David Mooney

Stem cell‐derived kidney organoids contain nephron segments that recapitulate morphological and functional aspects of the human kidney. However, directed differentiation protocols for kidney organoids are largely conducted using biochemical signals to control differentiation. Here, the hypothesis that mechanical signals regulate nephrogenesis is investigated in 3D culture by encapsulating kidney organoids within viscoelastic alginate hydrogels with varying rates of stress relaxation. Tubular nephron segments are significantly more convoluted in kidney organoids differentiated in encapsulating hydrogels when compared with those in suspension culture. Hydrogel viscoelasticity regulates the spatial distribution of nephron segments within the differentiating kidney organoids. Consistent with these observations, a particle‐based computational model predicts that the extent of deformation of the hydrogel–organoid …

Generating strong rapid adhesion between hydrogels has the potential to advance the capabilities of modern medicine and surgery. Current hydrogel adhesion technologies rely primarily on liquid-based diffusion mechanisms and the formation of covalent bonds, requiring prolonged time to generate adhesion. Here, we present a simple and versatile strategy using dry chitosan polymer films to generate instant adhesion between hydrogel–hydrogel and hydrogel–elastomer surfaces. Using this approach we can achieve extremely high adhesive energies (>3,000 J/m2), which are governed by pH change and non-covalent interactions including H-bonding, Van der Waals forces, and bridging polymer entanglement. Potential examples of biomedical applications are presented, including local tissue cooling, vascular sealing, prevention of surgical adhesions, and prevention of hydrogel dehydration. We expect these …

Complete sequestration of central nervous system tissue and cerebrospinal fluid by the dural membrane is fundamental to maintaining homeostasis and proper organ function, making reconstruction of this layer an essential step during neurosurgery. Primary closure of the dura by suture repair is the current standard, despite facing technical, microenvironmental, and anatomic challenges. Here, we apply a mechanically tough hydrogel paired with a bioadhesive for intraoperative sealing of the dural membrane in rodent, porcine, and human central nervous system tissue. Tensile testing demonstrated that this dural tough adhesive (DTA) exhibited greater toughness with higher maximum stress and stretch compared with commercial sealants in aqueous environments. To evaluate the performance of DTA in the range of intracranial pressure typical of healthy and disease states, ex vivo burst pressure testing was …

Dermal wounds and their healing are a collection of complex, multistep processes which are poorly recapitulated by existing 2D in vitro platforms. Biomaterial scaffolds that support the 3D growth of cell cultures can better resemble the native dermal environment, while bioelectronics has been used as a tool to modulate cell proliferation, differentiation, and migration. A porous conductive hydrogel scaffold which mimics the properties of dermis, while promoting the viability and growth of fibroblasts is described. As these scaffolds are also electrically conductive, the application of exogenous electrical stimulation directs the migration of cells across and/or through the material. The mechanical properties of the scaffold, as well as the amplitude and/or duration of the electrical pulses, are independently tunable and further influence the resulting fibroblast networks. This biomaterial platform may enable better recapitulation …

Medical adhesives are arising as an important clinical tool as adjuvants for sutures and staples in wound closure and healing, and in the achievement of hemostasis. However, clinical adhesives combining cytocompatibility, as well as strong and stable adhesion in physiological conditions are still in demand. Herein, a mussel‐inspired strategy is explored to produce adhesive coacervates using tannic acid (TA) and methacrylate pullulan (PUL‐MA). TA|PUL‐MA coacervates mainly comprise van der Waals forces and hydrophobic interactions. The methacrylic groups in PUL backbone increase the number of interactions in the adhesives matrix, resulting in enhanced cohesion and adhesion strength (72.7 Jm−2), comparing to the non‐methacrylated coacervate. The adhesive properties were kept in physiologic‐mimetic solutions (72.8 Jm−2) for 72 h. The photopolymerization of TA|PUL‐MA enabled the on‐demand …

Multivalent presentation of ligands often enhances receptor activation and downstream signalling. DNA origami offers a precise nanoscale spacing of ligands, a potentially useful feature for therapeutic nanoparticles. Here we use a square-block DNA origami platform to explore the importance of the spacing of CpG oligonucleotides. CpG engages Toll-like receptors and therefore acts to activate dendritic cells. Through in vitro cell culture studies and in vivo tumour treatment models, we demonstrate that square blocks induce Th1 immune polarization when CpG is spaced at 3.5 nm. We observe that this DNA origami vaccine enhances DC activation, antigen cross-presentation, CD8 T-cell activation, Th1-polarized CD4 activation and natural-killer-cell activation. The vaccine also effectively synergizes with anti-PD-L1 for improved cancer immunotherapy in melanoma and lymphoma models and induces long-term T …

FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4, 5-dihydroxy-6-(phosphanyloxy) oxan-3-yl] oxy}-4, 5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C (C (O)= O) C (P) C (O) C (O) C1OC1C (C (O)= O) OC (OP) C (O) C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 55

Adoptive T cell immunotherapies, including engineered T cell receptor (eTCR) and chimeric antigen receptor (CAR) T cell immunotherapies, have shown efficacy in treating a subset of hematologic malignancies, exhibit promise in solid tumors, and have many other potential applications, such as in fibrosis, autoimmunity, and regenerative medicine. While immunoengineering has focused on designing biomaterials to present biochemical cues to manipulate T cells ex vivo and in vivo, mechanical cues that regulate their biology have been largely underappreciated. This review highlights the contributions of mechanical force to several receptor–ligand interactions critical to T cell function, with central focus on the TCR–peptide-loaded major histocompatibility complex (pMHC). We then emphasize the role of mechanical forces in (i) allosteric strengthening of the TCR–pMHC interaction in amplifying ligand discrimination …