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Research Papers

The Effect of Antibody Size and Mechanical Loading on Solute Diffusion Through the Articular Surface of Cartilage

[+] Author and Article Information
Chris D. DiDomenico

Meinig School of Biomedical Engineering,
Cornell University,
145 Weill Hall,
Ithaca, NY 14853
e-mail: cdd72@cornell.edu

Andrew Goodearl

AbbVie Inc.,
100 Research Drive,
Worcester, MA 01605
e-mail: andrew.goodearl@abbvie.com

Anna Yarilina

AbbVie Inc.,
100 Research Drive,
Worcester, MA 01605
e-mail: anna.yarilina@abbvie.com

Victor Sun

AbbVie Inc.,
100 Research Drive,
Worcester, MA 01605
e-mail: victor.sun@abbvie.com

Soumya Mitra

AbbVie Inc.,
100 Research Drive,
Worcester, MA 01605
e-mail: soumya.mitra@abbvie.com

Annette Schwartz Sterman

AbbVie Inc.,
100 Research Drive,
Worcester, MA 01605
e-mail: annette.schwartz@abbvie.com

Lawrence J. Bonassar

Professor
Meinig School of Biomedical Engineering,
Sibley School of Mechanical and
Aerospace Engineering,
Cornell University,
149 Weill Hall,
Ithaca, NY 14853;
e-mail: lb244@cornell.edu

1Corresponding author.

Manuscript received January 9, 2017; final manuscript received June 28, 2017; published online July 14, 2017. Assoc. Editor: Carlijn V. C. Bouten.

J Biomech Eng 139(9), 091005 (Jul 14, 2017) (9 pages) Paper No: BIO-17-1009; doi: 10.1115/1.4037202 History: Received January 09, 2017; Revised June 28, 2017

Because of the heterogeneous nature of articular cartilage tissue, penetration of potential therapeutic molecules for osteoarthritis (OA) through the articular surface (AS) is complex, with many factors that affect transport of these solutes within the tissue. Therefore, the goal of this study is to investigate how the size of antibody (Ab) variants, as well as application of cyclic mechanical loading, affects solute transport within healthy cartilage tissue. Penetration of fluorescently tagged solutes was quantified using confocal microscopy. For all the solutes tested, fluorescence curves were obtained through the articular surface. On average, diffusivities for the solutes of sizes 200 kDa, 150 kDa, 50 kDa, and 25 kDa were 3.3, 3.4, 5.1, and 6.0 μm2/s from 0 to 100 μm from the articular surface. Diffusivities went up to a maximum of 16.5, 18.5, 20.5, and 23.4 μm2/s for the 200 kDa, 150 kDa, 50 kDa, and 25 kDa molecules, respectively, from 225 to 325 μm from the surface. Overall, the effect of loading was very significant, with maximal transport enhancement for each solute ranging from 2.2 to 3.4-fold near 275 μm. Ultimately, solutes of this size do not diffuse uniformly nor are convected uniformly, through the depth of the cartilage tissue. This research potentially holds great clinical significance to discover ways of further optimizing transport into cartilage and leads to effective antibody-based treatments for OA.

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Figures

Grahic Jump Location
Fig. 1

Schematic of sample preparation and experimental setup (left and center) with the fluid flow induced by the platen being perpendicular to the deep zone and the articular surface (AS). Fluorescence image obtained from the Ab (150 kDa) solute using confocal microscopy (right). Box (∼1000 μm wide and 500 μm tall) indicates the region of interest that was examined for this study. A 4 mm diameter sample of 2 mm thick was bisected, then a slice was cut from each half to obtain a final sample dimension of 4 × 2 × 1.15 mm.

Grahic Jump Location
Fig. 2

Representative normalized fluorescence curve for the Ab (150 kDa) solute under passive conditions (dotted line) compared against the 16-layer diffusion model (solid line) (left). For this sample, average coefficient of variance was 6.4%. All the solutes had average coefficient of variances less than 12.5%. Loaded and passive samples had equally good fits overall for all the solutes. Average normalized fluorescence curve for Ab (150 kDa) through the articular surface is shown (right). Standard deviations are represented by the shaded region for n = 8. For this solute, distinct changes in concavity were observed, and therefore, profiles could be roughly broken into three distinct regions. The articular surface region is characterized by a sharp decrease in fluorescence for the first 100 μm or so, followed by the plateau region where the fluorescence is relatively constant, followed by the deep region where there is a more rapid drop off of fluorescence.

Grahic Jump Location
Fig. 3

Passive fluorescence profile comparison of the four differently sized solutes used. Error bars (standard deviation for n = 6–8) for all the solutes are shown in shades surrounding average profiles. Depictions of the structure of these molecules are also shown.

Grahic Jump Location
Fig. 4

Passive fluorescence profile comparison of the four differently sized solutes used (left) along with the multilayer diffusivities (right). Error bars denote standard deviations for all the solutes (n = 7, 8, 7, and 6 for DVD, Ab, Fab, and scFv, respectively). Fluorescence curves for these solutes were visually similar up until 400 μm, where solute fluorescence diverged according to size. Overall, local diffusivities were heterogeneous throughout the depth of the tissue, and there were three distinct sections of these curves for each solute. On average, diffusivities for the DVD, Ab, Fab, and scFv, were 3.3, 3.4, 5.1, and 6.0 μm2/s from 0 to 100 μm, but size did not affect diffusivity significantly within this region (p > 0.05). Diffusivities increased to a maximum of 16.5, 18.5, 20.5, and 23.4 μm2/s for the DVD, Ab, Fab, and scFv, respectively, between 225 and 325 μm. Calculated diffusivities at 225 μm, 275 μm, and 325 μm were higher than all other diffusivities in the tissue, for all the solutes (p < 0.05). Diffusivities then decreased to similar values found within the surface region in the 400–800 μm range (deep region) and had no significant dependence on size (p > 0.05). Values obtained from 0–125 μm range to 400–800 μm range were not different from each other, for any solute (p > 0.05).

Grahic Jump Location
Fig. 5

All the four solutes' fluorescence profiles for passive and loaded conditions. Lighter shades of color indicate greater loading amplitude. All the cyclic loading was conducted at 1 Hz for 3 h. Most enhancement of the fluorescence profiles for all the solutes can be found from 0 to 400 μm from the articular surface. Sample sizes: N = 7, 8, 4, and 6 for passive, 1.25%, 2.5%, and 5% for DVD solute, respectively. Sample sizes: N = 8, 7, 6, and 5 for passive, 1.25%, 2.5%, and 5% for Ab solute, respectively. Sample sizes: N = 7, 6, 7, and 7 for passive, 1.25%, 2.5%, and 5% for Fab solute, respectively. Sample sizes: N = 6, 8, 7, and 8 for passive, 1.25%, 2.5%, and 5% for scFv solute, respectively.

Grahic Jump Location
Fig. 6

All the four solutes' depthwise diffusivities for passive and loaded conditions. Lighter shades of color indicate greater loading amplitude. Error bars denote standard deviations with n = 4–8 for all the solutes (see Fig. 5 for specific sample size information). Loading increased diffusivities most from 0 to 400 μm from the articular surface, with highest diffusivity enhancement occurring between 225 and 325 μm (p < 0.05). For most solutes, no significant transport enhancement was experienced in the first 125 μm of the tissue, at any loading condition (p > 0.05). As expected, solutes undergoing higher cyclic amplitudes (i.e., 5%) received more transport enhancement than solutes undergoing less loading, from 125 μm to 325 μm (p < 0.05). In general, larger solutes benefited from loading more than smaller solutes, especially within the range 225–325 μm (p < 0.05). Almost no loading-based enhancement can be observed deeper than 425 μm into the tissue.

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