Biomaterial-engineered intra-articular drug delivery systems for osteoarthritis therapy

Osteoarthritis (OA) is a progressive and degenerative disease, which is no longer confined to the elderly. So far, current treatments are limited to symptom relief, and no valid OA disease-modifying drugs are available. Additionally, OA relative joint is challenging for drug delivery, since the drugs experience rapid clearance in joint, showing a poor bioavailability. Existing therapeutic drugs, like non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, are not conducive for long-term use due to adverse effects. Though supplementations, including chondroitin sulfate and glucosamine, have shown beneficial effects on joint tissues in OA, their therapeutic use is still debatable. New emerging agents, like Kartogenin (KGN) and Interleukin-1 receptor antagonist (IL-1 ra), without a proper formulation, still will not work. Therefore, it is urgent to establish a suitable and efficient drug delivery system for OA therapy. In this review, we pay attention to various types of drug delivery systems and potential therapeutic drugs that may escalate OA treatments.</p

OCTN2-targeted nanoparticles for oral delivery of paclitaxel: differential impact of the polyethylene glycol linker size on drug delivery <i>in vitro</i>, <i>in situ</i>, and <i>in vivo</i>

Targeted nanocarriers have shown great promise in drug delivery because of optimized drug behavior and improved therapeutic efficacy. How to improve the targeting efficiency of nanocarriers for the maximum possible drug delivery is a critical issue. Here we developed L-carnitine-conjugated nanoparticles targeting the carnitine transporter OCTN2 on enterocytes for improved oral absorption. As a variable, we introduced various lengths of the polyethylene glycol linker (0, 500, 1000, and 2000) between the nanoparticle surface and the ligand (CNP, C5NP, C10NP and C20NP) to improve the ligand flexibility, and consequently for more efficient interaction with the transporter, to enhance the oral delivery of the cargo load into cells. An increased absorption was observed in cellular uptake in vitro and in intestinal perfusion assay in situ when the polyethylene glycol was introduced to link L-carnitine to the nanoparticles; the highest absorption was achieved with C10NP. In contrast, the linker decreased the absorption efficiency in vivo. As the presence or absence of the mucus layer was the primary difference between in vitro/in situ versus in vivo, the presence of this layer was the likely reason for this differential effect. In summary, the size of the polyethylene glycol linker improved the absorption in vitro and in situ, but interfered with the absorption in vivo. Even though this strategy of increasing the ligand flexibility with the variable size of the polyethylene glycol failed to increase oral absorption in vivo, this approach is likely to be useful for enhanced cellular uptake following intravenous administration of the nanocarriers.</p

The comparison of bleeding rate before and after insonation (g/s, –x±s).

<p>Data are the means±standard deviations. MEUS means microbubble-enhanced (therapeutic) ultrasound; TUS means therapeutic ultrasound only without microbubbles; MB means no pulses were transmitted by the transducer only injected microbubbles.</p><p>*P<0.05 indicates a significant difference between the MEUS groups before and after insonation; and ⁺P<0.05 indicates a significant difference between the MEUS group and the controls.</p

Comparison of acoustic density analysis before and after insonation(–x±s).

<p>Data are the means±standard deviations. MEUS means microbubble-enhanced (therapeutic) ultrasound; TUS means therapeutic ultrasound only without microbubbles; MB means no pulses were transmitted by the transducer only injected microbubbles.</p><p>*P<0.05 indicates a significant difference between before and after insonation of the MEUS group. ⁺P<0.05 indicates a significant difference between the MEUS group and the controls.</p

Hemostatic Effects of Microbubble-Enhanced Low-Intensity Ultrasound in a Liver Avulsion Injury Model

<div><p>Objectives</p><p>Microbubble-enhanced therapeutic ultrasound (MEUS) can block the blood flow in the organs. The aim of this study was to evaluate the hemostatic effect of microbubble-enhanced pulsed, low-intensity ultrasound in a New Zealand White rabbit model of avulsion trauma of the liver. The therapeutic ultrasound (TUS) transducer was operated with the frequency of 1.2 MHz and an acoustic pressure of 3.4 MPa. Microbubble-(MB) enhanced ultrasound (MEUS) (n = 6) was delivered to the distal part of the liver where the avulsion was created. Livers were treated by TUS only (n = 4) or MB only (n = 4) which served as controls. Bleeding rates were measured and contrast enhanced ultrasound (CEUS) was performed to assess the hemostatic effect, and liver hemoperfusion before and after treatment. Generally, bleeding rates decreased more than 10-fold after the treatment with MEUS compared with those of the control group (P<0.05). CEUS showed significant declines in perfusion. The peak intensity value and the area under the curve also decreased after insonation compared with those of the control group (P<0.05). Histological examination showed cloudy and swollen hepatocytes, dilated hepatic sinusoids, perisinusoidal spaces with erythrocyte accumulation in small blood vessels, obvious hemorrhage around portal areas and scattered necrosis in liver tissues within the insonation area of MEUS Group. In addition, necrosis was found in liver tissue 48 h after insonation. We conclude that MEUS might provide an effective hemostatic therapy for serious organ trauma such as liver avulsion injury.</p></div

CEUS images after insonation.

<p><b>a, b</b>, Uniform perfusion of contrast agent in the MB group; <b>c, d</b>, A representative CEUS image showed a perfusion defect (arrow indicates the trauma, breakage the wound, and dotted line shows the range of defects. The area beyond the dotted line also showed an irregular defect) in MEUS group.</p

Images of procedure for application of microbubble-enhanced therapeutic ultrasound.

<p><b>a</b>’, active bleeding of the wound before insonation; <b>b</b>, Direct insonation of the wound by a transducer during injection of microbubbles; <b>c</b>, <b>c’,</b> small exudates over the wound after insonation; <b>d</b>, The liver wound were smooth and no bleeding after 48 h.</p

A comparison of bleeding visual scores before and after insonation.

<p>*P<0.05 indicates a significant difference between before and after insonation of MEUS group. ⁺P<0.05 indicates a significant difference between MEUS group and the controls.</p

Representative histological HE sections after insonation of the TUS, and, MB groups.

<p>Hepatic cord and plate structure were clear, and blood cells were scattered in the sinusoids (<b>a,b</b>); In the MEUS group, hepatocytes swelled, and erythrocytes accumulated in the sinusoids (<b>c</b>), the swollen hepatocytes deformed and compressed the sinusoids and perisinusoidal space. A large number of erythrocytes accumulated in the central veins (<b>d</b>), periportal connective tissue hemorrhaged (<b>e</b>). The targets showed map-like necrosis in the MEUS group after 48 h (<b>f</b>).</p