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

Area of Science:

• Biomedical Engineering
• Pharmacokinetics
• Skeletal Muscle Physiology

Background:

• Mechanically active tissues, like skeletal muscle, exhibit dynamic architecture that affects drug distribution.
• Understanding how mechanical loads influence the pharmacokinetics of locally delivered agents is crucial for effective drug delivery.

Purpose of the Study:

• To investigate drug transport in skeletal muscle under controlled static and cyclic mechanical loads and isometric contractions.
• To determine the relationship between tissue mechanics, architecture, and the penetration of locally delivered agents.

Main Methods:

• Rat soleus muscles were subjected to static strains (0-20%), cyclic strains (1-3 Hz), and electrical stimulation-induced contractions (0.1-3 Hz).
• FITC-dextran (4-150 kDa) penetration and tissue porosity were measured.
• Active force-length relationships were assessed.
• Computational modeling was used to simulate intramuscular transport.

Main Results:

• Dextran penetration, tissue porosity, and force-length relationships correlated significantly (r=0.9-1.0), peaking at optimal fiber length (Lo).
• Penetration decreased with increasing dextran size but relative enhancement at Lo increased.
• Penetration increased linearly with cyclic stretch frequency and peaked at a contraction rate of 0.5 Hz.

Conclusions:

• Skeletal muscle architecture and mechanical function are key determinants of intramuscular pharmacokinetics.
• Mechanical loads and muscle contractions modulate drug dispersion and penetration.
• Targeted manipulation of tissue mechanics offers a potential strategy for controlled drug delivery.