Highly responsive and rapid hydrogen peroxide-triggered degradation of polycaprolactone nanoparticles.

We synthesized an oxidation-responsive polycaprolactone (O-PCL) bearing pendant arylboronic esters as H2O2-responsive motifs. H2O2 induces fast depolymerization of O-PCL within days. Nanoparticles formulated from O-PCL disintegrate and release payload in response to concentrations of H2O2 (50 µM) that are relevant to human disease.

Distinct ON/OFF fluorescence signals from dual-responsive activatable nanoprobes allows detection of inflammation with improved contrast.

Visualization of biochemical changes associated with disease is of great clinical significance, as it should allow earlier, more accurate diagnosis than structural imaging, facilitating timely clinical intervention. Herein, we report combining stimuli-responsive polymers and near-infrared fluorescent dyes (emission max: 790 nm) to create robust activatable fluorescent nanoprobes capable of simultaneously detecting acidosis and oxidative stress associated with inflammatory microenvironments. The spectrally-resolved mechanism of fluorescence activation allows removal of unwanted background signal (up to 20-fold reduction) and isolation of a pure activated signal, which enables sensitive and unambiguous localization of inflamed areas; target-to-background ratios reach 22 as early as 3 h post-injection. This new detection platform could have significant clinical impact in early detection of pathologies, individual tailoring of drug therapy, and image-guided tumor resection.

Light-responsive nanoparticle depot to control release of a small molecule angiogenesis inhibitor in the posterior segment of the eye.

Therapies for macular degeneration and diabetic retinopathy require intravitreal injections every 4-8 weeks. Injections are uncomfortable, time-consuming, and carry risks of infection and retinal damage. However, drug delivery via noninvasive methods to the posterior segment of the eye has been a major challenge due to the eye's unique anatomy and physiology. Here we present a novel nanoparticle depot platform for on-demand drug delivery using a far ultraviolet (UV) light-degradable polymer, which allows noninvasively triggered drug release using brief, low-power light exposure. Nanoparticles stably retain encapsulated molecules in the vitreous, and can release cargo in response to UV exposure up to 30 weeks post-injection. Light-triggered release of nintedanib (BIBF 1120), a small molecule angiogenesis inhibitor, 10 weeks post-injection suppresses choroidal neovascularization (CNV) in rats. Light-sensitive nanoparticles are biocompatible and cause no adverse effects on the eye as assessed by electroretinograms (ERG), corneal and retinal tomography, and histology.

Minimum ten-year follow-up of cemented total hip replacement in patients with osteonecrosis of the femoral head.

Between November 1970 and September 1984 the senior author performed fifty-three consecutive total hip arthroplasties with cement in forty-one patients with the diagnosis of osteonecrosis of the femoral head. Five hips in three patients with failed renal transplants requiring chronic hemodialysis were excluded. At the time of final review, a minimum of ten years after the procedure, twenty-one patients (twenty-eight hips) were living, fifteen patients (eighteen hips) had died, and two patients (two hips) were lost to follow-up. A minimum ten-year follow-up radiograph was obtained on twenty-two (79%) of the hips in surviving patients. During the follow-up period 17.4% of hips (eight hips) required revision: 13.0% (six hips) for aseptic loosening, 2.2% (one hip) for sepsis, and 2.2% (one hip) for recurrent dislocation. All eight revisions occurred in patients living at time of final review, giving a revision prevalence of 22.9% (17.1% for aseptic loosening, 2.9% for sepsis, and 2.9% for recurrent dislocation) in patients surviving ten years. The prevalence of revision of the femoral component for aseptic loosening was 6.5% (three hips) for all hips and 9.1% (three hips) in patients surviving at least ten years. The prevalence of femoral aseptic loosening, defined as those components revised for aseptic loosening and those that demonstrated definite or probable radiographic loosening, was 13.0% (six hips) for all hips and 28.6% (six hips) for hips with at least ten-year radiographic follow-up. The prevalence of revision of the acetabular component for aseptic loosening was 13.0% (six hips) for all hips and 18.2% (six hips) in patients surviving at least ten years. The prevalence of acetabular aseptic loosening was 15.2% (seven hips) for all hips and 29.2% (seven hips) for hips with at least ten-year radiographic follow-up. In patients with osteonecrosis of the femoral head survivorship was significantly inferior to that in the senior author's overall patient population with regard to revision for aseptic loosening (p=0.019), revision for acetabular loosening (p=0.01), revision for femoral loosening (p=0.008), and aseptic femoral loosening (p=0.004). Survivorship to aseptic acetabular loosening was not significantly different (p=0.32). Young age at the time of surgery significantly increased the risk of subsequent component loosening (p<0.008) and revision due to aseptic loosening (p<0.002). These findings demonstrate the relatively poor durability of cemented total hip arthroplasty in patients with osteonecrosis of the femoral head as compared to patients with other diagnoses and suggest that the younger age in this patient population compromises results.