Multi-scale imaging techniques to investigate solute transport across articular cartilage

Pouran, Behdad; Arbabi, Vahid; Bajpayee, Ambika G.; Tiel, Jasper van; Töyräs, Juha; Jurvelin, Jukka S.; Malda, Jos; Zadpoor, Amir A.

doi:10.1016/j.jbiomech.2018.06.012

Cited by 27 publications

(14 citation statements)

References 96 publications

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“…6). CPC +8 and +7 have applications in cartilage imaging due to their very fast transport rate and shorter intra-tissue residence time, which can help clear contrast agents from the joint post imaging [60]. …”

Section: Discussionmentioning

confidence: 99%

Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues

et al. 2019

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Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The constant turnover of synovial fluid results in short residence time of administered drugs in the joint space and the dense negatively charged matrix of cartilage hinders their diffusive transport. Drugs are, therefore, unable to reach their cell and matrix targets in sufficient doses, and fail to elicit relevant biological response, which has led to unsuccessful clinical trials. The high negative fixed charge density (FCD) of cartilage, however, can be used to convert cartilage from a barrier to drug entry into a depot by making drugs positively charged. Here we design cartilage penetrating and binding cationic peptide carriers (CPCs) with varying net charge, spatial distribution and hydrophobicity to deliver large-sized therapeutics and investigate their electro-diffusive transport in healthy and arthritic cartilage. We showed that CPC uptake increased with increasing net charge up to +14 but dropped as charge increased further due to stronger binding interactions that hindered CPC penetrability and uptake showing that weak-reversible binding is key to enable their penetration through full tissue thickness. Even after 90% GAG depletion, while CPC +14 uptake reduced by over 50% but still had a significantly high value of 148x showing that intra-tissue long-range charge-based binding is further stabilized by short-range H-bond and hydrophobic interactions. The work presents an approach for rational design of cationic carriers based on tissue FCD and properties of macromolecules to be delivered. These design rules can be extended to drug delivery for other avascular, negatively charged tissues.

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Section: Discussionmentioning

confidence: 99%

Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues

et al. 2019

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“…This underscores the unmet need for effective drug delivery strategies that can enhance IL-1Ra residence time inside the joint following its intra-articular administration and target both synovium-induced inflammation as well as chondrocytes throughout the full thickness of cartilage. Several methods for charge-based intra-cartilage [33, 52, 53] and joint depot drug delivery [54–56] are currently under development to address this need.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1 receptor antagonist (IL-1Ra) is more effective in suppressing cytokine-induced catabolism in cartilage-synovium co-culture than in cartilage monoculture

et al. 2019

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BackgroundMost in vitro studies of potential osteoarthritis (OA) therapies have used cartilage monocultures, even though synovium is a key player in mediating joint inflammation and, thereby, cartilage degeneration. In the case of interleukin-1 (IL-1) inhibition using its receptor antagonist (IL-1Ra), like chondrocytes, synoviocytes also express IL-1 receptors that influence intra-articular IL-1 signaling and IL-1Ra efficacy. The short residence time of IL-1Ra after intra-articular injection requires the application of frequent dosing, which is clinically impractical and comes with increased risk of infection; these limitations motivate the development of effective drug delivery strategies that can maintain sustained intra-articular IL-1Ra concentrations with only a single injection. The goals of this study were to assess how the presence of synovium in IL-1-challenged cartilage-synovium co-culture impacts the time-dependent biological response of single and sustained doses of IL-1Ra, and to understand the mechanisms underlying any co-culture effects.MethodsBovine cartilage explants with or without synovium were treated with IL-1α followed by single or multiple doses of IL-1Ra. Effects of IL-1Ra in rescuing IL-1α-induced catabolism in cartilage monoculture and cartilage-synovium co-culture were assessed by measuring loss of glycosaminoglycans (GAGs) and collagen using DMMB (dimethyl-methylene blue) and hydroxyproline assays, respectively, nitric oxide (NO) release using Griess assay, cell viability by fluorescence staining, metabolic activity using Alamar blue, and proteoglycan biosynthesis by radiolabel incorporation. Day 2 conditioned media from mono and co-cultures were analyzed by mass spectrometry and cytokine array to identify proteins unique to co-culture that contribute to biological crosstalk.ResultsA single dose of IL-1Ra was ineffective, and a sustained dose was necessary to significantly suppress IL-1α-induced catabolism as observed by enhanced suppression of GAG and collagen loss, NO synthesis, rescue of chondrocyte metabolism, viability, and GAG biosynthesis rates. The synovium exhibited a protective role as the effects of single-dose IL-1Ra were significantly enhanced in cartilage-synovium co-culture and were accompanied by release of anti-catabolic factors IL-4, carbonic anhydrase-3, and matrilin-3. A total of 26 unique proteins were identified in conditioned media from co-cultures, while expression levels of many additional proteins important to cartilage homeostasis were altered in co-culture compared to monocultures; principal component analysis revealed distinct clustering between co-culture and cartilage and synovium monocultures, thereby confirming significant crosstalk.ConclusionsIL-1Ra suppresses cytokine-induced catabolism in cartilage more effectively in the presence of synovium, which was associated with endogenous production of anti-catabolic factors. Biological crosstalk between cartilage and synovium is significant; thus, their co-cultures should better model the intra-articular actio...

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“…The absence of blood and lymphatic vessels restricts the direct access to nutrients and limits healing capability [2]. In an avascular tissue where nutrients and cytokines are mainly distributed by diffusion, joint motion assists to the transport rate of solutes [3]. Mechanical activity in joints supports the proper functionality of chondrocytes, improves ECM content, promotes glycosaminoglycan synthesis, and fiber organization [4,5].…”

Section: Introductionmentioning

confidence: 99%

Bioreactor for mobilization of mesenchymal stem/stromal cells into scaffolds under mechanical stimulation: Preliminary results

et al. 2020

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OPEN ACCESS Citation: Gamez C, Schneider-Wald B, Schuette A, Mack M, Hauk L, Khan AuM, et al. (2020) Bioreactor for mobilization of mesenchymal stem/ stromal cells into scaffolds under mechanical stimulation: Preliminary results. PLoS ONE 15(1): e0227553. https://doi.org/10.1371/journal. ResultsThe bioreactor was able to stimulate the scaffolds and the cells for 24.4 (±1.7) hours, exerting compression with vertical displacements of 185.8 (±17.8) μm and a force-amplitude of 1.87 (±1.37; min 0.31, max 4.42) N. Our results suggest that continuous mechanical stimulation hampered the viability of the cells located at the cell reservoir when comparing to intermittent mechanical stimulation (34.4 ± 2.0% vs. 66.8 ± 5.9%, respectively).Functionalizing alginate scaffolds with laminin-521 (LN521) seemed to enhance the mobilization of cells from 48 (±21) to 194 (±39) cells/mm 3 after applying intermittent mechanical loading. ConclusionThe bioreactor presented here was able to provide mechanical stimulation that seemed to induce the mobilization of MSCs into LN521-alginate scaffolds under an intermittent loading regime.Bioreactor for mobilization of MSCs under mechanical stimulation PLOS ONE | https://doi.

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Multi-scale imaging techniques to investigate solute transport across articular cartilage

Cited by 27 publications

References 96 publications

Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues

Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues

Interleukin-1 receptor antagonist (IL-1Ra) is more effective in suppressing cytokine-induced catabolism in cartilage-synovium co-culture than in cartilage monoculture

Bioreactor for mobilization of mesenchymal stem/stromal cells into scaffolds under mechanical stimulation: Preliminary results

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