Abstract
Research is ongoing to develop drug therapies to manage osteoarthritis (OA) and articular cartilage (AC) injuries. However, means to deliver drug to localized AC lesions are highly limited and not clinically available. This study investigates the capability of laser ultrasound (laser-induced plasma sound source) to deliver agents (methylene blue, MB, in PBS) into bovine AC. Treatment samples (n = 10) were immersed in MB solution simultaneously with LU exposure, while adjacent control 1 tissue (n = 10) was pre-treated with LU followed by immersion in MB and adjacent control 2 tissue (n = 10) was only immersed in MB. AC exposed (n = 22) or not exposed (n = 27) to LU were characterized for anomalies in structure, composition, viability or RNA expression. Optically detected MB content was significantly (p < 0.01) higher in treatment samples up to a depth of 500 µm from AC surface as compared to controls. No major unwanted short-term effects on AC structure, proteoglycan or collagen contents, chondrocyte viability or RNA expression levels were detected. In conclusion, LU can deliver agents into AC without major short-term concerns on safety. LU could reveal new strategies for the development of localized drug therapies in AC.
Highlights
Osteoarthritis (OA) can be considered as a group of joint diseases; the pathogenesis is characterized by regenerative, reparative, and degenerative structural changes in all tissues of the joint, including the articular cartilage (AC), bone, synovium, capsule and periarticular soft tissues[1, 2]
First we studied, using three experimental groups T1, C1 and C2 (Fig. 1, Table 1), whether LU (Fig. 2, fc = 3.0 ± 0.1 MHz; bandwidth at −3 dB = 2.5 ± 0.1 MHz; peak-positive-pressure = 9.14 ± 0.15 M Pa; peak-negative-pressure = 1.90 ± 0.05 MPa; ITP = 6017 ± 188 W/cm[2]; IPA = 1076 ± 90 W/cm[2]; ITA = 1.86 ± 0.04 mW/cm[2]; mechanical index = 1.01 ± 0.03; mean ± S.E.M, n = 100; parameters were defined with a needle hydrophone in ion-exchanged water at 3 mm distance from the plasma spark, which is equivalent to AC surface location) could enhance the delivery of methylene blue (MB) into AC
In field emission scanning electron microscopy (FESEM) images, no difference in morphology of superficial AC was observed in ST1 (n = 6) as compared to SC1 (n = 6) (Figs 1 and 5, Table 1)
Summary
Osteoarthritis (OA) can be considered as a group of joint diseases; the pathogenesis is characterized by regenerative, reparative, and degenerative structural changes in all tissues of the joint, including the articular cartilage (AC), bone, synovium, capsule and periarticular soft tissues[1, 2]. Forcing drug agents locally into AC lesions would (i) permit development of targeted and personalized OA therapy, (ii) enhance safety by preventing unnecessary drug exposure to adjacent tissue and the rest of the body, and (iii) increase the concentration and residence time of drug molecules within the target. The potential of HIU to contribute to drug delivery relates to its capability to manipulate material; e.g. HIU can (i) translate tissue, particles or voids, (ii) induce fluid and ionic streams, (iii) modify tissue or cell membrane permeability and (iv) generate controlled thermal effects[18]. MHz delivery of kDa-sized molecules did not demonstrate tissue damage, but is time-consuming (2.5 hrs to deliver up to half-way into the AC)[21]. We aim (i) to quantify the delivery of agents into AC by LU and (ii) to conduct an initial evaluation on whether major short-term safety effects are induced by LU
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