Caffeine-catalyzed gels.

Covalently cross-linked gels are utilized in a broad range of biomedical applications though their synthesis often compromises easy implementation. Cross-linking reactions commonly utilize catalysts or conditions that can damage biologics and sensitive compounds, producing materials that require extensive post processing to achieve acceptable biocompatibility. As an alternative, we report a batch synthesis platform to produce covalently cross-linked materials appropriate for direct biomedical application enabled by green chemistry and commonly available food grade ingredients. Using caffeine, a mild base, to catalyze anhydrous carboxylate ring-opening of diglycidyl-ether functionalized monomers with citric acid as a tri-functional crosslinking agent we introduce a novel poly(ester-ether) gel synthesis platform. We demonstrate that biocompatible Caffeine Catalyzed Gels (CCGs) exhibit dynamic physical, chemical, and mechanical properties, which can be tailored in shape, surface texture, solvent response, cargo release, shear and tensile strength, among other potential attributes. The demonstrated versatility, low cost and facile synthesis of these CCGs renders them appropriate for a broad range of customized engineering applications including drug delivery constructs, tissue engineering scaffolds, and medical devices.

Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals.

Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra-long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine large-animal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malaria-transmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malaria-transmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra-long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy.

The Mechanical, Structural, and Compositional Changes of Tendon Exposed to Elastase.

The mechanical response of tendon is dependent on the interaction of structural molecules that constitute the extracellular matrix. However, little is known about the role of elastic fibers that are present in this structure. Elastase treatments have been used to elucidate the mechanical role of elastic fibers in numerous tissues. Here, we show that a standard elastase treatment affects the mechanical properties of tendon, including the ultimate tensile strength and failure strain. Moreover, elastase-treated specimens exhibit significant structural and compositional changes including crimp undulation and release of glycosaminoglycans. These data demonstrate that a common elastase treatment has a complex digestion profile that influences the structure-function relationship of tendon. Thus, defining the mechanical role of elastic fibers in tendon using this technique is challenging. This introduces new and exciting questions regarding the function of elastic fibers in tendon, which may not be as well understood as previously thought.

Distribution and expression of type VI collagen and elastic fibers in human rotator cuff tendon tears.

There is increasing evidence for a progressive extracellular matrix change in rotator cuff disease progression. Directly surrounding the cell is the pericellular matrix, where assembly of matrix aggregates typically occurs making it critical in the response of tendon cells to pathological conditions. Studies in animal models have identified type VI collagen, fibrillin-1 and elastin to be located in the pericellular matrix of tendon and contribute in maintaining the structural and biomechanical integrity of tendon. However, there have been no reports on the localization of these proteins in human tendon biopsies. This study aimed to characterize the distribution of these ECM components in human rotator cuffs and gain greater insight into the relationship of pathology to tear size by analyzing the distribution and expression profiles of these ECM components. Confocal microscopy confirmed the localization of these structural molecules in the pericellular matrix of the human rotator cuff. Tendon degeneration led to an increased visibility of these components with a significant disorganization in the distribution of type VI collagen. At the genetic level, an increase in tear size was linked to an increased transcription of type VI collagen and fibrillin-1 with no significant alteration in the elastin levels. This is the first study to confirm the localization of type VI collagen, elastin and fibrillin-1 in the pericellular region of human supraspinatus tendon and assesses the effect of tendon degeneration on these structures, thus providing a useful insight into the composition of human rotator cuff tears which can be instrumental in predicting disease prognosis.

Elastic fibres are broadly distributed in tendon and highly localized around tenocytes.

Elastic fibres have the unique ability to withstand large deformations and are found in numerous tissues, but their organization and structure have not been well defined in tendon. The objective of this study was to characterize the organization of elastic fibres in tendon to understand their function. Immunohistochemistry was used to visualize elastic fibres in bovine flexor tendon with fibrillin-1, fibrillin-2 and elastin antibodies. Elastic fibres were broadly distributed throughout tendon, and highly localized longitudinally around groups of cells and transversely between collagen fascicles. The close interaction of elastic fibres and cells suggests that elastic fibres are part of the pericellular matrix and therefore affect the mechanical environment of tenocytes. Fibres present between fascicles are likely part of the endotenon sheath, which enhances sliding between adjacent collagen bundles. These results demonstrate that elastic fibres are highly localized in tendon and may play an important role in cellular function and contribute to the tissue mechanics of the endotenon sheath.