Bio-Inspired Drug Delivery Noting that platelets naturally migrate to narrowed blood vessels characterized by high fluid shear stress, Korin et al. (p. 738 , published online 5 July; see the Perspective by Lavik and Ustin ) developed a nanoparticle-based therapeutic that uses a similar targeting mechanism to deliver a drug to vessels obstructed by blood clots. Aggregates of nanoparticles coated with the clot-dissolving drug tPA (tissue plasminogen activator) were designed to fall apart and release the drug only when encountering high fluid shear stress. In preclinical models, the bio-inspired therapeutic dissolved clots and restored normal blood flow at lower doses than free tPA, suggesting that this localized delivery system may help reduce the risk of side effects such as excessive bleeding.

Injectable biomaterials are increasingly being explored to minimize risks and complications associated with surgical implantation. We describe a strategy for delivery via conventional needle-syringe injection of large preformed macroporous scaffolds with well-defined properties. Injectable 3D scaffolds, in the form of elastic sponge-like matrices, were prepared by environmentally friendly cryotropic gelation of a naturally sourced polymer. Cryogels with shape-memory properties may be molded to a variety of shapes and sizes, and may be optionally loaded with therapeutic agents or cells. These scaffolds have the capability to withstand reversible deformations at over 90% strain level, and a rapid volumetric recovery allows the structurally defined scaffolds to be injected through a small-bore needle with nearly complete geometric restoration once delivered. These gels demonstrated long-term release of biomolecules in vivo. Furthermore, cryogels impregnated with bioluminescent reporter cells provided enhanced survival, higher local retention, and extended engraftment of transplanted cells at the injection site compared with a standard injection technique. These injectable scaffolds show great promise for various biomedical applications, including cell therapies.syringe-injectable hydrogels | cryogelation | shape retention | controlled delivery | cell therapy H ydrogels are 3D networks that can absorb a large amount of water while maintaining their structural integrity. They are considered as appropriate scaffolds for tissue engineering applications mainly due to their structural similarities with native soft tissue, and are widely used as soft materials in many biomedical applications including cell culture, cell encapsulation, controlled delivery of therapeutic agents, and medical device fabrication (1-6).Hydrogels typically exhibit a nanoporous network structure, but it is advantageous to use hydrophilic networks with large interconnected pores (>10 μm) to allow cell infiltration and deployment, and provide an increased surface area for cell attachment and interaction. As a result, macroporous hydrogel scaffolds have been developed using various techniques such as fiber bonding, gas foaming, microemulsion formation, phase separation, freeze-drying, and porogen leaching (7-15). More recently, gelation at subzero temperatures, known as cryogelation, has been used to create hydrogels with large interconnected pores (16-18). During cryogelation, the reactants are restricted to the unfrozen/semifrozen phases and form a cross-linked network upon polymerization, while the ice crystals nucleated from the aqueous phase during freezing function as porogens. The melting of these ice crystals at temperature above the freezing temperature gives rise to interconnected macroporous networks. Cryogels typically exhibit enhanced mechanical stability with respect to traditional hydrogels (17). Recent studies have shown the potential application of cryogels as tissue engineering scaffolds (19)(20)(21).Due to the trauma resulting fro...

A biomaterial-based vaccination system that uses minimal extracorporeal manipulation could provide in situ enhancement of dendritic cell (DC) numbers, a physical space where DCs interface with transplanted tumor cells, and an immunogenic context. Here we encapsulate GM-CSF, serving as a DC enhancement factor, and CpG ODN, serving as a DC activating factor, into sponge-like macroporous cryogels. These cryogels are injected subcutaneously into mice to localize transplanted tumor cells and deliver immunomodulatory factors in a controlled spatio-temporal manner. These vaccines elicit local infiltrates composed of conventional and plasmacytoid DCs, with the subsequent induction of potent, durable, and specific anti-tumor T cell responses in a melanoma model. These cryogels can be delivered in a minimally invasive manner, bypass the need for genetic modification of transplanted cancer cells, and provide sustained release of immunomodulators. Altogether, these findings indicate the potential for cryogels to serve as a platform for cancer cell vaccinations.

T he majority of the patients having an emergent large vessel occlusion (ELVO) may develop severe and permanent neurological morbidity or death without urgent and successful treatment. Recently published randomized clinical trials have all shown that intra-arterial (IA) treatments in combination with intravenous recombinant tissuetype plasminogen activator (r-tPA) when indicated leads to improved clinical outcomes as compared with standard medical therapy alone. [1][2][3][4] Compared with prior randomized trials that showed no benefit for IA treatment, 5-7 most patients enrolled in these studies received stent-retriever mechanical thrombectomy (MT) that resulted in higher rates of modified thrombolysis in cerebral infarction score (mTICI) 2b or 3 recanalization. Despite high rates of successful recanalization, nearly half of the patients remained functionally dependent (mRS≥3) after 90 days.Background and Purpose-The goal of this study is to combine temporary endovascular bypass (TEB) with a novel shearactivated nanotherapeutic (SA-NT) that releases recombinant tissue-type plasminogen activator (r-tPA) when exposed to high levels of hemodynamic stress and to determine if this approach can be used to concentrate r-tPA at occlusion sites based on high shear stresses created by stent placement. Methods-A rabbit model of carotid vessel occlusion was used to test the hypothesis that SA-NT treatment coupled with TEB provides high recanalization rates while reducing vascular injury. We evaluated angiographic recanalization with TEB alone, intra-arterial delivery of soluble r-tPA alone, or TEB combined with 2 doses of intra-arterial infusion of either the SA-NT or soluble r-tPA. Vascular injury was compared against stent-retriever thrombectomy. Results-Shear-targeted delivery of r-tPA using the SA-NT resulted in the highest rate of complete recanalization when compared with controls (P=0.0011). SA-NT (20 mg) had a higher likelihood of obtaining complete recanalization as compared with TEB alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), intra-arterial r-tPA alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), or TEB with soluble r-tPA (2 mg; odds ratio 18.78, 95% confidence interval 1. 28, 275.05; P=0.0322). Histological analysis showed circumferential loss of endothelium restricted to the area where the TEB was deployed; however, there was significantly less vascular injury using a TEB as compared with stent-retriever procedure (odds ratio 12.97, 95% confidence interval 8.01, 21.02; P<0.0001). Conclusions-A novel intra-arterial, nanoparticle-based thrombolytic therapy combined with TEB achieves high rates of complete recanalization. Moreover, this approach reduces vascular trauma as compared with stent-retriever thrombectomy. 14 This observation is supported by results of histopathologic exams from animal studies, where extensive endothelial damage was observed after stent retriever usage. [15][16][17] Focal denudation of the vascular endothelium results in exposure of a hi...