Reginald K. Avery

Shear-thinning nanocomposite hydrogels for the treatment of hemorrhage.

Internal hemorrhaging is a leading cause of death after traumatic injury on the battlefield. Although several surgical approaches such as the use of fibrin glue and tissue adhesive have been commercialized to achieve hemostasis, these approaches are difficult to employ on the battlefield and cannot be used for incompressible wounds. Here, we present shear-thinning nanocomposite hydrogels composed of synthetic silicate nanoplatelets and gelatin as injectable hemostatic agents. These materials are demonstrated to decrease in vitro blood clotting times by 77%, and to form stable clot-gel systems. In vivo tests indicated that the nanocomposites are biocompatible and capable of promoting hemostasis in an otherwise lethal liver laceration. The combination of injectability, rapid mechanical recovery, physiological stability, and the ability to promote coagulation result in a hemostat for treating incompressible wounds in out-of-hospital, emergency conditions.

An injectable shear-thinning biomaterial for endovascular embolization

An engineered shear-thinning biomaterial is used as an embolic agent for vascular occlusion as treatment for bleeding. Stopping blood in its tracks Effective treatments for ruptured blood vessels must be rapidly deployed to promote hemostasis. Avery et al. formulated a gelatin and silicate nanoplatelet hydrogel material that occluded blood flow without requiring thrombus formation. When injected into arteries and veins in mice and pigs, the biomaterial occluded blood flow without evidence of fragmentation or displacement for up to 24 days. Occluded vessels showed evidence of connective tissue replacing the biomaterial in the vessel lumen. Shear-thinning biomaterials represent promising alternatives for stable endovascular embolization. Improved endovascular embolization of vascular conditions can generate better patient outcomes and minimize the need for repeat procedures. However, many embolic materials, such as metallic coils or liquid embolic agents, are associated with limitations and complications such as breakthrough bleeding, coil migration, coil compaction, recanalization, adhesion of the catheter to the embolic agent, or toxicity. Here, we engineered a shear-thinning biomaterial (STB), a nanocomposite hydrogel containing gelatin and silicate nanoplatelets, to function as an embolic agent for endovascular embolization procedures. STBs are injectable through clinical catheters and needles and have hemostatic activity comparable to metallic coils, the current gold standard. In addition, STBs withstand physiological pressures without fragmentation or displacement in elastomeric channels in vitro and in explant vessels ex vivo. In vitro experiments also indicated that STB embolization did not rely on intrinsic thrombosis as coils did for occlusion, suggesting that the biomaterial may be suitable for use in patients on anticoagulation therapy or those with coagulopathy. Using computed tomography imaging, the biomaterial was shown to fully occlude murine and porcine vasculature in vivo and remain at the site of injection without fragmentation or nontarget embolization. Given the advantages of rapid delivery, in vivo stability, and independent occlusion that does not rely on intrinsic thrombosis, STBs offer an alternative gel-based embolic agent with translational potential for endovascular embolization.

Toughening of Thermoresponsive Arrested Networks of Elastin-Like Polypeptides To Engineer Cytocompatible Tissue Scaffolds

Formulation of tissue engineering or regenerative scaffolds from simple bioactive polymers with tunable structure and mechanics is crucial for the regeneration of complex tissues, and hydrogels from recombinant proteins, such as elastin-like polypeptides (ELPs), are promising platforms to support these applications. The arrested phase separation of ELPs has been shown to yield remarkably stiff, biocontinuous, nanostructured networks, but these gels are limited in applications by their relatively brittle nature. Here, a gel-forming ELP is chain-extended by telechelic oxidative coupling, forming extensible, tough hydrogels. Small angle scattering indicates that the chain-extended polypeptides form a fractal network of nanoscale aggregates over a broad concentration range, accessing moduli ranging from 5 kPa to over 1 MPa over a concentration range of 5-30 wt %. These networks exhibited excellent erosion resistance and allowed for the diffusion and release of encapsulated particles consistent with a bicontinuous, porous structure with a broad distribution of pore sizes. Biofunctionalized, toughened networks were found to maintain the viability of human mesenchymal stem cells (hMSCs) in 2D, demonstrating signs of osteogenesis even in cell media without osteogenic molecules. Furthermore, chondrocytes could be readily mixed into these gels via thermoresponsive assembly and remained viable in extended culture. These studies demonstrate the ability to engineer ELP-based arrested physical networks on the molecular level to form reinforced, cytocompatible hydrogel matrices, supporting the promise of these new materials as candidates for the engineering and regeneration of stiff tissues.

Thermoresponsive and Mechanical Properties of Poly(l-proline) Gels

Gelation of the left helical N-substituted homopolypeptide poly(L-proline) (PLP) in water was explored, employing rheological and small-angle scattering studies at different temperatures and concentrations in order to investigate the network structure and its mechanical properties. Stiff gels were obtained at 10 wt % or higher at 5 °C, the first time gelation has been observed for homopolypeptides. The secondary structure and helical rigidity of PLP has large structural similarities to gelatin but as gels the two materials show contrasting trends with temperature. With increasing temperature in D2O, the network stiffens, with broad scattering features of similar correlation length for all concentrations and molar masses of PLP. A thermoresponsive transition was also achieved between 5 and 35 °C, with moduli at 35 °C higher than gelatin at 5 °C. The brittle gels could tolerate strains of 1% before yielding with a frequency-independent modulus over the observed range, similar to natural proline-rich proteins, suggesting the potential for thermoresponsive or biomaterial-based applications.

Endovascular Embolization by Transcatheter Delivery of Particles: Past, Present, and Future

Minimally invasive techniques to occlude flow within blood vessels, initially pioneered in the 1970s with autologous materials and subsequently advanced with increasingly sophisticated engineered biomaterials, are routinely performed for a variety of medical conditions. Contemporary interventional radiologists have at their disposal a wide armamentarium of occlusive agents to treat a range of disease processes through a small incision in the skin. In this review, we provide a historical perspective on endovascular embolization tools, summarize the current state-of-the-art, and highlight burgeoning technologies that promise to advance the field in the near future.

Chaotic printing: using chaos to fabricate densely packed micro- and nanostructures at high resolution and speed

Nature generates densely packed micro- and nanostructures to enable key functionalities in cells, tissues, and other materials. Current fabrication techniques, due to limitations in resolution and speed, are far less effective at creating microstructures. Yet, the development of extensive amounts of surface area per unit volume will enable applications and manufacturing strategies not possible today. Here, we introduce chaotic printing—the use of chaotic flows for the rapid generation of complex, high-resolution microstructures. A simple and deterministic chaotic flow is induced in a viscous liquid, and its repeated stretching and folding action deforms an “ink” (i.e., a drop of a miscible liquid, fluorescent beads, or cells) at an exponential rate to render a densely packed lamellar microstructure that is then preserved by curing or photocrosslinking. This exponentially fast creation of fine microstructures exceeds the limits of resolution and speed of the currently available 3D printing techniques. Moreover, we show that the architecture of the microstructure to be created with chaotic printing can be predicted by mathematical modelling. We envision diverse applications for this technology, including the development of densely packed catalytic surfaces and highly complex multi-lamellar and multi-component tissue-like structures for biomedical and electronics applications.