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Shell Osteochondral Allografts of the Knee: Comparison of MR Imaging Findings and Immunologic Responses¹

¹ From the Departments of Radiology (C.B.S., J.B., R.D.B., M.N.P., D.R.), Orthopedics (F.R.C., W.B.), and Immunogenetics (L.K.L.), and the General Clinical Research Center (R.D.), University of California, San Diego. From the 1996 RSNA scientific assembly. Received March 9, 2000; revision requested April 25; revision received June 15; accepted July 21. Supported in part by Johnson and Johnson Professional, Raynham, Mass, and National Institutes of Health grant M01RR00827. Address correspondence to D.R., Veterans Affairs Medical Center, 3350 La Jolla Village Dr, San Diego, CA 92161.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To define the magnetic resonance (MR) imaging appearance of shell osteochondral allografts of the knee and compare the MR findings with antibody responses.

MATERIALS AND METHODS: Thirty-six grafts were evaluated with a 1.5-T unit with T1-, intermediate-, and T2-weighted, and three-dimensional spoiled gradient-recalled MR imaging at 3, 6, 12, 24, and/or 36 months after surgery. Nineteen patients underwent imaging serially. Two osteoradiologists scored by consensus host marrow edema, thickness of graft-host interface, signal intensity of graft marrow, cyst formation, joint effusion, articular cartilage defects, and surface collapse. Patients were divided into antibody-positive (AP) (n = 11) and antibody-negative (AN) (n = 25) groups evenly distributed across the different time points on the basis of results of anti–human leukocyte antigen antibody screening. MR findings for the two groups were compared.

RESULTS: AP patients demonstrated greater mean edema (P < .002), thicker interface (P < .03), and more abnormal graft marrow (P < .04) than AN patients, and they had a higher proportion of surface collapse (P < .03).

CONCLUSION: Humoral immune responses were associated with more inflammation and less complete incorporation after allograft placement. MR imaging shows promise as a surrogate biomarker for success of shell osteochondral allograft implantation.

Index terms: Antibodies • Bones, grafts, 45.44 • Immunity • Knee, ligaments, menisci, and cartilage, 45.44 • Knee, MR, 45.121411, 45.121415, 45.121419

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The treatment of young patients with articular cartilage defects of the knee remains problematic. Conventional surgical procedures, such as arthrodesis and prosthetic resurfacing, are inappropriate for young patients owing to loss of function and limited longevity, respectively. More recent arthroscopic treatments, such as subchondral bone drilling (1,2) and chondral shaving and abrasion (3,4), have limited long-term benefit (5,6). Because of these limitations, several new procedures have been developed (5,7–9).

One promising procedure, fresh shell osteochondral allograft placement (5,6,8,10–16), involves resurfacing of articular cartilage defects with thin, approximately 5-mm-thick, osteochondral shells removed from cadaveric donor knees. Preliminary data suggest that fresh osteochondral allografts are immunogenic in humans (17,18). The development of humoral and cellular immune responses to osteochondral grafts is associated with prolonged inflammatory reactions, cartilage degeneration, and delayed graft incorporation in animal models (19–32), but the biologic effect of immune responses in humans is unknown.

The purpose of this study was to define the magnetic resonance (MR) imaging appearance of shell osteochondral allografts of the knee and compare the MR findings with antibody responses.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Fifty-two patients with femoral or tibial allografts, or both, underwent MR imaging. Five patients with incomplete antibody testing and 11 patients who received patellar grafts were subsequently excluded from the study. Patellar grafts (1 cm thick) are much thicker than nonpatellar grafts (<6 mm thick) and are associated with both greater immunologic response and worse clinical outcome.

The remaining 36 patients (21 male and 15 female patients; mean age, 36 years; age range, 15–60 years) formed the basis of this study. These patients had a total of 44 allografts (36 condylar, three trochlear, and five tibial) in 36 knees. Thirty knees had a single graft each, four had two grafts, and two had three grafts. The institutional human subjects committee approved this study. Each patient signed a separate informed consent form before surgery and before each MR imaging examination.

Surgical Technique
Osteochondral allografts were implanted by two experienced orthopedic surgeons (including F.R.C.) by using the standard published technique (5,6,15). At surgery, the patient’s chondral defect (Fig 1a) was excised, squared off, abraded to bleeding subchondral bone, and measured. A 5–6-mm-thick osteochondral shell was removed from an orthotopic site of a cadaveric donor knee, trimmed down to precise size, copiously lavaged with pulsatile saline spray to reduce immunogenic elements, and press fitted into the defect (Fig 1b). If necessary, supplementary fixation of the graft was provided by inserting polydioxanone biodegradable pins (Orthosorb Resorbable Pins; Johnson and Johnson Professional, Raynham, Mass).

View larger version (119K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. Intraoperative photographs depict a typical allograft procedure in a male patient with degenerative disease of the knee. (a) The left knee has a large osteochondral defect of the medial femoral condyle with eburnation (straight arrow). There is minor surface fibrillation of the lateral condyle (curved arrow). A size-matched cadaveric donor knee with normal articular cartilage is shown above. (b) The margins of the full-thickness portion of the defect are squared off (straight black arrows). An area of more minor irregularity (curved arrow) is left alone. An osteochondral graft with a 5-mm-thick osseous portion (white arrow) has been removed from an orthotopic site of the donor knee and is held above the defect. (c) The graft is press fitted into the defect (arrows). In this case, supplementary fixation with biodegradable pins was not necessary.

View larger version (140K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. Intraoperative photographs depict a typical allograft procedure in a male patient with degenerative disease of the knee. (a) The left knee has a large osteochondral defect of the medial femoral condyle with eburnation (straight arrow). There is minor surface fibrillation of the lateral condyle (curved arrow). A size-matched cadaveric donor knee with normal articular cartilage is shown above. (b) The margins of the full-thickness portion of the defect are squared off (straight black arrows). An area of more minor irregularity (curved arrow) is left alone. An osteochondral graft with a 5-mm-thick osseous portion (white arrow) has been removed from an orthotopic site of the donor knee and is held above the defect. (c) The graft is press fitted into the defect (arrows). In this case, supplementary fixation with biodegradable pins was not necessary.

View larger version (167K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. Intraoperative photographs depict a typical allograft procedure in a male patient with degenerative disease of the knee. (a) The left knee has a large osteochondral defect of the medial femoral condyle with eburnation (straight arrow). There is minor surface fibrillation of the lateral condyle (curved arrow). A size-matched cadaveric donor knee with normal articular cartilage is shown above. (b) The margins of the full-thickness portion of the defect are squared off (straight black arrows). An area of more minor irregularity (curved arrow) is left alone. An osteochondral graft with a 5-mm-thick osseous portion (white arrow) has been removed from an orthotopic site of the donor knee and is held above the defect. (c) The graft is press fitted into the defect (arrows). In this case, supplementary fixation with biodegradable pins was not necessary.

Immune Evaluation
Patients underwent screening for the presence of serum anti–human leukocyte antigen antibodies by using a standard National Institutes of Health lymphocytotoxicity technique (34) before and serially 2–36 months after surgery to detect the development of humoral immunity. An immunologist (L.K.L.) blinded to patients’ clinical and radiographic outcome evaluated the screening results. On the basis of the results, the 36 patients were divided into antibody-positive (AP; n = 11) and antibody-negative (AN; n = 25) groups.

MR Imaging
Nonenhanced MR imaging examinations were performed with a 1.5-T imager (Signa; GE Medical Systems, Milwaukee, Wis) with an extremity coil and the following pulse sequences: 4-mm contiguous T1-weighted (repetition time msec/echo time msec of 600/15) spin echo, 4-mm contiguous intermediate-weighted (3,000/40) and T2-weighted (3,000/63) fast spin echo (eight echo trains), and 3.3-mm contiguous three-dimensional spoiled gradient recalled (47/7; flip angle, 60°). All images were obtained with two signals acquired, a matrix size of 256 x 256, and, except for the T1-weighted spin-echo sequence, fat saturation. Sagittal and coronal images (field of view, 12 cm) were obtained routinely, and additional transverse images (field of view, 10 cm) were obtained with the same parameters to evaluate trochlear grafts.

The 36 patients underwent imaging a total of 57 times: at 3 (n = 8), 6 (n = 11), 12 (n = 22), 24 (n = 10), and 36 (n = 6) months. Seventeen patients underwent imaging once: at 3 (n = 3), 6 (n = 1), 12 (n = 8), 24 (n = 1), or 36 (n = 4) months. Seventeen patients underwent imaging twice: at 3 and 6 months (n = 3), 6 and 12 months (n = 5), 12 and 24 months (n = 7), or 24 and 36 months (n = 2). Two patients underwent imaging three times: at 3, 6, and 12 months.

MR Interpretation
Two osteoradiologists (J.B., R.D.B.), blinded to clinical outcomes and time after surgery, scored each graft by mutual consensus at each time point for the following seven variables.

Host marrow edema.—Host marrow edema was defined as marrow hyperintensity on T2-weighted images within the host marrow adjacent to the graft. Host edema was measured quantitatively to the nearest millimeter for its superior-to-inferior (on sagittal images), anterior-to-posterior (on sagittal images), and medial-to-lateral (on coronal images) dimensions. The three dimensions were then summed to yield a single composite score for each graft (Fig 2).

View larger version (151K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Sagittal fat-suppressed T2-weighted MR image (3,000/63) in an AP female patient 6 months after surgery exhibits extensive confluent edema within the host marrow (arrowheads). The superior-to-inferior and anterior-to-posterior dimensions are measured, and these values are added to the medial-to-lateral dimension obtained from coronal images to yield a single composite score. The graft-host interface (GHI) (arrows) is 3 mm thick.

Graft marrow SI grade.—Graft marrow SI was graded for the percentage of the graft marrow that showed abnormal hypointensity on T1-weighted images, approximated to the nearest 25% (Fig 3). A graft marrow SI grade of 0% indicated the presence of uniformly normal marrow SI throughout the graft. A graft marrow SI grade of 100% indicated uniformly abnormal SI.

View larger version (150K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Sagittal T1-weighted MR image (600/15) in an AN male patient 6 months after surgery shows abnormal low SI within the posterior portion of the graft (curved arrow) and normal SI in the anterior portion (straight arrow). As approximately half the marrow is abnormal, the graft marrow was scored as 50%. The anterior and posterior ends of the graft are marked (arrowheads).

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Sagittal fat-suppressed T2-weighted MR image (3,000/63) in an AP male patient 36 months after surgery depicts a large joint effusion (curved arrow) and focal intraosseous cysts (straight arrows) within the host marrow. The diameters of all cysts were measured to the nearest millimeter and summed to yield a single composite score.

Graft contour.—The graft surface contour was assessed in a binary fashion for the presence or absence of collapse. If collapse was seen, the depth of collapse was measured to the nearest millimeter. There were too few grafts with collapse, however, for statistical evaluation of collapse depth.

Effusion.—Effusion was graded subjectively on T2-weighted images on a binary scale as small (no to mild effusion) or large (moderate to severe effusion). Quantitative criteria were not used.

In patients with multiple grafts, each of the seven variables was scored independently for each graft, except for effusion, which was assigned the identical score for a particular knee.

Analysis
To avoid overrepresentation of the six knees with multiple grafts, only the largest femoral graft per knee was evaluated. In knees with no femoral grafts, the largest tibial graft was evaluated. The 36 grafts chosen for the final evaluation included 34 femoral surfaces (33 femoral condyles and one femoral trochlea) and two tibial plateaus.

To avoid overrepresentation of the 19 grafts evaluated with serial MR examinations, only the imaging data from the final evaluation for each graft were chosen for analysis, except for the two AN patients who underwent imaging at 24 and 36 months, for whom the data from the 24-month examination were used. The decision to use the 24-month rather than the 36-month data was made to ensure a more even distribution of AP and AN patients at each time point; any bias incurred by this decision should have a conservative effect on the results.

The AP and AN groups were similar populations with regard to patient age, sex, and body mass index (calculated as the patient’s weight in kilograms divided by the patient’s height in square meters), donor age and sex, graft surface area in square millimeters, and time after surgery to the MR imaging session used for analysis (Table 1). This allowed the data for AP and AN patients, respectively, to be pooled for statistical analysis.

Continuous variables that showed statistically significant (P < .05) differences between AP and AN patients were analyzed further. To determine the effect of time, these variables were reanalyzed at each of four time points (3, 6, 12, and 24–36 months). All images obtained at a particular time point were used regardless of whether some patients also underwent imaging at other time points. The sample size at each time point used in the temporal analysis is shown in Table 1.

Data for patients who underwent MR imaging at 24 or 36 months were pooled together (24–36-month time point) because only one AP patient underwent imaging at 36 months. For the two AN patients who underwent MR imaging at both 24 and 36 months, only one set of data (the data from the 24-month examination) was used in this analysis. The decision to use the 24-month rather than the 36-month data was conservative to minimize bias in favor of AN grafts. To determine the effect of graft size, the median surface area (9.0 cm²) of the grafts in AP patients was computed. Grafts were then divided into two subgroups on the basis of whether they were smaller than 9.0 cm² (small) or equal to or larger than 9.0 cm² (large). The chosen variables were reanalyzed for each subgroup. To determine the effect of graft location, study variables were reanalyzed for each graft location. We did not correct for multiple comparisons.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Grafts typically were easily identified within the host bone because of obvious SI abnormalities in or adjacent to the graft. Grafts occasionally blended almost imperceptibly into the host bone and were conspicuous only because of focal step offs or junctional clefts in the articular cartilage at the graft margins.

Host Marrow Edema
Edema was identified in the host marrow in 13 (52%) of 25 grafts in AN patients and in 10 (91%) of 11 grafts in AP patients (P < .04). Despite the smaller number of AP patients, four of the five grafts with the greatest composite edema dimension (95 mm) were in the immune-sensitized group (P < .03).

The edema ranged in appearance from patchy and ill defined to confluent and geographic (Fig 2). Subjectively, the edema tended to be patchier in AN patients and more confluent in AP patients, but this difference was not universal and was not assessed statistically. When present, the edema extended deep into the host marrow for variable distances, ranging from 5 to 52 mm.

Overall, the mean composite edema dimension was 38 mm ± 7 (Table 2), with a range of 0–112 mm in AN patients and of 0–158 mm in AP patients. AP patients had significantly (P < .002) greater mean edema (72 mm ± 15) than AN patients (25 mm ± 6) (Table 2).

When perceptible, the GHI was subjectively of low SI in 94% (30 of 32) and of high SI in 6% (two of 32) on T1-weighted images and of low SI in 59% (19 of 32) and of high SI in 41% (13 of 32) on T2-weighted images. There was no significant difference in proportion between the SI of the GHI on images obtained with the various sequences and the immune response.

Overall, the mean GHI thickness was 1.3 mm ± 0.1 (Table 2), with a range of 0–3 mm in AN patients and 1–3 mm in AP patients. Grafts in AP patients had significantly (P < .03) greater mean GHI (1.7 mm ± 0.2) than grafts in AN patients (1.1 mm ± 0.1) (Table 2).

Graft Marrow SI Grade
Abnormal graft marrow hypointensity on T1-weighted images was identified in the host marrow in 21 (84%) of 25 grafts in AN patients and in all 11 (100%) grafts in AP patients (P = .29). The AP group had a significantly greater proportion (five of 11) of grafts with diffusely abnormal marrow (score of 100%) than the AN group (three of 25) (P < .04).

On fat-saturated T2-weighted images, corresponding portions of the graft marrow were of high SI in 75% of grafts and of low SI in the remainder. There was no correlation between the pattern of graft marrow SI on T1- and T2-weighted images and immune responses. Portions of the graft marrow that had normal SI on T1-weighted images universally had normal SI on T2-weighted images.

Overall, the mean percentage of abnormal graft marrow was 56% ± 6 (Table 2), with a range of 0%–100% in AN patients and 25%–100% in AP patients. AP patients had significantly (P < .04) greater marrow abnormality (73% ± 9) than did AN patients (48% ± 6) (Table 2).

Cyst Formation
Cysts were identified in the graft or host marrow in 11 (44%) of 25 grafts in AN patients and in four (36%) of 11 grafts in AP patients (P = .73). The three grafts with the greatest cyst formation (cumulative cyst diameter of greater than 15 mm) were in AP patients. In none of the knees were cysts identified in unresurfaced compartments.

Overall, the mean cumulative cyst diameter was 3.2 mm ± 0.9, with a range of 0–19 mm in AP patients and a range of 0–11 mm in AN patients. The difference in mean cumulative cyst diameter between AP (5.2 mm ± 2.4) and AN (2.3 mm ± 0.7) patients was not significant (P = .13) (Table 2).

Cartilage Integrity
Three of 11 (27%) grafts analyzed in AP patients had focal articular cartilage defects, ranging in diameter from 2 to 25 mm, whereas two (8%) of 25 grafts in AN patients had focal cartilage defects, ranging from 2 to 4 mm (Table 3). The difference in these ratios (three of 11 vs two of 25) was not significant (P = .15). Differences in the sizes of the defects were not analyzed because of the small samples.

View larger version (165K): [in this window] [in a new window] [Download PPT slide]   Figure 5. Sagittal spoiled gradient-recalled MR image (47/7; flip angle, 60°) in the same patient as in Figure 4 36 months after surgery reveals a large joint effusion (e) and collapse of the articular cartilage into the posterior portion of the subjacent graft marrow (curved arrow). The graft marrow was diffusely abnormal on T1-weighted images. At subsequent arthroscopy (not shown), the cartilage had a normal appearance but buckled into the soft marrow.

Because the differences in mean host marrow edema, GHI, and graft marrow grade between AP and AN patients were significant, these variables were analyzed further. Figure 6 contains graphs that depict how AP and AN patients compared at each time point: Edema, GHI, and graft marrow abnormality all decreased in a stepwise fashion as a function of time for AN patients. In AP patients, edema and GHI decreased between the first and last time point but did not decrease in a stepwise fashion. Graft marrow abnormality remained remarkably stable, decreasing from 83% ± 8 at 3 months to 75% ± 18 at 24–36 months. Grafts in AN patients were associated with less edema, thinner GHI, and less marrow abnormality than grafts in AP patients at each successive time point at and after 6 months. Despite the small samples, the differences between AN and AP patients were significant for edema at 12 months (P < .006) and 24–36 months (P < .005) and for GHI at 12 months (P < .004). The differences were almost significant for graft marrow abnormality at 12 (P = .05) and 24–36 (P = .05) months. The results suggest that grafts in AN and AP patients were similar in appearance in the early postoperative period and differences between the two increased with time. The temporal differences between AN and AP patients are illustrated in Figures 7 (AN patient) and 8 (AP patient).

View larger version (35K): [in this window] [in a new window] [Download PPT slide]   Figure 6a. Bar graphs depict mean (a) host marrow edema, (b) GHI, and (c) graft marrow grade at various time points after surgery (error bars indicate the SEM). AN patients (white bars) have less edema, thinner GHIs, and more normal marrow SI at all time points after 3 months than do AP patients (gray bars). The differences tend to increase with time. At 3 months, results in the two groups are similar.

View larger version (33K): [in this window] [in a new window] [Download PPT slide]   Figure 6b. Bar graphs depict mean (a) host marrow edema, (b) GHI, and (c) graft marrow grade at various time points after surgery (error bars indicate the SEM). AN patients (white bars) have less edema, thinner GHIs, and more normal marrow SI at all time points after 3 months than do AP patients (gray bars). The differences tend to increase with time. At 3 months, results in the two groups are similar.

View larger version (36K): [in this window] [in a new window] [Download PPT slide]   Figure 6c. Bar graphs depict mean (a) host marrow edema, (b) GHI, and (c) graft marrow grade at various time points after surgery (error bars indicate the SEM). AN patients (white bars) have less edema, thinner GHIs, and more normal marrow SI at all time points after 3 months than do AP patients (gray bars). The differences tend to increase with time. At 3 months, results in the two groups are similar.

View larger version (164K): [in this window] [in a new window] [Download PPT slide]   Figure 7a. (a, c) T1-weighted (600/15) and (b, d) fat-suppressed T2-weighted (3,000/63) MR images of a condylar graft in a 46-year-old AN male patient at 3 (a, b) and 12 (c, d) months after surgery. (a) At 3 months, abnormal marrow SI (curved arrow) in the posterior quarter of the graft is obvious. The anterior portion of the graft has nearly normal marrow SI (straight solid arrow). A single pin track is incidentally seen (open arrow). (b) At 3 months, a large effusion (curved arrow), a thick GHI (straight solid arrows), and patchy but extensive edema (arrowheads) that obscures the pin track (open arrow) are depicted. (c) At 12 months, normal marrow SI is depicted in the posterior portion of the graft (curved arrow). The pin track has partially healed (open arrow). (d) Edema has resolved, the GHI is barely perceptible (straight solid arrow), and the effusion is smaller (curved arrow). With resolution of edema, the pin track (open arrow) is now visible.

View larger version (166K): [in this window] [in a new window] [Download PPT slide]   Figure 7b. (a, c) T1-weighted (600/15) and (b, d) fat-suppressed T2-weighted (3,000/63) MR images of a condylar graft in a 46-year-old AN male patient at 3 (a, b) and 12 (c, d) months after surgery. (a) At 3 months, abnormal marrow SI (curved arrow) in the posterior quarter of the graft is obvious. The anterior portion of the graft has nearly normal marrow SI (straight solid arrow). A single pin track is incidentally seen (open arrow). (b) At 3 months, a large effusion (curved arrow), a thick GHI (straight solid arrows), and patchy but extensive edema (arrowheads) that obscures the pin track (open arrow) are depicted. (c) At 12 months, normal marrow SI is depicted in the posterior portion of the graft (curved arrow). The pin track has partially healed (open arrow). (d) Edema has resolved, the GHI is barely perceptible (straight solid arrow), and the effusion is smaller (curved arrow). With resolution of edema, the pin track (open arrow) is now visible.

View larger version (176K): [in this window] [in a new window] [Download PPT slide]   Figure 7c. (a, c) T1-weighted (600/15) and (b, d) fat-suppressed T2-weighted (3,000/63) MR images of a condylar graft in a 46-year-old AN male patient at 3 (a, b) and 12 (c, d) months after surgery. (a) At 3 months, abnormal marrow SI (curved arrow) in the posterior quarter of the graft is obvious. The anterior portion of the graft has nearly normal marrow SI (straight solid arrow). A single pin track is incidentally seen (open arrow). (b) At 3 months, a large effusion (curved arrow), a thick GHI (straight solid arrows), and patchy but extensive edema (arrowheads) that obscures the pin track (open arrow) are depicted. (c) At 12 months, normal marrow SI is depicted in the posterior portion of the graft (curved arrow). The pin track has partially healed (open arrow). (d) Edema has resolved, the GHI is barely perceptible (straight solid arrow), and the effusion is smaller (curved arrow). With resolution of edema, the pin track (open arrow) is now visible.

View larger version (178K): [in this window] [in a new window] [Download PPT slide]   Figure 7d. (a, c) T1-weighted (600/15) and (b, d) fat-suppressed T2-weighted (3,000/63) MR images of a condylar graft in a 46-year-old AN male patient at 3 (a, b) and 12 (c, d) months after surgery. (a) At 3 months, abnormal marrow SI (curved arrow) in the posterior quarter of the graft is obvious. The anterior portion of the graft has nearly normal marrow SI (straight solid arrow). A single pin track is incidentally seen (open arrow). (b) At 3 months, a large effusion (curved arrow), a thick GHI (straight solid arrows), and patchy but extensive edema (arrowheads) that obscures the pin track (open arrow) are depicted. (c) At 12 months, normal marrow SI is depicted in the posterior portion of the graft (curved arrow). The pin track has partially healed (open arrow). (d) Edema has resolved, the GHI is barely perceptible (straight solid arrow), and the effusion is smaller (curved arrow). With resolution of edema, the pin track (open arrow) is now visible.

View larger version (151K): [in this window] [in a new window] [Download PPT slide]   Figure 8a. (a, c) T1-weighted (600/15) and (b, d) fat-suppressed T2-weighted (3,000/63) MR images of a condylar graft in a 36-year-old AP male patient at 6 (a, b) and 12 (c, d) months after surgery. (a) The graft marrow is diffusely abnormal (curved arrows). There is focal surface collapse (straight solid arrow). Incidentally, two pin tracks are visible (open arrows). (b) Extensive but patchy edema (arrowheads) and a moderate effusion (curved arrows) are depicted, as is GHI (straight solid arrows). One of the two pin tracks is visible (open arrow). (c) At 12 months, the graft marrow remains diffusely abnormal (curved arrows). The degree of surface collapse has progressed slightly (straight solid arrows). The pin tracks (open arrows) have partially healed. (d) Edema (arrowheads) has become slightly more confluent and extensive. A moderate effusion (curved arrows) persists. The anterior GHI (solid straight arrow) remains conspicuous. SI within the visible pin channel (open arrow) has diminished.

View larger version (173K): [in this window] [in a new window] [Download PPT slide]   Figure 8b. (a, c) T1-weighted (600/15) and (b, d) fat-suppressed T2-weighted (3,000/63) MR images of a condylar graft in a 36-year-old AP male patient at 6 (a, b) and 12 (c, d) months after surgery. (a) The graft marrow is diffusely abnormal (curved arrows). There is focal surface collapse (straight solid arrow). Incidentally, two pin tracks are visible (open arrows). (b) Extensive but patchy edema (arrowheads) and a moderate effusion (curved arrows) are depicted, as is GHI (straight solid arrows). One of the two pin tracks is visible (open arrow). (c) At 12 months, the graft marrow remains diffusely abnormal (curved arrows). The degree of surface collapse has progressed slightly (straight solid arrows). The pin tracks (open arrows) have partially healed. (d) Edema (arrowheads) has become slightly more confluent and extensive. A moderate effusion (curved arrows) persists. The anterior GHI (solid straight arrow) remains conspicuous. SI within the visible pin channel (open arrow) has diminished.

View larger version (163K): [in this window] [in a new window] [Download PPT slide]   Figure 8c. (a, c) T1-weighted (600/15) and (b, d) fat-suppressed T2-weighted (3,000/63) MR images of a condylar graft in a 36-year-old AP male patient at 6 (a, b) and 12 (c, d) months after surgery. (a) The graft marrow is diffusely abnormal (curved arrows). There is focal surface collapse (straight solid arrow). Incidentally, two pin tracks are visible (open arrows). (b) Extensive but patchy edema (arrowheads) and a moderate effusion (curved arrows) are depicted, as is GHI (straight solid arrows). One of the two pin tracks is visible (open arrow). (c) At 12 months, the graft marrow remains diffusely abnormal (curved arrows). The degree of surface collapse has progressed slightly (straight solid arrows). The pin tracks (open arrows) have partially healed. (d) Edema (arrowheads) has become slightly more confluent and extensive. A moderate effusion (curved arrows) persists. The anterior GHI (solid straight arrow) remains conspicuous. SI within the visible pin channel (open arrow) has diminished.

View larger version (174K): [in this window] [in a new window] [Download PPT slide]   Figure 8d. (a, c) T1-weighted (600/15) and (b, d) fat-suppressed T2-weighted (3,000/63) MR images of a condylar graft in a 36-year-old AP male patient at 6 (a, b) and 12 (c, d) months after surgery. (a) The graft marrow is diffusely abnormal (curved arrows). There is focal surface collapse (straight solid arrow). Incidentally, two pin tracks are visible (open arrows). (b) Extensive but patchy edema (arrowheads) and a moderate effusion (curved arrows) are depicted, as is GHI (straight solid arrows). One of the two pin tracks is visible (open arrow). (c) At 12 months, the graft marrow remains diffusely abnormal (curved arrows). The degree of surface collapse has progressed slightly (straight solid arrows). The pin tracks (open arrows) have partially healed. (d) Edema (arrowheads) has become slightly more confluent and extensive. A moderate effusion (curved arrows) persists. The anterior GHI (solid straight arrow) remains conspicuous. SI within the visible pin channel (open arrow) has diminished.

When the three parameters were reevaluated on the basis of exact graft location (medial femoral condyle, lateral femoral condyle, femoral trochlea, and tibial plateau), the same trends were observed for each variable at each graft location. In the process, however, significance was lost, with the exception of host marrow edema in medial femoral condylar grafts (P < .03), owing to small samples. After medial and lateral femoral condylar grafts were pooled together, significant differences for host marrow edema (P < .003), GHI thickness (P < .005), and graft marrow grade (P < .03) were reestablished.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Osteochondral allografts can be placed to resurface solitary or multiple defects, ranging from 1 to more than 30 cm² in size, involving any of the three articular compartments of the knee. The procedure was first developed in the 1970s and currently is performed at a limited number of centers in the United States (5,6,8,10–16). Results have been promising to date with good or excellent clinical results in as many as 76% of patients with a follow-up of 1–12 years (6).

Alternative procedures such as mosaicplasty (9) and autologous chondrocyte transplantation (7) reduce the risk of transmission of infectious disease and eliminate the risk of immunologic rejection. However, these techniques generally have not been successful in the treatment of patients with multiple or large osteochondral defects (7,9), and shell osteochondral allograft placement remains an attractive procedure in such patients.

Fresh osteochondral allografts elicit immune responses in animals, but the mechanism of sensitization is not fully understood. Although isolated chondrocytes are immunogenic (23,35–39), articular cartilage—owing to the mechanical protection that the inorganic cartilage matrix provides the embedded chondrocytes (40,41)—is considered immunologically privileged and does not sensitize the host (5,15,39,42,43). Therefore, the immune response probably is directed first a gainst the osseous portion of the graft, which contains unprotected cancellous bone and immunogenic elements (44). The initial response targeted against osseous tissue may lead to nonspecific inflammatory changes in the joint with consequent bystander injury to inorganic cartilage matrix (20,43). This, in turn, may expose embedded chondrocytes to the host’s immune system, sustaining host sensitization (43) even after host bone has grown into and replaced the osseous portion of the graft.

In animal models, immune responses to osteochondral allografts are associated with osseous resorption, cartilage degeneration, prolonged inflammation, and delayed or incomplete graft incorporation (19–32). However, the healing of shell allografts has not been rigorously investigated in human subjects. Studies have focused on clinical outcome (5,6,8, 10,13,15,45) or on histologic analyses of small numbers of failed grafts (11,14, 46,47).

Because routine histologic assessment is not possible in human subjects, we used MR imaging as a surrogate biomarker. Inflammatory responses were assessed by evaluating host marrow edema, cyst formation, and effusion. Grafts in AP patients were associated with significantly greater host edema, greater cyst formation, and larger effusions. The differences in edema were observed at all imaging time points and for all categories of graft size and location.

Graft marrow viability and incorporation were assessed by evaluating graft marrow SI, GHI thickness, and presence or absence of collapse. Our assumption was that portions of the graft marrow with abnormal SI were either edematous or necrotic, presumably from inflammation or incomplete incorporation, respectively. Similarly, portions of the GHI that were thick and conspicuous suggested incomplete osseous bridging across the interface, persistent granulation and other inflammatory tissue at the surgical bed, graft loosening or focal detachment, or a combination of these factors. In our study, AP patients had significantly greater graft marrow abnormality and thicker GHI than did AN patients. The differences in marrow grade and GHI thickness were observed at all imaging time points and for all categories of graft size and location. A minority (10 [28%] of 36) of grafts had near perfect marrow incorporation and viability, simultaneously exhibiting a GHI of 1 mm or less and a graft marrow SI of 25% or less. Nine of these 10 grafts were in AN patients. In contrast, the only grafts with collapse were in AP patients. Graft collapse probably resulted from softening of the graft osseous portion rather than from primary graft cartilage failure, as supported by animal studies (43). In our study, collapse occurred in the absence of focal cartilage defects but did not occur in the absence of diffuse graft marrow abnormality. In the one patient who underwent arthroscopy, the graft articular surface was normal, but the osseous portion was soft.

MR imaging may provide indirect evidence of chondrocyte viability. In our study, grafts in AP patients were more likely to have full-thickness cartilage defects than grafts in AN patients, but the difference was not significant. The extent to which cartilage defects resulted from loss of cartilage viability rather than from biomechanical stresses on otherwise viable cartilage remains to be determined. In our study, cartilage defects were less common than graft marrow or interface abnormalities, which supports the hypothesis that immune responses are directed first against the osseous portion.

The greater inflammatory responses and less complete graft incorporation in AP patients documented in this study suggest that antibody development adversely affects biologic healing. Although it theoretically is possible that defective healing, impaired for nonimmunologic reasons, predisposes to humoral sensitization, this is less likely. In immune-sensitized patients, antibodies were always detectable in the serum within 3 months of allograft placement, a period in which patients do not bear weight, making biomechanical factors less important. In addition, if defective healing led to antibody production, one might expect differences between AP and AN patients to be greater rather than smaller in the early postoperative period. Instead, grafts in the two groups of patients had similar MR appearances in the early postoperative period, and differences increased with time. One explanation for these temporal patterns is that early MR abnormalities represent nonspecific postoperative change, whereas abnormalities that persist or progress represent immune-mediated injury.

Because many factors likely contribute to the biologic outcome of grafts, we validated the comparison between AP and AN groups by confirming that the two populations were similar in age, sex, body mass index, donor age, donor sex, graft surface area, and time after surgery.

Our decision to evaluate the largest femoral graft at the last imaging session was arbitrary. However, the same qualitative results were obtained, without loss of significance, when we evaluated the smallest graft, when we evaluated all grafts, when we restricted the analysis to condylar grafts, or when we chose data from the first rather than last imaging session (data not shown). The same trends were seen when analysis was restricted by precise graft location, which suggests that graft location was not a confounder, although significance was usually lost owing to small samples. No patients underwent imaging at all time points. The largest sample undergoing imaging at one time point was 22 patients (14 AN and eight AP patients) at 12 months; data from only 15 of the 22 were analyzed because the 12-month session was not the final imaging session for seven patients. When we restricted our analysis to the 22 patients who underwent imaging at 12 months, we obtained the same qualitative results, while maintaining significance for host marrow edema (P < .01) and GHI (P < .005), although significance was lost for graft marrow grade (P = .05).

In two AN patients who underwent imaging at 24 and 36 months, the 24-month rather than 36-month imaging session was used. This conservative decision was made to ensure a more even distribution of AP and AN patients at each time point. Because differences between AP and AN groups increased with time, we would have achieved greater significance had we chosen the later time point instead for these two patients.

One weakness of our study is that we screened for only humoral immunity. Unfortunately, studies of cellular immunity in humans are prohibitively difficult because they require either surgical biopsy or maintenance of donor tissue in cell culture for testing against host lymphocytes (26,27,42,48). To the extent that cellular immune responses undetected with humoral screening occurred in AN patients and affected MR findings, findings in our study probably underestimated the true effect of immune sensitization on allograft healing. Another limitation was that gadolinium-based contrast material was not used because of expense and logistic factors. In particular, intravenous administration of a gadolinium-containing compound may have helped differentiate granulation tissue from other causes of edema and may have helped detect synovial proliferation.

In summary, MR imaging shows promise as a surrogate biomarker for success of shell osteochondral allograft implantation, but further study with longer follow-up and clinical outcome comparisons is needed. Ideally, confirmatory studies directly comparing MR and histologic findings should be performed, but these will be difficult to complete in human subjects. Findings in our study suggest that humoral immunity has potentially deleterious biologic consequences after shell osteochondral allograft placement, including greater inflammatory responses and less complete incorporation. In current practice, preoperative cross matching and postoperative immunosuppression are not routinely performed to avoid the expected delays and complications, respectively, that these measures would introduce. Preoperative graft freezing and irradiation, which reduce allograft immunogenicity in animals (27,43,49), are also not performed because of adverse effects on cartilage viability (20,43). Ultimately, the clinical effect of the biologic events depicted at MR imaging will determine if any of these immune-modulating practices are instituted.

	FOOTNOTES

 
Abbreviations: AN = antibody-negative, AP = antibody-positive, GHI = graft-host interface, SEM = standard error of the mean, SI = signal intensity

Author contributions: Guarantor of integrity of entire study, C.B.S.; study concepts, C.B.S., D.R., M.N.P., J.B., W.B., F.R.C.; study design, C.B.S., M.N.P., J.B.; definition of intellectual content, C.B.S.; literature research, C.B.S.; clinical studies, C.B.S.; data acquisition, C.B.S., J.B., R.D.B.; data analysis, C.B.S., J.B., R.D.B., L.K.L., R.D.; statistical analysis, C.B.S., R.D.; manuscript preparation, C.B.S., M.N.P.; manuscript editing, D.R.; manuscript review, all authors; manuscript final version approval, all authors.

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