Translational Challenges in Drug Therapy and Delivery Systems for Treating Chronic Lower Extremity Wounds.

Despite several promising preclinical studies performed over the past two decades, there remains a paucity of market-approved drugs to treat chronic lower extremity wounds in humans. This translational gap challenges our understanding of human chronic lower extremity wounds and the design of wound treatments. Current targeted drug treatments and delivery systems for lower extremity wounds rely heavily on preclinical animal models meant to mimic human chronic wounds. However, there are several key differences between animal preclinical wound models and the human chronic wound microenvironment, which can impact the design of targeted drug treatments and delivery systems. To explore these differences, this review delves into recent new drug technologies and delivery systems designed to address the chronic wound microenvironment. It also highlights preclinical models used to test drug treatments specific for the wound microenvironments of lower extremity diabetic, venous, ischemic, and burn wounds. We further discuss key differences between preclinical wound models and human chronic wounds that may impact successful translational drug treatment design.

Localization of chemical synapses and modulatory release sites in the cardiac ganglion of the crab, Cancer borealis.

The crustacean cardiac ganglion (CG) comprises nine neurons that provide rhythmic drive to the heart. The CG is the direct target of multiple modulators. Synapsin-like immunoreactivity was found clustered around the somata of the large cells (LC) and in a neuropil at the anterior branch of the CG trunk of Cancer borealis. This implicates the soma as a key site of synaptic integration, an unusual configuration in invertebrates. Proctolin is an excitatory neuromodulator of the CG, and proctolin-like immunoreactivity exhibited partial overlap with putative chemical synapses near the LCs and at the neuropil. A proctolin-like projection was also found in a pair of excitatory nerves entering the CG. GABA-like immunoreactivity was nearly completely colocalized with chemical synapses near the LCs but absent at the anterior branch neuropil. GABA-like projections were found in a pair of inhibitory nerves entering the CG. C. borealis Allatostatin B1 (CbASTB), red pigment concentrating hormone, and FLRFamide-like immunoreactivity each had a unique pattern of staining and co-localization with putative chemical synapses. These results provide morphological evidence that synaptic input is integrated at LC somata in the CG. Our findings provide a topographical organization for some of the multiple inhibitory and excitatory modulators that alter the rhythmic output of this semi-autonomous motor circuit.