Harry K.W. Kim

Ibandronate for prevention of femoral head deformity after ischemic necrosis of the capital femoral epiphysis in immature pigs.

BACKGROUND Femoral head deformity is the most serious sequela of ischemic necrosis of the immature femoral head. The purpose of this study was to determine if a highly potent antiresorptive agent, ibandronate, can inhibit bone resorption during the repair of the infarcted femoral head and thus alter the repair process. We hypothesized that preservation of the trabecular framework by inhibiting osteoclastic bone resorption would minimize the development of deformity in a piglet model of ischemic necrosis. The effect of ibandronate on long-bone growth was also assessed. METHODS Ischemic necrosis of the right femoral head was produced in twenty-four piglets by placing a ligature tightly around the femoral neck. The animals were divided into three groups according to whether they received saline solution, prophylactic treatment, or post-ischemia treatment. The contralateral, untreated femoral heads from the animals that had received saline solution served as the normal control group. At eight weeks, the femoral heads were assessed for deformity with radiography and for trabecular bone indices with histomorphometry. Also, the length of femur from the untreated side was measured on the radiographs and compared among the groups. RESULTS Radiographic assessment showed that the epiphyseal quotient, determined by dividing the maximum height of the osseous epiphysis by the maximum diameter, was better preserved in the prophylactic (p < 0.001) and post-ischemia (p = 0.02) treatment groups than in the group treated with saline solution. Histomorphometric assessment also showed that the trabecular bone indices were better preserved in the prophylactic and the post-ischemia treatment groups than in the group treated with saline solution (p < 0.01). The mean femoral length on the untreated side of the animals treated with ibandronate was reduced compared with the length on the untreated side of the animals that had received saline solution (p </= 0.01). CONCLUSIONS Ibandronate preserves the trabecular structure of the osseous epiphysis and prevents femoral head deformity during the early phase of repair of ischemic necrosis in the piglet model.

Biological resurfacing of full-thickness defects in patellar articular cartilage of the rabbit. Investigation of autogenous periosteal grafts subjected to continuous passive motion

We compared the effects of continuous passive motion with those of intermittent active motion on the results of the resurfacing with autogenous periosteal grafts of full-thickness defects on the articular surface of rabbit patellae. Of 45 rabbits with defects, 30 received grafts. Fifteen of these had continuous passive motion for two weeks and intermittent active motion for four weeks; the other 15 had intermittent active motion for six weeks. In 15 the defects were not grafted (control group) and they had intermittent active motion for six weeks. Ten more rabbits had a sham operation. Six weeks after surgery, the results were assessed by the gross appearance, histology, histochemistry, immunohistochemistry and electron microscopy. By all assessments the quality of neochondrogenesis produced by periosteal grafts was superior to that in ungrafted defects (p less than 0.05) and the results in continuous passive motion treated animals were superior to those in intermittent active motion treated animals (p less than 0.05). The periosteal grafts produced hyaline cartilage containing type II collagen but the organisation of its fibres was irregular.

Development of flattening and apparent fragmentation following ischemic necrosis of the capital femoral epiphysis in a piglet model

Background: The repair response that follows ischemic necrosis of the immature femoral head and the biological processes that are responsible for the development of femoral head deformity and fragmentation have not been clearly defined. A piglet model was used to study the radiographic and histopathologic changes that occur prior to and during the development of femoral head deformity and fragmentation following ischemic necrosis.Methods: Twenty-five male piglets were studied. A nonabsorbable ligature was placed tightly around the femoral neck to disrupt the blood supply to the capital femoral epiphysis. The animals were killed three days to eight weeks following the induction of ischemia. Radiographs of whole and sectioned femoral heads were made, and the radiographic findings were correlated with the histopathologic changes observed in the specimens.Results: Mild femoral head flattening was observed by four weeks after the induction of ischemia, and severe flattening and fragmentation were observed by eight weeks. The predominant repair response observed following revascularization was osteoclastic bone resorption. Prior to the development of flattening, a large area of osteoclastic bone resorption was observed in the central region of the femoral head. Many osteoclasts were present along the revascularization front, which we believe were responsible for active resorption of the necrotic trabecular bone. Appositional new-bone formation, the hallmark of the repair response in adult ischemic necrosis, was not observed in the area of bone resorption. Instead, the areas of resorbed bone were replaced with a fibrovascular tissue that persisted for up to eight weeks. Appositional new-bone formation was observed, but it was limited to small areas in which revascularization was not followed by osteoclastic bone resorption and in which necrotic trabecular bone was still present. The simultaneous presence of the areas of bone resorption and new-bone formation contributed to the fragmented radiographic appearance of the femoral head.Conclusions: The predominant repair response observed in the piglet model of ischemic necrosis was osteoclastic bone resorption. The early bone loss, the lack of new-bone formation, and the persistence of fibrovascular tissue in the areas of bone resorption compromised the structural integrity of the femoral head and produced progressive femoral head flattening over time. The repair response was different from that observed in femoral heads removed from adult patients with ischemic necrosis and from that observed in the adult rabbit model of ischemic necrosis.Clinical Relevance: The piglet model of ischemic necrosis may be useful for the investigation of the biological processes that lead to the development of femoral head deformity following ischemic necrosis of the immature femoral head.

Citric acid-derived in situ crosslinkable biodegradable polymers for cell delivery

Herein, we report a first citric acid (CA)-derived in situ crosslinkable biodegradable polymer, poly(ethylene glycol) maleate citrate (PEGMC). The synthesis of PEGMC could be carried out via a one-pot polycondensation reaction without using organic solvents or catalysts. PEGMC could be in situ crosslinked into elastomeric PPEGMC hydrogels. The performance of hydrogels in terms of swelling, degradation, and mechanical properties were highly dependent on the molar ratio of monomers, crosslinker concentration, and crosslinking mechanism used in the synthesis process. Cyclic conditioning tests showed that PPEGMC hydrogels could be compressed up to 75% strain without permanent deformation and with negligible hysteresis. Water-soluble PEGMC demonstrated excellent cytocompatibilty in vitro. The degradation products of PPEGMC also showed minimal cytotoxicity in vitro. Animal studies in rats clearly demonstrated the excellent injectability of PEGMC and degradability of the in situ-formed PPEGMC. PPEGMC elicited minimal inflammation in the early stages post-injection and was completely degraded within 30 days in rats. In conclusion, the development of CA-derived injectable biodegradable PEGMC presents numerous opportunities for material innovation and offers excellent candidate materials for in situ tissue engineering and drug delivery applications.

Histopathologic changes in growth-plate cartilage following ischemic necrosis of the capital femoral epiphysis. An experimental investigation in immature pigs.

Background: The developing capital femoral epiphysis consists of a secondary center of ossification surrounded by epiphyseal cartilage. Between the epiphyseal cartilage and the secondary center of ossification is a growth plate, which contributes to the circumferential increase in size of the secondary center of ossification during development. The main objective of this study was to describe the histopathologic changes that occur in the growth plate surrounding the secondary center of ossification during the early and reparative phases following the induction of ischemic necrosis of the capital femoral epiphysis in immature pigs. Methods: Ischemic necrosis of the capital femoral epiphysis was induced in eighteen piglets by placing a nonabsorbable suture ligature around the femoral neck following a capsulotomy and transection of the ligamentum teres. The animals were killed three days to eight weeks following the induction of ischemia, and visual, radiographic, and histologic assessments were performed. Results: Two to four weeks after the induction of ischemic necrosis, the growth plate surrounding the secondary center of ossification became necrotic. The observed histopathologic changes included chondrocyte death, loss of safranin-O staining of the matrix of the necrotic growth-plate cartilage, an absence of vascular invasion of terminal hypertrophic chondrocytes, and a decrease in the amount of primary spongiosa, indicating cessation of endochondral ossification. In the reparative phase, at four to eight weeks postoperatively, chondrocyte clusters and intense safranin-O staining were observed in the epiphyseal cartilage around the necrotic growth-plate cartilage. In the peripheral region of the femoral head, necrotic growth-plate cartilage surrounding the secondary center of ossification was resorbed by a fibrovascular tissue from the marrow space. By six weeks, new accessory centers of ossification with restored endochondral ossification were observed in the peripheral epiphyseal cartilage. New ossification centers contributed to the fragmented radiographic appearance of the secondary center of ossification. The physis appeared essentially normal in most animals, although five of the eighteen piglets showed mild or moderate histopathologic changes. Conclusions: In this model, ischemic necrosis of the capital femoral epiphysis resulted in necrosis of the growth plate surrounding the secondary center of ossification. Small new ectopic centers of ossification appeared in the epiphyseal cartilage, explaining in part the fragmented radiographic appearance of the secondary center of ossification. Clinical Relevance: This immature swine model may facilitate systematic study of the sequence of cellular and structural events that follow ischemic injury to the capital femoral epiphysis. Better understanding of the injury and repair processes that follow ischemia may lead to novel treatment strategies to stimulate the repair of the infarcted capital femoral epiphysis and to restore normal growth of the secondary center of ossification.

Pathophysiology and new strategies for the treatment of Legg-Calvé-Perthes disease.

Legg-Calvé-Perthes disease is a juvenile form of idiopathic osteonecrosis of the femoral head that can lead to permanent femoral head deformity and premature osteoarthritis. According to two recent multicenter, prospective cohort studies, current nonoperative and operative treatments have modest success rates of producing a good outcome with a spherical femoral head in older children with Legg-Calvé-Perthes disease. Experimental studies have revealed that the immature femoral head is mechanically weakened following ischemic necrosis. Increased bone resorption and delayed new bone formation, in combination with continued mechanical loading of the hip, contribute to the pathogenesis of the femoral head deformity. Biological treatment strategies to improve the healing process by decreasing bone resorption and stimulating bone formation appear promising in nonhuman preclinical studies.

A shortened course of parenteral antibiotic therapy in the management of acute septic arthritis of the hip.

We reviewed 20 consecutive patients with a culture-proven acute septic arthritis of the hip who were treated with a shortened course of parenteral antibiotic therapy after a surgical drainage. Patients were switched over to an oral antibiotic when they showed clinical improvement. Sixteen of the 20 patients had parenteral antibiotic therapy of <10 days, whereas nine of these patients received <7 days of parenteral therapy (mean, 8.2 days). No recurrence of infection, readmission, or osteomyelitis was observed after the discharge. At the follow-up interview (mean, 32 months), 18 patients were completely asymptomatic, and two patients had occasional hip pain with activity but no physical limitations. All 20 patients had normal hip range of motion and gait. Their latest radiographs (mean, 26 months) revealed 11 patients with normal findings, six patients with mild coxa magna, and three patients with a smaller ossific nucleus compared with the unaffected side. We conclude that a community-acquired, acute gram-positive septic arthritis of the hip can be managed safely with a surgical drainage and a shortened course of parenteral antibiotic therapy, which can be switched over to an oral therapy based on the patients response to the therapy.

RANKL inhibition: a novel strategy to decrease femoral head deformity after ischemic osteonecrosis.

A novel therapeutic strategy to decrease the development of femoral head deformity after ischemic osteonecrosis was studied in a large animal model of total head infarction. RANKL inhibition through exogenous osteoprotegerin administration significantly decreased pathologic bone resorption and deformity during repair of the infarcted head.

Indentation properties of growing femoral head following ischemic necrosis

Little is known about the mechanical properties of the growing femoral head as it develops deformity following ischemic injury. The purpose of this study was to determine the indentation stiffness of growing femoral head following ischemic injury and to correlate the changes in stiffness with radiographic and histopathologic changes in the femoral head as it develops deformity. Following the induction of ischemia in 24 piglets, indentation testing of whole femoral heads was performed at 2, 4, and 8 weeks, as well as on femoral heads from eight sham operated animals. At 2 weeks, a 52% reduction of indentation stiffness was observed in the infarcted femoral heads compared to the control heads (p = 0.004). The bony epiphyses in infarcted femoral heads were smaller due to growth arrest but they were not deformed. Histologically, no evidence of repair was seen. At 4 and 8 weeks, the indentation stiffness in the infarcted femoral heads was reduced by 75% (p < 0.000001) and 72% (p = 0.001) respectively compared to the control heads. Variable degree of femoral head deformity and repair was observed at 4 weeks. Severe deformity with extensive revascularization and repair were observed at 8 weeks. Although epiphyseal cartilage was thickened on the infarcted femoral heads only a weak correlation was found between the increase in the cartilage thickness and the decrease in the indentation stiffness (R2 = 0.55). These results indicate that the indentation properties of growing femoral head were significantly affected by ischemic injury, prior to the presence of repair process and deformity. A further decrease in the indentation stiffness was concomitant with repair of the infarcted head. These findings suggest that a reduction in the mechanical properties of the infarcted femoral head include both a cartilage and a bony component, which cannot be differentiated at this point. The study validates early institution of treatments that are aimed at limiting the mechanical loading of the affected hip. The study also suggests that in order to minimize the mechanical compromise of the infarcted femoral head, early institution of treatments aimed at stimulating new bone formation and retarding osteoclastic bone resorption may be beneficial.

Legg-Calvé-Perthes disease.

Legg-Calvé-Perthes disease is an idiopathic hip disorder that produces ischemic necrosis of the growing femoral head. Permanent femoral head deformity is the most significant sequela. Experimental studies indicate that the pathologic repair process, which is marked by an imbalance of bone resorption and formation, contributes to the pathogenesis of femoral head deformity. Important prognostic factors include degree of deformity, age at disease onset, extent of head involvement, head-at-risk signs, and lateral pillar collapse. Treatment should be guided by age at disease onset, current best evidence, and prognostic factors. Patients aged <6 years at onset are best managed nonsurgically, whereas older patients may benefit from surgical treatment. Good surgical results have been reported in 40% to 60% of older patients (>8 years), indicating the need to develop more effective treatments based on the pathobiology of the disease.