Structural biomechanics modulate intramuscular distribution of locally delivered drugs

Abstract

As local drug delivery continues to emerge as a clinical force, so does understanding of its potentially narrow therapeutic window. Classic molecular transport studies are of value but do not typically account for the local nature of drug transport or the regional dynamic function in target tissues like muscle that may undergo cyclical and variable mechanical motion and loading. We examine the impact of dynamic architecture on intramuscular drug distribution. We designed a tissue mounting technique and mechanical loading system that uniquely enables pharmacokinetics investigations in association with control of muscle biomechanics while preserving physiologic tissue architecture. The system was validated and used to elucidate the influence of architecture and controlled cyclic strain on intramuscular drug distribution. Rat soleus muscles underwent controlled deformations within a drug delivery chamber that preserved in vivo physiology. Penetration of 1 mM 20 kDa FITCdextran at planar surfaces of the soleus increased significantly from 0.52 ± 0.09 mm under 80 min of static (0%) strain to 0.81 ± 0.09 mm under cyclic (3 Hz, 0-20% peak-to-peak) strain, demonstrating the driving effect of cyclic loading on transport. Penetration at curved margins was 1.57-and 2.53-fold greater than at planar surfaces under static and cyclic strain, respectively, and was enhanced 1.6-fold more by cyclic strain, revealing architecturally dictated spatial heterogeneity in transport and modulation of motion dynamics. Architectural geometry and dynamics modulate the impact of mechanical loading on local drug penetration and intramuscular distribution. Future work will use the biomechanical test system to investigate mechanisms underlying transport effects of specific loading regimens. It is hoped that this work will initiate a broader understanding of intramuscular pharmacokinetics and guide local drug delivery strategies.

Intramuscular drug transport under mechanical loading: Resonance between tissue function and uptake

“…The soleus was measured, isolated, and resected with its tendons and segments of the calcaneus and fibula intact as described previously [16]. The in situ length of the soleus, measured using a Mitutoyo Digimatic caliper with ± 0.01 mm precision between the proximal and distal myotendinous junctions while flexing the knee and ankle at 90° and referred to as the nominal length, corresponded to the initial length, at which passive resistance to stretch first occurs.…”

“…All static and cyclic strains were applied on pairs of whole soleus muscles using a custom-built mechanical loading system described previously [16]. For all loading conditions described below, muscles were stretched for 1 h in 16 ml of 1 mM 20 kDa FITC-dextran (Sigma, No.…”

The anisotropic mechanical behaviour of passive skeletal muscle tissue subjected to large tensile strain

“…In contrast, suitably validated computational models have the potential to predict all of these parameters and thus hold significant promise in advancing health care (Taylor and Humphrey, 2009). In particular they are a powerful means for understanding the musculoskeletal system (Erdemir et al, 2007, Marjoux et al, 1998 and are therefore used in diverse applications from impact biomechanics (Muggenthaler et al, 2008, Ivancic et al, 2007 to rehabilitation engineering (Linder-Ganz et al, 2008, Linder-Ganz et al, 2007, surgical simulation (Lim andDe, 2007, Audette et al, 2004) and soft tissue drug transport (Wu and Edelman, 2008). There are also important applications in tissue engineering, as the engineered skeletal muscle tissue needs to have mechanical properties that match those of the replaced native tissue (Hinds et al, 2011, Goldstein et al, 2001.…”

A structural model of passive skeletal muscle shows two reinforcement processes in resisting deformation

“…This is particularly true for soft tissues, which exhibit nonlinearity, non-homogeneity, anisotropy, viscoelasticity (ArItan et al, 2008) and tension/compression asymmetry (Takaza et al, 2013). Skeletal muscle tissue accounts for almost half of human body weight (Wang et al, 1997), so the constitutive properties of passive muscle tissue are crucial for many musculoskeletal models in diverse applications from impact biomechanics (Muggenthaler et al, 2008, Ivancic et al, 2007 to rehabilitation engineering (Linder-Ganz et al, 2008, Linder-Ganz et al, 2007, surgical simulation (Lim andDe, 2007, Audette et al, 2004) and soft tissue drug transport (Wu and Edelman, 2008).…”