Marine-Inspired Polymers in Medical Adhesion.

Medical adhesives that are strong, easy to apply and biocompatible are promising alternatives to sutures and staples in a large variety of surgical and clinical procedures. Despite progress in the development and regulatory approval of adhesives for use in the clinic, adhesion to wet tissue remains challenging. Marine organisms have evolved a diverse set of highly effective wet adhesive approaches that have inspired the design of new medical adhesives. Here we provide an overview of selected marine animals and their chemical and physical adhesion strategies, the state of clinical translation of adhesives inspired by these organisms, and target applications where marine-inspired adhesives can have a significant impact. We will focus on medical adhesive polymers inspired by mussels, sandcastle worms, and cephalopods, emphasize the history of bioinspired medical adhesives from the peer reviewed and patent literature, and explore future directions including overlooked sources of bioinspiration and materials that exploit multiple bioinspired strategies.

A quantitative framework for the forward design of synthetic miRNA circuits.

Synthetic genetic circuits incorporating regulatory components based on RNA interference (RNAi) have been used in a variety of systems. A comprehensive understanding of the parameters that determine the relationship between microRNA (miRNA) and target expression levels is lacking. We describe a quantitative framework supporting the forward engineering of gene circuits that incorporate RNAi-based regulatory components in mammalian cells. We developed a model that captures the quantitative relationship between miRNA and target gene expression levels as a function of parameters, including mRNA half-life and miRNA target-site number. We extended the model to synthetic circuits that incorporate protein-responsive miRNA switches and designed an optimized miRNA-based protein concentration detector circuit that noninvasively measures small changes in the nuclear concentration of ß-catenin owing to induction of the Wnt signaling pathway. Our results highlight the importance of methods for guiding the quantitative design of genetic circuits to achieve robust, reliable and predictable behaviors in mammalian cells.

Supramolecular Cross-Links in Mussel-Inspired Tissue Adhesives.

Here we introduce a tissue-adhesive patch with orthogonal cohesive and adhesive chemistries; supramolecular ureido-4-pyrimidinone (UPy) cross-links provide cohesive strength, and catechols provide mussel-inspired tissue adhesion. In the development of tissue-adhesive biomaterials, prior research has focused on forming strong adhesive interfaces in wet conditions, leaving the use of supramolecular cross-links for cohesive strength underexplored. In developing this adhesive patch, the influence of the comonomers' composition and amphiphilicity on adhesion was investigated by lap shear adhesion to wet tissue. We determined failed lap joints' failure mechanism using catechol-specific Arnow's stain and identified formulations with improved cohesive strength. The adhesive materials were cytocompatible in mammalian cell conditioned media viability studies. We found that using orthogonal motifs to independently control adhesives' cohesive and adhesive strengths resulted in stronger tissue adhesion. The design principles presented here advance the development of wet tissue adhesives and could allow for the future design of biomaterials with desirable stimuli-responsive properties.

Laser-induced graphitization of polydopamine leads to enhanced mechanical performance while preserving multifunctionality.

Polydopamine (PDA) is a simple and versatile conformal coating material that has been proposed for a variety of uses; however in practice its performance is often hindered by poor mechanical properties and high roughness. Here, we show that blue-diode laser annealing dramatically improves mechanical performance and reduces roughness of PDA coatings. Laser-annealed PDA (LAPDA) was shown to be >100-fold more scratch resistant than pristine PDA and even better than hard inorganic substrates, which we attribute to partial graphitization and covalent coupling between PDA subunits during annealing. Moreover, laser annealing provides these benefits while preserving other attractive properties of PDA, as demonstrated by the superior biofouling resistance of antifouling polymer-grafted LAPDA compared to PDA modified with the same polymer. Our work suggests that laser annealing may allow the use of PDA in mechanically demanding applications previously considered inaccessible, without sacrificing the functional versatility that is so characteristic of PDA.

Biomaterials in fetal surgery.

Fetal surgery and fetal therapy involve surgical interventions on the fetus in utero to correct or ameliorate congenital abnormalities and give a developing fetus the best chance at a healthy life. Historical use of biomaterials in fetal surgery has been limited, and most biomaterials used in fetal surgeries today were originally developed for adult or pediatric patients. However, as the field of fetal surgery moves from open surgeries to minimally invasive procedures, many opportunities exist for innovative biomaterials engineers to create materials designed specifically for the unique challenges and opportunities of maternal-fetal surgery. Here, we review biomaterials currently used in clinical fetal surgery as well as promising biomaterials in development for eventual clinical translation. We also highlight unmet challenges in fetal surgery that could particularly benefit from novel biomaterials, including fetal membrane sealing and minimally invasive myelomeningocele defect repair. Finally, we conclude with a discussion of the underdeveloped fetal immune system and opportunities for exploitation with novel immunomodulating biomaterials.

Synthetic feedback control using an RNAi-based gene-regulatory device.

BACKGROUND: Homeostasis within mammalian cells is achieved through complex molecular networks that can respond to changes within the cell or the environment and regulate the expression of the appropriate genes in response. The development of biological components that can respond to changes in the cellular environment and interface with endogenous molecules would enable more sophisticated genetic circuits and greatly advance our cellular engineering capabilities. RESULTS: Here we describe a platform that combines a ligand-responsive ribozyme switch and synthetic miRNA regulators to create an OFF genetic control device based on RNA interference (RNAi). We developed a mathematical model to highlight important design parameters in programming the quantitative performance of RNAi-based OFF control devices. By modifying the ribozyme switch integrated into the system, we demonstrated RNAi-based OFF control devices that respond to small molecule and protein ligands, including the oncogenic protein E2F1. We utilized the OFF control device platform to build a negative feedback control system that acts as a proportional controller and maintains target intracellular protein levels in response to increases in transcription rate. CONCLUSIONS: Our work describes a novel genetic device that increases the level of silencing from a miRNA in the presence of a ligand of interest, effectively creating an RNAi-based OFF control device. The OFF switch platform has the flexibility to be used to respond to both small molecule and protein ligands. Finally, the RNAi-based OFF switch can be used to implement a negative feedback control system, which maintains target protein levels around a set point level. The described RNAi-based OFF control device presents a powerful tool that will enable researchers to engineer homeostasis in mammalian cells.