Avidin as a model for charge driven transport into cartilage and drug delivery for treating early stage post-traumatic osteoarthritis

Bajpayee, Ambika G.; Wong, Cliff; Bawendi, Moungi G.; Frank, Eliot H.; Grodzinsky, Alan J.

doi:10.1016/j.biomaterials.2013.09.091

Cited by 180 publications

(249 citation statements)

References 49 publications

(57 reference statements)

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“…In a previously published in vitro study using 1 mm thick young bovine cartilage explants, we reported >90% retention of Avidin for at least 15 days. 22 In vivo, a decrease in retention time is expected (compared to in vitro explants) due to the presence of convective transport and clearance by the lymphatic system. By day 7 in the rat model, Avidin retention was only 4.1% of the initial value at 24 h after i.a.…”

Section: Discussionmentioning

confidence: 99%

A rabbit model demonstrates the influence of cartilage thickness on intra‐articular drug delivery and retention within cartilage

Bajpayee

Scheu

Grodzinsky

et al. 2015

Journal Orthopaedic Research

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For evaluation of new approaches to drug delivery into cartilage, the choice of an animal model is critically important. Since cartilage thickness varies with animal size, different levels of drug uptake, transport and retention should be expected. Simple intra-articular injection can require very high drug doses to achieve a concentration gradient high enough for drug diffusion into cartilage. New approaches involve nanoparticle delivery of functionalized drugs directly into cartilage; however, diffusion-binding kinetics proceeds as the square of cartilage thickness. In this study, we demonstrate the necessity of using larger animals for sustained intra-cartilage delivery and retention, exemplified by intra-articular injection of Avidin (drug-carrier) into rabbits and compared to rats in vivo. Penetration and retention of Avidin within cartilage is greatly enhanced by electrostatic interactions. Medial tibial cartilage was the thickest of rabbit cartilages, which generated the longest intra-cartilage half-life of Avidin (t 1/2 ¼ 154 h). In contrast, Avidin half-life in thinner rat cartilage was 5-6 times shorter (t 1/2 $ 29 h). While a weak correlation (R 2 ¼ 0.43) was found between Avidin halflives and rabbit tissue GAG concentrations, this correlation improved dramatically (R 2 ¼ 0.96) when normalized to the square of cartilage thickness, consistent with the importance of cartilage thickness to evaluation of drug delivery and retention. ß

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Section: Discussionmentioning

confidence: 99%

A rabbit model demonstrates the influence of cartilage thickness on intra‐articular drug delivery and retention within cartilage

Bajpayee

Scheu

Grodzinsky

et al. 2015

Journal Orthopaedic Research

Self Cite

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“…This increase in density causes a reduction in pore size which results in the inability of many large solutes to penetrate through the depth of cartilage [22]. Penetration of solutes throughout the full thickness of tissue allows for longer retention times and as a result, longer therapeutic times.…”

Section: Articular Cartilagementioning

confidence: 99%

“…Penetration of solutes throughout the full thickness of tissue allows for longer retention times and as a result, longer therapeutic times. In a study conducted by Bajpayee et al, results showed that solutes having a hydrodynamic diameter of 10 nm or less were able to penetrate through the full thickness of cartilage, whereas larger sized solutes became trapped within the superficial zone of cartilage [22]. This implies that the use of either liposomes or microparticles as delivery mechanisms for cartilage therapy are not realistic approaches.…”

Section: Articular Cartilagementioning

confidence: 99%

“…Bajpayee et al recently showed that Avidin (~7 nm diameter, 66 kDa MW, pI 10.5), due to its small size and high positive charge, was able to penetrate the full thickness of cartilage explants within 24 hours, while the same-sized neutral counterpart, NeutrAvidin took 4 days to penetrate halfway [22]. Avidin also showed 400 times greater equilibrium uptake compared to NeutrAvidin as Avidin was able to be retained within the cartilage for 15 days, while NeutrAvidin was released within 24 hours [22].…”

Section: Drug Release Profilesmentioning

confidence: 99%

“…Therefore, therapeutics conjugated with a cationic domain such as Avidin would likely be able to increase retention time [22].…”

Section: Drug Release Profilesmentioning

confidence: 99%

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Development of in vitro joint tissue co-culture models for evaluating transport and biological crosstalk

Mehta¹

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Osteoarthritis (OA) affects the entire joint including tissues like synovium, cartilage, meniscus and bone. Abnormal mechanical stresses (from injury or aging) produce elevated levels of inflammatory cytokines that degrade joint tissues and cause excessive neovascularization and angiogenesis. It is critical to develop effective early interventions that target both synovium, the primary initiator and source of inflammation mediators, as well as tissues like cartilage, that are at risk of irreversible proteolytic degradation.Currently employed in vitro models, however, mostly use cartilage monocultures. Here we develop a co-culture model containing cartilage, synovium and meniscus to investigate biological and transport crosstalk between multiple joint tissues. Our data showed that co-culturing cartilage with synovium in the presence of inflammatory cytokine IL-1α, resulted in significantly higher chondrocyte death and reduced cell metabolism. Surprisingly, presence of synovium in co-culture helped significantly reduce chondrocyte nitrite production, suggesting release of anti-inflammatory factor by the synovium upon cytokine challenge. Presence of meniscus in co-culture did not present as significant of an effect as synovium did. However, culturing three tissues together increased cell death in cartilage by 3 weeks. These results confirm that significant biological crosstalk exists between various tissues. Thus co-culture systems should be preferred over monocultures to model the multiple complex pathways underlying OA.It is widely accepted that OA is a disease of the entire joint and that no single compound will be sufficient to treat every aspect of OA, thus requiring a combination of therapeutics. We therefore, investigated the role of receptor antagonist IL-1Ra, growth factor IGF-1 and chondrocyte differentiator Kartogenin (KGN) in suppressing IL-1α induced catabolic activity using monoculture or co-culture models. Drugs were introduced in either a single (mimicking one-time intraarticular injection) or continuous (mimicking multiple injections) dose regimen. Our results showed that single drug-dose was insufficient and that continuous dose, which helped maintain constant drug concentration over the entire culture period, is necessary to elicit an effective therapeutic response. This highlights the need for developing sustained and targeted drug-delivery systems for OA treatment. Future work will focus on designing strategies for co-targeting multiple tissues with multiple drugs to provide a combination OA therapy.iii ACKNOWLEDGEMENTS

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Charge‐Guided Micro/Nano‐Hydrogel Microsphere for Penetrating Cartilage Matrix

Lin

Wang

Xiang

et al. 2021

Adv Funct Materials

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The dense structure and the high-density negative charge of the cartilage matrix impede drug penetration into the cartilage. Effectively breaking through these barriers and transporting target drugs to the cartilage is currently difficult. Herein, an adhesive hydrogel microsphere characterized by its positively charged nanosized secondary structure that allows it to penetrate deep into the cartilage through charge guidance is introduced as an efficient drug delivery system for cartilage adhesion, cartilage matrix penetration, and chondrocytes targeting and solves the problem of drug-penetration impedance due to cartilage. The dopamine-modified structure on the surface of the microspheres can attach the microspheres onto the cartilage surface, while the charge-guided secondary structure can carry drugs to penetrate the cartilage matrix, release drugs under reactive oxygen species stimulation, act on chondrocytes. The experiments show that the injectable microspheres successfully deliver antioxidants to chondrocytes in osteoarthritis environments. The apoptosis rate of chondrocytes under oxidative stress decreases from 38.36 ± 5.48% to 12.86 ± 4.27%, which is significantly better than that in the direct drug treatment group (28.43 ± 5.87%). The micro/nano-hydrogel microsphere effectively penetrates the cartilage matrix and releases the drug in ROS response, realizing the improvement of drug utilization and efficacy and thereby demonstrating the efficient delivery of cartilage drugs.

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Avidin as a model for charge driven transport into cartilage and drug delivery for treating early stage post-traumatic osteoarthritis

Cited by 180 publications

References 49 publications

A rabbit model demonstrates the influence of cartilage thickness on intra‐articular drug delivery and retention within cartilage

A rabbit model demonstrates the influence of cartilage thickness on intra‐articular drug delivery and retention within cartilage

Development of in vitro joint tissue co-culture models for evaluating transport and biological crosstalk

Charge‐Guided Micro/Nano‐Hydrogel Microsphere for Penetrating Cartilage Matrix

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