Local drug delivery to the bone by drug-releasing implants: perspectives of nano-engineered titania nanotube arrays

Titania nanotube (TNT) arrays fabricated by electrochemical anodization of titanium are currently one of the most attractive nanomaterials due to their remarkable properties. In this review, we highlight recent research activities that are focused on the application of the TNT arrays for local drug delivery, specifically for addressing problems associated with orthopedic implants. The advantages of drug-releasing implants based on TNT arrays for local delivery of therapeutics in bone related to these challenging problems including inflammation, infection and osseointegration are discussed. An overview of recent research to advance the drug-releasing performance of TNT arrays and the potential of their future applications and development are presented.     

Toward soft-tissue elastography using digital holography to monitor surface acoustic waves

Measuring the elasticity distribution inside the human body is of great interest because elastic abnormalities can serve as indicators of several diseases. We present a method for mapping elasticity inside soft tissues by imaging surface acoustic waves (SAWs) with digital holographic interferometry. With this method, we show that SAWs are consistent with Rayleigh waves, with velocities proportional to the square root of the elastic modulus greater than 2-40 kPa in homogeneous tissue phantoms. In two-layer phantoms, the SAW velocity transitions approximately from that of the lower layer to that of the upper layer as frequency is increased in agreement with the theoretical relationship between SAW dispersion and the depth-dependent stiffness profile. We also observed deformation in the propagation direction of SAWs above a stiff inclusion placed 8 mm below the surface. These findings demonstrate the potential for quantitative digital holography-based elastography of soft tissues as a noninvasive method for disease detection.     

Substrate spectrum extension of PenA in Burkholderia thailandensis with a single amino acid deletion, Glu168del

We describe a deletion mutation in a class A β-lactamase, PenA, of Burkholderia thailandensis that extended the substrate spectrum of the enzyme to include ceftazidime. Glu168del was located in a functional domain called the omega loop causing expansion of the space in the loop, which in turn increased flexibility at the active site. This deletion mutation represents a rare but significant alternative mechanical path to substrate spectrum extension in PenA besides more common substitution mutations.     

A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias

BACKGROUND:

ARRY‐520 selectively inhibits the mitotic kinesin spindle protein (KSP), which leads to abnormal monopolar spindle formation and apoptosis.

METHODS:

A phase 1 trial was conducted to establish the safety and the maximum tolerated dose (MTD) of ARRY‐520 given as a 1‐hour infusion in either a single dose or on a day 1, 3, and 5 divided‐dose schedule per cycle in patients with advanced or refractory myeloid leukemias. Additional objectives were to characterize pharmacokinetics, assess preliminary clinical activity, and explore biomarkers of KSP inhibition with ARRY‐520. A total of 36 patients with acute myelogenous leukemia (n = 34) or myelodysplastic syndromes (n = 2) with a median age of 66 years (range, 21‐88 years) were enrolled: 15 in the single‐dose schedule (dose levels: 2.5, 3.75, 4.5, and 5.6 mg/m²) and 21 in the divided‐dose schedule (dose levels: 0.8, 1.2, 1.5, and 1.8 mg/m²/day).

RESULTS:

The MTD was 4.5 mg/m² total dose per cycle for both dose schedules. Dose‐limiting toxicities included mucositis, exfoliative rash, hand‐foot syndrome, and hyperbilirubinemia. Grades 3 or 4 reversible drug‐related myelosuppression were observed in 33 of 36 patients. Plasma pharmacokinetic analyses revealed low clearance of ARRY‐520 (～3 L/hour), a volume of distribution of ～450 L, and a median terminal half‐life of >90 hours. Monopolar spindles were observed in blood mononuclear cells, through use of 4′,6‐diamidino‐2‐phenylindole nucleic acid stain and antitubulin antibodies.

CONCLUSIONS:

On the basis of the relative lack of clinical activity, further development of ARRY‐520 as an antileukemic agent was halted. (Clinicaltrials.gov identifier NCT00637052). Cancer 2012;3556–3564. © 2011 American Cancer Society.     

A temporal pattern in the occurrence of aneurysmal subarachnoid hemorrhage in the Province of Vojvodina, Serbia

Background  

Numerous studies with conflicting results have tried to prove the influence of seasonal variations or different meteorological factors on the occurrence of aneurysmal subarachnoidal hemorrhage (SAH). The aim of this study was to establish a mathematical model of a series of aneurysmal rupture dates in different patients and verify a temporal pattern in the occurrence of SAH.     

Effects of cobalt and chromium ions at clinically equivalent concentrations after metal-on-metal hip replacement on human osteoblasts and osteoclasts: implications for skeletal health

Metal-on-metal hip replacement (MOMHR) using large diameter bearings has become a popular alternative to conventional total hip arthroplasty, but is associated with elevated local tissue and circulating levels of chromium (Cr) and cobalt (Co) ions that may affect bone health. We examined the effects of acute and chronic exposure to these metals on human osteoblast and osteoclast formation and function over a clinically relevant concentration range previously reported in serum and within hip synovial fluid in patients after MOMHR. SaOS-2 cells were cultured with Co²⁺, Cr³⁺ and Cr⁶⁺ for 3 days after which an MTS assay was used to assess cell viability, for 13 days after which alkaline phosphatase and cell viability were assessed and for 21 days after which nodule formation was assessed. Monocytes were isolated from human peripheral blood and settled onto dentine disks then cultured with M-CSF and RANKL plus either Co²⁺, Cr³⁺ or Cr⁶⁺ ions for 21 days from day 0 or between days 14 and 21. Cells were fixed and stained for TRAP and osteoclast number and amount of resorption per dentine disk determined. Co²⁺ and Cr³⁺ did not affect osteoblast survival or function over the clinically equivalent concentration range, whilst Cr⁶⁺ reduced osteoblast survival and function at concentrations within the clinically equivalent serum range after MOMHR (IC₅₀ = 2.2 μM). In contrast, osteoclasts were more sensitive to metal ions exposure. At serum levels a mild stimulatory effect on resorption in forming osteoclasts was found for Co²⁺ and Cr³⁺, whilst at higher serum and synovial equivalent concentrations, and with Cr⁶⁺, a reduction in cell number and resorption was observed. Co²⁺ and Cr⁶⁺ within the clinical range reduced cell number and resorption in mature osteoclasts. Our data suggest that metal ions at equivalent concentrations to those found in MOMHR affect bone cell health and may contribute to the observed bone-related complications of these prostheses.     

MRI manifestations of soft-tissue haemangiomas and accompanying reactive bone changes

Objectives

Soft tissue haemangiomas are common benign vascular lesions that can be accompanied by reactive changes in the adjacent bone structure. This study aimed to discuss the MRI features of soft-tissue haemangiomas with an emphasis on changes in bone.

Methods

The radiographic and MRI findings of 23 patients (9 males, 14 females; mean age 25 years; age range 2–46 years) with soft-tissue haemangiomas were analysed retrospectively. MR images were evaluated for location of the lesion, size, configuration, signal features, contrast patterns, proximity to adjacent bone and changes in the accompanying bone. Excisional biopsy was performed in 15 patients.

Results

Radiographs demonstrated phleboliths in 8 patients (34%) and reactive bone changes in 4 (19%). On MRI, T₁ weighted images showed that most of the lesions were isointense or isohyperintense, as compared with muscle tissue; however, on T₂ weighted images all lesions appeared as hyperintense. Following intravenous gadolinium-diethylene triamine pentaacetic acid (DTPA) administration, homogeneous enhancement was observed in 3 lesions and heterogeneous enhancement was seen in 19. No enhancement was observed in one patient. Bone atrophy adjacent to the lesion was observed in four patients.

Conclusion

MRI is the most valuable means of diagnosing deep soft-tissue haemangiomas. Bone changes can accompany deeply situated haemangiomas; in four of our patients, we found atrophy of the bone adjacent to the lesion. To our knowledge, this is the first report in the literature regarding atrophy of the bone adjacent to a lesion.Soft-tissue haemangioma, a frequently encountered benign vascular lesion, accounts for 7% of all benign soft-tissue tumours [1-5]. Such lesions can be cutaneous, subcutaneous, intramuscular or synovial [1]. Intramuscular haemangioma is rare and responsible for 0.8–1.8% of all haemangiomas [3,5,6]. Superficial haemangiomas are diagnosed easily because they cause discolorations of the skin; imaging techniques are rarely needed [1]. However, deep lesions are difficult to diagnose clinically, because they do not cause discolorations and grow slowly; imaging techniques are required to discriminate these deep haemangiomas from malignant lesions [1,2,7]. Bone changes accompanying haemangioma have been reported previously in the literature and include cortical thickening, erosion, medullary sclerosis, trabecular coarsening and hypertrophy [1,8]. Here, we present the MRI manifestations of soft-tissue haemangiomas and reactive changes to the neighbouring bones. To the best of our knowledge, this is the first report of its kind in the English literature.