Zirconia Phase Transformation in Zirconia-Toughened Alumina Ceramic Femoral Heads: An Implant Retrieval Analysis.

BACKGROUND: Zirconia-toughened alumina ceramic was introduced as a femoral head material for total hip arthroplasty. The material combines the stability of alumina with the toughness of zirconia. Despite inherent benefits for bearing surfaces, concern exists in the medical field that phase transformation of the zirconia grains could worsen wear resistance and lower the strength of the head. We examined these concerns in retrieved and artificially aged ceramic heads. METHODS: Twenty-eight ceramic composite heads retrieved at revision surgery were combined with 5 pristine heads (as negative controls for phase transformation) and 5 artificially aged pristine heads (as positive controls). The extent of zirconia phase transformation at the bearing surfaces was examined through confocal Raman spectroscopy and X-ray diffraction. Burst testing was conducted on all pristine and aged heads and the 4 retrieved implants with the longest lengths of implantation. RESULTS: Retrieved heads had higher maximum average volume fractions of the monoclinic phase compared to pristine or aged heads. Length of implantation was not correlated to the volume fraction of the monoclinic phase. All the heads achieved a burst load far above the 46 kN Food and Drug Administration acceptance criterion; 3 of the 4 retrieved heads had burst strengths exceeding 100kN. CONCLUSION: Our results showed that phase transformation occurs in vivo in ceramic composite femoral heads, but the amount transformed did not increase with the length of time the head had been implanted. The negligible effect upon burst strength of the retrieved and artificially aged heads is reassuring. These results support continued clinical use of this alumina-zirconia composite material as a head material.

Do Well-functioning THAs Retrieved at Autopsy Exhibit Evidence of Fretting and Corrosion?

BACKGROUND: Our understanding of fretting and corrosion at head-neck junctions in modular THAs in vivo is based largely on the analysis of retrieved implants removed for various diagnoses. Little is known about the condition of head-neck tapers in well-functioning THAs. QUESTIONS/PURPOSES: Regarding a cohort of well-functioning autopsy-retrieved modular THAs, we asked: (1) Does trunnion geometry or femoral head material affect the pull-off force of the femoral head? (2) Is there a relationship between trunnion damage and length of implantation time, head diameter, and neck length? (3) Does visual damage scoring accurately determine the presence or absence of corrosion on cobalt-chrome trunnions? METHODS: Sixty-six femoral stems and engaged femoral heads were retrieved at autopsy from 53 patients at Anderson Orthopaedic Research Institute from 1998 to 2014. Ten stems were excluded for low stem design group size or insufficient head-stem clearance for pull-off testing, leaving a cohort of 56 THAs with a median implantation time of 10 years (range, 1-24 years). The femoral stems included three cobalt-chrome (CoCr) designs from a single manufacturer with either a 12/14 or 14/16 trunnion design (N = 36 and 20, respectively) mated with alumina or CoCr heads (N = 13 and 43, respectively). The force required to pull off the femoral heads was measured using a uniaxial load frame according to ASTM F2009-00. Mating surfaces were visually examined to assess the presence and severity of fretting and corrosion using a modified Goldberg scoring system. Three 12/14 trunnions of similar implantation lengths and varied damage scores were selected for imaging with a scanning electron microscope (SEM) and energy dispersive x-ray analysis (EDAX) to confirm the absence or presence of corrosion damage. RESULTS: No difference was seen in pull-off force between groups based on trunnion geometry and head material (median [range], alumina-12/14: 3127 [2320-6992] N, alumina-14/16: 2670 [1095-7919] N, CoCr-12/14: 2255 [1332-5939] N, CoCr-14/16: 2812 [1655-4246] N; p = 0.132). A positive correlation was found between damage score and length of implantation (ρ = 0.543, p < 0.001). However, no correlation between damage score and either head diameter or neck length was found (ρ = -0.012, p = 0.930 and ρ < 0.001, p = 0.995, respectively). In all, 39 of 56 specimens demonstrated no fretting or corrosion, and 16 specimens had mild damage scores. One specimen demonstrated severe corrosion without visual evidence of fretting. The presence of intergranular corrosion on this trunnion was determined by SEM imaging and EDAX. The absence of corrosion products on two trunnions with no observed damage was confirmed. CONCLUSIONS: This study found little evidence of fretting and corrosion in a cohort of well-functioning CoCr-CoCr and alumina-CoCr head-neck couples. Further studies are necessary to characterize fretting and corrosion at head-neck junctions of well-functioning implants of other designs and manufacturers. CLINICAL RELEVANCE: The results from this study suggest that patients with well-functioning THAs using polyethylene bearing surfaces with alumina or CoCr heads appear to be at low risk for trunnion corrosion for the specific CoCr alloy stems and trunnion geometries analyzed here.

A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis.

Cryptosporidiosis has emerged as a leading cause of non-viral diarrhea in children under five years of age in the developing world, yet the current standard of care to treat Cryptosporidium infections, nitazoxanide, demonstrates limited and immune-dependent efficacy. Given the lack of treatments with universal efficacy, drug discovery efforts against cryptosporidiosis are necessary to find therapeutics more efficacious than the standard of care. To date, cryptosporidiosis drug discovery efforts have been limited to a few targeted mechanisms in the parasite and whole cell phenotypic screens against small, focused collections of compounds. Using a previous screen as a basis, we initiated the largest known drug discovery effort to identify novel anticryptosporidial agents. A high-content imaging assay for inhibitors of Cryptosporidium parvum proliferation within a human intestinal epithelial cell line was miniaturized and automated to enable high-throughput phenotypic screening against a large, diverse library of small molecules. A screen of 78,942 compounds identified 12 anticryptosporidial hits with sub-micromolar activity, including clofazimine, an FDA-approved drug for the treatment of leprosy, which demonstrated potent and selective in vitro activity (EC50 = 15 nM) against C. parvum. Clofazimine also displayed activity against C. hominis-the other most clinically-relevant species of Cryptosporidium. Importantly, clofazimine is known to accumulate within epithelial cells of the small intestine, the primary site of Cryptosporidium infection. In a mouse model of acute cryptosporidiosis, a once daily dosage regimen for three consecutive days or a single high dose resulted in reduction of oocyst shedding below the limit detectable by flow cytometry. Recently, a target product profile (TPP) for an anticryptosporidial compound was proposed by Huston et al. and highlights the need for a short dosing regimen (< 7 days) and formulations for children < 2 years. Clofazimine has a long history of use and has demonstrated a good safety profile for a disease that requires chronic dosing for a period of time ranging 3-36 months. These results, taken with clofazimine's status as an FDA-approved drug with over four decades of use for the treatment of leprosy, support the continued investigation of clofazimine both as a new chemical tool for understanding cryptosporidium biology and a potential new treatment of cryptosporidiosis.

Rational design of a Kv1.3 channel-blocking antibody as a selective immunosuppressant.

A variable region fusion strategy was used to generate an immunosuppressive antibody based on a novel "stalk-knob" structural motif in the ultralong complementary-determining region (CDR) of a bovine antibody. The potent Kv1.3 channel inhibitory peptides Moka1-toxin and Vm24-toxin were grafted into different CDRs of the humanized antibodies BVK and Synagis (Syn) using both ß-sheet and coiled-coil linkers. Structure-activity relationship efforts led to generation of the fusion protein Syn-Vm24-CDR3L, which demonstrated excellent selectivity and potency against effector human memory T cells (subnanomolar to picomolar EC50 values). This fusion antibody also had significantly improved plasma half-life and serum stability in rodents compared with the parent Vm24 peptide. Finally, this fusion protein showed potent in vivo efficacy in the delayed type hypersensitivity in rats. These results illustrate the utility of antibody CDR fusions as a general and effective strategy to generate long-acting functional antibodies, and may lead to a selective immunosuppressive antibody for the treatment of autoimmune diseases.

Hip dislocation increases roughness of oxidized zirconium femoral heads in total hip arthroplasty: an analysis of 59 retrievals.

The aims of this study were to assess damage on the surface of retrieved oxidized zirconium (OxZr) metal femoral heads, to measure surface roughness of scratches, and to evaluate the extent of surface effacement using scanning electron microscopy (SEM). Ceramic zirconia-toughened alumina heads were analyzed for comparison. OxZr femoral heads explanted for recurrent dislocation had the most severe damage (P<0.001). The median surface roughness of damaged OxZr femoral heads was 1.49µm, compared to 0.084µm for damaged ceramic heads and 0.052µm for undamaged OxZr (P<0.001). This may be of clinical concern because increased surface roughness has the potential to increase the wear of polyethylene liners articulating against these OxZr heads in THA.

Zirconia phase transformation, metal transfer, and surface roughness in retrieved ceramic composite femoral heads in total hip arthroplasty.

Ceramic femoral heads have had promising results as a bearing surface in total hip arthroplasty. Our objective was to evaluate a series of retrieved alumina-zirconia composite ceramic femoral heads for evidence of the tetragonal to monoclinic zirconia phase transformation, metal transfer and articular surface roughness. Raman spectra showed evidence of the zirconia phase transformation in all retrieved specimens, with distinct monoclinic peaks at 183, 335, 383, and 479 cm(-1). All components displayed metal transfer. An increase in the zirconia phase transformation was seen with increasing time in vivo. No correlation between extent of zirconia phase transformation and the surface roughness was found. These short-term results suggest that the use of an alumina-zirconia composite ceramic is a viable option for femoral heads in THA.

Mechanical performance of ceramic acetabular liners under impact conditions.

Although new generation alumina ceramics have exhibited a reduced incidence of fracture, concern still persists about the behavior of ceramic acetabular liners under impact conditions. The objective of this study was to explore whether fracture of a new generation alumina ceramic liner was likely to occur in vivo. Ceramic liners were impacted with forces of 23, 21, 15, and 12 kN (n = 3 at each force). At 23 kN, all 3 ceramic liners fractured on the first impact; at 12 kN none of the ceramic liners fractured after 20 impacts. The threshold force of 12 kN is large in comparison with estimated physiologic forces on the hip during falls or stumbling, suggesting that ceramic liner fracture is not a definite consequence of liner impact.