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Local myocardial application of inotropes may allow the study of pharmacologically augmented central myocardial contraction in the absence of confounding peripheral vasodilating effects and alterations in heart loading conditions. Novel alginate epicardial (EC) drug releasing platforms were used to deliver dobutamine to the left ventricle of rats. Pressure volume analyses indicated that while both local and systemic (IV) use of inotropic drugs increase stroke volume and contractility, systemic infusion does so through heart unloading. Conversely, EC application preserves heart load and systemic blood pressure. Epicardial dobutamine increased indices of contractility with less rise in heart rate and lower reduction in systemic vascular resistance than IV infusion. Drug sampling showed that dobutamine concentration was 650-fold higher in the anterior wall than in the inferior wall The plasma dobutamine concentration with local delivery was about half as much as with systemic infusion. These data suggest that inotropic EC delivery has a localized effect and augments myocardial contraction by different mechanisms than systemic infusion, with far fewer side effects. These studies demonstrate a pharmacologic paradigm that may improve heart function without interference from effects on the vasculature, alterations in heart loading and may ultimately improve the health of heart failure patients.

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.

Dynamic architecture and motion in mechanically active target tissues can influence the pharmacokinetics of locally delivered agents. Drug transport in skeletal muscle under controlled mechanical loads was investigated. Static (0-20%) and cyclic (±2.5% amplitude, 0-20% mean, 1-3 Hz) strains and electrically paced isometric contractions (0.1-3 Hz, 0% strain) were applied to rat soleus incubated in 1 mM 20 kDa FITC-dextran. Dextran penetration, tissue porosity, and active force-length relationship over 0-20% strain correlated (r = 0.9-1.0), and all increased 1.5-fold from baseline at 0% to a maximum at 10% (L o ), demonstrating biologic significance of L o and impact of fiber size and distribution on function and pharmacokinetics. Overall penetration decreased but relative enhancement of penetration at L o increased with dextran size (4-150 kDa). Penetration increased linearly (0.084 mm/Hz) with cyclic stretch, demonstrating dispersion. Penetration increased with contraction rate by 1.5-fold from baseline to a maximum at 0.5 Hz, revealing architectural modulation of dispersion. Impact of architecture and dispersion on intramuscular transport was computationally modeled. Mechanical architecture and function underlie intramuscular pharmacokinetics and act in concert to effect resonance between optimal physiologic performance and drug uptake. Therapeutic management of characteristic function in tissue targets may enable a physiologic mechanism for controlled drug transport.

This article provides a broad overview of the clinical nonpharmacologic treatment options for managing acute and chronic pain. Physical therapy and modalities, interventional techniques, emerging regenerative medicine, and cognitive behavioral paradigms of treatment are presented. Recommendations are evidence-based and are a practical resource for the musculoskeletal pain and sports medicine practitioner.

Poor nutrient transport through the cartilage endplate (CEP) is a key factor in the etiology of intervertebral disc degeneration and may hinder the efficacy of biologic strategies for disc regeneration. Yet, there are currently no treatments for improving nutrient transport through the CEP. In this study we tested whether intradiscal delivery of a matrix-modifying enzyme to the CEP improves solute transport into whole human and bovine discs. Ten human lumbar motion segments harvested from five fresh cadaveric spines (38–66 years old) and nine bovine coccygeal motion segments harvested from three adult steers were treated intradiscally either with collagenase enzyme or control buffer that was loaded in alginate carrier. Motion segments were then incubated for 18 h at 37 °C, the bony endplates removed, and the isolated discs were compressed under static (0.2 MPa) and cyclic (0.4–0.8 MPa, 0.2 Hz) loads while submerged in fluorescein tracer solution (376 Da; 0.1 mg/ml). Fluorescein concentrations from site-matched nucleus pulposus (NP) samples were compared between discs. CEP samples from each disc were digested and assayed for sulfated glycosaminoglycan (sGAG) and collagen contents. Results showed that enzymatic treatment of the CEP dramatically enhanced small solute transport into the disc. Discs with enzyme-treated CEPs had up to 10.8-fold (human) and 14.0-fold (bovine) higher fluorescein concentration in the NP compared to site-matched locations in discs with buffer-treated CEPs (p < 0.0001). Increases in solute transport were consistent with the effects of enzymatic treatment on CEP composition, which included reductions in sGAG content of 33.5% (human) and 40% (bovine). Whole disc biomechanical behavior—namely, creep strain and disc modulus—was similar between discs with enzyme- and buffer-treated CEPs. Taken together, these findings demonstrate the potential for matrix modification of the CEP to improve the transport of small solutes into whole intact discs.

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