Long-term survival of concurrent meniscus allograft transplantation and repair of the articular cartilage: a prospective two- to 12-year follow-up report.

We describe 119 meniscal allograft transplantations performed concurrently with articular cartilage repair in 115 patients with severe articular cartilage damage. In all, 53 (46.1%) of the patients were over the age of 50 at the time of surgery. The mean follow-up was for 5.8 years (2 months to 12.3 years), with 25 procedures (20.1%) failing at a mean of 4.6 years (2 months to 10.4 years). Of these, 18 progressed to knee replacement at a mean of 5.1 years (1.3 to 10.4). The Kaplan-Meier estimated mean survival time for the whole series was 9.9 years (sd 0.4). Cox's proportional hazards model was used to assess the effect of covariates on survival, with age at the time of surgery (p = 0.026) and number of previous operations (p = 0.006) found to be significant. The survival of the transplant was not affected by gender, the severity of cartilage damage, axial alignment, the degree of narrowing of the joint space or medial versus lateral allograft transplantation. Patients experienced significant improvements at all periods of follow-up in subjective outcome measures of pain, activity and function (all p-values < 0.05), with the exception of the seven-year Tegner index score (p = 0.076).

Kinematic magnetic resonance imaging of the effect of bracing on patellar position: qualitative assessment using an extremity magnetic resonance system.

OBJECTIVE: To use an extremity magnetic resonance system to perform kinematic magnetic resonance imaging (MRI) of the patellofemoral joint to qualitatively assess the effect of bracing on patellar position. DESIGN AND SETTING: Subjects underwent kinematic MRI of the symptomatic extremity with a 0.2-Tesla extremity magnetic resonance system. Images were obtained using a knee coil and a T1-weighted, spin echo pulse sequence. SUBJECTS: Seven female patients with patellofemoral joint symptoms. MEASUREMENTS: FOUR DIFFERENT AXIAL SECTIONS WERE OBTAINED FOR EACH POSITION: extension and 3 positions of flexion up to 36 degrees . An appropriate-sized patellofemoral brace was applied, and the kinematic MRI procedure was repeated. RESULTS: Six patients had lateral displacement of the patella, and 1 patient had medial displacement of the patella. After application of the brace, 6 patients (5 with lateral displacement and 1 with medial displacement, 86%) exhibited correction (5) or improvement (1 with lateral displacement) in the abnormal patellar positions, and 1 patient had worsening of the abnormal position of the patella. CONCLUSIONS: We used kinematic MRI to determine the presence of abnormal patellar positioning. Application of the brace counteracted the abnormal patellar positions in most of the patients studied.

Current and future directions for meniscus repair and replacement.

Torn meniscal cartilages and the consequences of missing meniscus tissue represent the major indications for operative arthroscopy of the knee. After recognizing the importance of the meniscus, clinicians made the shift away from complete meniscectomy to partial meniscectomy aided by the development of arthroscopic instrumentation. Despite extensive basic science data showing the importance of a complete meniscus for normal force transference, meniscus repair occurs in less than 10% of all meniscal tears found at arthroscopy. This paper will discuss the reasons for the common clinical approach and compare that approach with an aggressive approach of salvaging and replacing meniscus tissue, and will offer speculations about future directions for meniscus repair, reconstruction, and replacement.

Development and clinical application of kinematic MRI of the patellofemoral joint using an extremity MR system.

PURPOSE: Kinematic magnetic resonance imaging (MRI) of the patellofemoral joint provides diagnostic information pertaining to patellar alignment and tracking during the earliest increments of joint flexion, when abnormalities that affect this joint are the most apparent. Recently, a low-field strength (0.2 Tesla) dedicated extremity MR system has been designed, such that only the body part that is being imaged is placed inside of the magnet bore. The purpose of this investigation was to develop a kinematic MRI technique for the patellofemoral joint using the extremity MR system and to apply this procedure in the clinical setting. METHODS: An incremental, passive positioning kinematic MRI technique was developed for the patellofemoral joint that involved obtaining three different axial section locations with the patellofemoral joint extended and then imaging these same section locations repeatedly as the patellofemoral joint was flexed in four increments up to 36 degrees of flexion. MR images were obtained using a T1-weighted spin echo sequence. Five (10 PFJ) asymptomatic volunteers and nine patients (9 PFJ) with patellofemoral joint symptoms were studied. RESULTS: Volunteers had normal kinematic MRI examinations. Seven patients had lateral subluxation, and two patients had excessive lateral pressure syndrome. Two patients with lateral subluxation seen on their kinematic MRI studies had Merchant views (x-rays obtained at 45 degrees) that showed "normal" patellar alignment, illustrating the importance of imaging the patellofemoral joint at 30 degrees or less. CONCLUSIONS: A kinematic MRI technique was successfully developed for the low-field extremity MR system and utilized for clinical applications. This procedure may be used to determine the presence and severity of patellar malalignment and abnormal tracking patterns.

Porcine cartilage transplants in the cynomolgus monkey. III. Transplantation of alpha-galactosidase-treated porcine cartilage.

BACKGROUND: Studies on transplantation of porcine meniscus and articular cartilage into monkeys are important for evaluating the possible use of such tissues in humans. In addition, such studies shed light on the chronic xenograft rejection process in primates. Transplantation of porcine cartilage into cynomolgus monkeys for 2 months results in a many-fold increase in anti-Gal activity and in a strong cellular inflammatory response of T lymphocytes and macrophages within the implants. The objective of this study was to determine whether elimination of Galalpha1-3Galbeta1-4GlcNAc-R (alpha-gal epitopes) from the xenograft may alter the immune response and the inflammatory reaction. METHODS: Porcine meniscus and articular cartilage specimens were treated with recombinant alpha-galactosidase (100 U/ml), and the absence of alpha-gal epitopes was assessed by the binding of the monoclonal anti-Gal antibody M86. The treated cartilage specimens were transplanted into the suprapatellar pouch of cynomolgus monkeys. The immune response to cartilage was monitored in the serum and the inflammatory reaction was assessed in the xenografts, which were explanted after 2 months. RESULTS: Incubation with alpha-galactosidase resulted in complete removal of alpha-gal epitopes from the cartilage. The increase in anti-Gal activity in the transplanted monkeys was marginal. However, most monkeys produced antibodies to antigens specific to porcine cartilage. The inflammatory response within the alpha-galactosidase-treated xenografts was much lower than in nontreated cartilage and the proportion of T lymphocytes within the cellular infiltrates was greatly reduced. CONCLUSIONS: Treatment of cartilage xenografts with alpha-galactosidase successfully removes alpha-gal epitopes from porcine cartilage. Transplantation of the treated cartilage results in the production of only anti-porcine cartilage-specific antibodies and a reduced inflammatory response consisting primarily of macrophages infiltrating into the cartilage.

Regeneration of meniscal cartilage with use of a collagen scaffold. Analysis of preliminary data.

A collagen scaffold was designed for use as a template for the regeneration of meniscal cartilage and was tested in ten patients in an initial, Food and Drug Administration-approved, clinical feasibility trial. The goal of the study was to evaluate the implantability and safety of the scaffold as well as its ability to support tissue ingrowth. The study was based on the findings of in vitro and in vivo investigations in dogs that had demonstrated cellular ingrowth and tissue regeneration through the scaffold. Nine patients remained in the study for at least thirty-six months, and one patient voluntarily withdrew after three months for personal reasons. The collagen scaffold was found to be implantable and to be safe over the three-year period. Histologically, it supported regeneration of tissue in meniscal defects of various sizes. No adverse immunological reactions were noted on sequential serological testing. On second-look arthroscopy, performed either three or six months after implantation, gross and histological evaluation revealed newly formed tissue replacing the implant as it was resorbed. At thirty-six months, the nine patients reported a decrease in the symptoms. According to a scale that assigned 1 point for strenuous activity and 5 points for an inability to perform sports activity, the average score was 1.5 points before the injury, 3.0 points after the injury and before the operation, and 2.4 points at six months postoperatively, 2.2 points at twelve months, 2.0 points at twenty-four months, and 1.9 points at thirty-six months. According to a scale that assigned 0 points for no pain and 3 points for severe pain, the average pain score was 2.2 points preoperatively and 0.6 point thirty-six months postoperatively. One patient, who had had a repair of a bucket-handle tear of the medial meniscus and augmentation with the collagen scaffold, had retearing of the cartilage nineteen months after implantation. Another patient had debridement because of an irregular area of regeneration at the scaffold-meniscus interface twenty-one months after implantation. Magnetic resonance imaging scans demonstrated progressive maturation of the signal within the regenerated meniscus at three, six, twelve, and thirty-six months. These findings suggest that regeneration of meniscal cartilage through a collagen scaffold is possible. Additional studies are needed to determine long-term efficacy.

Porcine and bovine cartilage transplants in cynomolgus monkey: I. A model for chronic xenograft rejection.

Transplantation of discordant xenograft tissues usually results in antibody-mediated hyperacute rejection response. It has been speculated that because cartilage has a limited vascular, neural, and lymphatic supply, it might be immunologically privileged and may not undergo hyperacute or chronic rejection. Moreover, porcine and bovine cartilage were found to express very low amounts of alpha-galactosyl epitopes (Gal alpha1-3Gal beta1-4GlcNAc-R). To evaluate animal cartilage for possible human transplantation, xenograft meniscal cartilage was transplanted from pigs and cows into the suprapatellar pouches of six cynomolgus monkeys (group 1). In a second group of six monkeys (group 2), porcine meniscal cartilage and porcine articular cartilage plugs were evaluated. During the 2-month evaluation period in group 1, all monkeys displayed an extensive humoral response to the xenograft, as indicated by the increase in production of antibodies against bovine and porcine cartilage. Upon explant, all meniscal cartilage samples in this group demonstrated histological evidence of chronic rejection, including fibroplasia, encapsulation, mononuclear infiltrates, foreign body giant cells, and eosinophilic infiltrates. There was no difference between the response seen in untreated tissues and that seen in tissues treated with UV irradiation or ozone oxidation. In group 2, the menisci explanted after 1 month displayed extensive infiltration of eosinophils alone or eosinophils mixed with mononuclear cells. The mononuclear infiltrates consisted primarily of CD4+ and CD8+ T cells and of macrophages. The articular cartilage plugs demonstrated only a small area of fibrous encapsulation and leukocyte infiltration at the periphery. This study suggests that xenograft cartilage tissue does not appear to be immunoprivileged and is unsuitable for human implantation due to a chronic rejection mechanism, which is evident already within 1 month after transplantation. In addition, this study may serve as a general model for the primate immune response against xenografts in the absence of hyperacute rejection.

Porcine and bovine cartilage transplants in cynomolgus monkey: II. Changes in anti-Gal response during chronic rejection.

The recent advances in avoiding hyperacute rejection by producing transgenic pigs with complement regulatory proteins call for the analysis of posttransplantation changes in anti-Gal activity in the absence of hyperacute rejection. Transplantation of cynomolgus monkeys with porcine or bovine meniscus and articular cartilage enabled the study of anti-Gal IgG response to xenografts that are not subjected to hyperacute rejection. The cartilage implants were kept in suprapatellar pouches of the recipients for 1 or 2 months and anti-Gal activity was measured in the serum at various time intervals after transplantation. Within 2 weeks after transplantation, titer of anti-Gal IgG, in all transplanted monkeys, increased by 20- to 100-fold, as measured in ELISA with synthetic alpha-galactosyl epitopes linked to bovine serum albumin or with mouse laminin. Furthermore, binding of serum anti-Gal to porcine endothelial cells increased by 10-fold or more after transplantation. Complement-mediated cytotoxicity also increased by two- to eightfold after transplantation. The elevated activity of anti-Gal was maintained for the 2-month period during which the grafts were kept in the monkeys, and returned to the pretransplantation level 6 months after graft removal. All these data suggest that the primate immune system responds vigorously to alpha-galactosyl epitopes on xenografts by activating many B lymphocytes that produce increased amounts of anti-Gal IgG, which may also be of high affinity. These antibodies are likely to bind to the xenograft cells, even if these cells express low numbers of alpha-galactosyl epitopes. Such antibody binding may play an important role in chronic rejection of xenografts.

The frequency of Baker's cysts associated with meniscal tears.

We reviewed the films of 1760 patients who had magnetic resonance image scanning of the knee joint to assess the most common pathologic changes associated with an incidental finding of a Baker's cyst. Of the 1760 knees scanned, Baker's cysts were noted in 238. The cysts were classified as small (55%), medium (30%), or large (15%) and were primarily found on the medial side of the knee (94%). The menisci were evaluated and changes were classified as complete tears, where signal contacts the surface, or degenerative intrasubstance tears. One hundred eleven (47%) complete meniscal tears were found, and 88 (37%) degenerative tears. The majority of tears were found in the posterior horn of the medial meniscus (65 complete tears and 45 degenerative tears). Thus, 199 tears were found in 170 knees, and 106 of the 170 knees (62%) had tears of the posterior horn of the medial meniscus. Baker's cysts are frequent findings on physical examinations and on magnetic resonance imaging scans of the knee. They are thought to be due to intraarticular pathologic changes, usually posterior meniscal tears. This study documents the association between Baker's cysts and meniscal tears and notes that a complete tear is not necessary for the cyst to be present.

Meniscus replacement.

Replacement of the meniscus cartilage presents challenges not easily met by the application of technology or transplantation biology. No studies have demonstrated definitely that there are benefits to a replaced meniscus. Regeneration of the body's own meniscus cartilage may be successful, but confirmation of this phenomenon awaits further data.

Autogenous replacement of the meniscus cartilage: analysis of results and mechanisms of failure.

Autogenous replantation of meniscal cartilage (resection of 80% of the meniscus cartilage followed by immediate replantation) was performed in 14 dogs as a control arm of a meniscal replacement study. The purpose was to assess the ability of the excised tissue to heal to the intact rim and function as a meniscus cartilage. This procedure is an idealized model of allografting meniscus cartilage in that the tissue is fresh, autogenous, and perfectly sized. If this procedure did not succeed, it seemed likely to the authors that allografting meniscal cartilage would have diminished chances for success. Evaluation of these replant failures led us to speculate that the causes and mechanisms might include slow or incomplete revascularization, inadequate mechanical fixation or stabilization, and, perhaps, some type of rejection phenomenon not examined or confirmed in the present study. We believe these mechanisms will be particularly deleterious for allografted meniscal cartilages and recommend further extensive evaluation of meniscal allografts before wide clinical use.

Evaluation of a new hemostatic agent in experimental splenic laceration.

OBJECTIVES: To compare the effectiveness of several hemostatic agents and to evaluate a new hemostatic agent (ReClot) in controlling splenic hemorrhage. DESIGN: Rabbits were anesthetized and catheters placed. A celiotomy was performed and a splenic injury produced; hemostatic agent and compression were applied. EXPERIMENTAL GROUPS: In group 1 (n = 8), the splenic laceration was compressed with a dry sponge and 75 g of pressure until hemorrhage ceased. In groups 2, 3, and 4 (n = 10 each), splenic injury was treated with Avitene, Collastat, and ReClot, respectively. Hemostatic agent was applied to the splenic laceration and a dry sponge and pressure were applied as described for group 1. In group 5 (n = 9), a splenic laceration was produced, ReClot applied, and aggressive fluid resuscitation was initiated; the volume of crystalloid was adjusted to maintain mean arterial pressure. RESULTS: Application of a hemostatic agent reduced total blood loss compared with that measured in the control group, but there was no difference in blood loss among experimental groups treated with a hemostatic agent. The time required to achieve control of blood loss was less in the ReClot-treated group compared with the Avitene- and Collastat-treated groups. CONCLUSIONS: The hemostatic agent ReClot had a significant advantage over other hemostatic agents for the time required to achieve control of splenic bleeding. Aggressive fluid resuscitation did not limit the ability of ReClot to produce hemostasis.

3D MRI volume sizing of knee meniscus cartilage.

Meniscal replacement by allograft and meniscal regeneration through collagen meniscal scaffolds have been recently reported. To evaluate the effectiveness of a replaced or regrown meniscal cartilage, a method for measuring the size and function of the regenerated tissue in vivo is required. To solve this problem, we developed and evaluated a magnetic resonance imaging (MRI) technique to measure the volume of meniscal tissues. Twenty-one intact fresh cadaver knees were evaluated and scanned with MRI for meniscal volume sizing. The sizing sequence was repeated six times for each of 21 lateral and 12 medial menisci. The menisci were then excised and measured by water volume displacement. Each volume displacement measurement was repeated six times. The MRI technique employed to measure the volume of the menisci was shown to correspond to that of the standard measure of volume and was just as precise. However, the MRI technique consistently underestimated the actual volume. The average of the coefficient of variation for lateral volumes was 0.04 and 0.05 for the water and the MRI measurements, respectively. For medial measurements it was 0.04 and 0.06. The correlation for the lateral menisci was r = 0.45 (p = 0.04) and for the medial menisci it was r = 0.57 (p = 0.05). We conclude that 3D MRI is precise and repeatable but not accurate when used to measure meniscal volume in vivo and therefore may only be useful for evaluating changes in meniscal allografts and meniscal regeneration templates over time.

Surgical technique of meniscal replacement.

Meniscal replacement by allograft and prosthesis is under laboratory and investigational clinical practice. In order to succeed, a replacement must duplicate the exact mechanical function of the original meniscal cartilage. The technique of replacement described in this article permits minimal disruption of the joint tissues, accurate placement of the meniscal horns, and secure fixation of the meniscal synovial junction.

Meniscal regeneration with copolymeric collagen scaffolds. In vitro and in vivo studies evaluated clinically, histologically, and biochemically.

We sought to create a regeneration template for the meniscal cartilage of the knee to induce complete meniscal regeneration, and to develop the technique for implanting the prosthetic appliance in vivo. We designed a resorbable collagen-based scaffold and conducted in vitro and in vivo studies. In vivo, the scaffold was implanted in the knees of immature swine and mature canines and evaluated clinically, histologically, and biochemically. Because the canine stifle joint meniscus is more clinically relevant to the human meniscus, this paper emphasizes those results. We studied 24 mixed breed dogs (14 males and 10 females) with an average weight of 25.5 kg (range, 20 to 35) that were obtained from a USDA-licensed supplier. The dogs were deemed clinically and radiographically skeletally mature. None of the dogs had a preexisting knee joint abnormality. All dogs underwent an 80% subtotal resection of the medial meniscus bilaterally. A collagen template was implanted in one stifle (N = 24). The contralateral side served as a control: 12 dogs had a total resection alone and the other 12 dogs had an immediate replantation of the autologous meniscus. Results were tabulated at 3, 6, 9, and 12 months. At final evaluation, before the animals were euthanized, the results were submitted for statistical analysis as well as histologic and biochemical analyses. The results demonstrated that a copolymeric collagen-based scaffold can be constructed that is compatible with meniscal fibrochondrocyte growth in vitro and in vivo, that does not inhibit meniscal regeneration in an immature pig, and that may induce regeneration of the meniscus in the mature dog.(ABSTRACT TRUNCATED AT 250 WORDS)

Future directions. Collagen-based prostheses for meniscal regeneration.

Prosthetic meniscal replacement offers the ability to stabilize the meniscectomized knee and provide prophylaxis against early degenerative arthritis. Since prosthetic meniscal replacement may be performed in the setting of normal articular cartilage, a prosthesis will be required to match the exact joint configuration, induce the same lubricity, produce the same coefficient of friction, and absorb and dampen the same joint forces (without incurring significant creep or abrasion) as does the normal meniscus. This feat is currently beyond the capabilities of artificial materials alone. Alternatively, collagen-based prostheses acting as resorbable regeneration templates offer the possibility of inducing regrowth of new menisci. This paper presents a summary of hypotheses, considerations, and laboratory evidence for the use of collagen-based, resorbable matrices as regeneration templates.

Cloning of ligand-specific cell lines via gene transfer: identification of a D2 dopamine receptor subtype.

Using rat genomic DNA, we have established a transfected mouse fibroblast cell line that expresses a spiperone binding site with the pharmacological characteristics of a D2 dopamine receptor. The expressed D2 receptors are the product of a gene that is distinct from that reported by Bunzow et al. [Bunzow, J. R., Van Tol, H. H. M., Granoly, D. K., Albert, P., Salon, J., Christie, M., Machida, C. A., Neve, K. A. & Civelli, O. (1988) Nature (London) 336, 783-787]. Flow cytometry with the Ca2+-sensitive dye indo-1 demonstrated that activation of the expressed D2 sites resulted in increases in intracellular calcium that were dependent on the influx of external Ca2+. These general cloning procedures should be applicable to the production of cell lines expressing a variety of genes for which only functional assays are available.

Flow cytometric analysis of breast needle aspirates.

This study investigated two hypotheses: (1) sufficient cells may be obtained by needle aspiration of breast nodules to produce good flow cytometric DNA profiles; and (2) benign breast lesions do not produce aneuploid G0G1 peaks, and therefore a distinct aneuploid peak is sufficient for a diagnosis of malignancy. Breast specimens received in Surgical Pathology between December 1985 and February 1987 were aspirated, and the cells stained with propidium iodide for flow cytometric DNA analysis. A total of 344 specimens were aspirated, of which 204 (59%) were malignant and 140 (41%) benign. One hundred fifty-three malignant and 111 benign specimens contained sufficient cells for analysis. Cytologic smears were available for 177 malignant and 123 benign specimens. DNA histograms were considered diagnostic of malignancy if an aneuploid peak was present which contained at least 20% of the cells in the distribution, and had a DNA index greater than or equal to 1.2. Using these criteria, 73 of 153 (48%) carcinomas could be identified. None of the benign lesions satisfied these criteria. One fibroadenoma with atypical hyperplasia produced a distinct peak which contained less than 5% of the cells in the histogram, and had a DNA index of 1.25. Flow cytometric analysis provides objective data that complement the subjective cytologic interpretation of fine needle aspirates.