Osteochondral defects of the talus, historically difficult to treat and often leading to decreased functionality,1 commonly occur after traumatic injury in young adults.2 Osteochondral injuries are characterized by loss of articular cartilage and subchondral bone of the affected area.3–5 When osteochondral injuries are caused by traumatic mechanisms, treatment is further challenged by greater area of involvement, weight-bearing concerns, and increased risk of posttraumatic osteoarthritis.5–7 Current treatment options for osteochondral talar defects include nonoperative management, arthroplasty, mosaicplasty, subchondral drilling, microfracture, autogenous osteochondral allografting, and autologous chondrocyte implantation.2,5,6,8–11 However, complications, such as infection, joint stiffness, pain, failure to regenerate viable cartilage, prosthesis term of service, and early-onset arthritis, remain concerns.4,10,12,13
Fresh osteochondral allografting is an increasingly popular treatment option,1,9,10 as the tissue can effectively address large defects, contains hyaline cartilage, can delay progression of arthritis, and can concurrently treat chondral and osseous defects.9 Early-term positive outcomes have been reported, but the technique is limited by delayed graft incorporation, loss of chondrocyte viability, and loss of cartilage properties (eg, graft structure and composition) following extended storage times.4,9,11,14–18 A recent study also described the delayed collapse of fresh osteochondral allografts of the talus due to an immune-mediated reaction resembling the CD4+ and CD8+ T-cell response characteristic of graft-versus-host disease.19
Augmentation of graft storage conditions may improve and/or extend chondrocyte viability and specific compounds and biomolecules that augment storage media to extend the “shelf life” of the grafts. The authors present the results from a pilot study investigating the in vitro and in vivo effects of supplementing standard storage media with bisphosphonates, a common class of pharmaceuticals used to decrease osteoclastic bone resorption associated with metabolic bone disorders.
Materials and Methods
In Vitro Analysis of Bisphosphonate-Treated Fresh Osteochondral Allografts
An in vitro study was performed with osteochondral cores harvested from fresh human distal femora. Gross observation of the knees did not indicate cartilage damage or other joint-related pathology. Cores were retrieved from fresh femoral condyles of 2 male donors (Musculoskeletal Transplant Foundation, Jessup, Pennsylvania). Cores from the distal femur were used because of clinical relevance, as allografts from the knee are often used in the reconstruction of osteochondral defects of the talus, especially large-volume grafts. Additionally, distal cores were used for translation and continuity with the subsequent in vivo study of a swine knee osteochondral defect model.
A total of 45 cylindrical cores of osteochondral tissue with a diameter of 10 mm were taken from the condyles and randomized to experimental treatment groups and time points (3 per group per time point). Following harvest, cores were immediately immersed in fresh osteochondral allograft storage media (Musculoskeletal Transplant Foundation). Five different media solutions were assessed. Control cores were immersed in unmodified media. The remaining cores were place in either a first-generation, nonnitrogenated bisphosphonate (etidronate [Didronel]; Procter & Gamble Pharmaceuticals, Cincinnati, Ohio) or a current-generation, nitrogenated bisphosphonate (risedronate [Actonel]; Warner Chilcott, Dublin, Ireland) at 2 different concentrations (low dose, 0.01 M; high dose, 0.1 M). All grafts were stored at 4°C for 1 of 3 time points—16, 35, or 43 days—to simulate clinical use, encompassing 1 typical and 2 long-term storage periods.
At each endpoint, samples were removed from solution and fixed in 10% neutral-buffered formalin in preparation for decalcified histologic analysis. Thin sections were stained with Safranin-O/Fast Green for assessment of proteoglycan content throughout the cartilage matrix of the osteochondral cores. Additional slides were stained with terminal deoxynucleotidyl transferase neck end labeling to assess chondrocyte viability. Histological sections were digitized (TurboScan AT; Leica Biosystems, Buffalo Grove, Illinois) and magnified (20×) before grading with an Osteoarthritis Research Society International (OARSI)–modified Mankin classification system to quantitatively assess structure of cartilage, cell appearance, sulfated glycosaminoglycan content, and tidemark integrity. Specifically, each category is scored on a scale of 0 to 14, with low scores signifying normal cartilage.
In Vivo Analysis of Bisphosphonate-Treated Fresh Osteochondral Allografts
The Yucatan miniature pig has been used as a preclinical model to assess cartilage regeneration and degeneration.20 Under an Institutional Animal Care and Use Committee–approved protocol, 1 female Yucatan miniature pig served as a donor animal for osteochondral tissue. Following euthanasia, cores 6 mm in diameter were harvested bilaterally from the trochlea of the hind stifle joints with an osteoarticular transfer system set (OATS; Arthrex Inc, Naples, Florida). Cores were immediately immersed in storage media. Control cores were immersed in unmodified storage media, as in the in vitro study. Cores in the experimental groups were immersed in media augmented with the high dose (0.1 M) of either etidronate or risedronate, based on in vitro study findings. All immersed grafts were stored at 2°C to 4°C for 13 days to simulate clinical time lines and then removed from media for transplantation.
At transplantation, each miniature pig received 1 control graft and 1 bisphosphonate-treated graft per knee, with etidronate- and risedronate-treated grafts assigned to contralateral knees, placed bilaterally into the trochlea of the hind knees. Fresh osteochondral allografts were press-fit into prepared defects, confirming the cartilage surface was congruent and level. After the patella was returned to a normal anatomic position, the limb was passively ranged to ensure a normal traverse over the grafts. Animals were recovered from anesthesia and allowed ad libitum activity.
Six weeks postoperatively,21–23 the recipient animals were euthanized and all stifle joints of each animal were harvested en bloc, followed by fixation in neutral-buffered formalin for 96 hours. After tissue fixation, specimens were rinsed in saline 3 times during a 24-hour period and then placed in a saline-soaked towel for μCT scanning (Flex Triumph PET/SPECT/CT; Gamma Medica, Salem, New Hampshire). Scans were performed using a voltage of 80 kVp, current of 260 μA, and magnification factor of 2.0 with an average of 5 frames, yielding a 120-μm isotropic voxel size. The scan region was defined as the entire core in situ within the trochlea. Each specimen was aligned using the z-axis, and then total volume, calcified tissue volume, volume fraction, bone mineral density, and calcified tissue mineral density of the core were obtained. For the interface tissue, average thickness and tissue mineral density were calculated. The bone volume fraction was determined for both the bone core and the interface tissue. Following μCT analysis, the medial trochlea was sectioned (5 mm thick), decalcified, and stained with Safranin-O/Fast Green for histologic analysis, with 3 to 5 slides per graft per condyle. Slides were histologically evaluated using a grading system described by Solchaga et al.24
In Vitro Study of Proteoglycan Content and Chondrocyte Viability
After immersing cores in media at the 3 time points, Safranin-O/Fast Green–staining histologic analysis was performed to assess proteoglycan content (Figure 1). At the 16-day time point, specimens stored in media augmented with low-dose risedronate exhibited the greatest Safranin-O staining intensity, followed by specimens stored in high-dose risedro-nate. Similar to the early time point, cores treated with low-dose risedronate also showed the greatest staining intensity at the 35-day time point compared with all other specimens. At the 43-day time point, cores from the high-dose risedronate group were most intense, followed closely by the low-dose risedronate and control groups. Qualitative analysis of terminal deoxynucleotidyl transferase neck end labeling–stained sections at the 43-day time point showed more viable cells in the specimens treated with low-dose risedronate, but differences between groups were not significant.
Representative Safranin-O/Fast Green–stained histologic sections of human osteochondral allograft tissue as a function of duration in cold storage and composition of storage media.
On comparison of the 2 types of etidronate-treated cores, those treated with a high dose exhibited greater staining intensity at all 3 time points than those treated with a low dose. In risedronate-treated cores, the low-dose specimens showed greater staining intensity at 16- and 35-day time points, while the high-dose specimens showed greater staining intensity after 43 days of storage. In control and risedronate-treated specimens, staining was less intense near cells; however, cores stored in etidronate-augmented media showed an absence of Safranin-O staining throughout all zones. Also, for all specimens, staining was more focal and confined to the pericellular environment and staining intensity decreased as a function of depth, with the superficial zone exhibiting the lowest staining intensity.
Cores were also graded according to the OARSI–modified Mankin classification system (Figure 2). At the earliest time point (16 days), specimens treated with low-dose risedronate showed the lowest (most normal) OARSI–modified Mankin score, on average, followed by specimens treated with high-dose etidronate, high-dose risedronate, and low-dose etidronate and control specimens. The OARSI–modified Mankin scores were greatest at the 35-day time point for all specimens, on average, except for the control specimens, which had a greater Mankin score at the 16-day time point. At the 35-day time point, control specimens exhibited the lowest scores, on average, followed by low-dose risedronate and high-dose etidronate specimens, which were approximately equivalent. After 43 days of storage, specimens treated with low-dose risedronate showed the lowest Mankin score, on average, followed by control specimens, which had an approximately equivalent score.
Osteoarthritis Research Society International–modified Mankin scores for fresh human osteochondral cores immersed in media supplemented with 1 of 2 different doses of a nitrogenated (risedronate) or non-nitrogenated (etidronate) bisphosphonate vs storage media alone (control).
Pilot Study of Osteochondral Allograft Incorporation in a Miniature Swine Model
Based on in vitro study results, a small pilot study was performed to assess the effect of bisphosphonate-augmented storage media on the incorporation of fresh osteochondral allografts in a Yucatan miniature swine trochlear defect model at a 6-week endpoint. Histologic analysis of transplanted grafts showed distinct differences between controls, etidronate-immersed grafts, and risedronate-immersed grafts (Figure 3).
Safranin-O/Fast Green–stained decalcified histologic sections after 6 weeks of transplantation in miniature swine after grafts were stored in media alone (control) (A), etidronate-supplemented storage media (B), or risedronate-supplemented storage media (C) (all original magnification ×1.2). Corresponding µCT imaging of grafts stored in media alone (control) (D), etidronate-supplemented storage media (E), or risedronate-supplemented storage media (F).
On assessment for graft incorporation and integrity, the control group showed a significant loss of subchondral bone, surrounded by dense fibrous tissue, and bone resorption at the base of the graft. Etidronate-immersed grafts maintained a greater volume of subchondral bone compared with control grafts; however, incomplete osseous incorporation was observed, with zones of fibrous tissue at the graft periphery. Etidronate-treated grafts also subsided from the articular surface, and Safranin-O staining intensity decreased in the cartilaginous tissue. Grafts treated with risedronate exhibited direct osseous incorporation throughout the graft–host interface, without evidence of bone resorption. Further, risedronate-treated grafts maintained Safranin-O staining, consistent with surrounding host articular cartilage.
The μCT analysis showed stark differences between the treatment groups and the control group; however, data from one knee of one animal (etidronate group) were unusable because of the proximity of the transplanted grafts, which precluded complete analysis of the histomorphometric properties at the graft–host interface. To directly compare the bisphosphonate-treated samples with their internal controls, the ratio (experimental/control) of each μCT parameter was calculated (Table). Risedronate-treated grafts showed the greatest bone volume fraction within the body of the graft itself. At the graft–host interface, risedronate-treated grafts showed the lowest volume of connective tissue and greatest tissue mineral density. Quantitative μCT analysis also corresponded with histologic images, with thicker interface tissue measured in the control samples (an approximately 6-μm difference, on average) compared with the bisphosphonate-treated grafts.
Ratios of µCT Parameters for Bone Core and Interface Tissue
Fresh osteochondral allograft transplantation simultaneously addresses both cartilaginous and bony defects. Despite relatively positive clinical outcomes in treating defects in the knee,25–28 osteochondral defects of the talus, especially large lesions greater than 1.5 cm, have historically been difficult to repair because of recipient articular cartilage avascularity and decreased local cell population. Numerous studies have highlighted the high failure rate associated with fresh osteochondral allograft transplantation for talar defects.6,19,29,30 Graft resorption and mechanical collapse is a common failure mechanism in talar allografts, and histopathologic analyses have shown osteoclast-mediated bone resorption at the graft–host interface.19 In addition to osteoclast-mediated bone resorption and subsequent collapse, fresh osteochondral allograft tissue has been associated with challenges related to graft processing, handling, and outcomes, including maintenance of graft structure, and preservation of chondrocyte viability.4
Maintenance of chondrocyte viability during storage is crucial to allograft survival and performance.2 Tissues are typically placed in cold storage for 15 to 28 days prior to transplantation,31 while serologic and microbiologic testing are performed to decrease the risk of disease transmission, and processing may take up to 14 days.32 Previous in vitro studies have shown decreased chondrocyte viability, cell density, and metabolic activity after 20- and 28-day storage periods, predominately in the superficial zone, which reduces joint friction via expression of lubricin.9,31 Rohde et al20 assessed chondrocyte viability in miniature swine osteochondral allograft tissue in cold storage and reported a reduction in chondrocyte viability after a 7-day storage period, confirmed by the inability of grafts to retain metabolic competence. Therefore, to maintain chondrocyte viability, transplantation before 7 days was recommended.20
Numerous preclinical studies have investigated the effects of augmenting storage media.33–35 Garrity et al33 showed that chondrocyte viability was maintained by storing grafts at physiologic temperature (37°C), compared with transforming growth factor-β3 and dexamethasone augmentation; however, bacterial or fungal growth may be increased at higher temperatures. Similarly, the improvements in chondrocyte viability and proteoglycan synthesis through modification of storage media with fetal bovine serum must be weighed against the potential for disease transmission.34
Although bisphosphonates are used clinically as antiresorptive agents, nonnitrogenated bisphosphonates have been shown to prevent dexamethasone-induced apoptosis of bovine articular chondrocytes and inhibit nitric oxide production.36,37 Muehleman et al38 also reported a chondroprotective effect of systemically administered risedronate in a miniature swine model of osteochondral defect repair with an engineered graft. Because of differences in antiresorptive mechanisms, non-nitrogenated and nitrogenated bisphosphonates may differentially impact cartilage health.36 Rosa et al39 showed that a non-nitrogenated bisphosphonate (clodronate disodium) had a proanabolic effect on bovine articular chondrocytes, facilitated by stimulation of the purinergic receptor pathway, whereas the mevalonate pathway is associated with chondroprotective effects in nitrogenated bisphosphonates.
The mevalonate pathway is also related to the antiresorptive properties of bone in the setting of nitrogenated bisphosphonates, as enzymatic inhibition of farnesyl pyrophosphate synthase and interference of protein prenylation lead to cytoskeleton abnormalities in osteoclasts, thereby promoting detachment of the osteoclast from the bone surface and decreased bone resorption. Nitrogenated bisphosphonates also decrease osteoclast progenitor growth and recruitment via osteoclast apoptosis and increase osteoblast formation.40 In non-nitrogenated bisphosphonates, however, bony resorption is inhibited as osteoclasts metabolize the bisphosphonates, which ultimately leads to apoptosis. Fleisch41 has also described effective stimulation of bone formation by bisphosphonates.
Fresh osteochondral allografts have historically been categorized as immune-privileged tissue because articular cartilage is avascular and alymphatic. However, Phipatanakul et al42 described an immunologic response to cartilage-specific protein antigens in 57% (8 of 14) of patients after fresh osteochondral allograft transplantation of the knee, compared with 14% (2 of 14) of nonoperative controls. Co-localization of CD4+ and CD8+ T-lymphocytes in failed osteochondral talus allografts, indicative of a graft-versus-host–like reaction, may be suppressed by local delivery of nitrogenated bisphosphonates acting on monocytes to inhibit antigen-presentation function.19,43
The current pilot studies were limited by small sample precluding statistical analysis. However, the authors performed multiple characterization methods for both the in vitro and the in vivo experiments, which showed corresponding data that will add to the current body of literature in this research area. Also, because of the few donors in both the in vitro and the in vivo studies, differences in tissue characteristics could not be analyzed. The single, 6-week endpoint used in the in vivo study represented an early time point in osteochondral graft healing; however, this endpoint follows several other swine osteochondral defect model studies,21–23 which use an earlier time point to assess the effects of bisphosphonates on early bony incorporation vs later cartilaginous incorporation.
The effect of storage media supplementation with bisphosphonates was investigated. The hypothesis was that the addition of bisphosphonates to storage media would lead to improved maintenance of chondrocyte viability and graft structure during cold storage, while also promoting graft incorporation via both anti-osteoclast and pro-osteoblast activities. In vitro studies with fresh human osteochondral tissue showed a positive effect of nitrogenated bisphosphonates on maintenance of structural characteristics via OARSI–modified Mankin scoring. In vitro, risedronate-treated grafts showed the lowest (most normal) OARSI–modified Mankin scores at the 43-day time point, although time point was not the primary variable and grafts were compared based on bisphosphonate type and concentration. An in vivo pilot study of fresh osteochondral allograft transplantation 13 days after storage in a miniature swine model showed decreased fibrous tissue formation and increased mineralization of the graft–host interface in allografts stored in risedronate-augmented solution, compared with etidronate-treated and control grafts, at “high” (0.1 M) concentration and a 6-week endpoint. Clinically, allograft incorporation may be improved with the addition of risedronate-based bisphosphonates to storage solutions, although further work is warranted to determine optimal concentrations and storage times.
The effect of bisphosphonate-supplemented storage media on the viability of osteochondral allograft tissue was investigated. In vitro studies with fresh human osteochondral tissue showed a positive effect of nitrogenated bisphosphonates on maintenance of structural characteristics via OARSI–modified Mankin scoring. Most notably, sulfated glycosaminoglycan staining was maintained throughout the cartilaginous tissue with nitrogenated bisphosphonate storage media supplementation. A small in vivo pilot study in a miniature swine model showed a reduction of fibrous tissue as well as increased mineralization at the graft–host interface in allografts stored in risedronate-augmented solution.
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Ratios of µCT Parameters for Bone Core and Interface Tissue
|Sample||Sample Description||Bone Core||Interface Tissue||Bone Core and Interface Tissue: Bone Volume Fraction|
|Total Volume, mm3||Calcified Tissue Volume, mm3||Volume Fraction||Bone Mineral Density, HU||Calcified Tissue Mineral Density, HU||Total Volume, mm3||Average Thickness, µm||Tissue Mineral Density, HU|