Andrea Bailey, Nicola Goodstone, Sharon Roberts, Jane Hughes,. Simon Roberts, Louw van Niekerk, James Richardson, and Dai Rees. Objective: To develop ...
Rehabilitation After Oswestry Autologous-Chondrocyte Implantation: The OsCell Protocol Andrea Bailey, Nicola Goodstone, Sharon Roberts, Jane Hughes, Simon Roberts, Louw van Niekerk, James Richardson, and Dai Rees Objective: To develop a postoperative rehabilitation protocol for patients receiving autologous-chondrocyte implantation (ACI) to repair articular-cartilage defects of the knee. Data Sources: A careful review of both basic science and clinical literature, personal communication with colleagues dealing with similar cases, and the authors’ experience and expertise in rehabilitating numerous patients with knee pathologies, injuries, and trauma. Data Synthesis: Postoperative rehabilitation of the ACI patient plays a critical role in the outcome of the procedure. The goals are to improve function and reduce discomfort by focusing on 3 key elements: weight bearing, range of motion, and strengthening. Conclusions: The authors present 2 flexible postoperative protocols to rehabilitate patients after an ACI procedure to the knee. Key Words: cartilage, physiotherapy, patellofemoral joint, tibiofemoral joint Bailey A, Goodstone N, Roberts S, et al. Rehabilitation after Oswestry autologous-chondrocyte implantation: the OsCell protocol. J Sport Rehabil. 2003;12:104-118. © 2003 Human Kinetics Publishers, Inc.
Because of its avascular nature, articular cartilage has a poor capacity for self-repair. Full-thickness chondral and osteochondral defects are difficult problems commonly seen in sports injury and orthopedic practice. There are a number of surgical techniques including drilling, abrasion chondroplasty, and microfracture used to stimulate the formation of a new articular surface (for review see reference 1). These approaches can give satisfactory results, but intrinsic remodeling and reorganization promote the formation of fibrocartilage, not of the native hyaline cartilage. Peterson and Brittberg2,3 pioneered autologous-chondrocyte implantation (ACI) in Sweden in 1987. ACI involves harvesting host chondrocytes, expanding the number of cells in culture,4 and then reimplanting them beneath a periosteal autograft covering the defect via an arthrotomy incision. To date, ACI has proven clinically effective in restoring hyalinelike cartilage to
The authors are with the Robert Jones & Agnes Hunt Orthopedic Hospital, Oswestry, Shropshire, SY10 7AG, UK. Bailey, Roberts, and Hughes are with the Dept of Physiotherapy. Goodstone is with the Arthritis Research Centre. Roberts, van Niekerk, Richardson, and Rees are consultant orthopedic surgeons. 104
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isolated chondral defects of the knee.5-8In 1996, a surgeon now with the OsCell team in Oswestry was the first to perform the ACI procedure in the UK. To date, the OsCell team has treated 115 patients. Ninety-eight had moderate to severe defects isolated to the knee. The defects were located on the patella and medial and lateral femoral condyles. Seventeen patients had more than 1 defect. ACI patients require extensive postoperative rehabilitation. This article describes the development of 2 postoperative rehabilitation protocols for patients who have had knee defects treated with ACI. In order to restore function and relieve discomfort, the OsCell rehabilitation program combines 3 elements: weight bearing, range of motion, and strengthening. Furthermore, the holistic nature of the rehabilitation of the individual patients’ needs is also considered.
Cartilage Healing An appreciation of the complexities of in vivo cartilage healing is critical. There are essentially 3 phases of tissue healing: inflammation, fibroblastic repair, and remodeling. The inflammatory phase is a key stage in tissue healing because without it, healing does not occur. In vivo regeneration of articular cartilage is not only complex but also very slow, taking years. Furthermore, the depth, position, and geometry of a cartilage injury strongly influence the type of healing. This is partly a result of the avascular, alymphatic, and aneural nature of articular cartilage. Chondral defects have little or no inflammatory response and rely on chondrocytes for self-repair. Osteochondral injuries damage blood vessels within the bone, enabling inflammatory cells to gain access to the injured site and initiate a repair response. Tissue remodeling can take several months, however, and often results in a disorganized repair tissue termed fibrocartilage that lacks mechanical strength. The paucity of cells and their decline with age in metabolic activity, matrix synthesis, and cell division also contribute to the poor in vivo regeneration of cartilage. The tissue is composed of chondrocytes surrounded by extracellular matrix that comprises water and a macromolecular framework.9 As the chondrocytes occupy less than 1% of the tissue volume, the extracellular matrix is of considerable importance and provides the majority of the functionality of the tissue. Chondrocytes are responsible for mediating tissue homeostasis with ongoing maintenance and remodeling of the macromolecular framework. Animal models have been used in an attempt to understand the process of cartilage healing.10,11 Breinan et al10 created osteochondral defects in dog knees, treated them with ACI, and studied their course of healing. Their study identified 3 stages of cartilage healing; proliferation (0–6 weeks), transition (7–26 weeks), and remodeling (>27 weeks). Proliferation was identified as the rapid response of the defect to fill with primitive repair tissue, which is soft. The transitional phase is the gradual “firming up” of the
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graft tissue, which takes on the texture of gelatin at 3–6 months. Increased cellular activity, matrix production, and mechanical hardening are identified in the remodeling stage. Although these stages of healing might be reflected in humans, the time frames might differ. This study and others like it clearly illustrate that cartilage healing in vivo is complex. Furthermore, many factors such as species, joint, age, geometry, and position of the defect emphasize the variability. They do provide a basis for the design of a rehabilitation protocol.
Design of the Postoperative Rehabilitation Protocols for OsCell ACI Patients Currently, there is limited information in the literature describing rehabilitative exercise after an ACI procedure.12 In a review article, Gillogly et al12 described a comprehensive but generic rehabilitation protocol. This protocol and other postoperative rehabilitation guides for patients with knee injury suggest the avoidance of symptoms and the focus on protection and facilitation of full function.12,13 Based on these findings, the OsCell protocols focus on regaining full function, resistance training, proprioception, and muscle balance, which in turn might prevent future injury and possibly degenerative diseases. The 98 patients treated at Oswestry had cartilage defects of the knee that differed in severity, location, and geometry. Initially we chose to divide patients into 2 groups based on the location of their defect: tibiofemoral or patellofemoral. This decision also relates to the difference in knee biomechanics that are discussed later in the article. Two protocols were designed to treat each defect. Subsequently, the geometry and location of the defect are considered because they can influence the healing potential under differing loads and stresses at varying degrees of motion. The surgeons at Oswestry carefully map the size and site of the treated defect, which aids specificity of the rehabilitation. Our previous experience indicates that postoperative rehabilitation should always establish attainable goals in agreement with the patient. Consequently, location and geometry were used in conjunction with age, training history, medical history, and psychology to help tailor the program to the patient’s needs. Our ultimate goals are to relieve discomfort and improve function without jeopardizing the articularcartilage in vivo repair process. To achieve these goals we gave careful consideration to knee biomechanics in developing our protocols.
Biomechanics of the Knee Knee biomechanics relating to the patellofemoral (PF) and tibiofemoral (TF) joints are described. The soft tissue stability of the PF joint depends on both passive (retinacular) and dynamic (quadriceps) restraints. During
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extension and flexion, the patella glides on the femur. Any limitation to superior and inferior patella glide can result in restricted active extension and flexion. The OsCell protocol indicates early passive patella mobilization to prevent any adherence of the patellofemoral joint and suprapatellar pouch, which can restrict patella glide and ultimately limit the movement of the knee joint, which might result from the arthrotomy incision (Table 1a, Week 2, and Table 2a, Day 1). In all movements except full extension, only 1 part of the patella articulates with the femur at any given time. In extension, the patella sits above the trochlea notch without significant compressive load. It is not until 20° flexion that the inferior pole of the patella is in contact. The contact area moves proximally on the patella as the knee flexes. As the angle of knee flexion progresses from 20° to 90° the area of contact increases.14 By 90° flexion, the superior portion of the patella is in contact with the trochlea. Beyond 90° the patella rides down into the intercondylar notch and the quadriceps tendon articulates with the trochlea groove. It is not until 135° of flexion that the odd facet of the patella makes contact with the medial femoral condyle. Thus, ACI patients with defects proximal on the patella wishing to avoid exercises that engage the lesion should not exercise between 60° and 90° flexion. This is an example of how the protocol should be adapted according to a specific location site and an individual’s precise needs. The patellofemoral joint-reaction force (PFJRF) is a measure of compression of the patella against the femur and depends on the quadriceps and patellar tendon tension and the angle of knee flexion.14 During closed kinetic chain (CKC) exercises, the PFJRF is increased with flexion. Using various exercises for comparison, Reilly and Martens15 showed that the PFJRF could increase from half body weight during level walking to 8 times body weight during squatting. Therefore, the OsCell protocol gradually introduces a progression of such exercises over time (Tables 1a and 1b, Strengthening). During open kinetic chain (OKC) exercises, however, a greater quadriceps force is required, especially during terminal extension.13 Therefore, straight-leg raises (SLR) and inner-range quadriceps (IRQ) exercises provide maximum stress to the quadriceps with minimal stress to the patellofemoral joint and are indicated early in the OsCell protocol. In 1979, Hungerford and Barry16 showed that contact stress on the patellofemoral joint was lower during an OKC knee extension (9-kg resistance) than during squatting against body weight alone between 90° and 53° of knee flexion. The reverse was true between 0° and 53° of knee flexion. Further studies have reached similar conclusions.14,17 McGinty et al14 suggest that CKC exercises between 0° and 45° of knee flexion (eg, stepups, minisquats, leg presses) are better tolerated than CKC exercises involving greater degrees of flexion in PF joint problems (Table 1a, Week 4). OKC exercises between 90° and 50° and between 20° and 0° (eg, SLR, IRQ, multiple-angle isometrics) are thought to be most effective and safe during the initial stages of the PF-joint ACI rehabilitation (Table 1a, Day 1).
Goals
Allow early cell adherence. Low-resistance isometric Restore full passive extension, exercises; multiangle Q prevent adhesions, aid joint and H contractions, includ- nutrition, relieve pain, reduce ing early proprioceptive deconditioning, improve exercises; OKC exercises confidence, restore function 0°–30°, no resistance, for discharge home. concentric and eccentric work; maintenance exercises for rest of body. Prevent patellofemoral adhesion, which can limit normal physiological range. Active exercises against Increase strength. gravity. Add low resistances to ac- Continue to increase strength tive exercises, vary speed and proprioception, improve of contractions, low-resiscardiovascular and muscle tance stationary cycling endurance, gain physiological (1-legged) or Unicam bike, benefits from exercise. CKC exercises (as weight bearing allows), hydrotherapy.
Circulatory exercises.
Strengthening
*ACI indicates autologous-chondrocyte implantation; Q, quadriceps; H, hamstrings; OKC, open kinetic chain; and CKC, closed kinetic chain.
Wk 4
Wk 3
Passive patella mobilizations.
Wk 2
2: Proliferation/ Protective
Rest in full Non-weight-bearing. extension splint. Continuous passiveProgress as symptoms movement machine; allow. 0°–30° (as comfort allows), for 4–12 h/day; limit active and passive range 0°–30° until wk 6.
0–6 h post-op 6 h to day 3
Weight bearing
1: Post-op
Range of motion
Time
Phase
Table 1a Summary Phases 1–2 of the OsCell Rehabilitation Protocol for Patellofemoral Defects Treated With ACI*
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Sport-specific agility training. Earliest return to contact sport.
Mo 12
No limit to active movement.
Progress duration and resistances, low-resistance stationary cycling, OKC Q between 0°–30° and 90° –50°, active assisted OKC Q 50°–30°, early plyometric exercises, correct muscle balance as indicated. Driving if can perform an emergency stop. Dynamic strength training, progress proprioceptive exercises. Unrestricted static cycling, stepping and rowing machines, through-range OKC exercises, rest periods between exercise sessions. Light jogging on a sprung surface; swimming, including breaststroke; independent cycling. Running.
Strengthening
Mo 9
Mo 8
Mo 6
Mo 3
Wk 9
No limit to passive movement, care with active 50°–30° range.
Range of motion
*ACI indicates autologous-chondrocyte implantation; OKC, open kinetic chain, and Q, quadriceps.
5: Remodel/ Function
4: Strengthening
Wk 6
3: Transitional/ Loading
Wk 7
Time
Phase
Normal function to encourage continued remodeling.
Increase load and functional activities to aid remodeling, increase confidence. Prevent injury.
Improve sport-specific function.
Continue to improve strength, power, and endurance; vary exercises to prevent staleness; prevent overtraining.
Increase dynamic stability and balance.
As transitional stage of repair is reached, increase beneficial loading in “safe” range; improve strength, power, and endurance; promote neuromuscular response; improve range of motion.
Goals
Table 1b Summary Phases 3–5 of the OsCell Rehabilitation Protocol for Patellofemoral Defects Treated With ACI*
Rehabilitation After Autologous-Chondrocyte Implantation 109
Increase as symptoms allow.
Touch weight-bear, gradually progress to 1/4 body weight as symptoms allow.
Non-weight-bearing.
Weight bearing
Active exercises against gravity. Add low resistances to active exercises, vary speed of contractions, low-resistance stationary cycling or Unicam bike, CKC exercises (as weight bearing allows), hydrotherapy.
Low-resistance isometric exercises; multiangle Q and H contractions, including early proprioceptive exercises; OKC exercises 60°–75°, no resistance, concentric and eccentric work; maintenance exercises for rest of body.
Circulatory exercises.
Strengthening
*ACI indicates autologous-chondrocyte implantation; Q, quadriceps; H, hamstrings; and OKC, open kinetic chain.
Wk 5
Wk 4
Wk 3
Continue to progress as symptoms allow.
Wk 2
2: Proliferation/ Protective
Rest in full-extension splint. Continuous passivemovement machine; 0°–40° (as comfort allows), for 4–12 h/day; passive patella mobilizations.
0–6 h post-op 6 h to day 3
1: Post-op
Range of motion
Time
Phase
Improve range of motion, continue to increase strength and proprioception, improve cardiovascular and muscle endurance, gain physiological benefits from exercise. Increase loading to stimulate hyalinelike cartilage formation without disturbing primitive repair tissue.
Improve range of motion, restore kinematics, increase function. Increase strength.
Restore full passive extension, prevent adhesions, aid joint nutrition, relieve pain, reduce deconditioning, improve confidence, restore function for discharge home.
Allow early cell adherence.
Goals
Table 2a Summary Phases 1–2 of the OsCell Rehabilitation Protocol for Tibiofemoral Defects Treated With ACI* 110 Bailey et al
Earliest return to contact sport.
Mo 12
Dynamic strength training, progress proprioceptive exercises. Unrestricted static cycling, stepping and rowing machines, through range of OKC exercises, rest periods between exercise sessions. Light jogging on a sprung surface; swimming, including breaststroke; independent cycling. Running. Sport-specific agility training.
Gradually progress to full weight bearing.
Driving if can perform an emergency stop. Gait reeducation.
Progress duration and resistances, early plyometric exercises, correct muscle balance as indicated.
Strengthening
Mo 9
Mo 8
Mo 6
Mo 3
Wk 9
Wk 8
1/2 body weight.
Weight Bearing
Normal function to encourage continued remodeling.
Increase load and functional activities to aid remodeling, increase confidence. Prevent injury.
Improve sport-specific function.
Continue to improve strength, power, and endurance; vary exercises to prevent staleness; prevent overtraining.
Increase dynamic stability and balance.
Promote full function.
As transitional stage of repair is reached, increase beneficial loading; improve strength, power, and endurance; promote neuromuscular response.
Goals
*ACI indicates autologous-chondrocyte implantation; Q, quadriceps; H, hamstrings; OKC, open kinetic chain; and CKC, closed kinetic chain.
5: Remodel/ Function
4: Strengthening
Wk 6
3: Transitional/ Loading
Wk 7
Time
Phase
Table 2b Summary Phases 3–5 of the OsCell Rehabilitation Protocol for Tibiofemoral Defects Treated With ACI*
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The TF joint is free to move in flexion and extension, mediolateral translation, varus and valgus angulation, anteroposterior translation, medial and lateral rotation, and superoinferior translation. Normal range of movement ranges from 0° to 15° hyperextension and 120° to 160° of flexion. At 90° flexion the knee can laterally rotate up to 40° and medially rotate up to 30°.14 Because of both joint articulation and passive/active restraints, the TF joint has a combination of movements during flexion and extension. Several recent studies18-21 have used a combination of magnetic resonance imaging and roentgen stereophotogrammetric analysis on both cadaveric and living loaded and unloaded knees in order to establish the normal kinematics of the tibiofemoral joint. These studies showed that as the knee extends from 120º flexion, the lateral femoral condyle moves forward by approximately 19 mm until 5º hyperextension is reached. This movement occurs by a combination of rolling and sliding (a ratio of 1:7). During the final 10º of extension, however, pure sliding is thought to occur. This corresponds with the tibia externally rotating 15º from 110º–60º flexion/extension and a further 1º from 60º–0º flexion/extension and a final 4º as the knee hyperextends 5º to “screw home.” During extension there is no anteroposterior translation at the medial femoral condyle, pure sliding occurs, rotating around the flexion facet center until approximately 50º–0º extension when the MFC has been found to translate approximately 5 mm forward. At 30º–10º flexion/extension the medial femoral condyle is said to “rock” back and forth as a result of its articulation. These combined movement patterns at the TF joint are thoroughly considered in the OsCell TF-joint-site protocol design (Tables 2a and 2b, from Day 1 onward). Initially, care is taken during middle and late range of knee extension, where excessive combined movement patterns of the knee might be detrimental to the immature graft. In order for the TF joint to function normally in this way the knee must be stable. The menisci increase the tibiofemoral contact area and therefore reduce the contact stress on the articular cartilage, which in turn might prevent degeneration.13 The 4-bar linkage system formed by the posterior and anterior cruciate ligaments (PCL and ACL) must be intact. During OKC knee extension, the quadriceps causes both compressive and shear forces. The anterior shear of the tibia on the femur and the posterior shear force of the femur on the tibia are increased if resistance is added. The ACL is thought to provide 85% of the restraining force against this movement, especially during the last 45° of knee extension in a healthy knee.14 Therefore, it is imperative that the knee be stable before ACI in order to prevent any abnormal movement patterns. Our operative ACI criterion rejects patients with unstable knees. McGinty14 suggests that shear forces during an isometric contraction against a 10-lb resistance in a stable knee were greatest between 30° and 45° of flexion. There was little translation, however, between 60° and 75° of flexion. The angle at which the quadriceps produced no translatory force was found to be between 60° and 75° and is termed
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the quadriceps-neutral angle. Larger angles produced posterior translation of the tibia. Smaller angles produced an anterior translation of the tibia. Awareness of such shear movements is vital not only to protect the immature ACI site but also to promote function and restore normal joint biomechanics. For example, if there is a limit to TF-joint extension, passive anterior glide mobilizations to the tibia might be therapeutically indicated.22 The 2 OsCell rehabilitation protocols are based on knee biomechanics and focus on 3 key issues: weight bearing, range of motion, and strengthening.
Weight Bearing By skeletal maturity, articular cartilage has a specific geometry and structural composition. Weight-bearing regions tend to have thicker23 and stiffer24 cartilage. To date, many studies indicate that mechanical loading also regulates the maintenance of cartilage in vivo.25,26 Furthermore, animal studies have demonstrated that joint immobilization results in decreased synthetic activity of chondrocytes and subsequent loss of articular-cartilage thickness.27-31 Exercise, particularly at low intensity, can reverse the effects of short-term immobilization.29 The longer the period of immobilization, however, the more difficult it was to restore all the mechanical functions.31 Some studies have reported that a period of non-weight-bearing13 or protected touch-weight bearing32 for up to 6 weeks followed by a further 4–6 weeks of partial weight bearing before full weight bearing for TF-lesion sites can achieve cartilage healing. In contrast, PF-joint lesion sites can progress to normal weight bearing as soon as possible, because this joint is not detrimentally loaded during normal gait. Clearly, progression should be guided by patient discomfort, mechanical symptoms, and swelling (Tables 1a, 2a, and 2b, Weight Bearing and Strengthening). This contrasts with the less flexible progression criteria described by Gillogly et al.12
Range of Motion Range-of-motion exercises might prevent adhesions and promote circulation and can aid in pain relief.28 A large body of evidence including both animal and human studies supports the concept that controlled, continuous passive range of motion could potentially improve cartilage healing and retard degeneration.33-37 These studies concluded that 6–8 hours per day is most effective. In addition, continuous passive motion can potentially produce better quality repair tissue. The precise duration and optimal time of initiation of continuous passive motion have yet to be determined.12 Minas and Peterson32 recommend that it be introduced 6 hours postoperatively, when the transplanted cells have attached within the defect. With ACI patients, however, it is vital to ensure that the range of motion is
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neither too forceful nor too extensive to disturb the periosteal autograft. Therefore, in order to protect the immature graft for a PF-joint, range of motion is limited initially within the protocol (Tables 1a and 1b, Range of Motion). However, due to the differing biomechanics of the TF joint, full range of motion is encouraged early in the protocol as the stresses on the graft are thought to be less detrimental (Table 2a, Range of Motion). In our protocols we try to avoid potentially detrimental sliding movements with high contact loads but encourage contact load and range without shear movement.
Strengthening The dynamic stability of the knee relies largely on the proprioception and strength, endurance, and power provided by the quadriceps and hamstrings. Strength training can be beneficial to the knee joint, provided that the size and location of the treated defect are carefully considered to avoid strengthening exercises that create unwanted shear movement, especially when combined with compression. As a rule, rehabilitation programs should limit deconditioning and encourage the patient to progress to resistance training as soon as possible. Deconditioning can be limited by ensuring a period of “prehabilitation” before surgery. As soon as symptoms and stage of healing allow, specific strengthening exercises should be introduced (Tables 1a, 1b, 2a, and 2b, Strengthening). Muscle strength can be increased by working the muscle against a heavy resistance such as 3–5 repetitions maximum (ie, the maximum weight that can be controlled for 3–5 continuous repetitions); muscle endurance can be increased by working the muscle against a lighter resistance such as 20 repetitions maximum. Adequate rest periods between sets are important, and up to 3 sets can be performed. Initially, neural recruitment or adaptations are thought to be responsible for the strength gains,38,39 but from 8 weeks the contractile proteins in the muscle fibers and the muscle-fiber size might be influenced.40 This time frame should be considered when devising strengthening goals with the patient. The progression of resistance will depend on individual circumstances. Consequently, our protocol is less stringent than that of Gillogly et al12 in that it includes flexibility in the progression and amount of resistance. Certain types of muscle contraction are important in ACI rehabilitation. Eccentric contraction of the quadriceps facilitates shock absorption during activities such as walking, running, and jumping. Eccentric muscle contraction is also the basis for plyometric-type work; an eccentrically loaded muscle converts potential energy to a forceful concentric contraction. In the early stages of the OsCell rehabilitation protocol, these exercises are performed in a partial-weight-bearing manner to allow the smooth transition of exercise progression by establishing or maintaining the neural pathways for such functional activities.
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The speed with which a resisted exercise is performed and the ability of the muscle to rapidly halt a resisted movement should be introduced as part of the strengthening regime. In the early stages isometric exercises either side of the lesion might be the safest (Tables 1a and 2a, from Day 1, Strengthening). Although this might not be classed as “functional,” there is a carryover of strength gained at set angles to other ranges of the joint that have not been isometrically resisted, especially if some of the isometric exercises are carried out at 90° flexion.41,42 At this stage, the OsCell ACI protocol cannot be more specific because it is still unclear whether shear movements and compressive loads generated by exercises used to strengthen muscles are detrimental to cartilage repair.
Conclusions We presented 2 flexible, safe, and effective postoperative protocols to rehabilitate patients after an ACI procedure to the knee based on current literature and clinical experience. The OsCell protocol treats patellofemoral and tibiofemoral lesions differently because the biomechanics at these joints differ. Both protocols incorporate the 3 key elements, however: range of motion, weight bearing, and strengthening. These are thought to be the key elements that influence the regeneration of hyalinelike cartilage. The protocol is designed to be flexible and allow for individuals’ needs and specific functional goals. For patients with more than one defect, the protocol was modified after liaising with the surgeon to discuss which area might require the greater protection or priority. Early preliminary results of patients who followed this protocol are encouraging.
Acknowledgments The authors wish to acknowledge the following members of the OsCell team: Paul Harrison, Sarah Turner, Dr Jan Kuipers, Dr Jo Taylor, Dr Brian Ashton, Dr Sally Roberts, Dr Alan Darby, Dr Ian MaCall, Dr Karen Ashton, Mr Daniel Barnes, and Mr Tony Smith. Thanks also to the Physiotherapy Department at the Gothenburg Medical Centre for their kind assistance.
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5. Peterson L, Minas T, Brittberg M, Nilsson A, Sjogren-Jansson E, Lindahl A. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop Rel Res. 2000;374:212-234. 6. Peterson L, Brittberg M, Kiviranti I, Akerlund EL, Lindahl, A. Autologous chondrocyte transplantation. Biomechanics and long-term durability. Am J Sports Med. 2002;30:2-12. 7. Richardson J, Caterson B, Evans EH, Ashton BA, Roberts S. Repair of human cartilage after implantation of autologous chondrocytes. J Bone Joint Surg Br. 1999;81:1064-1068. 8. Roberts S, Hollander AP, Caterson B, Menage J, Richardson JB. Matrix turnover in human cartilage repair tissue in autologous chondrocyte implantation. Arthritis Rheum. 2001;44:2586-2598. 9. Buckwalter J, Mankin H. Articular cartilage. Part I: tissue design and chondrocyte-matrix interactions. J Bone Joint Surg. 1998;79:600-611. 10. Breinan H, Minas T, Barone L, et al. Histological evaluation of the course of healing of canine articular cartilage defects treated with cultured chondrocytes. Tiss Eng. 1998;4:101-114. 11. Grande DA, Pitman MI, Peterson L, Menche D, Klein M. The repair of experimentally produced defects in rabbit articular cartilage by autologous chondrocyte transplantation. J Orthop Res. 1989;7:208-215. 12. Gillogly SD, Voight M, Blackburn T. Treatment of articular defects of the knee with autologous chondrocyte implantation. J Orthop Sports Phys Ther. 1998; 28:241-251. 13. Irrgang JJ, Pezzullo D. Rehabilitation following surgical procedures to address articular cartilage lesions in the knee. J Orthop Sports Phys Ther. 1998;28(4):232240. 14. McGinty G, Irrgang JJ, Pezzullo D. Biomechanical considerations for rehabilitation of the knee. Clin Biomech. 2000;15:160-166. 15. Reilly DT, Martens M. Experimental analysis of the quadriceps muscle force and patellofemoral joint reaction force for various activities. Acta Orthop Scand. 1972;43:126-137. 16. Hungerford DS, Barry M. Biomechanics of the patellofemoral joint. Clin Orthop. 1979;144:9-15. 17. Steinkamp LA, Dillinghan MF, Markel MD, Hill JA, Kaufman KR. Biomechanical considerations in patellofemoral joint rehabilitation. Am J Sports Med. 1993;21(3):438-444. 18. Iwaki H, Pinskerova V, Freeman M. Tibiofemoral movement 1: the shape and relative movements of the femur and tibia in the unloaded cadaver knee. J Bone Joint Surg. 2000;82(8):1189-1195. 19. Hill P, Vedi V, Williams A, Iwaki H, Pinskerova M, Freeman M. Tibiofemoral movement 2: the loaded and unloaded living knee studied by MRI. J Bone Joint Surg. 2000;82(8):1196-1198. 20. Nakagawa S, Kadoya Y, Todo S, et al. Tibiofemoral movement 3: full flexion in the living knee studied by MRI. J Bone Joint Surg 2000;82(8):1199-2000.
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21. Karrholm J, Brandsson S, Freeman M. Tibiofemoral movement 4: changes of axial rotation caused by forced rotation at the weight-bearing knee studied by RSA. J Bone Joint Surg. 2000;82(8);1201-1203. 22. Maitland GD. Peripheral Manipulation. 2nd ed. London: Butterworth; 1977. 23. Eggli PS, Hunziker EB, Schenk RK. Quantitation of structural features characterizing weight- and less-weight-bearing regions in articular cartilage: a stereological analysis of medial femoral condyles in young adult rabbits. Anat Rec. 1998;222:217-227. 24. Swann AC, Seedhom BB. The stiffness of normal articular cartilage and predominant acting stress levels: implications for the aetiology of osteoarthritis. Brit J Rheum. 1993;32:16-25. 25. Jin M, Frank EH, Quinn TM, Hunziker EB, Grodzinsky AJ. Tissue shear deformation stimulates proteoglycan and protein biosynthesis in bovine cartilage explants. Arch Biochem Biophys. 2001;395:41-48. 26. Li KW, Williamson AK, Wang AS, Sah RL. Growth responses of cartilage to static and dynamic compression. Clin Orthop Rel Res. 2001;391S:S34-S48. 27. Behrens F, Kraft E, Oegema T. Biochemical changes in articular cartilage after joint immobilization by casting or external fixation. J Orthop Res. 1989;7:335343. 28. Buckwalter J. Effects of early motion on healing musculoskeletal tissues. Hand Clin. 1996;12(1):13-24. 29. Jurvelin J, Kiviranta I, Saamanen A, Tammi M, Helminen HJ. Partial restoration of immobilization-induced softening of articular cartilage after remobilization of the knee (stifle) joint. J Orthop Res. 1989;7:352-358. 30. Palmoski M, Perricone E, Brant KD. Development and reversal of proteoglycan aggregation defect in normal canine knee cartilage after immobilisation. Arthritis Rheum. 1979;22:508-517. 31. Finsterbush A, Friedman B. Reversibility of joint changes produced by immobilization in rabbits. Clin Orthop. 1975;236:279-285. 32. Minas T, Peterson L. Advanced techniques in autologous chondrocytes transplantation. Clin Sports Med. 1999;18:13-44. 33. Alfredson H, Lorentzon R. Superior results with continuous passive motion compared to active motion after periosteal transplantation. Knee Surg Sports Traumatol Arthrosc. 1999;7:232-238 34. Rodrigo JJ, Steadman RJ, Fulstone HA. Improvement of full-thickness chondral defect healing in the human knee after debridement and microfracture using continuous passive motion. Am J Knee Surg. 1994;7:109-116. 35. Salter RB, Simmonds DF, Malcolm BW, Rumble EJ, MacMichael D, Clements ND. The biological effects of continuous passive motion on healing of full thickness defects in articular cartilage: an experimental study in the rabbit. J Bone Joint Surg. 1980;62(8):1232-1251. 36. Salter RB. The biological concept of continuous passive motion of synovial joints. The first eighteen years of basic research and its clinical application. Clin Orthop. 1989;242:12-25.
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