrocyte Implantation (C-ACI & MACI)
for the Treatment of Isolated Chondral Defects of the
Patellofemoral Joint.
vi
Appendix Two – An Australian Experience of ACI and MACI
In G. Bentley (ed) Current Developments in Autologous
Chondrocyte Transplantation. The Royal Society of
Medicine Press Ltd, London, 2000 pages 7 – 16.
vii
CHAPTER ONE
THE PROBLEM
INTRODUCTION
Hyaline articular cartilage is a highly specialised tissue consisting of chondrocytes
embedded in a matrix of proteoglycan and collagens. Hyaline articular cartilage
withstands high levels of mechanical stress and continuously renews its extracellular
matrix. Despite this durability, mature articular cartilage is vulnerable to injury and
disease processes that cause irreparable tissue damage. Native hyaline articular
cartilage has poor regenerative capacity following injury, largely due to the tissue’s lack
of blood and lymphatic supply, as well as the inability of native chondrocytes to migrate
through the dense extracellular matrix into the defect site. Articular cartilage injuries
that fail to penetrate the subchondral bone plate evoke only a short-lived metabolic and
enzymatic response, which fails to provide sufficient new cells or matrix to repair even
minimal damage. Clinically, it has previously been accepted that treatment of such
defects does not result in the restoration of normal hyaline articular cartilage, which is
able to withstand the mechanical demands that are placed on the joint during every day
activities of daily living.
The concept of autologous chondrocyte implantation (ACI) began almost four decades
ago [75], but only recently has the technique become a viable therapeutic option
[11,31,63]. The first evidence supporting ACI came from animal studies by Peterson et
al. [63]. This work led to human trials and subsequently, ACI using periosteal
membrane (PACI) has become a well-established technique for the treatment of
articular cartilage defects, with evidence of improved joint function and formation of
hyaline or hyaline-like cartilage [6,12,34,41,42,64].
1
The four cornerstones for successful outcome following ACI are:
1. GMP standard cell culture and stability of cell phenotype;
2. Effective surgical procedure;
3. Complimentary postoperative rehabilitation; and
4. Patient cooperation.
Historically, rehabilitation following ACI has not kept pace with the advances in cell
culture and surgical technique. Subsequently, there exists a significant gap in
knowledge regarding ‘best practice’ in post operative rehabilitation following ACI. The
importance of structured rehabilitation in ACI should not be underestimated when
evaluating the clinical success of this chondral treatment. Patients should not be left to
their own devices following ACI surgery, as the risk of damage to their implant (via
delamination) is high if immediate postoperative movement is not controlled.
Furthermore, the biological longevity and clinical success of the graft is dependent on a
controlled and graduated return to ambulation and physical activity, and the
biomechanical stimulation of the implanted chondrocytes.
SIGNIFICANCE OF THE STUDY
Articular cartilage defects of the knee occur commonly in sports injury and trauma,
often affecting the young. From 1993 to 1997, over 210,000 knee arthroscopies were
performed on patients below the age of 55 in Australia alone. At least five percent of
this patient population were diagnosed with full thickness cartilage defects [20]. In an
unfavourable location (i.e. medial femoral condyle), such defects may progress and lead
to premature degeneration of the articulating surface of the joint. The repair tissue
formed in response to these procedures consists of fibrocartilage, which does not
possess the biomechanical or biochemical properties of hyaline articular cartilage. End
2
stage osteoarthritis of the knee is commonly treated by total arthroplasty, but this
presents further problems for the younger age group including limited life span of the
prosthesis, prosthesis loosening, bone fracture and the possible risk of infection [18,
22,25,33].
Requisite Research
In Australia, there was a sequential evolution of the ACI technique from the
conventional periosteum covered ACI (PACI), to the use of a porcine collagen type I/III
membrane sutured as a periosteal substitute (CACI). The CACI technique was then
further modified to the current practice of a): first seeding the cultured autologous
chondrocytes onto the cambium layer of the type I/III membrane and then, b):
implanting the cell-seeded membrane as a single construct via the matrix-induced
Status: Submitted to British Journal of Bone and Joint Surgery,
(31/10/2006), under review.
Finally, a summary and conclusions chapter provides a synthesis of these studies in
order to demonstrate the advancements made in the body of knowledge relating to ACI
procedures. Special emphasis on rehabilitation, and post-surgery evaluation of the
morphology of repair and patient function, are the cornerstones of this thesis.
Changes in style and language
References for chapters 1-2 and chapter 7 are listed at the end of this thesis, and all
figures and tables within these chapters are listed in numerical order. Chapters 4-6 are
presented in the required manuscript format of the journal to which they were submitted
for publication, so some variation in language and style may arise in these chapters. All
references in these chapters are specific to that paper only and are listed at the back of
each individual chapter.
Ancillary Work
The following ancillary work, invited conference presentations and presentations to
learned societies were conducted during my PhD candidature.
Appendix 1: Combined anteromedialisation tibial tubercle osteotomy and
autologous chondrocyte implantation (C-ACI & MACI) for the
treatment of isolated chondral defects of the patellofemoral joint.
Ledger M., Robertson W.B., Fick D., Wood D.J., Zheng M.H. and
Ackland T.R.
9
Status: Submitted to Australian and New Zealand Journal of
Orthopaedics, (31/10/2006), under review.
Appendix 2: An Australian experience of ACI and MACI.
Wood D., Zheng M.H., and Robertson B.
In G.Bently (ed) Current Developments in Autologous Chondrocyte
Transplantation. The Royal Society of Medicine Press Ltd, London,
2000 pages 7-16..
Invited Conference Presentation
6th International Cartilage Repair Society (ICRS) Symposium, San Diego, CA, United States of America. January 8-11th 2006. Comprehensive Approaches to Articular Cartilage Disorders, Etiology, Pathogenesis and Management “All roads meet in Rome”. Invited to present at the Rehabilitation Session entitled: Cartilage repair rehabilitation: A multidisciplinary approach to challenges, controversies and future directions. Presentation Topic: (7a-C) “Biomechanics of Cartilage Repair Rehabilitation: The Perth Experience.”
Presentations to Learned Societies
Invited Speaker: Garvan Institute of Medical Research, Matrix-Induced Autologous Chondrocyte Implantation Workshop, 384 Victoria St Darlinghurst, Sydney, 27th November 2003.
Invited Speaker: Orthopaedic Learning Centre, The Chinese University of Hong Kong, Matrix-Induced Autologous Chondrocyte Implantation Workshop, 1/F Li Ka Shing Specialist Centre, North Wing, Prince of Wales Hospital, Shatin N.T., Hong Kong, November 2002.
Invited Speaker: Royal National Orthopaedic Hospital NHS Trust, Cartilage transplantation user group meeting, “Perioperative Rehabilitation for the ACI patient: An Australian Perspective”, Royal National Orthopaedic Institute, Stanmore, United Kingdom, 24th June 2002.
Invited Speaker: Sir Hector Stewart Surgical Club Symposium, Autologous Chondrocyte Implantation Workshop, “Functional Rehabilitation of ACI”, CTEC University of Western Australia, 2nd Entrance Hackett Drive Crawley WA 6009. 31st May 2002.
Invited Speaker: Orthopaedic Learning Centre, The Chinese University of Hong Kong, Frontiers of cell based tissue engineering in orthopaedics: Autologous chondrocyte implantation workshop. Orthopaedic
10
Learning Centre, 1/F Li Ka Shing Specialist Centre, North Wing, Prince of Wales Hospital, Shatin N.T., Hong Kong. 13th November 2001.
Invited Speaker: Royal National Orthopaedic Hospital NHS Trust, Cartilage transplantation user group meeting, “Perioperative Rehabilitation for the CACI patient: An Australian Perspective”, Royal National Orthopaedic Institute, Stanmore, United Kingdom. December 2000.
DEFINITION OF TERMS
The following terms used throughout this thesis require definition, as follows:
This material does not constitute medical advice. It is intended for informational purposes only. All rights reserved. The material included in this publication, is solely for the purpose of education, treatment or rehabilitation of patients within your facility. Reproduction of materials in advertising or in other publications is not permitted. No other comerical or non-comercial use of the ‘Standard Practice Exercise Rehabilitation Protocols for Matrix-Induced Autologous Chondrocyte Implantation: Femoral Condyles is permitted, without the prior permission of the copyright owner.
Outcomes: By one year post surgery patients are expected to achieve the following:
1. Able to perform all activities of daily living;
2. Able to commence return to running program, for example: walk/jog,
jog/run, run on soft surface (grass or soft sand only); and
3. Resume dynamic recreational activities. However, sports with high
knee loading and twisting or shear forces are to be avoided.
Please note that all sport and recreational activities involve an element of risk regardless of knee condition and patients should make a value judgement regarding their personal safety prior to participation.
- MACI is indicated for symptomatic full thickness weight-bearing chondral injuries of the articular surfaces of the femoral condyles, trochlea groove, patella and talar dome in physiologically young patients. The procedure is designed for the treatment of symptomatic unipolar lesions. Defects that are grades 3 or 4 on the Outerbridge classification of chondral injuries and have no greater that grade 1 to 2 changes on the opposing surface are amenable to treatment using MACI.
2. WHAT ARE THE PATIENT SELECTION GUIDELINES?
- Patients are selected along the following guidelines based on the Swedish clinical experiences of Lars Peterson, the pioneer of ACI technology:
• Size and depth: <10cm2 down to intact subchondral bone plate;
• Aetiology: trauma or osteochondritis dissecans;
• Age: 15 – 55 years;
• Joint condition: absence of progressive inflammatory or osteoarthritis;
• Joint stability: absence of menisectomy or instability;
• Abnormal weight bearing: absence of significant varus/valgus
abnormality, patella maltracking or obesity > 50% body weight (Metropolitan Life Index); and
• Compliance with rehabilitation: must be able, willing.
3. IF A PATIENT HAS ENDSTAGE OSTEOARTHRITIS AND IS SCHEDULED FOR TOTAL KNEE ARTHROPLASTY, ARE THEY CANDIDATES FOR MACI?
- No. If a patient is scheduled for knee replacement, the joint degeneration has progressed beyond the treatment parameters of MACI.
4. IS MACI SUITABLE TO REPLACE TORN CARTILAGE?
- There are two types of cartilage in the knee, firstly the joint lining and secondly the menisci, which act as shock absorbers between the two joint surfaces. It is the joint lining that is suitable for MACI. The so called “torn cartilage” or meniscus is not suitable for this kind of technique although research is currently being conducted on the development of transplant menisci and this technology will be available in time.
5. IS MACI SUITABLE FOR TREATING RHEUMATOID
ARTHRITIS?
- No. Progressive inflammatory or rheumatoid arthritis would simply continue to erode the area of repair.
6. WHY ISN’T MACI RECOMMENDED FOR PEOPLE OVER THE AGE OF 55?
- The chondrocyte cells of older patients do not grow as successfully as those from young patients. In addition, the articular cartilage within the knees of patients over 55 years are usually too damaged for the procedure to be beneficial.
7. IS MACI SUITABLE TO TREAT CARTILAGE DEFECTS IN OTHER JOINTS OF THE BODY?
- Whilst MACI is restricted currently to treatments of defects within the knee, ankle and shoulder joints, the use of MACI for articular cartilage defects in other joints is under investigation.
8. WHEN SHOULD PATIENTS COMMENCE DRIVING FOLLOWING SURGERY?
- Approval needs to be obtained from the operating surgeon; however, it has been our experience that patients are usually are given clearance to recommence driving approximately 4/6 weeks following implantation.
9. WHEN SHOULD PATIENTS RETURN TO WORK FOLLOWING SURGERY?
- Upon clearance from the operating surgeon, but timing also depends on the demands of the job. For example, it has been our experience that patients can return to desk jobs after three weeks.
10. WHAT IS THE LENGTH OF HOSPITAL STAY FOLLOWING IMPLANTATION?
- This depends on the extent of the surgery and whether there are any post surgery complications. Most patients are generally are eligible for discharge after three to four days.
11. SHOULD PATIENTS CONTINUE TO TAKE ANTI-INFLAMMATORY MEDICATION FOLLOWING MACI?
- This is not recommended, but check with the operating surgeon.
12. ARE CARTILAGE SUPPLEMENTS SUCH AS GLUCOSAMINE AND CHONDROTIN SULPHATE BENEFICAL PRIOR TO AND FOLLOWING MACI?
- The benefits have yet to be proven, however, patients may take these supplements if the operating surgeon agrees.
13. WHAT HAPPENS TO THE TYPE I/III COLLAGEN MEMBRANE FOLLOWING IMPLANTATION?
- Animal studies conducted by the School of Surgery and Pathology, UWA, indicate that the type I/III collagen membrane used in the MACI procedure degrades over time. It was discovered that in the mouse model 50% of the implanted membranes had completely disappeared 21 days following implantation. According to Associate Professor Ming-Hao Zheng from the School of Surgery and Pathology, UWA, the extent of degeneration of the collagen membrane depends on the degree of cross linking of the collagens and the elastin content. In humans the degradation of the membrane is thought to be complete by the six months postsurgery.
14. WHEN SHOULD PATIENTS RECOMMENCE HIGH IMPACT SPORT AND RECREATION ACTIVITIES?
- Approval needs to be obtained from the operating surgeon, however, it has been our experience that return to heavy manual work, sport and recreational activities should be carefully controlled and gradually progressed. Although the cartilage defect may be filled with hyaline-like cartilage within the first few months, it is not advisable to undertake resisted knee extension or activities, such as squats or running before 12 months post-surgery. Maturation and hardening of the new-formed cartilage will not be complete until this time.
There exists great individual variation between patients (including age, defect size, defect location and type of auxiliary procedure performed in conjunction with MACI) that must be taken into consideration whilst considering a player’s long term outcome and ability to return to competition at an elite level. It is our experience that patients accrue the full functional benefits from MACI between the first and second year following surgery. Cartilage implantation is not a quick-fix procedure, but a highly specialised and involved biological regeneration process. Cellular regeneration, matrix production and adaptation of the regenerating tissue to natural function, takes time and it is unrealistic and impractical to expect players to return to elite competition within the first postoperative year. We advise that patients suffering from an isolated, well contained defect on the medial femoral condyle should be given the benefit of the doubt and recommence playing after an appropriately managed rehabilitation program of sufficient intensity and duration. The long term prognosis of this patient sub-group is excellent and it is reasonable to expect that they will be able to return to elite competition. The elite level playing potential of patients that suffer from defects on the lateral femoral condyle, patella, trochlea groove or from multiple defects and those that have undergone MACI in conjunction with a ligamentous reconstruction or have meniscal damage, is uncertain and should be evaluated using the following criteria:
• Overall value of the patient as a player; • Have undergone clinical assessment with an orthopaedic surgeon appropriately
experienced with the results of MACI; and • The commitment and psychological profile of the player.
1. Curl WW, Krane J, Gordon ES, Rushing J, Smith BP, and Poehling GG.
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2. March LM and Bachmeier CJ. Ecomonics of osteoarthritis: a global perspective. Baillieres Clin Rheumatol 1997; 11(4):817-834.
3. Nerher S, Spector M and Minas T. Histological analysis of failed cartilage repair procedures. Clin Orthop 1999; 365:149-162.
4. Willers C, Wood D, and Zheng MH. A current review on the biology and treatment of articular cartilage defects (part I & part II). Journal of musculoskeletal research 2003; 7(3&4):157-181.
5. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O and Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994; 331(14): 889-895.
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13. Briggs TWR, Mahroof S, David LA, Flannelly J, Pringle J and Bayliss M. Histological evaluation of chondral defects after autologous chondrocyte implantation of the knee. J Bone Joint Surg 2003; 85[Br]:1077-1083.
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Date of Referral: ______________ Date of Initial Assessment: _______________
Name Date of Birth
Address Phone No:
(Wk) (Mb)
GP Other Referring Specialist Insurance Company or Health Fund Address & Contact
Claim/Ref No Phone No Fax No
Approval Fax : Date Sent / / Date Approved: / /
1. DESCRIPTION OF CLIENTS CONDITION AT PRESENTATION: Date of Injury/Surgery: ____/____/____ 2. MEDICAL HISTORY 3. GENERAL HEALTH / OTHER HEALTH PROBLEMS: (CHD, Diabetes, Asthma, other
KNEE INJURY AND OSTEOARTHRITIS OUTCOME SCORE (Roos, E., et al., 1998).
Appendix C
SUBJECT No: ___________________ TEST : PRE / POST______ DATE:________ Instructions: Please tick ( ) the most appropriate response.
PAIN Never Monthly Weekly Daily Always
1. How often is your knee painful? What degree of pain have you experienced in the last week when…..? None Mild Moderate Severe Extreme 2. Twisting/pivoting on your knee 3. Straightening your knee fully 4. Bending knee fully 5. Walking on a flat surface 6. Going up or down stairs 7. At night while in bed 8. Sitting or lying 9. Standing upright
SYMPTOMS None Mild Moderate Severe Extreme 1. How severe is your stiffness after first
waking in the morning? 2. How severe is your stiffness after
sitting, lying or resting later in the day?
3. Do you have swelling in your knee? 4. Do you feel grinding, hear clicking, or
any other type of noise when your knee moves?
5. Does your knee catch or hang up when moving?
6. Do you have any difficulty
straightening your knee fully? 7. Do you have any difficulty bending your knee fully?
What degree of difficulty (not pain) have you experienced in the last week….? None Mild Moderate Severe Extreme 1. Descending stairs 2 Ascending stairs 3 Rising from sitting 4 Standing 5 Bending to floor/pick up object 6 Walking on flat surface 7 Getting in/ out of car 8 Going shopping 9 Putting on socks/ stockings 10 Rising from bed 11 Taking off socks/ stockings 12 Lying in bed (turning over maintaining
knee position)
13 Getting in/out of bath or shower 14 Sitting 15 Getting on/ off toilet 16 Heavy domestic duties (shoveling,
scrubbing floors etc.)
17 Light domestic duties (cooking, dusting)
SPORT AND RECREATION FUNCTION
What difficulty have you experienced in the last week ….? None Mild Moderate Severe Extreme 1. Running 2. Jumping 3. Turning/Twisting on you injured knee 4. Kneeling 5. Squatting
KNEE-RELATED QUALITY OF LIFE Never Monthly Weekly Daily Always
1. How often are you aware of your knee problems?
Not at all Mildly Moderately Severely Totally
2. Have you modified your lifestyle to avoid potentially damaging activities to your knee?
3. How troubled are you with lack of
confidence in your knee?
None Mild Moderate Severe Extreme 4. In general, how much difficulty do
you have with your knee?
------------------------------------------------------------------------------------------------------------------------ Official Use Only ---------------------------------------------------------------------------------------------------------- Score all items from 0 = Best 4= Worst Scale Possible Raw Actual Transformed
Score Range Raw Score Score 0-100 Pain 36 Symptoms 28 ADL 68 Sport/Rec 20 QOL 16 Transformed scale = 100 – Actual raw score x 100 Possible raw score range ----------------------------------------------------------------------------------------------------------
Patient category: A. Unilateral B. Unilateral with other knee symptomatic C. Bilateral D. Multiple joint involvement or medical infirmity Patient Details: Pt No: DOB: Name: Height: Tester’s Name: Weight: Assessment (circle & date) Pre-op: Date: Blood Pressure: Post-op: Date: Knee: L / R
- Support the remainder of the body’s weight on the left leg;
- Place the right hand on your right buttock, directly behind the right hip;
- Use the right hand to push the right hip forwards as far as comfortable;
- Holding this position, bend the left knee and arch the back slightly to allow
your body weight to push down and stretch the front of the right hip;
- Hold for 20 seconds and return to the starting position;
- Repeat on the opposite side.
5. Groin
a. Adductor stretch
- Sit on the floor;
- Place the heels together and pull the feet towards the groin;
- Use the elbows to help push the thighs towards the floor;
- Look forward, keeping the back straight;
- Hold the final position for 20 s.
6. Calf
a. Gastrocnemius stretch
- Stand close to the wall;
- Extend one leg behind you keeping the knee straight, and slightly flex the
front knee;
- Keeping the heels on the floor, lean into the wall, focusing on stretching the
upper calf of the rear leg;
- Hold the final position for 20 s and repeat on the opposite side.
b. Soleus stretch
- Stand close to the wall;
- Extend one leg behind you keeping the knee straight, and slightly flex the
front knee;
- With both feet facing forward transfer your weight onto the rear leg and bend that knee;
- Focus on stretching the lower calf of the rear leg;
- Hold the final position for 20 seconds, repeat on the opposite side.
* Adequate emphasis to be placed on additional stretching that may be deemed necessary to individual patients, to be decided at the therapists’ discretion.
c. Isometric quadriceps (with muscle stimulation).
7. Foot Plantar Flexors
a. Standing heel raises.
8. Trunk Flexors*
a. Trunk flexion: resistance machine; or
b. Partial sit-up.
9. Shoulder/Arm Flexors and Extensors*
a. Reverse lateral pulldown;
b. Tricep extension (resistance machine); and
c. Bicep curls: free weights.
* Adequate emphasis to be placed on trunk and upper body strengthening and endurance in order to assist with postoperative bed to chair transfers and crutch walking.
MACI KNEE: Appendix H PRE SURGERY HYDROTHERAPY PROGRAM
(See Appendix N for description of italicized exercises)
Water depth for presurgery patients is dependent on severity of knee pain (eg. intense pain = deeper water).
1. Introductory Activity - WALKING (10 minutes)
Patients cued for improved gait pattern without use of the guard-rail. a. Forwards b. Backwards c. On toes - forwards and backwards d. Side stepping, Left and Right 2. Stretching (5 minutes)
In the standing position, patients use the wall or ladder for active stretching exercises.
a. Hamstring group b. Quadriceps group c. Thigh adductor group d. Thigh flexor group e. Calf (gastrocnemius & soleus)
3. Knee ROM
a. Floatation assisted flexion b. Gentle ROM Lunge
4. Strengthening for Knee, Hip and Ankle
A selection of these exercises are included if the subject has completed a clinic program. Exercises begin in the buoyancy assisted position and progressed to buoyancy resisted exercises (with floats added to the extremity for resistance).
a. Heel raise b. Thigh flexion/extension c. Thigh abduction/adduction d. Diagonals e. Thigh circles
5. Exercise Program in Deep Water
A selection of these exercises are carried out using appropriate floatation equipment.
Vertical position
a. Abduction adduction of legs b. Straight leg flexion/extension
MACI KNEE: Appendix IPRE SURGERY HOME EXERCISE PROGRAM GUIDELINES
GENERAL INSTRUCTIONS 1. Remember to exercise within a pain-free/pain tolerant range of motion if possible.
2. Brace abdominal muscles to protect your low back when performing strength
exercises.
3. Flexibility and strength exercises should be performed slowly.
4. If an exercise causes undue pain or discomfort, discontinue that exercise until you
have spoken to your therapist.
5. Monitor your pain/discomfort level both before and after exercise using a 0 to 10
scale.
If your pre-exercise pain level is elevated for 2 hours or more after exercise then you have either done too much, or you have performed the exercise incorrectly. Contact the clinic.
6. Breathe normally when performing the flexibility exercises.
7. Do not hold your breath when performing the strength exercises. Try to breathe
out during the hardest part of the exercise.
9. Complete the exercise log to keep a track of your progress. This is very important.
If you cannot complete the number of sets or repetitions, write down the number you have done. Do not complete more repetitions than advised.
STRENGTH (See Appendix O for description of italicized exercises)
Teach Abdominal Bracing to protect lower back whilst performing strength
activities 1. Thigh abductors a. Side lying abduction (ankle weights) 2. Thigh adductors a. Side lying adduction (ankle weights) 3. Thigh Extensors
a. Prone thigh extension (ankle weights) - straight leg - bent knee
b. Isometric gluteals 4. Thigh Flexors
c. Seated hip flexion (ankle weights) - standing - seated
5. Leg Flexors (open chain)
d. Prone leg flexion (ankle weight) e. Standing leg flexion (ankle weight)
6. Leg Extensors (open chain) a. Straight leg raises (ankle weights) b. 45° straight leg raises (ankle weights) 7. Plantar Flexors a. Standing heel raises
8. Shoulder/Arm Flexors and Extensors
d. Bicep curls: free weights e. Tricep extension: free weights
Courtesy of HPH Physiotherapy Services (For further information please contact Hollywood Private Hospital, Monash Avenue, NEDLANDS, WA 6009. Ph: (08) 9346 6000)
Orders specified on the operation report override routine protocol. These MUST be documented & read by the therapist prior to treatment
ACI CARTILAGE IMPLANTATION
KNEE ARTHROSCOPY/ MENISECTOMY
Precautions
Must wear brace at all times
Encourage ↓ activity levels 1/52
to allow wound healing
Inpatient Exercise
Day 1-2
1 hour CPM 0-30 ° or as tolerates (Consultant must specify safe range in post-op orders before any
physiotherapy intervention)
Wear Brace while exercising SQ, IRQ, SLR, ROM exercises (outlined in ex handout)
Day 0 or 1
SQ, IRQ, SLR, ROM exercises
(outlined in ex handout)
Ambulation
Day 1 Touch WB (< 20%) with brace on
Practice stairs prior to D/C
Day 0 or 1 mobilise with crutches (if required)
Practice stairs prior to D/C
Rehabilitation Following D/C
Provided with Physiotherapy D/C letter
↑rom flexion aim 60° by 3/52, 90° 6/52, full 12/52 Progressive ↑WB aim one crutch by 8/52
Advised when to safely cease use of crutches Follow-up physiotherapy usually not required
Date of Operation: Name: Unit No: MACI: (use sticker if available) Surgical Approach (tick): Incision Size: cm Medial parapatellar Lateral Defect Details: Mid vastus Defect Size: mm X mm Other Details: Defect Location (please indicate):
Auxiliary Procedures (tick): ACL reconstruction Details: PCL reconstruction Medial ligament reconstruction Lateral ligament reconstruction Oesteotomy Tibial tubicle transfer Menisectomy Other (please specify): Lateral Release: Yes / No Extent of soft tissue release: lateral patellofemoral ligament (please tick) other (please specify) Patella Tracking: Satisfactory / Unsatisfactory Technical Problems? (please specify) Surgery Time mins Tourniquet Time mins Hospital: Surgeon/Doctor: Signature: Date:
Post surgery between weeks 2-6: patients must exercise in deep water (xiphoid process to C7 levels).
1. Introductory Activity - WALKING (15 minutes)
Patients cued for improved gait pattern without use of the guard-rail. a. Forwards b. Backwards c. Side stepping, Left and Right 2. Stretching (5 minutes)
In the standing position, patients use the wall or ladder for active stretching exercises. a. Hamstring group* b. Quadriceps group* c. Adductors group* d. Thigh flexor group* e. Calf (gastrocnemius & soleus)*
3. Knee ROM
a. Floatation assisted flexion* b. Gentle ROM lunge* c. Floatation assisted quadriceps stretch*
4. Strengthening for Knee, Hip and Ankle
A selection of these exercises are included if the subject has completed a clinic program.
Exercises begin in the buoyancy assisted position and progressed to buoyancy resisted exercises (with floats added to the extremity for resistance).
a. Thigh abduction/adduction b. Thigh flexion/extension c. Thigh circles d. Heel raise e. Diagonals f. Thigh half “clock”
5. Exercise Program in Deep Water
A selection of these exercises are carried out using appropriate floatation equipment.
Vertical position a. Abduction/adduction of legs
b. Straight leg flexion/extension c. Bicycle/running movements with legs*
Advanced Postsurgery Exercises in the prone position a. Flutter kick * b. Step ups* c. Squats* d. Squat lunge variations*
6. Proprioception Activities Complexity of activities increases from week 9 to week 24 postsurgery
a. Single leg balance – eyes open/closed b. Side step - crossover Left & Right * c. Bouncing, jogging, hopping interspersed with single leg balance *
* Therapist will indicate at which stage the exercise is to be included in program.
During Phase 1, when full weight bearing on land is contraindicated, partial weight bearing exercises can be commenced in water depth at the level of the
xiphoid process.
Walking - Forwards Time: 5 minutes
Patient walks forward with emphasis on bilateral heel-to-toe motion;
Patients who have difficulty with gait or lack confidence in the water can begin forwards walking at the side of the pool using the guide rail.
Walking - Backwards Time: 5 minutes
Patient walks backwards with emphasis on bilateral toe-to-heel motion;
Patients who have difficulty with gait or lack confidence in the water can begin backwards walking at the side of the pool using the guide rail.
Walking - Sideways Time: 5 minutes
Patient walks sideways with feet in neutral position, placing emphasis on maintaining straight legs;
Patients who have difficulty with gait or lack confidence in the water can begin sideways walking at the side of the pool using the guide rail.
Thigh Abduction/Adduction Sets: Reps:
Patient is stationary, abducts the thigh while weight bearing on non-operated leg and supported by rail. Motion paused for 2 seconds at end and beginning of range.
Emphasis is placed on correct upright posture, with abdominal bracing.
Patient is stationary. Perform movements of the thigh whereby the final poses approximate the position of half of the numbers on an analog clock face.
The patient begins by flexing the thigh of the operated limb to “12 o’clock”, and then extends to neutral. This movement is repeated through to “6 o’clock”, with the numbers in between gauging the angle at which motion is to occur.
Movement paused for 2 seconds at end and beginning of range.
Emphasis is placed on correct upright posture, with abdominal bracing.
Flotation Assisted Flexion Time: 2-5 minutes
Patient is stationary with floatation device attached to the leg. Performs leg flexion, focusing on using the ‘floaty’ to assist the movement. Patient bears weight on non-operated leg and is supported by rail. Motion paused for 2 seconds at beginning and end of range.
Emphasis is placed on correct upright posture, with abdominal bracing.
Gentle AROM Lunge Time: 2-5 minutes
Patient initially stands stationary supported by rail. The knee of the operated limb is flexed to 90 degrees by placing the foot on a low box or step. The knee must be inline with the ankle. Focus is placed on increasing range of knee movement by slowly moving knee over and beyond the toes. Motion paused for 2 seconds at end of range.
Emphasis is placed on correct upright posture, with abdominal bracing.
During Phase 3, when full weight bearing on land is being gradually introduced, weight bearing exercises can be performed in water depth at the level of the
umbilicus. COMMENCE….
Walking - Forwards Time: 5-10 minutes
Patient walks forward with emphasis on bilateral heel-to-toe motion;
Patients who have difficulty with gait or lack confidence in the water can begin forwards walking at the side of the pool using the guide rail.
Walking - Backwards Time: 5-10 minutes
Patient walks backwards with emphasis on bilateral toe-to-heel motion;
Patients who have difficulty with gait or lack confidence in the water can begin backwards walking at the side of the pool using the guide rail.
Walking - Sideways Time: 5-10 minutes
Patient walks sideways with feet in neutral position, placing emphasis on maintaining straight legs;
Patients who have difficulty with gait or lack confidence in the water can begin sideways walking at the side of the pool using the guide rail.
COMMENCE (Week 8/9): Single Leg Balance Time: 2-5 minutes
Patient is stationary, flexes non-operated thigh so as to be bearing weight on operated leg, then attempts to maintain balance for 10 seconds, assisted by rail (when needed). Emphasis is placed on correct upright posture, with abdominal bracing.
Cycling
Time: 2-5 minutes
The patient moves to the corner of the pool. Facing the inside of the pool, with the arms supported by the rails, the patient lifts the legs off the floor, so that the trunk and lower limb are suspended in the water.
A cycling motion is then initiated with the legs. Emphasis is placed on improving knee and hip ROM and muscular coordination.
Thigh Abduction/Adduction
Time: 2-5 minutes
The patient moves to the corner of the pool. Facing the inside of the pool, with the arms supported by the rails, the patient lifts the legs off the floor, so that the trunk and lower limb are suspended in the water.
While maintaining knee extension, the patient abducts the thighs to their end of range, and then adducts them to neutral. Motion paused for 2 seconds at end of range.
This movement is then repeated for the desired time.
Thigh “Scissors”
Time: 2-5 minutes
The patient moves to the corner of the pool. Facing the inside of the pool, with the arms supported by the rails, the patient lifts the legs off the floor, so that the trunk and lower limb are suspended in the water. While maintaining knee extension, the patient performs a “scissor-like” movement of the legs by reciprocally flexing and extending the thighs.
Patient stands facing the step. Proceeds to step up straight ahead with the operated leg. Emphasis on maintaining balance, with correct upright posture, and abdominal bracing.
Retro Step-Up Sets: Reps:
Patient stands with back to step. Steps up backwards with the operated leg.
Emphasis on maintaining balance, with correct upright posture, and abdominal bracing.
Lateral Step-up Sets: Reps:
Patient stands with operated side parallel the steps. Proceeds to step up side ways. Emphasis on maintaining balance, with correct upright posture, and abdominal bracing.
Patient moves to the termination point of the entry rails to the pool. Using the rails on either side as support, the patient performs a squat movement. The trunk and back should be kept straight, with the gaze directed forward. The body is lowered by flexing the thighs and hips, until leg flexion reaches 90 degrees. The knees and thighs are then extended and the body is elevated to neutral.
Squat Lunge Variations
Sets:
Reps:
Patient stands stationary. Performs a standard lunge, followed by lunges in various directions (ie. to the side and diagonal lunges). Emphasis is placed on correct upright posture, with abdominal bracing.
“Patter” Kick Time: 2 minutes
With the aid of a floatation device, the patient executes a kicking action sufficient to maintain motion across the pool. Emphasis is placed on keeping the body horizontal.
Sit on the arm ergometer with the feet on the foot rests.
By gripping the handles, and performing a cycling motion with the arms, maintaining the set work load.
The emphasis is on cardiovascular fitness and endurance.
Thigh Adduction Sets: Reps: Load:
Sit on the machine, placing the feet in the foot rests, with the thighs pressing against the thigh pads. Grip the handles of the machine. While exhaling, pull the legs in together until they touch. Hold this position for 2 seconds before returning to the start position. Inhale as you return to the start position.
Thigh Abduction Sets: Reps: Load:
Sit on the machine, placing the feet in the foot rests, with the thighs pressing against the thigh pads. Grip the handles of the machine. While exhaling, push the legs apart as far as they can go. Hold this position for 2 seconds before returning to the start position. Inhale as you return to the start position.
Seated Leg Curls Sets: Reps: Load:
Sit on the leg flexion machine with your legs straight, and your ankles resting on the roller pad.
Lower the leg restraint over your thighs to secure them.
Grasp the handles provided on each side. Exhale as you bend your knees to move the roller pad downwards.
PROGRESSIONS: Supine to ¼ Seated Leg Raise Sets: Reps:
Rest upon elbows in ¼ seated position.
Bend knee of non-affected side to flatten lumbar spine.
Lock knee of affected side and lift leg to a height parallel to the thigh of the bent knee.
Lower leg under control.
45° Side Leg Raises Sets: Reps:
Bend knee of non-affected side to flatten lumbar spine.
Lock knee of affected side, and externally rotate the thigh by pointing the toes outwards 45 degrees.
Lift leg to a height just below the opposite the bent knee,
Lower leg under control.
Seated Leg Curls (single leg) Sets: Reps: Load:
Sit on the leg flexion machine with your legs straight, and your ankles resting on the roller pad.
Lower the leg restraint over your thighs to secure them.
Grasp the handles provided on each side. Exhale as you bend the knee of the operated limb (whilst keeping the non-affected leg extended) to move the roller pad downwards.
Stand with the back against wall, and the heels placed about a thighs length from the wall. Using the wall as support, slowly lower the trunk until the thighs are parallel to the floor. Hold the position for 3 seconds
Tighten the thigh muscles as you return to the starting position.
Increase intensity by holding end position for 10 – 20 seconds.
Leg Extension - Single Legged Sets: Reps:
Sit on a chair, with your hips and knees both flexed to 90 degrees.
Slowly extend the involved knee, until it is completely straight.
The thigh should remain stationary, and only movement of the lower leg observed.
Hold the position for 2 seconds before returning to the start position.
Increase intensity by holding end position for 10 - 60 seconds. Isometric Wall Press with Theraball – Both Legs
Sets:
Reps:
Lie on your back with your feet against a wall. Place a theraball between your feet and the wall, and position yourself so your thighs and knees are flexed to 90 degrees. With an exhalation, push your feet firmly into the ball. Hold the position for 3 seconds and then relax.
Increase intensity by holding end position for 10 – 20 seconds.
Continued…. Isometric Wall Press with theraball – Single Legged
Sets:
Reps:
Lie on your back with your feet against a wall. Place a thereball between your feet and the wall, and position yourself so your thighs and knees are flexed to 90 degrees. Remove the uninvolved foot from the ball, and then straighten that leg and rest it on the floor, so that the ball is held with the other foot. With an exhalation, push your foot firmly into the ball. Hold the position for 3 seconds and then relax. Increase intensity by holding end position for 10 – 20 seconds.
Terminal leg extension Sets: Reps: Load:
Lie on your back on the bed.
With your knee bent over a bolster, straighten the knee by actively tightening the quadriceps.
Be sure to keep the bottom of the knee on the bolster,
Hold the position for 2 seconds, and then lower to starting position.
COMMENCE: (Nb. All exercises to be performed with due caution)
Forwards Step-up Sets: Reps:
Patient stands facing the step (step height = 10-15cm). Proceeds to step up straight ahead with the operated leg. Step down leading with non-operated leg.
Emphasis on maintaining balance, with correct upright posture, and abdominal bracing.
Retro Step-up Sets: Reps:
Patient stands with back to step (step height = 10-15cm). Steps up backwards with the operated leg. Step down leading with non-operated leg.
Emphasis on maintaining balance, with correct upright posture, and abdominal bracing.
Lateral Step-up Sets: Reps:
Patient stands with operated side parallel to the step (step height = 10-15cm). Proceed to step up side ways. Emphasis on maintaining balance, with correct upright posture, and abdominal bracing.
Squat lunge variations Sets: Reps:
Patient stands stationary. Performs a standard lunge, followed by lunges in various directions (i.e. to the side and diagonal lunges). Emphasis is placed on correct upright posture, with abdominal bracing.
Phase 6: 9 months to 1 year post surgery Continued….
Seated Leg Press Sets: Reps:
Sit on the leg press machine positioning yourself so your thighs and knees are flexed to 90 degrees with your feet resting on the foot plate about shoulder width apart.
Grasp the handles provided on each side.
Exhale as you push firmly against the foot plate straightening your legs to 5 degrees off full extension.
• Seated with feet on rocker board, Duradisc or wobble board
- Forward/backward rocking with both legs for 2-3 minutes pain-free, - Progress to one leg.
• As above but seated on Theraball.
2. Full weight-bearing (3-6months)
• Standing on rocker board, Duradisc or wobble board (both legs)
- 2-3 minutes CW and CCW - Double leg balance for 15-20 seconds, rest 10-20 seconds, - Single leg balance
• Progressively increase complexity
- arms out in front of body - eyes closed - knee bends - bounce/catch ball
• Balance on mini trampoline (progressions as above)
- gentle bounce, toes remain in contact with trampoline - alternate heel raise in jogging motion, toes remain in contact with trampoline - side stepping Left & Right
3. Advanced Exercises and Proprioception Activities (9-12 months)
• Bounce / jog on mini trampoline with increased leg lift.
- with one-quarter turn and return - progress to half turn - increase time of jogging
• Walking on soft sand
• Power walking on grass
• Power walk on grass leading to
- Light jog forwards, backs wards, sidestep - Light jogging with change of direction (45º angle or in/out/around cones)
MRI AND CLINICAL EVALUATION OF COLLAGEN-COVERED AUTOLOGOUS CHONDROCYTE IMPLANTATION (CACI)
AT TWO YEARS Note 1. References cited in this chapter appear in a reference list at the end of the
chapter. Note 2. Tables and figures noted within this chapter appear at the end of the
chapter.
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Title: MRI and clinical evaluation of collagen-covered autologous chondrocyte implantation (CACI) at two years.
Keywords: Osteochondral defect, Autologous chondrocyte implantation, Correlation of outcome and MRI.
1.) W.B. Robertson MSc* ** PhD Student University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA
2.) D. Fick MBBS* PhD Student University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA
3.) D.J. Wood BSc. MBBS MS FRCS FRACS*. Professor University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA
4.) J.M. Linklater FRANZCR Musculoskeletal Radiologist Castlereagh Sports Imaging North Sydney Orthopaedic and Sports Medicine Centre 286 Pacific Hwy, CROWS NEST NSW 2065 AUSTRALIA
5.) M.H. Zheng DM., PhD., FRCPath* Professor University of Western Australia 2nd Flr M Block, QEII Medical Centre,Nedlands, WA 6009 AUSTRALIA
6.) T.R. Ackland PhD FASMF**. Professor University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA
* School of Surgery and Pathology (Orthopaedics), University of Western Australia, Nedlands, WA 6009 Australia. ** School of Human Movement and Exercise Science, University of Western Australia, Nedlands, WA 6009 Australia. Correspondence: Mr William Brett Robertson University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA Fax +61 89 346 6462 Email [email protected]
ABSTRACT We present our experience with the collagen covered autologous chondrocyte implantation (CACI) technique. Thirty two implantations were performed in thirty one patients. Clinical outcome was measured using the KOOS score and the 6-minute walk test, as well as an MRI scoring protocol (75% of patients had a complete data set for MRI follow-up) to describe the repair tissue generated by CACI. We have also correlated our MRI results with our clinical outcome. To the authors knowledge there are no comparative studies of MRI and clinical outcome following CACI in the current literature.
Patients demonstrated an increased walk distance that improved significantly from 3 months to 24 months postoperatively (p<0.05). Analysis of the KOOS results demonstrated a significant (p<0.05) improvement in four of the five subscales from 3 months to 24 months after CACI, with the most substantial gains made in the first 12 months. Patients demonstrated an increased MRI outcome score over time that improved significantly from 3 months to 24 months postoperatively (p<0.05). We observed an 8% incidence of hypertrophic growth following CACI. We report one partial graft failure, defined by clinical, MRI and histological evaluation, at the one year time point. In contrast to the current literature we report no incidence of manipulation under anesthesia (MUA) following CACI.
This research demonstrates that autologous chondrocytes implanted under a type I/III collagen patch regenerates a functional infill material, and as a result of this procedure, patients experienced improved knee function and MRI scores. Whilst our results indicated a significant relationship between the MRI and functional outcome following CACI, MRI cannot be used as surrogate measure of functional outcome following CACI, since the degree of association was only low to moderate. That is, functional outcome following CACI cannot be predicted by the morphological MRI assessment of the repair tissue at the post surgery time points to 24 months.
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INTRODUCTION
The concept of autologous chondrocyte implantation (ACI) began almost four decades
ago [1], but only recently has the technique become a viable therapeutic option [2-4].
The first evidence supporting ACI came from animal studies by Peterson et al. [2]. This
work led to human trials and subsequently, ACI using periosteal membrane (PACI) has
become a well-established technique for the treatment of articular cartilage defects, with
evidence of improved joint function and formation of hyaline or hyaline-like cartilage
[5-10]. The PACI has a number of short-comings, namely, the requirement for a large
surgical incision, peripheral graft hypertrophy [11,23], graft delamination [11-13], and
potential ectopic calcification of the periosteal patch [12,14]. Postoperatively, it has
been documented that a clinically significant percentage of patients (20-36%) present
with symptomatic “catching” of the knee joint due to hypertrophic graft edges, leading
to the need for revision arthroscopy [15,16].
Complications associated with the use of periosteum in the ACI procedure have
stimulated the search for an alternative scaffold for the containment of implanted
chondrocytes. According to Geistlich Biomaterials [17], the use of a type I/III collagen
membrane (CACI) instead of periosteum to seal the cartilage defect is a better choice,
and this membrane has been used extensively in dental and maxillofacial surgery since
1980. Recently, several studies have been published evaluating the CACI procedure
[7,16,18-22] by clinical and arthroscopic assessment. Authors of these studies
concluded that CACI produces favorable clinical and histological results [7,18-22],
which are at least comparable to PACI [16]. This paper reports non-invasive MRI in
conjunction with routine clinical assessment to evaluate the outcome of CACI with a
minimum of 2 year follow up. To the authors’ knowledge, this study provides the most
117
comprehensive MRI evaluation of CACI to date and is the first to correlate MRI scores
with functional outcome measures following CACI. The study provides novel insight
into the morphological progression of the regenerative tissue produced following CACI
through the use of established MRI evaluation parameters as recommended by the
literature. The results of this study complement the currently available clinical and
histological information on CACI, with MRI assessment of the cartilage repair, a better
understanding of the outcome of ACI with a collagen membrane is afforded.
In the present study, we have evaluated the CACI graft by MRI assessment, as well as
the function of the grafted joint following surgery, in order to establish whether the
CACI procedure may produce a potentially durable repair tissue. We postulate that the
use of the type I/III collagen membrane would address the issue of graft hypertrophy
that is associated with using a periosteal membrane and thus, CACI would provide a
better capacity to facilitate cartilage regeneration compared to historical PACI data.
Furthermore, it is our intention to demonstrate that early mobilization via continuous
passive motion (CPM) following CACI is safe and leads to a lower incidence of
postoperative knee stiffness and subsequent manipulation under anaesthesia (MUA)
than the current practice of immobilization in plaster that is currently advocated in the
literature.
MATERIALS AND METHODS
Sample
Patients were selected according to the inclusion and exclusion criteria guidelines
outlined by Peterson [23]. Patients exhibiting varus or valgus deformities that required
surgical correction (<5°) were excluded from the study. Thirty two CACI surgeries
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were performed in 31 patients between March 1999 and June 2001. Thirty one
implantations survived to a minimum of 24 months, one patient was lost to follow up
after emigrating overseas, and three patients had sporadic data sets as they were poor
attendees to scheduled postoperative follow up.
The mean age at assessment of the clinical outcomes of CACI for focal chondral defects
of the knee was 37.4 years (range: 19-60 years) and mean BMI was 27.3 (range: 19-35).
All had full thickness chondral lesions, with no clinical sign of bi- or tri-compartmental
osteoarthritis as diagnosed by preoperative MRI and confirmed at arthroscopic biopsy
(range: 1.0-10.0 cm2). Of the cohort, two cases presented with bipolar defects; the
remainder had single defects. Aeitology of defects in order of frequency was trauma
(14 cases), idiopathic (12 cases) and osteochondritis dessicans (five cases). The
anatomical distribution of defects was: medial femoral condyle (20 cases), lateral
femoral condyle (two cases), patella (eight cases), and multiple defects (two cases). All
patients recruited in this series had failed prior surgical intervention and underwent
arthroscopic and MRI evaluation prior to CACI surgery. Previous procedures included
(n=2), extensor realignment (n=2), and other (n=2). Patients were screened for joint
instability (clinically) or malalignment (>0.9 cm lateralization of the tibial tuberosity on
CAT-scan) and if present, were corrected at the time of CACI surgery. Concomitant
surgical procedures included patellar realignment (tibial tubercle transfers (n=6),
performed in accordance with Fulkerson’s principles of extensor mechanism
realignment and Hughston’s surgical technique [24]), lateral retinacular releases (n=6),
vastus medialis corrections (n=2) and two anterior cruciate ligament reconstructions.
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Surgical Technique
All surgery was performed by a single surgeon (DJW) and arthroscopic harvesting of
cartilage was performed as day surgery from the non-weightbearing supracondylar
region. Using a 4 mm concave chisel, a cartilage chip 3-4 mm long was excised (100-
150 mg cartilage), placed into nutrient media, and transported to code of good
managing practice (GMP) approved culture laboratories in Denmark (Verigen®,
Denmark Pty Ltd) with approximately 100 mls of autologous serum for cell culture.
Transportation and packaging was undertaken within strict GMP guidelines. Upon
arrival, the biopsy sample was placed in normal saline and digested with clostridial
collagenase and deoxyribonuclease, before filtration through nylon mesh. The cells
were then incubated in sterile flasks containing Ham’s F12 with HEPES buffer and
autologous patient’s serum (10 percent). Cell density (over 5 x 106 cells) was confirmed
three to four weeks later, and cells were transported (within 48 hrs) to theatre within
nutrient media for CACI surgery.
During implantation, defects were curetted to the subchondral bed to remove fibrous
tissue build-up and define vertical defect walls. Care was taken to avoid penetration of
the subchondral lamina as blood has been shown to affect chondrocyte viability [25].
The Chondro-gide® type I/III collagen membrane (Geistlich Biomaterials, Wolhusen,
Switzerland) was then shaped to match defect geometry, secured with interrupted 6.0
mm vicryl sutures at 3-4 mm intervals, before fibrin sealant (Baxter AG, Vienna,
Austria) was applied to the interface (except for a small proximal portal) to ensure a
water tight seal. The chondrocyte suspension was then carefully injected into the defect
through the proximal portal using a 1 ml syringe and 18 g cannula. The injection portal
was then sutured closed and sealed with a final application of fibrin glue. A full range
of motion of the joint was made prior to closure to assure implant stability.
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Rehabilitation
Structured rehabilitation is important to the clinical success of the CACI procedure.
The biological healing and clinical success of the graft is dependent on a controlled and
graduated return to ambulation and physical activity, and the biomechanical stimulation
of the implanted chondrocytes [26,27]. Patients participated in an eight week pre-
surgery exercise program and a 12 week post-surgery rehabilitation program. The post-
surgery program was designed to initially prevent disruption of the implanted collagen
patch (first six weeks following implantation), followed by a graduated loading phase to
give the implanted chondrocytes the necessary stimulus to cause hypertrophy and
adaptation in order to restore their natural function [26,27]. It is advocated that the
postoperative rehabilitation program following ACI be designed in accordance to defect
size, location, age of the patient, concomitant surgical procedures and in accordance to
the diverse variation that exists between patients [26,27]. The generic CACI
rehabilitation protocol was summarized as follows.
Pre-surgery Program
Preparation of patients began eight weeks prior to surgery with the goal of increasing
the muscular strength, cardiovascular fitness, and range of motion (ROM) of the knee
and lower limb. The structured preclinical program involved a twice-weekly exercise
program of 1.5 hours duration that was individually tailored to each patient. Patients
were supervised using variable resistance machines for upper and lower body strength
training as well as an aerobic fitness program. If a patient was unable to participate due
to pain or functional limitation, hydrotherapy (water-based) resistance and aerobic
programs were implemented. Patients were also given exercises to perform at home
several times a week.
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Post-surgery Rehabilitation Program
Following CACI surgery, a coordinated rehabilitation program of progressive exercise
and weight-bearing was implemented with the dual purpose of protecting the graft and
stimulating the healing process. During the early stages of the postoperative recovery
process, the primary goals were to maintain joint stability and muscle tone and to
prevent joint stiffness and excessive muscle atrophy, while adhering to all postoperative
precautions. The immediate postoperative inpatient treatment program included the
following:
1. Appropriate analgesic prescription;
2. Continuous passive motion (0 to 30 degrees) on the operated knee begun 12 to
24 hours after surgery for a minimum of 1 hour daily;
3. Postoperative ROM control brace worn 24 hours per day for three weeks to
protect the repaired cartilage surface;
4. Cryotherapy applied as standard edema control (20 minutes at least three times
daily);
5. Active dorsiflexion and plantar flexion of the ankle to encourage lower
extremity circulation;
6. Isometric contraction of the quadriceps, hamstrings, and gluteal musculature to
maintain muscle tone;
7. Breathing exercises to ensure patient uses the proper breathing technique during
therapy;
8. Proficient toe-touch ambulation allowing only 15-20 percent of body weight
transmission through the limb;
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9. Instructions on how to perform activities of daily living and functional tasks
while adhering to the postoperative precautions and proper weight-bearing
schedule.
The six phases we used in the rehabilitation of the postoperative knee during the first
year are summarized in Table 1. Along with each phase and the associated timeframe,
this table summarizes the milestones patients were expected to reach towards the end of
each phase.
(Table 1)
Patients were gradually returned to weight-bearing activities over several months, and
by postoperative week six, land-based exercises were introduced to strengthen the
stabilizing muscles of the knee. Between postoperative months three and six, full load-
bearing proprioception retraining was begun with the degree of difficulty increased as
tolerated. Between postoperative months six and nine, load-bearing exercises continued
and low impact recreational activities were introduced. In the final three months of the
first postoperative year, patients were gradually allowed to perform functional activities
such as power walking or striding, walking on soft sand, and agility drills on grass.
Outcome Measures
Functional Evaluation
Evaluation of patient function following CACI was conducted postoperatively at three,
six, 12, and 24 months. The ability to walk for distance is a cornerstone of functional
independence and can influence quality of life, as it is a fundamental component of
many activities of daily living. Functional capacity and general gait function were
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determined by the six-minute walk test (6MWT) [28], which was conducted indoors on
a flat, 25m course. This test was first introduced by Lipkin in 1986 [29] and its results
are highly correlated with those of the 12-minute walk test from which it was derived
[30] and with those of cycle ergometer and treadmill based exercise tests [31]. The
6MWT has been demonstrated to be a reliable measure of general gait function and has
been widely used for pre- and postoperative evaluation [32]. Subjects were instructed
to walk as fast as possible, trying to cover the maximum distance without over exerting
themselves. The final score was calculated as the total distance walked to the nearest
1.0 m. Quality of life and functional outcome was determined by the Knee Injury and
Osteoarthritis Outcome Score (KOOS) [33]. The KOOS score assesses pain,
symptoms, activities of daily living, sport and recreation function, and knee-related
quality of life.
Magnetic Resonance Imaging Assessment
Articular cartilage is approximately 70 percent water by weight. The remainder of the
tissue consists predominantly of type II collagen fibres and glycosaminoglycans. The
latter contain negative charges that attract sodium ions (Na+) in intact cartilage. MRI is
an accurate and non-invasive imaging modality that can delineate signal and
morphological changes in articular cartilage [34] making it an attractive research tool in
the evaluation of chondrocyte grafting [35-39]. The correlation between MRI outcome
and graft histological outcome has yet to be determined, though recent studies have
attempted to correlate these two outcome measures with mixed results [38,40]. MRI
imaging allows non-invasive serial follow-up of patients postoperatively. It assesses the
entire graft and its integration to the subchondral bone plate and the adjacent native
articular cartilage [39]. In addition, it allows non-invasive detection of postoperative
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complications and its role in the evaluation of cartilage repair is well supported in the
literature [38-41].
MRI in this study was conducted at three, 12 and 24 months postoperatively using a 1.5
Tesla closed unit with an extremity coil (Siemens Vision; Siemens, Erlangen,
Germany). The imaging sequence protocol [41] is outlined in Table 2. A blinded
evaluation was performed by a consultant musculoskeletal radiologist. Intra-observer
reliability assessment was conducted using 20 image pairs in which a significant
(p<0.01) correlation (Spearmans Rank Order Correlation) between samples was
observed (rho=0.787) and no significant difference was recorded between test and retest
images p<0.01.
(Table 2)
The MRI scoring system employed by this study (Table 3) to describe the repair tissue
generated by CACI was based upon the international cartilage repair society (ICRS)
outcome recommendations [42] and closely followed the system reported by Trattnig et
al [43]. Due to regional discrepancies in MRI machines and sequence protocols, the
previously reported scoring system was slightly modified for this study. Each MRI
parameter (defect infill, signal intensity, surface contour, structure, border integration,
subchondral lamina, subchondral bone and effusion) was scored against a series of
sample images, ranked from 1 – “Poor” to 4 – “Excellent” then multiplied by a
weighting factor [43] to obtain the final MRI composite score (Table 3). MRI data was
also assessed in disaggregated fashion by category in accordance to the
recommendations of Marlovits et al. [44,45]. Synovitis was also recorded by the
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musculoskeletal radiologist as compared with prior MRI scans. It was graded in
accordance with the definition given by Marlovits et al. [44].
(Table 3)
Determination of Graft Failure
Graft failure was determined both clinically and radiologically. Clinically graft failure
was defined as the deterioration of the knee condition upon examination, clinical
indicators of failure included the presence of mechanical symptoms such as locking,
catching and/or associated knee joint pain. Radiological graft failure was defined by
evidence of suboptimal defect infill and/or evidence of internal derangement (such as
clefts, fissures, or basal delamination). Grafts that showed clinical and radiological
evidence of failure were referred back to the operating orthopaedic surgeon (DJW) for
patient specific management.
Histological Assessment
Failed grafts requiring revision surgery were biopsied for histological analysis. After
fixation in 4 percent parafenaldchyde, the biopsy was decalcified with 10 percent formic
acid. The biopsy was then dehydrated by a graded series of alcohol and xylene washes
and paraffin-embedded. Sections were cut to 5 µm and stained with haematoxylin and
eosin (H&E) and Alcian Blue (proteoglycan stain).
Statistical Analysis
Data were stored on Microsoft Excel spreadsheets and analyzed using SPSS (version
9.0) for Windows. Four data cells were missing at the three month time point and two
data cells were missing at the 24 month time point (MRI data only). An intention to
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treat analysis was performed using the ‘last value carried forward’ technique, and
changes between assessment time points compared using repeated measures analysis of
variance (ANOVA). Post-hoc analysis was performed using Tukey’s HSD. All
reported p-values were two-tailed and p-values less than 0.05 were considered
significant. Correlation of MRI and functional scores was undertaken using a Spearman
rank order correlation.
RESULTS
Of the 32 patients consecutively treated with CACI, 27 had data to 24 months for
analysis of clinical outcome over time. Of these 27 patients, MRI data were only
available for 24 patients due to different recording format and MRI sequencing of the
first three study patients.
Functional Outcomes of CACI
Statistical analysis of the KOOS subscales indicated that patients experienced a
significant (p<0.05) improvement in knee pain, sports and recreation function, activities
of daily living (ADLs), and knee-related quality of life from presurgery to 24 months
after CACI (Table 4).
(Table 4)
CACI patients demonstrated an increased distance covered in the 6WMT that improved
significantly from pre-surgery to 24 months postoperatively (Table 4). Post-hoc analysis
demonstrated the improvement occurred predominantly in the first 12 months (p<0.05)
and that this improvement was maintained out to the 24 month postoperative time point
(Figure 1).
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(Figure 1)
Post-hoc analysis revealed the improvement of knee pain, sports and recreation
function, and knee-related quality of life occurred predominantly in the first 12 months
following CACI then plateaued, whereas the improvement in ADLs increased linearly
to 24 months (Figure 2). The symptoms subscale of the KOOS score improved
significantly following surgery, then only marginal improvement was experienced
during the rehabilitation phase, but this was not significant (p=0.643).
(Figure 2)
MRI Assessment of CACI
CACI patients demonstrated an increased MRI composite score over time that improved
significantly from three months to 24 months postoperatively (p<0.05). Post-hoc
analysis demonstrated the improvement occurred predominantly in the first 12 months
(Figures 3 and 4).
(Figure 3)
(Figure 4)
Three months following surgery 62 percent (n=15) of the CACI patients exhibited good
to excellent filling of the chondral defect, the remaining 38 percent (n=9) exhibited fair
to poor defect infill. The signal intensity at this time point was described as good to
excellent in 50 percent (n=12) of patients. Good to excellent border integration of
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reparative tissue with adjacent native articular cartilage was evident in 67 percent
(n=16) of patients, with fair to poor integration present in the remaining 33 percent
(n=8) of cases. The surface of the reparative tissue at this stage of recovery was good to
excellent in 83 percent (n=20) of cases with the remaining 17 percent (n=4) exhibiting
fair to poor surface structure. Good to excellent subchondral lamina was evident in 96
percent (n=23) of the patient population (indicative that it was intact at the time of
surgery) and 75 percent (n=18) of the patients exhibited good to excellent resolution of
preoperative subchondral bone edema. Joint effusion was evident in 38 percent (n=9)
of the patients and 58 percent (n=14) exhibited synovitis at the three month
postoperative time point. No graft hypertrophy was reported at the three month
postoperative time point.
Twelve months following CACI good to excellent filling of the defect had increased to
79 percent (n=19) of patients. The signal intensity had increased from 50 percent
(n=12) reported as good to excellent to 71 percent (n=17). Good to excellent border
integration of reparative tissue with adjacent native articular cartilage was seen in 79
percent (n=19) of cases. The surface of the reparative tissue was intact in 83 percent
(n=20) of patients with the remaining 17 percent (n=4) fair to poor surface structure at
the twelve month postoperative time point. Good to excellent restoration of the
subchondral lamina was evident in all patients and 79 percent (n=19) of patients showed
a resolution of subchondral bone edema. Fair to poor effusion remained in 46 percent
(n=11) of the patient population and 58 percent (n=14) of cases had persistent synovitis.
There was one incidence of graft hypertrophy reported at this time point and this patient
was subsequently monitored closely as to ascertain whether further surgical intervention
was necessary.
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By 24 months following CACI surgery defect filling, signal intensity and surface
integrity had achieved a good to excellent rating in 83 percent (n=20) of cases. Effusion
was present in only 25 percent (n=6) of patients and 54 percent (n=13) had persistant
synovitis. A second case exhibited graft hypertrophy at this time point, however,
surgical intervention was not deemed necessary as the patient was asymptomatic and
the hypertropic tissue did not cause any mechanical obstruction to joint function.
Correlation of MRI scores with Functional Outcome
Low to moderate positive correlations between the MRI composite score and the
functional outcome scores were obtained for MRI and 6MWT distance (rho = 0.390,
p<0.01), MRI and KOOS pain (rho = 0.356, p<0.01), MRI and KOOS activities of daily
living (rho = 0.341, p<0.01), MRI and sport and recreation function (rho = 0.509,
p<0.01), MRI and knee related quality of life (rho = 0.246, p<0.01). No significant
correlation was obtained between the MRI composite score and the symptoms sub score
of the KOOS (rho = 0.065).
Complications
Most patients completed surgery and rehabilitation without complication. One patient
developed a deep vein thrombosis (DVT) and was anti-coagulated, while two had
superficial wound infections which were successfully treated with antibiotics.
There were three complications directly related to the CACI procedure: a focal area of
graft hypertrophy that became symptomatic, an asymptomatic case of graft hyperthropy
at the 24 month postoperative time point and a partial graft failure. The case involving
the symptomatic focal hypertrophy was successfully treated by arthroscopic
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debridement at 16 months following the initial implantation (Figure 5). The non-
symptomatic case continues to be managed conservatively.
(Figure 5)
Histological Assessment of a Failed Case
The failed case was a 12 cm2 medial femoral condyle defect that had poor infill in the
inferior half of the defect. This area was debrided to healthy bone, then implanted with a
matrix-induced autologous chondrocyte implantation (MACI) graft. Tissue from the
patient was biopsied during revision surgery and histologically processed (Figure 6).
Immediately following biopsy, the sample was placed into 4 percent paraformaldehyde
fixative.
(Figure 6)
DISCUSSION
The CACI technique addresses many of the problems associated with PACI by
replacing the perisoteum with an inert collagen membrane. As a result, the operative
technique is simplified, anaesthetic time is reduced, and periosteal harvesting is
abolished. Also, the incidence of tissue hypertrophy is minimized because unlike
periosteum, the collagen membrane is acellular. Graft hypertrophy incidence after
PACI has been reported as being as high as 20-36 percent in the literature [15,16], yet
we observed only two cases (8 percent incidence) of hypertrophic growth in this study.
This result is consistent with others reported in the literature [16,20]. Related literature
also revealed a 3-8 percent incidence of retarded knee flexion following CACI,
requiring manipulation under anesthetic [7,16,20,21]. Further investigation identified
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that immobilization of the operated knee joint for 10-14 days was routine in numerous
studies irrespective of defect location [7,16,18-22]. This is in contrast with the
recommendation of Hambly et al. [27] who stated that immobilization led to decreased
joint ROM, followed by adaptation of articular structures to the immobilized
circumstance. We observed no incidence of knee stiffness requiring manipulation under
anesthetic in this study and, therefore, advocate early mobilization via CPM in
conjunction with a rehabilitation protocols that incorporate all of the complexities
associated with each individual case [36,37].
Several studies investigating the CACI procedure are reported in the literature [18-22].
All used clinical and histological evaluation postoperatively to measure durability and
outcome of the CACI procedure. The results generally indicate improved functional
outcome from pre-operative scores following CACI and a lower rate of postoperative
graft hypertrophy, with reported incidences ranging from 6-9 percent compared with the
20-36 percent reported in PACI [15,16]. Arthroscopic evaluation was performed using
the ICRS grading system and biopsy samples were obtained at one year “whenever
possible” [16, 20-22]. It is important to note that only two of these studies collected
biopsy data on the entire sample [18,19]. On average, the remaining studies reported
biopsy data on 44 percent of the sample (range: 32-62 percent) [16,20-22].
Furthermore, the use of “gold standard” biopsies has been stated by one author to render
MRI evaluation of “limited” benefit [21]. However, durability of the implanted tissue
remains undetermined due to limited biopsy data taken in the majority of studies at the
1-year post-surgery time point [16,20-22].
Clinical follow-up is reported ranging from 2-7 years, but it is questionable if clinical
follow-up alone has sufficient sensitivity to accurately reflect graft durability.
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Arthroscopic examination and biopsy as routine follow-up is controversial, and
provides an inconsistent measure of durability, especially considering biopsy is not
always possible [7,16]. Many consider it unethical to subject ACI patients to routine
‘second-look’ arthroscopy and biopsy when the ACI graft is considered to be
functioning well from a clinical perspective. Also, the high incidence of inadequate
biopsies (55 percent as reported by ICRS Histological Endpoint Committee [42])
precludes meaningful interpretation in the majority of specimens that are obtained
arthroscopically. The majority of biopsy specimens obtained in these studies were
collected at the one year postoperative time point, despite the general consensus in the
literature that the neocartilage regenerated by ACI continues to remodel and mature up
until 24 months postoperatively [5,7]. Our biopsy data were obtained opportunistically
at revision of a failed case, and we would only consider arthroscopic assessment or
biopsy of the graft in instances where further surgical intervention was deemed
appropriate.
MRI evaluation of the defect infill and tissue regeneration following CACI revealed a
similar maturation pathway to other studies of PACI and CACI procedures [38-
40,44,45]. The present study demonstrated an increased MRI composite score over
time that improved significantly from three to 24 months postoperatively (p<0.05).
Post-hoc analyses revealed the improvement occurred predominantly in the first 12
months, then plateaued, but did not decline. This indicated that regenerated graft tissue
following CACI maintains its maturity and function up to the 24 month postoperative
time point, a result that is comparable to the PACI procedure [8].
The regeneration process following CACI does not appear complete until at least the 12
month postoperative time point; a result that is consistently reported in the literature
133
[8,36,45]. A consistent pattern was also observed in the evolution of the MRI scores
from the CACI grafts. In the early postoperative phase (first three months), the grafts
were uniformly hyperintense relative to native hyaline articular cartilage. The degree of
fill was usually more than 50 percent of the thickness of native hyaline articular
cartilage. Linear signal hyperintensity at the interface between the graft and native
cartilage was observed, often without breach of the graft surface. Signal hyperintensity
at the basal layer of the graft was typical in the early postoperative phase. In most
patients, the subchondral plate lamina was intact at three months post-surgery,
suggesting it had been intact at the time of surgery. Subchondral bone marrow edema
was common in the early postoperative phase.
Several consistent changes were observed on the follow-up scans at 12 and 24 months.
The graft signal intensity typically decreased from that observed at the three month
MRI, to become isointense or hypointense relative to native hyaline articular cartilage.
In most patients there was a reduction in the extent of subchondral bone marrow edema.
Resolution of the linear signal intensity was observed at the interface between the graft
and native hyaline articular cartilage, and at the interface between the graft and the
subchondral plate.
The incidence and natural history of chondral defects has been well documented [46-
48]. In many patients, the degeneration of the articular cartilage and the subsequent
alterations in knee function and loading cause pain and loss of motion in the affected
joint. Knee function was assessed via the KOOS, a superset of the Western Ontario and
MacMaster Universities osteoarthritis index (WOMAC) [50], which has been
previously validated for the assessment of knee pain and function during daily
activities. This survey tool has proven to be reliable, responsive to surgery and physical
134
therapy, and evaluates the course of knee injury and treatment outcome [33]. At the
three month time point following surgery, the poor knee function, as evidenced in the
KOOS, was primarily due to the postoperative restraints placed on the patient in order
to protect the integrity of an immature graft [26,27].
Subjective knee function in the CACI patients improved over time in parallel with the
maturation process of the regenerating graft. At the 12 month time point, the KOOS
results reported in our study were comparable to those by Marlovitis et al. [51].
Patients in our study experienced significant improvement in knee pain, sports and
recreation function, activities of daily living, and knee-related quality of life from three
to 24 months. The majority of this improvement, and that observed for the MRI results,
occurred in the first 12 months. The 24 month KOOS results from our study were also
comparable to those reported by Marlovitis et al. [45], thereby indicating that
improvements following surgery were maintained over time.
The ability to walk for a distance is a cornerstone of functional independence and
greatly influences patients’ quality of life since it is a fundamental component of many
activities of daily living. Prior to surgery, the average 6MWT distance was 492 m. This
capacity decreased to 434 m at the three month postoperative time point (p<0.05), most
probably the result of the trauma of surgery and early postoperative restraints [26,27].
Following this initial decrease, 6MWT distance improved significantly (p<0.005) to the
12 month postoperative time point, and this capacity was maintained through to 24
months.
Even though our results indicated a significant relationship between the MRI and
functional outcome following CACI, MRI grading alone should not be used as
135
surrogate measure of functional outcome following CACI, since the degree of
association was only low to moderate. That is, functional outcome following CACI
cannot be predicted by the morphological MRI assessment of the repair tissue at the
post-surgery time points to 24 months.
The partially failed case observed in this series has helped to highlight the possibly
detrimental effect of suturing both collagen membrane and periosteum to the defect
boundary. The cleft observed in the recovered biopsy of this case suggests that
superficial graft integration may be hindered by suturing and the creation of micro-
defects in the anchoring cartilage. Whilst good integration of this series was seen under
MRI, it is possible that small clefts at the interface of repair and healthy tissues may
leave the treated area susceptible to surface degeneration and cell leakage.
In summary, this study demonstrated that autologous chondrocytes implanted under a
type I/III collagen patch (CACI) regenerate functional infill material, and as a result of
this procedure, patients experienced improved knee function and MRI scores in the
short to mid-term. Further investigation of the relationship between MRI and clinical
outcome following chondrocyte implantation is imperative as it remains to be
determined whether the native ultra structure of cartilage needs to be restored in order to
achieve good, durable, clinical results.
ACKNOWLEDGEMENTS
This study was funded by a research grant provided by The National Health and
Medical Research Council (ID Number: 254622), and was administered by the council
on behalf of the Australian Government. Unless otherwise specified, the data given in
this review are based on work carried out at the University of Western Australia. We
136
would like to acknowledge Mr Craig Willers for his assistance in the description of the
biological aspects of CACI.
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(42) Mainil-Varlet P, Aigner T, Brittberg M, Bullough P. Histological assessment of cartilage repair: A report by the Histology Endpoint Committee of the
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(43) Trattnig S, Pinker K, Krestan C, Plank C, Millington S, Marlovitis S. Matrix-based autologous chondrocyte implantation for cartilage repair with Hyalograft®C: Two-year follow-up by magnetic resonance imaging. Eur J Radiol 2006; 57(1):9-15.
(44) Marlovits S, Striessnig G, Resinger CT, Aldrian SM, Vecsei V, Imhof H, Trattnig S: Definition of pertinent parameters for the evaluation of articular cartilage repair tissue with high-resolution magnetic resonance imaging. Eur J Radiol 2004; 52(3):310-319.
(45) Marlovitis S, Singer P, Zeller P, Mandl I. Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: Determination of interobserver variability and correlation to clinical outcome after 2 years. Eur J Radiol 2006; 57(1):16-23.
(46) Chevalier X. Autologous chondrocyte implantation for cartilage defects: development and applicability to osteoarthritis. Joint Bone Spine 2000; 67:572- 578.
(48) Cole BJ, Harner CD. Degenerative Arthritis of the knee in active patients: Evaluation and Management. J Am Acad Orthop Surg 1999; 7:389-402.
(49) Herborg JS, Nilsson BE. The natural course of untreated osteoarthritis of the knee. Clinical Orthopeadics and Related Research 1977; 123:130-37.
(50) Bellamy N, Buchanan W, Goldsmith C, Campbell J, Sitt L. Validation study of WOMAC: A health status instrument for measuring clinically-important patient-relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. Journal of Rheumatology 1988; 15:1833-1840.
(51) Marlovits S, Resinger C, Aldrian S, Kutscha-Lissberg F, Vécsei V. Hyaluronan matrix-associated chondrocyte transplantation for the treatment of post traumatic chondromalacia patella – early clinical results of a pilot study. 5th Symposium of the International Cartilage Repair Society (ICRS), International Congress Centre, Gent/Belgium, May 26-29, 2004.
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Table 1. Rehabilitation Phases Following CACI Surgery
Rehabilitation Phase
Postoperative Time Point Expected Outcome by Phase End
1 1 to 3 weeks 1. Pain free knee active ROM of ≥60°; 2. Heel toe gait with toe touch pressure (≤20% body weight) using 2
crutches and knee brace; 3. Reduced oedema and pain; 4. Full passive extension; and 5. Able to generate a quadriceps contraction.
2 3 to 6 weeks 1. Pain-free active knee ROM of ≥90°; 2. Proficient straight leg raise; and 3. Pain-free gait using one crutch, knee brace and 50% body weight
pressure.
3 6 to 12 weeks 1. Pain free knee active ROM of ≥130° 2. Pain-free 6-minute walk test with or without walking aids 3. Use cycle ergometers pain-free without knee brace 4. Full passive extension; 5. Ability to generate a voluntary quadriceps contraction
4 3 to 6 months 1. Normal gait pattern without pain and without walking aids 2. Return to work (depending on demands of job) 3. Perform proprioception activities: 30 second single leg balance on
trampette
5 6 to 9 months 1. Able to tolerate walk distances of up to 5 kms 2. Able to negotiate stairs and mild gradients 3. Able to effectively traverse uneven ground 4. Able to return to preoperative low impact recreational activities
6 9 to 12 months 1. Able to perform all activities of daily living 2. Able to commence return to running program, for example:
walk/jog, jog/run, run on soft surface 3. Resume dynamic recreational activities (however, sports with
high knee loading and twisting or shear forces are to be avoided.)
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Table 2: MRI cartilage sequence
Sequence Coronal T2 Fat
Saturated (COR T2 FS)
Coronal Proton Density (COR PD)
Sagittal Proton Density (SAG PD)
Sagittal T2 Fat
Saturated (SAG T2 FS)
Axial Proton Density
Fat Saturated (AX PD FS)
Time to Repetition (TR) 4650.0 2060.0 2720.0 3400.0 3000.0 Time to Echo (TE) 81.0 34.0 32.0 72.0 38.0 Turbo Factor (echo train) 11.0 3.0 7.0 9.0 5.0 Acquistions 2.0 1.0 2.0 2.0 1.0 Bandwidth (hertz per pixel) 100.0 100.0 150.0 130.0 130.0 Slice Thickness (mm) 3.0 3.0 4.0 4.0 3.0 Distance Factor (%) 40.0 40.0 25.0 25.0 30.0 Field of view in the Frequency Direction (Read FOV)
Activities of Mean 61.5 abcd 72.3e 79.0f 85.5 83.4 daily living SD 16.1 18.2 15.2 13.2 16.0 17.1 p<0.001
Sport & Mean 8.8bcd 4.3e 22.6f 35.8 38.0 recreation SD 12.8 9.0 30.4 31.9 31.6 13.3 p<0.001
Function Knee related Mean 23.5 abcd 32.1e 41.4 45.7 48.2 quality of life SD 14.5 18.4 18.6 20.8 21.6 10.2 p<0.001
a = significant difference (p<0.05) presurgery vs 3 months b = significant difference (p<0.05) presurgery vs 6 months c = significant difference (p<0.05) presurgery vs 12 months d = significant difference (p<0.05) presurgery vs 24 months e = significant difference (p<0.05) 3 months vs 6 months f = significant difference (p<0.05) 6 months vs 12 months g = significant difference (p<0.05) 12 months vs 24 months
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Fig. 1. Changes in six-minute walk distance (m) at pre- and post-surgery assessment time points ( x ± SE, n = 27).
Fig. 2. Changes in the five sub domains of KOOS at pre- and post-surgery assessment time points ( x ± SE, n = 27). Total KOOS scores (0 = extreme knee problems and 100 = no knee problems), ADL = activities of daily living, Sport&Rec = sport and recreation function, KQOL = knee-related quality of life.
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Fig. 3. Changes in MRI composite score at post-surgery assessment time points ( x ± SE).
Fig. 4. Sagittal proton density fast spin echo magnetic resonance image of a CACI graft (depicted between the two arrow heads) to the medial femoral condyle in a patient who had a previously full thickness chondral defect. A. At three months post-surgery the graft is hyperintense and of reduced thickness when compared with the adjacent normal articular cartilage. B. One year post-surgery the CACI graft has a heterogeneous appearance and is of similar thickness to the adjacent normal cartilage. C. At two years post-surgery, the CACI graft remains intact and demonstrates equivalent signal characteristics to the adjacent normal cartilage. Border integration is smooth with no radiological evidence of fissures or clefts between the graft and the native cartilage.
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Fig. 5. Sagittal proton density fast spin echo magnetic resonance image of a CACI graft to the lateral femoral condyle in a patient who had a previously full thickness chondral defect. A. Focal graft hypertrophy was detected at the 12 month post-surgery time point (indicated by the arrow head). B. Following arthroscopic debridement at the 16 month postoperative time point, the 24 month MRI of the graft revealed a reduction in the height of the graft at the lateral femoral condyle and with the graft demonstrating a similar height to adjacent native cartilage.
Fig. 6. A. Photomicrograph taken of an obvious cleft (arrow) abutting the repair-healthy interface (dashed line) created by suturing the collagen membrane to the adjacent cartilage during surgery. B. Alcian Blue staining showed that the repair tissue was positive for proteoglycan (blue). The repair tissue was composed of a mixture of hyaline islands of chondrocyte within lacunae groups (C), and isolated chondrocytes within a hyaline-like matrix (D).
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CHAPTER FIVE
MRI AND CLINICAL EVALUATION OF MATRIX-INDUCED AUTOLOGOUS CHONDROCYTE IMPLANTATION (MACI)
AT TWO YEARS Note 1. References cited in this chapter appear in a reference list at the end of the
chapter. Note 2. Tables and figures noted within this chapter appear at the end of the
chapter.
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Title: MRI and clinical evaluation of matrix-induced autologous chondrocyte implantation (MACI) at two years. Keywords: Osteochondral defect, Autologous chondrocyte implantation, Correlation of outcome and MRI.
1.) W.B. Robertson MSc* ** PhD Student University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA
2.) Craig Willers M. (Med) Sc* PhD Student University of Western Australia 2nd Flr M Block, QEII Medical Centre,Nedlands, WA 6009 AUSTRALIA
3.) D.J. Wood BSc. MBBS MS FRCS FRACS*. Professor University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA
4.) J.M. Linklater FRANZCR Musculoskeletal Radiologist Castlereagh Sports Imaging North Sydney Orthopaedic and Sports Medicine Centre 286 Pacific Hwy, CROWS NEST NSW 2065 AUSTRALIA
5.) M.H. Zheng DM., PhD., FRCPath* Professor University of Western Australia 2nd Flr M Block, QEII Medical Centre,Nedlands, WA 6009 AUSTRALIA
6.) T.R. Ackland PhD FASMF**. Professor University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA
* School of Surgery and Pathology (Orthopaedics), University of Western Australia, Crawley, WA 6009 Australia. ** School of Human Movement and Exercise Science, University of Western Australia, Crawley, WA 6009 Australia. Correspondence: Mr William Brett Robertson University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA Fax +61 89 346 6462 Email [email protected]
This study presents MRI and clinical outcomes for 31 matrix-induced autologous chondrocyte implantations (MACI) over 24 months post surgery. Following MACI knee surgery, patients underwent a coordinated rehabilitation program of progressive exercise and graduated load bearing to protect then stimulate the healing process. In contrast to the current literature we report no incidence of manipulation under anesthesia following MACI.
Clinical outcomes were measured using the KOOS score and the six-minute walk test, whereas an MRI scoring protocol described the quality and quantity of the repair tissue. Patients demonstrated an increased walk distance that improved significantly from three months to 24 months postoperatively (p<0.001). Analysis of the KOOS results demonstrated a significant (p<0.001) improvement in all of the five subscales from three months to 24 months after CACI, with the most substantial gains made in the first 12 months. Patients also demonstrated an increased MRI composite score over time that improved significantly from three months to 24 months postoperatively (p<0.001). Post-hoc analysis demonstrated the improvement occurred predominantly in the first 12 months, then plateaued at 24 months postoperatively. A 10 percent incidence of hypertrophic growth following MACI was observed.
The MACI technique addresses many of the problems associated with use of a periosteum cover by replacing this with an inert collagen membrane. As a result, the operative technique is simplified, anaesthetic time is reduced, and periosteal harvesting is abolished. This study provides novel insight into the morphological progression of the regenerative tissue produced following MACI through the use of established MRI evaluation parameters. These results supplement the clinical, radiological and histological information on MACI, so that a better understanding of the outcome of ACI with a collagen membrane is afforded.
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INTRODUCTION:
Conventional autologous chondrocyte implantation (ACI) was the first surgical
technique to highlight the therapeutic potential of autologous cell therapy in the field of
orthopaedics [7,36]. However, the original surgical technique described by Peterson et
al. [7], required the use of a periosteum cover (PACI), which was successful in the
majority of patients but associated with numerous postoperative complications such as
extensive surgical incision, graft hypertrophy, delamination and potiential ectopic
calcification of the periosteal membrane [7,13,24,35,50]. Use of a collagen membrane
in place of perisoteum has been advocated recently [8-11], and related studies indicated
that ACI using a type I/III collagen membrane (CACI) produced clinical, histological
and radiographical results that were at least comparable to PACI [18,19,26,41].
Importantly, the favorable outcomes gained through CACI were obtained with a
decreased incidence of postoperative complications.
Although CACI had been shown to exhibit commendable postoperative outcomes, its
surgical technique remains cumbersome. A large surgical incision is required in order
to suture the membrane to the circumference of the chondral defect - a tedious task that
increases the length and technical difficulty of the surgical procedure. Furthermore,
concern remains regarding the uneven distribution of chondrocytes within the fluid
suspension, possible leakage of suspension fluid through the graft-cartilage interface,
and creation of microdefects in the native cartilage by the suturing process [10,41,48].
The associated complications with the PACI and CACI procedures have resulted in the
search for alternative bioscaffolds that are thought to be less problematic. Naturally-
derived bioscaffolds such as collagen, hyaluronan, fibrin glue, chitosan and various
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polysaccharides have been investigated to act as three-deminsional templates for
cellular propagation and growth factor seeding [52]. Matrix-induced autologous
chondrocyte implantation (MACI) has applied the concept of direct cell inoculation
onto a collagen scaffold for implantation. In this procedure the chondrocytes are no
longer injected under a collagen membrane into a sealed defect compartment. Instead,
they are directly seeded onto the type I/III collagen membrane and delivered into the
chondral defected as a cell-scaffold construct. This modified delivery method, obviates
the need for periosteal harvest and is generally suture free. Once prepared, the cell-
seeded membrane can be secured to the base of the recipient defect using a thin layer of
fibrin glue. The MACI procedure can be performed through mini-arthrotomy or
arthroscopically depending upon the defect location [44], and since the first introduction
of the MACI technique in 1998, more than 3000 patients have been treated across
Europe, Australia and Asia. Figure 1 outlines the paradigm of MACI cartilage
regeneration.
(Figure 1)
A prospective clinical investigation was conducted to evaluate the efficacy of the MACI
procedure over time (two year follow-up). The morphologic characteristics of the
MACI graft were assessed by MRI, as was the function of the grafted joint following
surgery, in order to establish whether the MACI procedure produced a potentially
durable repair tissue. It was hypothesized that use of the cell-seeded type I/III collagen
membrane would reduce the incidence of graft hypertrophy that is often associated with
using a periosteal membrane [24,32]. Thus, MACI could be regarded as providing a
better capacity to facilitate cartilage regeneration than PACI. Furthermore, it was our
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intention to demonstrate that early mobilization via continuous passive motion (CPM)
following MACI is safe and leads to a lower incidence of postoperative knee stiffness
and subsequent need for manipulation under anesthesia (MUA) than the practice of
immobilization in plaster that has been advocated by some in the literature [3].
MATERIALS AND METHODS:
Sample
A consecutive series of 31 procedures in 28 patients (18 male; 10 female) between
August 2001 and March 2004. Thirty-one implantations survived to a minimum of 24
months, however, one claustrophobic patient was excluded from MRI evaluation. The
mean age at assessment of the clinical outcomes of MACI for focal chondral defects of
the knee was 36.5 years (range: 13-60 years) and mean BMI was 25.9 (range: 17.2–
33.9). All subjects suffered from persistent pain associated with full thickness chondral
lesions (Outbridge grade III or IV [36], range: 1.5–9.6 cm2), with no clinical sign of bi-
or tri-compartmental osteoarthritis as diagnosed by preoperative MRI and confirmed at
arthroscopic biopsy. Patient demographics are described further in Table 1.
(Table 1)
Patient Selection
Patients were recruited based on the following inclusion/exclusion criteria:
• Age: 13–60 years;
• Defect location: medial or lateral femoral condyle, trochlea, or patella (non-
opposing lesions only);
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• Area and depth: < 10cm2, down to stable subchondral bone plate;
• Aetiology: trauma or osteochondritis dessicans;
• Joint condition: absence of progressive inflammatory disease or osteoarthritis;
• Joint stability: absence of full menisectomy or instability;
• Abnormal weight-bearing: absence of significant varus/valgus abnormality (>5°),
patella maltracking, or obesity (body mass index >35); and
• Sensitivities: no history of gentamycin sensitivity.
Membrane
The membrane employed in this study was a type I/III collagen membrane composed of
a purified collagen fibrous network. It was produced from porcine peritoneal membrane
using controlled manufacturing processes. Starting materials for the production of the
membrane were harvested in European Union certified slaughterhouses under strict
veterinary controls from animals declared fit for human consumption. The membrane
complied with the relevant provisions of Schedule 3 – Part 1.6 of the Therapeutic
Goods (Medical Devices) Regulations 2002 and had a TGA conformity assessment
certificate (Certificate Number: AU DE00026/01). The bi-layered structure had an
outer flat layer with relatively low friction and closely aggregated fibres, while the inner
surface was rough with a loose arrangement of collagen fibres. This presents a larger
surface area for chondrocyte adhesion [52]. Manufacture involved moving excess flesh
and fat, washing with a NaOH, treating it with hydrochloric acid, saline and sodium
bicarbonate. This was followed by dehydration, degreasing and lyophilisation. The
membrane was then sterilized by gamma radiation (minimum dose 25 kGy). Clinical
and preclinical [51] studies revealed that selected collagen membranes are
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biocompatible, well tolerated and effective. They have been used extensively in the
clinical setting, including guided bone repair, cartilage repair, skin care and skin
surgery. This acellular membrane shows no evidence of genotoxicity and, on
broadband viral testing, is designated virus free.
Chondrocyte Characterization
The chondrocytes were harvested in a similar way to the traditional PACI and CACI
techniques. At day case arthroscopic surgery, a small volume of normal articular
cartilage was harvested from the medial femoral condylar ridge, usually at the junction
between the patellofemoral and tibiofemoral joints. The site, geometry, containment of
the defect, ligamentous stability, and meniscus health were also evaluated during
primary surgery to determine the condition of the joint. Approximately 1x105 cells
were obtained at biopsy and expanded to 12x106 cells in a laboratory over a period of
four to six weeks. Initially, the cells were treated in normal saline for transport to the
GMP laboratory where there were lysed with chlostridial collagenase. They were
cultured at 37ºC in an atmosphere of CO2 with HEPPS buffer and hemes medium in
autologous patient’s serum. Three days prior to implantation, the cells were seeded
onto the collagen membrane, held ‘rough-side-up’ and stabilized with a plastic ring.
The inoculation of chondrocytes onto the porous surface of the collagen membrane has
been shown to increase chondrocyte differentiation and proliferation within the three-
dimensional scaffold [10,17,28].
Fibrin Glue
Initially, there was some concern that fibrin glue may alter the differentiation or the
viability of chondrocytes [8], however, we have demonstrated that the glue is chemo-
attractant to chondrocytes, the cells penetrate and migrate through fibrin glue and retain
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their chondrocyte phenotype [15,51,52]. Fibrin glue has also been shown to be a
suitable adhesive for MACI grafts, as determined by MRI [32].
Surgical Technique
A single surgeon performed all surgery. The defect site was accessed via a medial or
lateral parapatellar arthrotomy approach in a tourniquet-controlled field. If additional
realignment or ligament reconstruction was required, the surgical approach was
modified accordingly. The defect was prepared by removing all damaged and loose
cartilage down to, but not through, the subchondral plane. Care was taken to avoid
bleeding, as blood has been shown to affect chondrocyte viability [53]. Adrenaline
soaked patches or fibrin glue may have been used for haemostasis. Vertical walls of
normal cartilage should exist at the periphery of the defect and the MACI membrane
was secured into this contained area. Once a thin layer of fibrin glue was applied and
the membrane pressed into the defect, 30 s was allowed for the glue to set and a further
two minutes for the fibrin glue to cure. The knee was put through a full range of
passive motion five to 10 times in order to test graft stability. Any evidence of de-
lamination or instability was corrected with strategic 6/0 vicryl sutures. Meticulous
layer closure was then performed. The synovial membrane was closed as a separate
layer to the capsule with 2/0 vicryl. The capsule was closed using 1/0 vicryl and the
skin closed according the surgeon’s preference.
Rehabilitation
Following MACI knee surgery, patients underwent a coordinated rehabilitation program
of progressive exercise and graduated weight bearing to protect and stimulate the
healing process (Figure 2). Continuous passive motion was routinely commenced one
day after surgery and patients were gradually returned to weight bearing activity over
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the ensuing months by participation in a graduated rehabilitation program designed
specifically for MACI [42].
(Figure 2)
Structured exercise sessions (which included extensive education regarding the MACI
procedure) commenced prior to surgery in order to prepare patients physically and
pscyhologically for a traumatic surgery and the lengthy post-operative recovery.
Following surgery, patients underwent an intensive, individually tailored MACI
rehabilitation program. The underlying principle for this program was to encourage and
maximize the chondrocyte maturation process, whilst minimizing the risk of graft
failure through overload or delamination.
Outcome Measures – Functional Assessments
Six-Minute Walk Distance Test
Functional capacity and general gait function (cadence and stride length) were
determined by the six-minute walk test (6MWT) [1,41], which was conducted indoors
on a flat, 25 m course. Subjects were instructed to walk as fast as possible, trying to
cover the maximum distance without over exertion. The final score was calculated as
the total distance walked to the nearest 1.0 m. The 6MWT has been demonstrated to be
a reliable measure of general gait function and has been widely used for pre- and
postoperative evaluation [14,41].
The Knee Injury and Osteoarthritis Outcome Score
Subjective knee function was assessed pre- and postoperatively using the knee injury
and osteoarthritis outcome score (KOOS), a knee-specific instrument developed by
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Roos et al. [46]. The KOOS evaluates both short-term and long-term consequences of
knee injury, is self-administered, and is responsive to changes over time and between
groups [45]. The questionnaire comprises 42 items within five domains: Pain (nine
items), Symptoms (seven items), Function in activities of daily living (ADL, 17 items),
Function in sport and recreation (Sport/Rec, five items), and Knee-related quality of life
(KQOL, four items) [46].
Outcome Measures - MRI Assessment
MRI scans were conducted at three, 12 and 24 months postoperatively using a 1.5 Tesla
closed unit with an extremity coil (Siemens Vision; Siemens, Erlangen, Germany),
employing an established cartilage imaging sequence protocol [5,41]. A blinded
evaluation was performed by a consultant musculoskeletal radiologist using a
previously described scoring system [41]. Each MRI parameter (defect infill, signal
subchondral bone and effusion) was scored against a series of sample images, ranked
from 1=“Poor” to 4=“Excellent” then multiplied by a weighting factor [41] to obtain the
final MRI composite score. MRI data was also assessed in disaggregated fashion by
category in accordance to the recommendations of Marlovits et al. [31,33]. Synovitis
was recorded and graded separately in accordance with the definition given by
Marlovits et al. [33]. Intra-observer reliability assessment was conducted using 20
image pairs in which a significant (p<0.01) correlation (Spearmans Rank Order
Correlation) between samples was observed (rho=0.787) and no significant difference
was recorded between test and retest images p<0.01.
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Determination of Graft Failure
Graft failure was determined both clinically and radiographically. Clinically, graft
failure was defined as the deterioration of the knee condition upon examination, with
indicators that included the presence of mechanical symptoms such as locking, catching
and/or associated knee joint pain. Radiographically, graft failure was defined by
evidence of suboptimal defect infill and/or evidence of internal derangement (such as
clefts, fissures, or basal delamination). Any that showed clinical and radiographical
evidence of failure would be referred back to the surgeon for patient-specific
management.
Statistical Analysis
Data were stored on Microsoft Excel spreadsheets and analyzed using SPSS (version
10.0) for Windows. One cell was missing at the three month time point, three at the 12
month and two data cells were missing at the 24 month time point. An intention to treat
analysis was performed using the ‘last value carried forward’ technique (five percent of
data cells), and changes between postoperative time points compared using repeated
measures analysis of variance (ANOVA). Post-hoc analysis was performed using
Tukey’s HSD. All reported p-values were two-tailed and p-values less than 0.05 were
considered significant.
RESULTS:
Functional Outcomes of MACI
Statistical analysis of the functional outcome variables indicated that patients
experienced a significant (p<0.001) improvement in 6MWT distance and KOOS
subscales - knee pain, symptoms, ADLs, sports and recreation function, and knee-
related quality of life from pre-surgery to 24 months after MACI (Table 2).
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(Table 2)
Though MACI patients demonstrated an increased distance covered in the 6MWT from
pre-surgery to 24 months postoperatively, scores on this parameter were artificially
suppressed at the three month time point due to the weight bearing constraints of the
rehabilitation protocols. Post-hoc analysis demonstrated the improvement occurred
predominantly in the first 12 months (p<0.05) and that this improvement was
maintained out to the 24 month postoperative time point (Figure 3).
(Figure 3)
Post-hoc analyses also revealed the improvement of knee pain, symptoms and ADLs
occurred predominantly in the first 12 months following MACI then plateaued, whereas
the improvement in sport and recreation function increased linearly from three to 24
months (Figure 4). The knee related quality of life subscale of the KOOS score
improved significantly from three to 12 months following surgery, then only marginal
improvement was experienced from 12 to 24 months (p>0.05).
(Figure 4)
MRI Assessment of MACI
MACI patients demonstrated an increased MRI composite score over time that
improved significantly from three to 24 months postoperatively (p<0.001). Post-hoc
analysis demonstrated the improvement occurred predominantly in the first 12 months
(Figures 5 and 6), then plateaued at 24 months postoperatively.
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(Figure 5)
(Figure 6)
At three months following surgery, 45 percent (n=13) of the MACI grafts exhibited
good to excellent filling of the chondral defect, the remaining 55 percent (n=16)
exhibited fair to poor defect infill. The signal intensity at this time was described as
good to excellent in 28 percent (n=8) of grafts. Good to excellent border integration of
reparative tissue with adjacent native articular cartilage was evident in 76 percent
(n=22) of grafts, with fair to poor integration present in the remaining 24 percent (n=7)
of cases. The surface of the reparative tissue at this stage of recovery was good to
excellent in 83 percent (n=24) of cases with the remaining 17 percent (n=5) exhibiting
fair to poor surface structure. Good to excellent subchondral lamina was evident in 96
percent (n=28) of the cases (indicative that it was intact at the time of surgery) and 83
percent (n=24) of the cases exhibited good to excellent resolution of preoperative
subchondral bone edema. Joint effusion was evident in 24 percent (n=7) of cases and
55 percent (n=16) exhibited synovitis at the three month postoperative time point. No
graft hypertrophy was reported at this time.
At 12 months following MACI, good to excellent filling of the defect had increased to
76 percent (n=22) of grafts. The signal intensity had improved from 28 percent
reported as good to excellent at three months to 93 percent (n=27) by 12 months post-
surgery. Good to excellent border integration of reparative tissue with adjacent native
articular cartilage was seen in 79 percent (n=23) of cases. The surface of the reparative
tissue was intact in 86 percent (n=25) of grafts with the remaining 14 percent (n=4) fair
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to poor surface structure at the 12 month postoperative time point. Good to excellent
restoration of the subchondral lamina was evident in all cases and 93 percent (n=27) of
cases showed a resolution of subchondral bone edema. Joint effusion improved from 24
percent down to only three percent (n=1) of cases, though 28 percent (n=8) of cases had
persistent synovitis. Minor graft hypertrophy was reported in two cases.
By 24 months following MACI surgery, defect signal intensity and graft structure had
achieved a good to excellent rating in 86 percent (n=25) of cases. There was no change
in infill from the 12 to 24 month time point. Good to excellent border integration of
reparative tissue with adjacent native articular cartilage was seen in 83 percent (n=24)
of cases. The surface of the reparative tissue was intact in 83 percent (n=24) of grafts
with the remaining 17 percent (n=5) fair to poor surface structure at the 24 month
postoperative time point. Effusion was present in only one case and synovitis had
improved from 28 percent down to 20 percent (n=6) of sample. A third case exhibited
graft hypertrophy at this time point.
Complications
Most patients completed surgery and rehabilitation without complication. Five patients
developed a deep vein thrombosis (DVT) and were anti-coagulated.
There were four complications directly related to the MACI procedure including three
cases of graft hypertrophy. Surgical intervention was not deemed necessary in any of
the reported cases of hypertrophy, as all patients were asymptomatic and the
hypertropic tissue did not cause any mechanical obstruction to joint function. These
cases continue to be managed conservatively. The fourth complication involved a
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patient who was diagnosed with patella tendonitis of severe intensity that was probably
related to MACI and the tibial tubercle transfer surgical procedure. This patient
underwent physiotherapy and injection of corticosteroids, which alleviated the majority
of symptoms. This case continues to be managed conservatively.
A traumatic graft delamination was detected at the three month post-surgery time point.
An MRI scan revealed the MACI graft had become detached and was lodged near the
head of the gastrocnemeus. Upon clinical review, the patient revealed an incidence of
accidental non-compliance to postoperative rehabilitation due to inebriation in the tenth
postoperative week. The detached graft was removed arthroscopically and assessment
of the graft revealed residual tissue infill approximating 25 percent of the height of the
adjacent native cartilage. This patient had exhibited good to excellent infill upon MRI
examination at the 12 month postoperative time point. A possible explanation for such
a positive result at the 12 month time point is that the cell migration of chondrocytes
from the cambium surface of the membrane was practically complete at the time of
delamination. Thus the delamination of the membrane only dislodged the superficial
layer of the graft, leaving residual reparative tissue intact in the base of the defect,
which continued to develop and mature over time.
DISCUSSION
The MACI technique addresses many of the problems associated with PACI by
replacing the perisoteum with an inert collagen membrane. As a result, the operation is
simplified, anaesthetic time is reduced, and periosteal harvesting is abolished. Also, the
incidence of tissue hypertrophy is minimized because unlike periosteum, the collagen
membrane is acellular. Graft hypertrophy incidence, requiring arthroscopic
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debridement, after PACI has been reported in the literature [18,34] to be as high as 20-
36 percent of patients, yet only three cases (10 percent incidence, no debridement
required) of minor hypertrophic growth were noted in this study. This result is
consistent with others reported in the literature [3] for ACI using a type I/III collagen
membrane.
A review of the literature revealed a 6-8 percent incidence of retarded knee flexion
following MACI, requiring MUA [3]. Further investigation identified that
immobilization of the operated knee joint, irrespective of defect location, for 10-14 days
was advocated by some authors in the current literature [3]. This view is in contrast
with the recommendation of Hambly et al. [20] who stated that immobilization led to
decreased joint ROM, followed by adaptation of articular structures to the immobilized
circumstance. No incidence of knee stiffness requiring MUA was observed in this
study. Therefore, the results support early mobilization via CPM in conjunction with
rehabilitation protocols that incorporate all of the complexities associated with each
individual case [20,42].
The biological longevity and clinical success of the graft is dependent on a controlled
and graduated return to ambulation and physical activity, and the resultant
biomechanical stimulation of the implanted chondrocytes. This has been evidenced at a
cellular level with various studies showing the relationship between cartilage matrix
synthesis and biomechanical stimuli [9,16,47,49]. Dynamic compression of cartilage
stimulates matrix biosynthesis dependent on loading frequency and amplitude, whereas
increased static compression by mechanical or osmotic stress has been shown to
164
decrease matrix biosynthesis in a dose-dependent manner [9,47,49]. Using CPM also
improves matrix biosynthesis postoperatively by controlled dynamic compression [43].
The rehabilitation protocol adopted in this study [42] was well tolerated by all patients;
however, the single incidence of graft delamination highlights the clinical importance of
a protection phase coupled with patient compliance during the first three months
following implantation. The cellular regeneration, matrix production and adaptation of
the regenerating tissue to natural function involves a combination of time and
appropriate biomechanical stimulus. Therefore, it is not only important to encourage
successful maturation of the implanted graft, but it is vital that the integrity of the graft
be appropriately protected during all phases of the postoperative rehabilitation process.
Whilst structured rehabilitation cannot guarantee clinical success following MACI,
results from this study show that the introduction of biomechanical stimuli through
controlled postoperative rehabilitation may indeed act to enhance cartilage matrix
synthesis and aid both qualitative and quantitative aspects of cartilage repair.
Arthroscopic examination and biopsy as routine follow up is controversial. Also, the
high incidence of inadequate biopsies (55 percent as reported by ICRS [29]) precludes
meaningful interpretation in the majority of specimens. We consider it unethical to
subject ACI patients to routine ‘second-look’ arthroscopies and biopsy when the ACI
graft is considered to be functioning well clinically. Therefore, we have sought to
examine the potential for MRI assessment as a postoperative measure of graft outcome
and durability. MRI allows evaluation of articular cartilage thickness, graft
incorporation and congruity of the articular surface. Post-operative complications such
as delamination, arthrofibrosis, fissure formation and hypertrophy of implant material
can be reliably assessed with this technology, along with the signal characteristics of the
165
subchondral bone. Thus, MRI allows non-invasive, serial follow-up of patients and
detection of postoperative complications. Its role in the evaluation of cartilage repair is
well supported in the literature [2,11,39,40].
MRI evaluation of the defect infill and tissue regeneration following MACI revealed a
similar maturation pathway to that reported by previous studies of the PACI and CACI
procedures [3,21,23,34]. The present study demonstrated an increased MRI composite
score over time that improved significantly from three to 24 months postoperatively.
Post-hoc analyses revealed the improvement occurred predominantly in the first 12
months, then plateaued, but did not decline. This indicated that regenerated graft tissue
following MACI maintains its maturity and function from the 12 to 24 month
postoperative time point, a result that is comparable to the PACI and CACI procedures
[19,41].
The incidence and natural history of chondral defects has been well documented
[12,22]. In many patients, degeneration of the articular cartilage and the subsequent
alterations in knee function and loading cause pain and loss of motion in the affected
joint. Knee function was assessed via the KOOS [45], which has been validated
previously for the assessment of knee pain and function during activities of daily living.
This survey tool has proven to be reliable, responsive to surgery and physical therapy,
and evaluates the course of knee injury and treatment outcome [45]. At the three month
time point following surgery, the poor knee function, as evidenced in the KOOS, was
primarily due to the postoperative restraints placed on the patient in order to protect the
integrity of an immature MACI graft [20,42].
166
Subjective knee function among MACI patients improved over time in parallel with the
maturation process of the regenerating graft. At the 12 month time point, the KOOS
results reported here were comparable to those by Marlovitis et al. [30]. Patients in our
study experienced significant reduction in knee pain, and improvements in sports and
recreation function, activities of daily living, and knee-related quality of life from three
to 24 months, with the majority of this improvement, occurring in the first 12 months.
The 24 month KOOS results from our study were also comparable to those reported by
Marlovitis et al. [31], thereby indicating that improvements following surgery were
maintained over time.
The ability to walk for a distance is a cornerstone of functional independence and
greatly influences patients’ quality of life since it is a fundamental component of many
activities of daily living. Prior to surgery, the average 6MWT distance was 542 m. This
capacity decreased to 444 m at the three month postoperative time point, most probably
the result of the trauma of surgery and early postoperative restraints [20,41]. Following
this initial decrease, six-minute walk distance improved to the 12 month postoperative
time point, and this capacity was maintained through to 24 months.
CONCLUSION
Initially, collagen membrane was simply used to replace the periosteal patch which
sealed the cell solution into the chondral void. This was termed collagen-covered ACI.
Although CACI has exhibited commendable histological and clinical outcomes, its
surgical efficiency is impeded by the need to microsuture the membrane to the defect
border, a tedious task that increases the length and technical difficulty of the operation.
Furthermore, concerns surrounding cell delivery, the possibility of cell leakage through
the graft-cartilage interface, and the creation of microdefects by suturing remain [40].
167
The MACI technique involves direct cell inoculation onto a collagen scaffold for
implantation. Instead of an injection of chondrocytes under the collagen membrane into
the sealed defect compartment (CACI), chondrocytes are directly inoculated onto type
I/III collagen membrane and delivered as a cell-scaffold construct for implantation.
This study demonstrated that the MACI approach with complementary rehabilitation
yields regenerated functional infill material, and patients experienced improved knee
function and MRI scores in the short to mid-term. The development of MACI
decreases operative time, allows a smaller surgical incision, and facilitates postoperative
recovery. These data also show that the MACI procedure reduces the incidence of
postoperative complications, especially the incidence of tissue hypertrophy.
The biological longevity and clinical success of the graft is dependent on a controlled
and graduated return to ambulation and physical activity, as well as the biomechanical
stimulation of the implanted chondrocytes. Therefore, reduced cartilage thickness
and/or matrix synthesis observed in some patients may be related to a lack of
biomechanical stimulation of the graft. The introduction of biomechanical stimuli
through controlled postoperative rehabilitation in the first three months may enhance
cartilage matrix synthesis and aid both qualitative and quantitative aspects of cartilage
repair.
This study provides novel insight into the morphological progression of the regenerative
tissue produced following MACI through the use of established MRI evaluation
parameters. These results supplement the clinical, radiographical and histological
information on MACI, so that a better understanding of the outcome of ACI with a
collagen membrane is afforded. Further investigation of the relationship between MRI
168
and clinical outcome following chondrocyte implantation is imperative as it remains to
be determined whether the native ultra structure of cartilage needs to be restored in
order to achieve good, durable, clinical results.
ACKNOWLEDGEMENTS
This study was funded by a research grant provided by The National Health and
Medical Research Council (ID Number: 254622), it was administered by the council on
behalf of the Australian Government. Unless otherwise specified, the data given in this
review is based on work carried out at the University of Western Australia.
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Activities of Mean 65.0bcdef 68.3e 80.3f 89.0 88.7 daily living SD 18.0 18.1 18.0 13.4 13.0 19.4 p<0.001
Sport & Mean 18.4adefg 3.2 15.8f 32.0g 51.4 recreation SD 21.3 7.0 23.4 30.0 34.7 17.9 p<0.001
function Knee related Mean 21.4bcde 26.2e 38.8 42.7 47.7 quality of life SD 18.0 23.5 26.1 25.5 26.0 18.8 p<0.001
a = significant difference (p<0.05) presurgery vs 3 months b = significant difference (p<0.05) presurgery vs 6 months c = significant difference (p<0.05) presurgery vs 12 months d = significant difference (p<0.05) presurgery vs 24 months e = significant difference (p<0.05) 3 months vs 6 months f = significant difference (p<0.05) 6 months vs 12 months g = significant difference (p<0.05) 12 months vs 24 months
174
Fig. 1. Paradigm of matrix-induced autologous chondrocyte implantation (MACI) cartilage regeneration. 1) Implantation of chondrocyte seeded membrane (blue) into the fibrin sealant-covered (pink) base of the debrided chondral defect (day of implantation). 2) Cell migration of chondrocytes from the cambium surface of the membrane into the fibrin sealant matrix. Host resorption of the collagen membrane has also commenced (2-5 days following implantation). 3) Matrix production by implanted autologous chondrocytes. Type II collagen, aggrecan and other matrix proteins important for healthy articular cartilage function are synthesised by the newly implanted cells (1-9 months following implantation). 4) Matrix maturation and hyaline-like/hyaline cartilage formation. Cartilage infill is complete, chondrocyte morphology and surrounding matrix appears healthy (or similar to surrounding native tissue) and graft cartilage is well integrated with the adjacent cartilage (12-24 months following implantation).
175
Fig. 2. The graduated return to weight-bearing administered to patients during functional rehabilitation following their MACI surgery. Gradual loading of the joint is conducted to stimulate hypertrophy and adaptation of hyaline-like cartilage in-fill tissue through physiologically induced maturation of chondrocyte biosynthesis.
Fig. 3. Changes in six-minute walk distance (m) at pre- and post-surgery assessment time points (x ± SE, n = 28).
176
Fig. 4. Changes in the five sub domains of KOOS at pre- and post-surgery assessment time points (x ± SE, n = 28). Total KOOS scores (0 = extreme knee problems and 100 = no knee problems), ADL = activities of daily living, Sport&Rec = sport and recreation function, KQOL = knee-related quality of life.
Fig. 5. Changes in MRI composite score at post-surgery assessment time points (x ± SE).
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Fig. 6. Sagittal proton density fast spin echo magnetic resonance image of a MACI graft to the medial femoral condyle in a patient who had a previously full thickness chondral defect. B. At three months post-surgery the graft is hyperintense and of reduced thickness when compared with the adjacent normal articular cartilage. C. One year post-surgery the MACI graft has a heterogeneous appearance and is of similar thickness to the adjacent normal cartilage, it is interesting to note the reconstitution of the sub-chondral bone plate from three to 24 months (depicted by red arrow heads). D. At two years post-surgery, the MACI graft remains intact and demonstrates heterogeneity in graft signal compared to the adjacent native cartilage. Border integration is smooth with no radiological evidence of fissures or clefts between the graft and the native cartilage.
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CHAPTER SIX
COMBINED HIGH TIBIAL OSTEOTOMY AND MATRIX-INDUCED AUTOLOGOUS CHONDROCYTE IMPLANTATION (MACI)
FOR EARLY OSTEOARTHRITIS OF THE KNEE Note 1. References cited in this chapter appear in a reference list at the end of the
chapter. Note 2. Tables and figures noted within this chapter appear at the end of the
chapter.
179
Title: Combined high tibial osteotomy and matrix-induced autologous chondrocyte implantation (MACI) for early osteoarthritis of the knee.
1.) W.B. Robertson MSc* ** PhD Student University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA
2.) R.J.K Khan FRCS, FRACS* Senior Lecturer University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA
3.) D.J. Wood BSc. MBBS MS FRCS FRACS*. Professor University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA
4.) J.M. Linklater FRANZCR Musculoskeletal Radiologist Castlereagh Sports Imaging North Sydney Orthopaedic and Sports Medicine Centre 286 Pacific Hwy, CROWS NEST NSW 2065 AUSTRALIA
5.) M.H. Zheng DM., PhD., FRCPath* Professor University of Western Australia 2nd Flr M Block, QEII Medical Centre,Nedlands, WA 6009 AUSTRALIA
6.) T.R. Ackland PhD FASMF**. Professor University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA
* School of Surgery and Pathology (Orthopaedics), University of Western Australia, Crawley, WA 6009 Australia. ** School of Human Movement and Exercise Science, University of Western Australia, Crawley, WA 6009 Australia. Correspondence: Mr William Brett Robertson Schools of Surgery & Pathology and Human Movement & Exercise Science University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA Fax +61 89 346 6462 Email [email protected]
ABSTRACT Early symptomatic osteoarthritis (OA) of the knee poses a difficult challenge to orthopaedic surgeons, particularly in the presence of lower limb malalignment. Most surgical options are palliative. Our aim was to assess combined high tibial osteotomy (HTO) and matrix-induced autologous chondrocyte implantation (MACI) as a treatment option. Patients with localised medial compartment OA and varus malalignment were identified. Diagnosis was supported with radiographs and MRI, and suitability for ACI confirmed at arthroscopy; where a cartilage specimen for culture were obtained. HTO and MACI procedures were performed in one sitting by a single surgeon. The HTO was performed through an inverted hockey-stick incision. The MACI procedure was performed via a small medial arthrotomy; the defect was debrided to subchondral bone and graft applied. Patients received three months rehabilitation and function was assessed preoperatively and at three-monthly intervals. MRI and radiographs were repeated at three months and then annually to the 24 month time point. Fifteen patients were identified: 12 were male and the average age was 46 years (27-58). Mean varus deformity was 6 degrees. As well as medial compartment OA two patients had evidence of osteochondritis dissecans, and two early patello-femoral OA. Eight patients had previous surgery to the knee. Average time between cartilage harvest and implantation was six weeks. Fourteen patients had a lateral closing wedge osteotomy; a medial opening wedge was performed in a case of leg shortening. Mean operation duration was 72 minutes (range 60-90 minutes). The graft was fixed with fibrin glue in all cases, and augmented with stitches or vicryl pins in five cases. Mean defect size was 6.2cm2 (range 2-12 cm2). There were three complications: one DVT, a haemarthrosis and a graft detachment; the latter was successfully treated with a second procedure. MRI scans at three months showed oedematous tissue at the defect sites, contrasting with the fluid filled defects seen preoperatively. Scans at one year showed hyaline-like cartilage infill with similar signal characteristics to native hyaline cartilage. Six minute walk test and knee injury and osteoarthritis outcome score (KOOS) indicated improved functional capacity at six months and one year when compared to preoperative scores. This is the first series of HTO and MACI published in the literature. Preliminary results suggest a significant functional improvement, supported by radiologic evidence of deformity correction and filling-in of articular defects on MRI. Definitive conclusions will be made with longer term follow-up.
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INTRODUCTION
The knee joint is required to withstand large forces over a wide range of daily activities.
On weight bearing the medial compartment of the knee is exposed to 70% of the knee
joint load generated [1]. Subsequently, the hyaline articular cartilage of the medial
compartment is prone to degeneration. Among active individuals, osteoarthritis (OA)
compromises activities of daily living and participation in sport and recreational
activities.
Hyaline articular cartilage is a terminally differentiated tissue with an inability to
regenerate. It consists of chondrocytes embedded in a matrix of proteoglycan and
collagens. This tissue can withstand high levels of mechanical stress and continuously
renews its extracellular matrix. Despite this durability, mature articular cartilage is
vulnerable to injury and disease processes that cause irreparable tissue damage. It has a
limited capacity of repair and does so through the formation of fibrocartilage.
Early unicompartmental osteoarthritis (OA) of the knee in the young and active patient
groups poses a treatment challenge, particularly in the presence of lower limb
malalignment, since preservation of native joint structures where possible is highly
desirable. Until recently, surgical options were limited to arthroscopic lavage and
debridement, marrow-tapping techniques, osteotomy and arthroplasty [2,3]. Research
into newer, alternative techniques has included osteochondral grafts [4], periosteal and
function Knee related Mean 18.1 32.4a 34.0 41.3 43.0 quality of life SD 10.0 17.0 13.1 22.5 25.0 7.6 p<0.001
a = significant difference (p<0.05) presurgery vs 3 months b = significant difference (p<0.05) 3 months vs 6 months c = significant difference (p<0.05) 6 months vs 12 months d = significant difference (p<0.05) 12 months vs 24 months
201
1.
2.2.
1.
2.
Fig. 1.A. Schematic diagram of the MACI surgerical technique (picture curtesy of Verigen Australia). B. Surgical incision sites 1. MACI incision site (medial parapatellar) 2. HTO ‘inverted hockey stick’ incision site. C. Postoperative fluroscope of HTO insitu.
Fig. 2. Changes in six-minute walk distance (m) at pre- and post-surgery assessment time points (x±SE, n = 15).
202
Fig. 3. Changes in the five sub domains of KOOS at pre- and post-surgery assessment time points (x±SE, n=15). Total KOOS scores (0 = extreme knee problems and 100 = no knee problems), ADL = activities of daily living, Sport&Rec = sport and recreation function, KQOL = knee-related quality of life.
Fig. 4. Changes in MRI composite score at post-surgery assessment time points (x±SE).
203
Fig. 5.A. Coronal proton density fast spin echo magnetic resonance image of a combined HTO and MACI patient one year following surgery. The graft (depicted between the two arrow heads) is hypointense compared to surrounding native tissue. B. The Saggital view reveals that the graft approximates the height of the surrounding native tissue. The signal intensity is hypointense when compared to the native tissue, however, border integration is smooth and the preoperative subchondral bone oedema that was present preoperatively has resolved.
Fig. 6.A. Sagittal proton density fast spin echo magnetic resonance image of a delaminated MACI graft 3 days post implantation (arrow). B. Sagittal proton density fast spin echo magnetic resonance image of the MACI graft following reattachment augmented with Vicryl pins).
204
REFERNCES
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4. Horas U, Pelinkovic D, Herr G, Aigner T, and Schnettler R. Autologous chondrocyte implantation and osteochondral cylinder transplantation in cartilage repair of the knee joint. J Bone Joint Surg [Am] 2003; 2:185-192.
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CHAPTER SEVEN
SUMMARY, RECOMMENDATIONS
AND CONCLUSIONS
SUMMARY
In Australia, there was a sequential evolution of the ACI technique from the
conventional periosteum covered ACI (PACI), to the use of a porcine collagen type I/III
membrane sutured as a periosteal substitute (CACI). The CACI technique was then
further modified to the current practice of a): first seeding the cultured autologous
chondrocytes onto the cambium layer of the type I/III membrane and then, b):
implanting the cell-seeded membrane as a single construct via the matrix-induced
autologous chondrocyte implantation technique (MACI). This thesis has concentrated
on the CACI and MACI techniques, since the PACI method has been shown to involve
a number of short comings [21,30,40,54,55,81].
Complications associated with the use of periosteum in the ACI procedure stimulated
the search for an alternative scaffold for the containment of implanted chondrocytes.
To address these problems, a biodegradable type I/III collagen membrane was
developed for use in conjunction with ACI. This membrane comprised highly purified
porcine collagen and exhibited excellent biocompatibility and low immunogenicity.
The membrane was designed to reproduce the physiological barrier functions of the
periosteum. Prior to the commencement of this thesis, definitive evidence regarding the
role of the membrane in enhancing chondrocyte-mediated cartilage regeneration was
sparse. There also existed discrepancies in the literature with regard to the
quantification of the ACI surgical outcome. The effectiveness of this new treatment
was often limited to clinical evaluation and opportunistic arthroscopic examination.
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Arthroscopic examination and biopsy as routine follow-up remains controversial.
Clinical evaluation is important to track the patient symptoms, however, it is yet to be
correlated with arthroscopic or MRI data. This thesis provides novel insight into the
morphological progression of the regenerative tissue produced following CACI and
MACI through the use of established MRI evaluation parameters [50,51]. The results
compliment the currently available clinical and histological information on CACI and
MACI, and with MRI assessment of the cartilage repair, a better understanding of the
outcome of ACI with a collagen membrane is afforded.
At the point in time that CACI was introduced into Australia (February 1999),
information pertaining to the most appropriate post-operative rehabilitation pathway
following implantation was scarce, while that for the newer MACI technique was non-
existent. As no guidelines other than those pertaining to PACI existed, it was necessary
to develop a specific rehabilitation protocol for collagen covered and matrix induced
ACI that was based on biological principles underlying postoperative biomechanical
stimulation of chondrocyte biosynthesis. Whilst structured rehabilitation cannot
guarantee clinical success following MACI, results from this series of studies
demonstrate that the introduction of biomechanical stimuli through controlled
postoperative rehabilitation may indeed act to enhance cartilage matrix synthesis and
aid both qualitative and quantitative aspects of cartilage repair.
Rehabilitation
The biological principle underlying our rehabilitation protocol for MACI is based on
postoperative biomechanical stimulation leading to chondrocyte biosynthesis. That is,
the rehabilitation protocol is designed to activate the cell-mediated progression of
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regenerative cartilage into physiologically functional articular cartilage. The
neocartilage formed following MACI surgery is characterised by tissue that is high in
cell density, water, and type II collagen content, but of weak biomechanical resilience.
After cell cultivation and surgical technique, the key to the therapeutic success of MACI
is the maturation of neocartilage to functional cartilage through healthy extracellular
matrix production by chondrocytes post-implantation, a process heavily reliant on
effective rehabilitation.
The rehabilitation protocol presented in this thesis (Chapter three) was well tolerated by
all patients; however, the single incidence of graft delamination (Chapter five)
highlights the clinical importance of a protection phase coupled with patient compliance
during the first three months following implantation. The cellular regeneration, matrix
production and adaptation of the regenerating tissue to natural function involves a
combination of time and appropriate biomechanical stimulus. Therefore, it is not only
important to encourage successful maturation of the implanted graft, but it is vital that
the integrity of the graft be appropriately protected during all phases of the
postoperative rehabilitation process. Additionally, the results support early mobilisation
via CPM (rather than immobilisation) in conjunction with rehabilitation protocols that
incorporate all of the complexities associated with each individual case [81,83].
Magnetic Resonance Imaging
Routine arthroscopic examination and biopsy is costly and it is often difficult to gain the
patient’s consent to a third invasive procedure. Also, the high incidence of inadequate
biopsies (55% as reported by ICRS [38]) precludes meaningful interpretation in the
majority of specimens. We consider it unethical to subject ACI patients to routine
207
‘second-look’ arthroscopies and biopsy when the ACI graft is considered to be
functioning well from a clinical perspective. Therefore, we have sought to examine the
potential for MRI assessment as a postoperative measure of graft outcome and
durability. Its role in the evaluation of cartilage repair is well supported in the literature
[4,20,63,84]. This series of studies provided novel insight into the morphological
progression of the regenerative tissue produced following CACI and MACI through the
use of established MRI evaluation parameters. These results supplement the clinical,
radiographical and histological information on MACI, so that a better understanding of
the outcome of ACI with a collagen membrane is afforded.
Substitution of Periosteum with a Type I/III Collagen Membrane
Results from these studies also revealed that many of the problems associated with
PACI could be addressed by replacing the periosteum with an inert collagen membrane.
Additional benefits of the collagen membrane include simplification of the operative
technique, reduced anaesthetic time, and the abolishment of periosteal harvesting. Our
results also indicated that the incidence of tissue hypertrophy was minimised, because
unlike periosteum, the collagen membrane is acellular. This result is consistent with
others reported the literature [31] for ACI using a type I/III collagen membrane.
RECOMMENDATIONS FOR FUTURE RESEARCH
This thesis provides novel insight into the morphological progression of the
regenerative tissue produced following CACI and MACI through the use of established
MRI evaluation parameters. The development of our graduated load-bearing
rehabilitation protocol has been specifically targeted to provide an appropriate
biomechanical stimulus over the first postoperative year to maximise chondrocyte-
208
mediated defect regeneration. However, the problem still faced is what constitutes
‘optimal’ postoperative rehabilitation?
Current rehabilitation protocols are based on theoretical models since randomised,
controlled trials investigating various postoperative rehabilitation protocols following
ACI have yet to be reported. This is because, historically, the primary focus in the
literature has been on surgical technique, modification of delivery systems, histological
versus radiological assessments and chondrocyte biology. Whilst the role of
postoperative rehabilitation has been acknowledged, it has taken a ‘back seat’ to the
aforementioned topics.
From a rehabilitation clinician’s point of view, this lack of knowledge is extremely
frustrating, as we have been effectively forced to ‘fly blind’. Postoperatively, if we
push the patient too aggressively, we risk graft delamination and subsequent graft
failure. However, if we progress too conservatively, we risk affecting the regeneration
of tissue due to inadequate loading stimuli. In turn, this may lead to the associated
problems of muscle atrophy, interarticular adhesions, gait abnormalities and thus
generate a subsequent pain-inactivity spiral. Every patient is unique as they present
with different defect locations and inherent individual regenerative capacity.
Rehabilitation therapists require defect-specific rehabilitation protocols guided by
accurate, non-invasive methods of graft assessment that are predictive of functional
capacity. This will allow the patient safe progression of functional activity, which will
be of direct benefit to patient outcome and to clinical practice. Additionally,
randomised controlled trials investigating current versus alternative methods of load
bearing are required in order to provide evidence-based treatment parameters. Further
209
research into the role of postoperative rehabilitation following ACI is required, as
current practice has not kept pace with the recent advances in the field of cartilage
repair.
Young and active patients with OA associated with varus deformity of the knee are a
difficult patient group to treat, and to date no defined protocols exist. Most surgical
options are palliative. Within this thesis, the first patient series treated with combined
MACI and HTO was described. Results show a significant functional improvement,
supported by radiographic evidence of deformity correction. The data provide novel
insight regarding the morphological progression of regenerative tissue produced
following combined MACI and HTO through the use of established MRI evaluation
parameters. However, several of the MACI and HTO cases in this series exhibited graft
infill of the majority of the defect, with a small residual Outerbridge Grade IV defect.
All of the grafts were scored according to the worst appearance area of the graft.
Subsequently, this limited the ability of the scoring system to accurately represent the
status of the graft.
Further investigation of the relationship between MRI and clinical outcome following
chondrocyte implantation is imperative as it remains to be determined whether the
native ultra structure of cartilage needs to be restored in order to achieve good, durable,
clinical results. The current focus needs to shift from morphological assessment of the
ACI graft, to the development of reliable, in vivo measures of the quality of regenerated
tissue. Advanced MRI techniques such as T2 mapping have the capability to map the
distribution of collagen throughout the articular surface. Alternatively, the distribution
of cartilage glycosaminoglycan (GAG) can now be measured by delayed Gadolinium
210
Enhanced MRI of Cartilage (dGEMRIC). The ability to monitor GAG content in a
cartilage repair site will assist in determining the physiological state of the repair tissue.
The information provided by these advanced MRI protocols will complement the
current morphological assessment techniques and have the potential to bridge the
current gap between histological and radiological outcome following ACI.
CONCLUSIONS
Initially, collagen membrane was simply used to replace the periosteal patch which
sealed the cell solution into the chondral void. This was termed collagen-covered ACI.
Although CACI has exhibited commendable histological and clinical outcomes, its
surgical efficiency is impeded by the need to microsuture the membrane to the defect
border, a tedious task that increases the length and technical difficulty of the operation.
Furthermore, concerns remain surrounding cell delivery, the possibility of cell leakage
through the graft-cartilage interface, and the creation of microdefects by suturing [84].
The MACI technique involves direct cell inoculation onto a collagen scaffold for
implantation. Instead of an injection of chondrocytes under the collagen membrane into
the sealed defect compartment (CACI), chondrocytes are directly inoculated onto type
I/III collagen membrane and delivered as a cell-scaffold construct for implantation. This
study demonstrated that the MACI approach with complementary rehabilitation yields
regenerated functional infill material, and patients experienced improved knee function
and MRI scores in the short to mid-term. The development of MACI decreases
operative time, allows a smaller surgical incision, and facilitates postoperative recovery.
These data also show that the MACI procedure reduces the incidence of postoperative
complications, especially the incidence of tissue hypertrophy.
211
Based on our experience with MACI to the medial femoral condyle, we have reported
the first patient series treated with combined MACI and HTO. Our aim was to assess
combined HTO and MACI as a therapeutic option for young patients with medial
compartment OA and varus malalignment. The rationale was to establish whether by
off-loading the medial compartment, the hostile loading environment of the arthritic
knee was assuaged, allowing chondrocyte regeneration to proceed. Results showed a
significant functional improvement, supported by radiographic evidence of deformity
correction. However, this study had a number of limitations, including a small sample
size (n=15), and perhaps more importantly, we did not have a control group for
comparison. The latter limitation makes establishment of the relative benefit of the
individual procedures performed impossible. Ideally, we would have performed a
randomised controlled trial, but the limited number of patients suitable for this
treatment precluded such a research design. However, we have commented on the
presence and quality of the graft at 24 months and believe it is reasonable to attribute
some of the clinical improvement to the combined intervention.
The biological longevity and clinical success of the graft is dependent on a controlled
and graduated return to ambulation and physical activity, as well as the biomechanical
stimulation of the implanted chondrocytes. Therefore, reduced cartilage thickness
and/or matrix synthesis observed in some patients may be related to a lack of
biomechanical stimulation of the graft. The introduction of biomechanical stimuli
through controlled postoperative rehabilitation in the first three months may enhance
cartilage matrix synthesis and aid both qualitative and quantitative aspects of cartilage
repair.
212
This thesis provides new insight into the morphological progression of the regenerative
tissue produced following CACI, MACI and combined HTO and MACI through the use
of the established MRI evaluation parameters. These results supplement the clinical,
radiological and histological information on ACI, so that a better understanding of the
outcome of ACI with a collagen membrane is afforded. Further investigation of the
relationship between MRI and clinical outcome following chondrocyte implantation is
imperative as it remains to be determined whether the native ultra structure of cartilage
needs to be restored in order to achieve good, durable, clinical results.
213
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APPENDIX ONE
COMBINED ANTEROMEDIALISATION TIBIAL TUBERCLE OSTEOTOMY AND AUTOLOGOUS CHONDROCYTE IMPLANTATION (C-ACI & MACI) FOR THE TREATMENT OF ISOLATED CHONDRAL DEFECTS OF THE
PATELLOFEMORAL JOINT.
Note 1. References cited in this appendix appear in a reference list at the end of
the paper. Note 2. Tables and Figures noted within this appendix appear at the end of the
paper.
Title: Combined anteromedialisation tibial tubercle osteotomy and autologous chondrocyte implantation (C-ACI & MACI) for the treatment of isolated chondral defects of the patellofemoral joint. Keywords: Osteochondral defect, Autologous chondrocyte implantation, Patellofemoral joint.
1.) M. Ledger MBBS* University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA
2.) W.B. Robertson MSc* ** PhD Student University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA
3.) D. Fick MBBS* PhD Student University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA
4.) D.J. Wood BSc. MBBS MS FRCS FRACS*. Professor University of Western Australia Perth Orthopaedic Institute Hollywood Private Hospital Entrance 3 Verdun St Nedlands, WA 6009 AUSTRALIA
5.) M.H. Zheng DM., PhD., FRCPath* Professor University of Western Australia 2nd Flr M Block, QEII Medical Centre,Nedlands, WA 6009 AUSTRALIA
6.) T.R. Ackland PhD FASMF**. Professor University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA
* School of Surgery and Pathology (Orthopaedics), University of Western Australia, Nedlands, WA 6009 Australia. ** School of Human Movement and Exercise Science, University of Western Australia, Nedlands, WA 6009 Australia. Correspondence: Mr William Brett Robertson University of Western Australia 35 Stirling Highway Crawley, WA 6009 AUSTRALIA Fax +61 89 346 6462 Email [email protected]
ABSTRACT Despite initial failures, Autologous Chondrocyte Implantation (ACI) treatment for patellofemoral cartilage defects has improved more recently when combined with attention to, and surgical correction of patellofemoral pathomechanics. ACI technology has also progressed to collagen-covered (C-ACI) and matrix-induced ACI (MACI) 16 patients with 17 patellofemoral cartilage defects were treated with either C-ACI or MACI and realignment procedures when indicated. 6-minute walk test, Knee Injury and Osteoarthritis Outcome Scores (KOOS), and Magnetic Resonance Imaging studies were obtained at regular intervals to 24 months. Changes between pre- and post-operative time points were compared using repeated measures analysis of variance. As a combined group, 6-minute walk test significantly improved from pre-surgery to 24 months (p<0.001). There was also significant improvement across all five KOOS subscales (p<0.05). There was no significant difference detected in functional outcomes between the C-ACI or MACI groups. There were no graft failures and MRI composite graft scores improved significantly from 3 months to 24 months postoperatively (p<0.05).
INTRODUCTION
Patients with chondral defects involving the articulating surfaces of the patellofemoral
joint are a difficult group to treat. This is because these defects are usually secondary
to pathological abnormalities or imbalances between the static (osseous and
ligamentous) elements or dynamic (neuromuscular) factors contributing to
patellofemoral function [1]. Autologous chondrocyte implantation (ACI) for the
repair of articular cartilage defects in the knee has gained increasing acceptance in the
last decade as a useful treatment modality, however, the initial results of ACI for
repair of patella defects were poor [2]. With time, the results for patella ACI have
improved, with attention to patella maltracking, realignment of the extensor
mechanism where indicated, and a subsequent reduction in abnormal forces across the
patellofemoral joint likely to cause graft failure [3-6].
There are few studies examining the outcomes of newer techniques of collagen-
covered autologous chondrocyte implantation (C-ACI) and matrix-induced
autologous chondrocyte implantation (MACI) in patients with isolated patellofemoral
cartilage defects. Further complicating matters, the success of anteromedialisation
tibial tubercle osteotomy alone without ACI has been shown to correlate the anatomic
location of the patella defect [7]. This potentially obscures a review of combined ACI
/ patellofemoral realignment procedures and many previous studies reviewing the
success of patellofemoral ACI have not allowed for this.
We present our functional and MRI outcome measures of C-ACI and MACI
techniques applied to the treatment of anatomically defined cartilage defects in the
patellofemoral joint.
MATERIALS AND METHODS
Sample
Patients were selected according to the inclusion and exclusion criteria guidelines
outlined by Peterson [8]. Seventeen patellofemoral ACI surgeries were performed in
16 patients (8 male and 8 female) between December 1999 and June 2005. All
implantations survived to a minimum of 24 months. Preoperative assessment
included a clinical examination with particular attention to patellofemoral tracking, a
patellofemoral computerized topography (CT) geometry scan, and an magnetic
resonance imaging (MRI) scan.
The mean age at time of surgery was 37.5 years (range: 23-57 years). All had full
thickness chondral lesions as diagnosed by preoperative MRI and confirmed at
arthroscopic biopsy with a mean of 4.3 cm2 (range: 1.0-9.0 cm2). Of the cohort, one
case presented with a concomitant medial femoral condyle lesion; the remainder had
single defects. The etiology of defects in order of frequency was patellofemoral
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Descriptive Statistics and ANOVA Summary for CACI&MACI Patella Patients (n=17).
Postoperative time point (months)
Variable Pre - surgery 3 6 12 24 F P
6-min Walk Distance Mean 545 438 529 581 590a Combined (n=17)
6-min walk (m) SD 166 88 112 124 105 12.5 p<0.001
Mean 509 440 526 574 592 CACI (n=7)
6-min walk (m) SD 148 74 140 175 142 Mean 580 436 531 589 590 MACI (n=10)