Breakdown of cartilage proteoglycan in a tissue culture model of rheumatoid arthritis.

Proteoglycan breakdown was studied in a coculture model which mimics the confrontation between synovium and cartilage that occurs in rheumatoid arthritis. Bovine nasal-septum cartilage discs radioactively labeled (35SO2-4 with or without [3H]glucosamine) and 'chased' in non-radioactive medium were cultured in contact with minced rheumatoid synovial membranes for intervals up to 8 days. Synovium-stimulated (2-3-fold) cartilage breakdown was unaffected by ascorbate supplementation. Labeled products (small molecules plus proteoglycan complexes) in culture media were characterized by chromatographic, sedimentation and enzymic digestion methods. Breakdown was dominated by the release of a range of proteoglycan products, fully disaggregated and incapable of reaggregation with added hyaluronate. Because constituent glycosaminoglycans were of uniform size, proteoglycan polydispersity was attributed to differences in core protein length. Hydrocortisone inhibited degradation and partially prevented the shift of proteoglycans to lower average molecular weight. An additional breakdown pattern occasionally noted during the initial 48 h of coculture was characterized by release of a subpopulation of low charge-density proteoglycan bearing shortened glycosaminoglycan chains, consistent with glycosidase action. We conclude that rheumatoid synovia exhibit two distinct cartilage degradative potencies in vitro that may be important in vivo: (a) A variable hyaluronidase-like activity at early culture times, and (b) a dominant proteolytic activity generating an array of disaggregated proteoglycan products that differ largely on the basis of their core lengths. The response to hydrocortisone is consistent with inhibition of proteolysis through the stabilization of cellular membranes.

Synovium-like tissue from loose joint replacement prosthesis: comparison of human material with a canine model.

The formation of synovium-like tissue is a biological response to a loose joint replacement prosthesis. Histological examination of this tissue has shown a synovial lining with a predominance of fibroblasts and macrophages, some multinucleated giant cells, and dispersed particles from the implant. Previous studies have reported elevated interleukin 1 (IL-1), prostaglandin E2 (PGE2), and collagenase in this tissue. We developed a canine model for the loose cemented femoral stem. Tissue harvested from the canine model was compared with human tissue retrieved at revision arthroplasty. Histology showed synovium, similar to that observed around loose human prostheses, adjacent to the canine cement sheath. Cells were isolated from this tissue and incubated in culture medium with or without naproxen for 3 days. Aliquots of the conditioned media were tested in the thymocyte proliferation assay to determine IL-1-like activity. IL-1 beta levels in human cell-conditioned media were analyzed by enzyme-linked immunosorbent assay, and PGE2 levels were measured by radioimmunoassay (RIA) using a PGE2 RIA kit (New England Nuclear). Human tissue contained levels of IL-1 beta in the range of 150 to 7,040 pg/mL and PGE2 levels of 82 to 952 ng/mL. The canine specimens contained IL-1-like activity and significant amounts of PGE2 (76 to 1,720 ng/mL). Naproxen decreased PGE2 levels in vitro. This animal model provides the means to investigate the in vivo and in vitro activity of the synovial cells around loose total joint prostheses.

Investigation of the activation of a human serum complement protein, C3, by orthopedic prosthetic particulates.

Myriad molecular, cellular, and physiological processes underlie the inflammatory and osteolytic processes induced by particles of biomaterials resulting from the wear of implants such as total joint replacement prostheses. The objective this study was to investigate the role that the complement system may be playing in these phenomena. The aim was to evaluate the degree to which particles of selected orthopaedic materials--high density and ultrahigh molecular weight polyethylene, polymethylmethacrylate, and commercially pure titanium--cause the elevation of a key complement molecule, C3a, in an in vitro assay that directly measured the concentration of C3a. The results demonstrated that HDPE particles, at high concentration, are capable of causing the elevation of C3a in the in vitro assay. This finding is discussed in the context of other work and the mechanics of the complement system as it may affect the osteolytic process.

Biochemical and histological evaluation of the synovial-like tissue around failed (loose) total joint replacement prostheses in human subjects and a canine model.

The tissue around loose total joint replacement prostheses displays a synovial-like lining comprised of cells that produce IL-1 and PGE2, mediators of inflammation that stimulate bone resorption. Particles of titanium alloy, as well as cobalt-chromium alloy and polyethylene, were found to aggravate the histiocytic response and production of IL-1 and PGE2. Tissue with similar histological and biochemical features was produced in a canine model of the aseptic loose cemented femoral stem.

Healing of chondral and osteochondral defects in a canine model: the role of cultured chondrocytes in regeneration of articular cartilage.

In this study a canine model was developed to investigate the nature of early healing responses to both chondral and osteochondral defects and to evaluate the tissue regenerative capacity of cultured autologous chondrocytes in chondral defects. The healing response to surgically created chondral defects was minor, with little cellular infiltration. In contrast, osteochondral defects exhibited a rapid cellular response, resulting ultimately in the formation of fibrous tissue. The lack of significant cellular activity in chondral defects suggests that an evaluation of the capacity of cultured autologous chondrocytes to regenerate articular cartilage is best studied in chondral defects using the canine model. When dedifferentiated cultured articular chondrocytes were implanted into chondral defects, islands of type II collagen staining were demonstrated in the regenerative tissue within 6 weeks. The relatively early expression of cartilage specific markers by the implanted chondrocytes, coupled with the inability of untreated chondral defects to repair or regenerate, demonstrates the utility of the canine model in evaluating novel materials for cartilage repair and regeneration.

Matrix collagen type and pore size influence behaviour of seeded canine chondrocytes.

This study directly compared the behaviour of chondrocytes in porous matrices comprising different collagen types and different pore diameters. There was a dramatic difference in the morphology of the cells in the type I and type II collagen matrices. The cells in the type II collagen matrix retained their chondrocytic morphology and synthesized glycosaminoglycans, while in the type I matrix the chondrocytes displayed a fibroblastic morphology with less biosynthetic activity than those in the type II. Small pore diameter affected morphology initially in the type I matrices and showed a higher increase of DNA content, but with time the cells lost the chondrocytic morphology. Our results demonstrate the marked influence of collagen type and pore characteristics on the phenotypic expression of seeded chondrocytes.

Chondrocyte-seeded collagen matrices implanted in a chondral defect in a canine model.

The objective of our study was to evaluate reparative tissues formed in chondral defects in an adult canine model implanted with cultured autologous articular chondrocytes seeded in type I and II collagen GAG matrices. Two defects were produced in the trochlea grooves of the knees of 21 dogs, with cartilage removed down to the tidemark. This study includes the evaluation of 36 defects distributed among five treatment groups: Group A, type II collagen matrix seeded with autologous chondrocytes under a sutured type II collagen flap; Group B, type I collagen matrices seeded with chondrocytes under a sutured fascia flap; Group C, unseeded type I collagen matrix implanted under a sutured fascia flap; Group D, fascia lata flap alone; and Group E, untreated defects. All animals were killed 15 weeks after implantation. Six other defects were created at the time of death and evaluated immediately after production as 'acute defect controls'. In three additional defects, unseeded matrices were sutured to the defect and the knee closed and reopened after 30 min to determine if early displacement of the graft was occurring; these defects served as 'acute implant controls'. The areal percentages of four tissue types in the chondral zone of the original defect were determined histomorphometrically: fibrous tissue (FT); hyaline cartilage (HC); transitional tissue (TT, including fibrocartilage); and articular cartilage (AC). New tissue formed in the remodeling subchondral bone underlying certain defects was also assessed. Bonding of the repair tissue to the subchondral plate and adjacent cartilage, and degradation of the adjacent tissues were evaluated. There were no significant differences in the tissues filling the original defect area of the sites treated with chondrocyte-seeded type I and type II matrices. Most of the tissue in the area of the original defect in all of the groups was FT and TT. The areal percentage of HC plus AC was highest in group E, with little such tissue in the cell-seeded groups, and none in groups C and D. The greatest total amount of reparative tissue, however, was found in the cell-seeded type II matrix group. Moreover, examination of the reparative tissue formed in the subchondral region of defects treated with the chondrocyte-seeded collagen matrices (Groups A and B) demonstrated that the majority of the tissue was positive for type II collagen and stained with safranin O. These results indicate an influence of the exogenous chondrocytes on the process of chondrogenesis in this site. In all groups with implants (A-D), 30(50% of the FT and TT was bonded to the adjacent cartilage. Little of this tissue (6-22%) was attached to the subchondral plate, which was only about 50% intact. Remarkable suture damage was found in sections from each group in which sutures were used. Harvest sites showed no regeneration of normal articular cartilage, 18 weeks after the biopsy procedure. Future studies need to investigate other matrix characteristics, and the effects of cell density and incubation of the seeded sponges prior to implantation on the regenerative response.

Synovial factors and chondrocyte-mediated breakdown of cartilage: inhibition by hydrocortisone.

Cartilage-synovium interactions were explored in a model culture system. Bovine nasal-cartilage discs were cocultured with minced rheumatoid synovium or synovium-conditioned media (SCM) in the presence or absence of hydrocortisone. Cartilage breakdown was assessed by the release of proteoglycan (PG) and hydroxyproline, and matrix biosynthesis by [35S]sulfate incorporation during pulse labeling. Chondrocyte-dependent breakdown in response to synovial factors (i.e., "catabolin" activity) was assessed by the difference in PG release between living and dead cartilages. Short-term contact with minced synovial membrane or exposure to its products released at a distance was sufficient to induce cartilage degradation in coculture; continued exposure was not required for breakdown to persist. Conditioned media from short-term synovial culture were similarly potent, and the induced breakdown was chondrocyte dependent. Matrix biosynthesis was inhibited in exposed cartilage but could be rapidly restored to normal on synovium removal despite the persistence of cartilage breakdown. Early hydrocortisone treatment suppressed the initiation of cartilage breakdown in cocultures and largely abolished the appearance of inductive factors in SCM. Later applications had little effect either in cocultures or in catabolin assays. We conclude that synovium-induced breakdown is an early event and that chondrocyte catabolic mechanisms once they have been activated are sufficient to maintain breakdown at a high level. Hydrocortisone, as well as limiting proteolysis, inhibits early tissue interactions at the level of synovial catabolin production or release.

Effects of isolated rheumatoid synovial cells on cartilage degradation in vitro.

Rheumatoid synovium in coculture with cartilage has been shown to release a factor(s) that stimulates the depletion of glycosaminoglycans (GAG) from cartilage matrix. Human rheumatoid synovium was enzymatically disaggregated and the isolated cells were subjected to a variety of mechanical and immunological treatments. Synovial cell conditioned media (SCCM) were prepared and analyzed for their ability to stimulate GAG depletion. SCCM prepared from increasing concentrations of isolated synovial cells demonstrated cartilage degradative activity in a dose-dependent manner. This activity was characterized as interleukin-1 like and was found mostly within the adherent cell population where the synovial macrophages retained significant degradative ability. T cells alone were found to have no direct degradative effect on cartilage, but their presence appeared to augment the response of the adherent cells. The techniques described here provide a quantitative model for examining the degradative factors from synovium as well as the cellular interactions that promote their release.

Treatment of antigen-induced arthritis in rabbits with dysprosium-165-ferric hydroxide macroaggregates.

Dysprosium-165-ferric hydroxide macroaggregates (165Dy-FHMA) was used as an agent of radiation synovectomy in an antigen-induced arthritis model in New Zealand white rabbits. Animals were killed up to 6 months after treatment. 165Dy-FHMA was found to have a potent but temporary antiinflammatory effect on synovium for up to 3 months after treatment. Treated knees also showed significant preservation of articular cartilage architecture and proteoglycan content compared with untreated controls, but only during the first 3 months after treatment. In animals killed 3 and 6 months after treatment there were only minimal differences between the treated and untreated knees, indicating that the antiinflammatory effects on synovial tissue and articular cartilage preservation were not sustained.

Effect of purified human interleukin-1 on cartilage degradation.

The effects of highly purified human monocyte-derived interleukin-1 (IL-1) on bovine nasal cartilage breakdown were investigated. Cartilage degradation was determined by quantifying the fraction of total proteoglycan released from cartilage during 8 days of culture. The response appeared to be chondrocyte-dependent, for IL-1 stimulated proteoglycan (PG) release from living but not from dead (frozen-thawed) cartilage. IL-1 action on living cartilage was heat labile and concentration dependent, with significant effect at 5 U/ml and maximal effect at 10-20 U/ml. Kinetic studies showed significant stimulation of PG release by 3 days of incubation with 10 U/ml IL-1. Studies in which IL-1 was removed on day 1 or day 4 showed that the cartilage-degrading effect of this monokine was reversible. Although IL-1 caused little change in the Sepharose CL-2B chromatographic profile of released PGs using an associative elution buffer, a significant shift to lower mol wt was observed under dissociative conditions. To probe the mechanism of IL-1 action, cartilage samples were incubated with IL-1 in the presence of the protein synthesis inhibitor, cycloheximide, or the lysosomal membrane-stabilizing steroid, hydrocortisone. Cycloheximide at 5-10 micrograms/ml completely blocked IL-1-induced breakdown. One the other hand, 3 x 10(-7) M hydrocortisone had little or no effect on IL-1 action. IL-1 was also shown to stimulate the degradation of human articular cartilage.

Tissue reactions to particles of bone-substitute materials in intraosseous and heterotopic sites in rats: discrimination of osteoinduction, osteocompatibility, and inflammation.

Two rat models were used to characterize tissue-specific reactions to particles of bone-substitute materials: one for osteocompatibility in a healing tibial wound and the other in a heterotopic, subcutaneous site. Small, unicortical tibial wounds in rats healed spontaneously, beginning with the rapid proliferation of intramedullary woven bone. That temporary bone was resorbed by osteoclasts and finally, the cortical wound was healed with lamellar bone and the medullary space was repopulated with marrow. When various particulate materials were implanted into fresh wounds, three types of reactions were observed. (1) Demineralized bone powder (DBP) and non-resorbable calcium phosphate (nrCP) were incorporated into the reactive medullary and cortical bone. (2) Polymethylmetlhacrylate (PMMA) particles were surrounded with a fibrous layer, but did not impair bone healing. (3) Polyethylene (PE) shards and resorbable calcium phosphates (rCPs) were inflammatory and inhibited osseous repair. Subcutaneous sites showed osteoinductive, fibrotic, or inflammatory responses to these materials. Only DBP induced endochondral osteogenesis subcutaneously. The nrCP evoked a fibrous reaction. In contrast, rCPs, PMMA, and PE shards generated inflammatory reactions with each particle being surrounded by fibrous tissue and large multinucleated giant cells. In conclusion, only DBP showed osteoinductive as well as osteocompatible properties. The nrCP was osteocompatible. The rCPs stimulated various degrees of inflammatory responses. PMMA was osteocompatible and did not interfere with the bone healing process. PE was not osteocompatible and generated foreign body reactions in both sites. Use of the two sites distinguishes osteoinductive, osteocompatible, and inflammatory properties of particles of bone-substitute materials.

Parameters of longitudinal growth rate in rabbit epiphyseal growth plates.

UNLABELLED: Three parameters have been identified that provide useful indices of longitudinal growth rate in rabbit epiphyseal plates. Specifically, we have examined the relationship between longitudinal growth rate and (1) growth-plate thickness; (2) the rate of cell division by proliferating chondrocytes; and (3) 35SO4 incorporation associated with matrix synthesis. There were statistically significant correlations between growth rate and each of the three experimentally determined parameters. Growth rate increased in direct proportion to growth-plate thickness, rate of chondrocyte proliferation, or 35SO4 incorporation associated with matrix synthesis. Of the three parameters, the rate of cell division of proliferative chondrocytes, as determined by counts of 3H thymidine-labeled cells following autoradiography, appeared to provide the most sensitive index of growth rate. However, used in combination, determination of the three parameters should make it possible to assess the relative contributions of changes in the numbers of cells, in the rate of chondrocyte proliferation, and in extracellular matrix synthesis to over-all growth rate. CLINICAL RELEVANCE: Methods are described and data are presented that should make it possible to design studies of the factors that regulate and control the longitudinal growth rate of epiphyseal cartilage growth plates. The experimental design of this work is applicable to the study of hormonal regulation of over-all growth rates and to determination of whether the effects of certain hormones are due to their effect on cell proliferation or matrix synthesis. Such studies should contribute to a better understanding of the control of growth in normal individuals and in patients with disease.

The weight-bearing shoulder. The impingement syndrome in paraplegics.

The cases of ninety-four patients who had complete paraplegia were studied to determine whether they had complaints about the shoulder during transfer activities. Thirty-one patients reported pain on transferring, and twenty-three of these patients were found to have a chronic impingement syndrome with subacromial bursitis. Arthrography of the shoulder was done for each of these twenty-three patients, and fifteen were found to have a tear of the rotator cuff. Five of the thirty-one patients were found to have aseptic necrosis of the head of the humerus. We also measured the intra-articular pressure in the shoulder in five patients during different activities, including transfer from wheelchair to bed, and found that this pressure exceeded the arterial pressure by two and one-half times. We believe that this high pressure, in conjunction with abnormal distribution of stress transmitted across the subacromial area during transfer or propulsion of a wheelchair, contributes to the high rate of problems about the shoulder in paraplegics.

Complications of total hip-replacement arthorplasty in patients with rheumatoid arthritis.

During the period 1969 through 1974, 716 total hip-replacement arthorplasties were performed. The results of the surgery in 275 cases of rheumatoid arthritis as regards complications were compared with those in 382 procedures in cases of osteoarthritis. In contrast to the reports of others,the incidence of deep would infection in the two groups was found to be equal. Patients undergoing total hip-replacement arthroplasty as a revision of a previous operation had a substantially increased risk of infection. Patients with rheumatoid arthritis, however, were more subject to certain other complication (intraoperative fracture, difficulties with anesthesia, and malposition of prosthetic components), in addition to the complications that were predictable because of the involvement of multiple joints and the systemic disease process.

Pitfalls of using patient recall to derive preoperative status in outcome studies of total knee arthroplasty.

BACKGROUND: It is essential to adjust for the level of preoperative pain and functional status when measuring the outcome of total knee arthroplasty. Some study designs rely on postoperative patient recall to derive preoperative status. In this study, we compared prospectively collected preoperative data with data derived from patient recall of preoperative status three months after total knee arthroplasty. METHODS: Patients were recruited as part of a prospective observational study of the outcome of primary total knee arthroplasty for osteoarthritis at four centers in the United States, six centers in the United Kingdom, and two centers in Australia. Independent research assistants recruited patients and collected data with use of a uniform documentation system preoperatively and three months postoperatively. Preoperative data included the findings of a clinical history and physical examination, demographic information, socioeconomic status, and scores from two health-status instruments: the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and the Medical Outcomes Study Short Form-36 Health Survey (SF-36). Postoperative data included the WOMAC and SF-36 scores and patient recall of preoperative status on selected items from these health-status measures. RESULTS: A total of 862 patients were recruited, and recall data were available for 770 patients (89%). The mean age was seventy years (range, thirty-eight to ninety years), and 59% of the patients were women. Comparisons of prospective and recall data on individual pain and function items showed poor-to-fair agreement (weighted kappa, 0.20 to 0.41). Patients recalled significantly more pain than they had reported preoperatively (p < 0.001), but there were random recollection errors for the function items. There was only moderate correlation between the prospective and recalled summary scores for pain (Spearman r = 0.53) and function (Spearman r = 0.48). In addition, 61% of the recalled pain scores and 50% of the recalled function scores differed from the prospective scores by more than 10 points (10% of the total range). CONCLUSIONS: Patients' recall of preoperative pain and functional status three months after total knee arthroplasty demonstrated only moderate agreement with what the patients had reported prospectively. Researchers who use recall data to derive preoperative status must recognize these limitations when drawing conclusions about the effectiveness of total knee arthroplasty.

Long-term complications after total knee arthroplasty with or without resurfacing of the patella.

The long-term complications related to the patella were retrospectively evaluated for 891 knees (684 patients) that had had a total arthroplasty, with or without resurfacing of the patella, with use of an unconstrained, condylar, posterior-cruciate-preserving prosthesis. The study population comprised two groups of patients who were similar in size, age, sex distribution, and diagnosis. One group (396 knees [303 patients]) had had a total knee arthroplasty with patellar resurfacing and the other group (495 knees [381 patients]) had had the same procedure without resurfacing. The average duration of follow-up was six and one-half years (range, two to fifteen years). The decision to resurface the patella was based on subjective inspection of the articular surface and on assessment of patellar tracking at the time of the operation. Resurfacing was performed if there was loss of cartilage, exposed bone, gross surface irregularities, or tracking abnormalities. Complications occurred an average of three years (range, immediately postoperatively to nine years) after the operation in the group that had had resurfacing and an average of four years (range, immediately post-operatively to ten years) postoperatively in the group that had not had resurfacing. In the group that had had resurfacing, there was loosening of the patellar component in five knees, patellar subluxation in four knees, fracture of the patella in three knees, rupture of the patellar tendon in three knees, and chronic peripatellar pain in one knee. In the group that had not had resurfacing, the complications included patellar subluxation in five knees, rupture of the patellar tendon in two knees, and chronic peripatellar pain in fifty-one knees.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-constrained total shoulder replacement in patients who have rheumatoid arthritis and class-IV function.

The results of twenty-four non-constrained total shoulder replacements that were done in twenty patients who had treatment of rheumatoid arthritis were retrospectively reviewed to determine how those results were affected by the severity of the disease. All of the patients had Class-IV functional capacity, and 92 per cent had Stage-III or IV rheumatoid progression. Nine (38 per cent) of the shoulders had a tear of the rotator cuff. The mean length of clinical follow-up was 4.5 years (range, two to ten years). Preoperatively, all of the patients had disabling pain and limited function. Postoperatively, twenty-two (92 per cent) of the patients had no appreciable pain, and eighteen (75 per cent) had no significant functional limitation (p less than 0.001). Active elevation improved by 88 per cent, and external and internal rotation also improved significantly. Motion, relief of pain, and functional improvement were not significantly greater in the patients who had an intact rotator cuff. Radiolucent lines developed around ten (42 per cent) of the glenoid prostheses, but only two of the prostheses were surrounded by a complete line and were thought to be loose. No revisions were done. We believe that a non-constrained total shoulder replacement affords excellent relief of pain, satisfactorily improves range of motion, and improves function in patients who have severe rheumatoid involvement of the shoulder. However, because motion and function are severely restricted preoperatively, the end-results are not comparable with those that have been reported for patients who have less severe rheumatoid disease.

Total hip arthroplasty with cement for juvenile rheumatoid arthritis. Results at a minimum of ten years in patients less than thirty years old.

We retrospectively reviewed the clinical and radiographic results of total hip arthroplasty with cement in patients with juvenile rheumatoid arthritis who were less than thirty years old at the time of the index procedure. Thirty-nine patients (sixty-six hips) were managed with this procedure at our institution between 1971 and 1983. Six patients (eleven hips) died before a minimum of ten years of follow-up; the remaining thirty-three patients (fifty-five hips) were followed for at least eleven years. Twenty-eight patients (forty-six hips) had at least one original component in situ after an average duration of clinical follow-up of 15.1 years, and twenty-three of these patients (thirty-eight hips) were followed radiographically for an average of 14.7 years. At the time of the latest follow-up examination, all twenty-eight patients were able to walk outside the home; twenty of these patients (thirty-five hips; 76 per cent) had no pain with activity, and eight patients (eleven hips; 24 per cent) had mild-to-moderate pain with activity. Over-all, twelve (18 per cent) of the sixty-six femoral components and twenty-three (35 per cent) of the sixty-six acetabular components were revised after an average of 12.8 and 11.8 years, respectively. The fifteen-year survival rate for the femoral components was 85 per cent with revision or radiographic loosening as the end point. The fifteen-year survival rate for the acetabular components was 70 per cent with revision as the end point and 61 per cent with revision or radiographic loosening as the end point. The benefits of total hip arthroplasty were maintained over the long term in most of our patients who had juvenile rheumatoid arthritis. However, the durability of the components in these young patients remains a concern.

Leakage of radioactive particle systems from a synovial joint studied with a gamma camera. Its application to radiation synovectomy.

UNLABELLED: We have determined rates of leakage of radioactivity from a rabbit synovial pouch in vivo for a number of particle systems of varying sizes and differing resistance to degradation. The estimates were made using a gamma scintillation camera and without killing the test animals. The lowest leakage at twenty-four hours was seen with inert carbonized microspheres and the highest rates were seen with surface-labeled particles of biodegradable denatured human serum albumin and with erythrocytes. The carbonized microspheres had no adverse long-term effects on the health of the animals' articular cartilage. CLINICAL RELEVANCE: Results obtained with inert particles indicate that reducing the biodegradability of the particle or increasing its diameter, or both, reduces radioactivity losses from the knee joint. Large (twenty-five-micrometer-diameter) microspheres of human serum albumin incorporating the radioactivity and carbonized microspheres are suggested as potential carriers of isotopes for human radiation synovectomy.