Robotically handled whole-tissue culture system for the screening of oral drug formulations.

Monolayers of cancer-derived cell lines are widely used in the modelling of the gastrointestinal (GI) absorption of drugs and in oral drug development. However, they do not generally predict drug absorption in vivo. Here, we report a robotically handled system that uses large porcine GI tissue explants that are functionally maintained for an extended period in culture for the high-throughput interrogation (several thousand samples per day) of whole segments of the GI tract. The automated culture system provided higher predictability of drug absorption in the human GI tract than a Caco-2 Transwell system (Spearman's correlation coefficients of 0.906 and 0.302, respectively). By using the culture system to analyse the intestinal absorption of 2,930 formulations of the peptide drug oxytocin, we discovered an absorption enhancer that resulted in a 11.3-fold increase in the oral bioavailability of oxytocin in pigs in the absence of cellular disruption of the intestinal tissue. The robotically handled whole-tissue culture system should help advance the development of oral drug formulations and might also be useful for drug screening applications.

Fatigue exhaustion of the mitral valve tissue.

Sudden failure and rupture of the tissue is a rare but serious short-term complication after the mitral valve surgical repair. Excessive cyclic loading on the suture line of the repair can progressively damage the surrounding tissue and finally cause tissue rupture. Moreover, mechanical over-tension, which occurs in a diseased mitral valve, gradually leads to tissue floppiness, mitral annular dilation, and leaflet rupture. In this work, the rupture mechanics of mitral valve is studied by characterizing the fracture toughness exhaustion of healthy tissue. Results of this study show that fracture toughness of the posterior mitral valve is lower than its anterior counterpart, indicating that posterior tissue is more prone to failure. Moreover, the decrease in fracture toughness by increasing the number of fatigue cycles shows that excessive mechanical loading leads to progressive failure and rupture of mitral valve tissue within a damage accumulative process.

Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy.

The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. Here we describe an oral dosage form composed of distinct drug-polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases. In sum, weekly administration of long-acting antiretrovirals via a novel oral dosage form is a promising intervention to help control the HIV epidemic worldwide.

Flexible piezoelectric devices for gastrointestinal motility sensing.

Improvements in ingestible electronics with the capacity to sense physiological and pathophysiological states have transformed the standard of care for patients. Yet, despite advances in device development, significant risks associated with solid, non-flexible gastrointestinal transiting systems remain. Here, we report the design and use of an ingestible, flexible piezoelectric device that senses mechanical deformation within the gastric cavity. We demonstrate the capabilities of the sensor in both in vitro and ex vivo simulated gastric models, quantify its key behaviours in the gastrointestinal tract using computational modelling and validate its functionality in awake and ambulating swine. Our proof-of-concept device may lead to the development of ingestible piezoelectric devices that might safely sense mechanical variations and harvest mechanical energy inside the gastrointestinal tract for the diagnosis and treatment of motility disorders, as well as for monitoring ingestion in bariatric applications.

Architected Materials with Ultra-Low Porosity for Vibration Control.

Periodic structures with extremely low porosities capable of forming large band gaps-frequency ranges with strong wave attenuation-are designed by patterning an elastic sheet with an array of alternating crack-like pores separated by small ligaments. The results indicate that the presence and size of the band gaps are controlled by the smallest geometric -feature in the system (which can be easily controlled by tuning the aspect ratio of the pores), providing an important guideline for the design of systems with the -desired response.

Dimpled elastic sheets: a new class of non-porous negative Poisson's ratio materials.

In this study, we report a novel periodic material with negative Poisson's ratio (also called auxetic materials) fabricated by denting spherical dimples in an elastic flat sheet. While previously reported auxetic materials are either porous or comprise at least two phases, the material proposed here is non-porous and made of a homogeneous elastic sheet. Importantly, the auxetic behavior is induced by a novel mechanism which exploits the out-of-plane deformation of the spherical dimples. Through a combination of experiments and numerical analyses, we demonstrate the robustness of the proposed concept, paving the way for developing a new class of auxetic materials that significantly expand their design space and possible applications.

Nanoscale viscoelasticity of extracellular matrix proteins in soft tissues: A multiscale approach.

It is hypothesized that the bulk viscoelasticity of soft tissues is determined by two length-scale-dependent mechanisms: the time-dependent response of the extracellular matrix (ECM) proteins at the nanometer scale and the biophysical interactions between the ECM solid structure and interstitial fluid at the micrometer scale. The latter is governed by poroelasticity theory assuming free motion of the interstitial fluid within the porous ECM structure. In a recent study (Heris, H.K., Miri, A.K., Tripathy, U., Barthelat, F., Mongeau, L., 2013. J. Mech. Behav. Biomed. Mater.), atomic force microscopy was used to measure the response of porcine vocal folds to a creep loading and a 50-nm sinusoidal oscillation. A constitutive model was calibrated and verified using a finite element model to accurately predict the nanoscale viscoelastic moduli of ECM. A generally good correlation was obtained between the predicted variation of the viscoelastic moduli with depth and that of hyaluronic acids in vocal fold tissue. We conclude that hyaluronic acids may regulate vocal fold viscoelasticity. The proposed methodology offers a characterization tool for biomaterials used in vocal fold augmentations.