In situ forming macroporous biohybrid hydrogel for nucleus pulposus cell delivery.

Degenerative intervertebral disc disease is a common source of chronic pain and reduced quality of life in people over the age of 40. While degeneration occurs throughout the disc, it most often initiates in the nucleus pulposus (NP). Minimally invasive delivery of NP cells within hydrogels that can restore and maintain the disc height while regenerating the damaged NP tissue is a promising treatment strategy for this condition. Towards this goal, a biohybrid ABA dimethacrylate triblock copolymer was synthesized, possessing a lower critical solution temperature below 37 °C and which contained as its central block an MMP-degradable peptide flanked by poly(trimethylene carbonate) blocks bearing pendant oligoethylene glycol groups. This triblock prepolymer was used to form macroporous NP cell-laden hydrogels via redox initiated (ammonium persulfate/sodium bisulfite) crosslinking, with or without the inclusion of thiolated chondroitin sulfate. The resulting macroporous hydrogels had water and mechanical properties similar to those of human NP tissue and were mechanically resilient. The hydrogels supported NP cell attachment and growth over 28 days in hypoxic culture. In hydrogels prepared with the triblock copolymer but without the chondroitin sulfate the NP cells were distributed homogeneously throughout in clusters and deposited collagen type II and sulfated glycosaminoglycans but not collagen type I. This hydrogel formulation warrants further investigation as a cell delivery vehicle to regenerate degenerated NP tissue. STATEMENT OF SIGNIFICANCE: The intervertebral disc between the vertebral bones of the spine consists of three regions: a gel-like central nucleus pulposus (NP) within the annulus fibrosis, and bony endplates. Degeneration of the intervertebral disc is a source of chronic pain in the elderly and most commonly initiates in the NP. Replacement of degenerated NP tissue with a NP cell-laden hydrogel is a promising treatment strategy. Herein we demonstrate that a crosslinkable polymer with a lower critical solution temperature below 37 °C can be used to form macroporous hydrogels for this purpose. The hydrogels are capable of supporting NP cells, which deposit collagen II and sulfated glycosaminoglycans, while also possessing mechanical properties matching those of human NP tissue.

Adhesive Wearable Sensors for Electroencephalography from Hairy Scalp.

Electroencephalography has garnered interest for applications in mobile healthcare, human-machine interfaces, and Internet of Things. Conventional electroencephalography relies on wet and dry electrodes. Despite favorable interface impedance of wet electrodes and skin, the application of a large amount of gel at their interface with skin limits the electroencephalography spatial resolution, increases the risk of shorting between electrodes, and makes them unsuited for long-term mobile recording. In contrast, dry electrodes are better suited for long-term recordings but susceptible to motion artifacts. In addition, both wet and dry electrodes are non-adhesive to the hairy scalp and mechanical support, or chemical adhesives are used to hold them in place. Herein, a conical microstructure array (CMSA) based sensor made of carbon nanotube-polydimethylsiloxane composite is reported. The CMSA sensor is fabricated using the innovative, cost-effective, and scalable method of viscosity-controlled dip-pull process. The sensor adheres to the hairy scalp by generating negative pressure in its conical microstructures when it is pressed against scalp. Aided by the application of a trace amount of gel, CMSA sensor establishes good electrical contact with the skin, enabling its applications in mobile electroencephalography over extended periods. Notably, the signal quality of CMSA sensors is comparable to that of medical-grade wet gel electrodes.

One-Pot Synthesis of Unsaturated Polyester Bioelastomer with Controllable Material Curing for Microscale Designs.

Synthetic polyester elastomeric constructs have become increasingly important for a range of healthcare applications, due to tunable soft elastic properties that mimic those of human tissues. A number of these constructs require intricate mechanical design to achieve a tunable material with controllable curing. Here, the synthesis and characterization of poly(itaconate-co-citrate-co-octanediol) (PICO) is presented, which exhibits tunable formation of elastomeric networks through radical crosslinking of itaconate in the polymer backbone of viscous polyester gels. Through variation of reaction times and monomer molar composition, materials with modulation of a wide range of elasticity (36-1476 kPa) are generated, indicating the tunability of materials to specific elastomeric constructs. This correlated with measured rapid and controllable gelation times. As a proof of principle, scaffold support for cardiac tissue patches is developed, which presents visible tissue organization and viability with appropriate elastomeric support from PICO materials. These formulations present potential application in a range of healthcare applications with requirement for elastomeric support with controllable, rapid gelation under mild conditions.

High modulus, enzyme-degradable poly(trimethylene carbonate)-peptide biohybrid networks formed from triblock prepolymers.

Biohybrid networks have the potential to have stiffnesses equivalent to that of native soft connective tissues as well as cell-mediated degradation behavior. Most strategies to generate such materials to date have utilized crosslinking of two separate and orthogonally functionalized polymers. Herein we describe a triblock prepolymer consisting of a central enzyme degradable peptide block flanked by two synthetic, hydrolysis resistant poly(trimethylene carbonate) blocks (PTMC) or poly(ethylene glycol)-PTMC blocks terminated in methacrylate groups. To form these prepolymers heterobifunctional PTMC and PEG-PTMC were prepared, possessing a vinyl sulfone terminus and a methacrylate terminus. These polymers were conjugated to a di-cysteine containing peptide through a Michael-type addition to form cross-linkable prepolymers. These prepolymers were then photo-cured to form enzyme degradable networks. The compressive moduli of the resulting water swollen networks was within the range of many soft connective tissues and was inversely proportional to the water solubility of the prepolymers. The prepolymer water solubility in turn could be tuned by adjusting PTMC molecular weight or by the addition of a PEG block. In vitro degradation only occurred in the presence of matrix metalloproteinases, and was fastest for networks prepared with prepolymers of higher water solubility.

Combinatorial and sequential delivery of gemcitabine and oseltamivir phosphate from implantable poly(d,l-lactic-co-glycolic acid) cylinders disables human pancreatic cancer cell survival.

Combination therapies against multiple targets are currently being developed to prevent resistance to a single chemotherapeutic agent and to extirpate pre-existing resistance in heterogeneous cancer cells in tumors due to selective pressure from the single agent. Gemcitabine (GEM), a chemotherapeutic agent, is the current standard of care for patients with pancreatic cancer. Patients with pancreatic cancer receiving GEM have a low progression-free survival. Given the poor response rate to GEM, cancer cells are known to develop rapid resistance to this drug. Metronomic chemotherapy using combinatorial and sequential delivery systems are novel developmental approaches to disrupt tumor neovascularization, reduce systemic drug toxicity, and increase the sensitivity of chemotherapeutics in cancer. Here, implantable double-layered poly(d,l-lactic-co-glycolic acid) (PLGA) cylinders were engineered to sequentially release GEM in combination with oseltamivir phosphate (OP) over an extended time. Double-layered PLGA cylindrical implants loaded with these active hydrophilic drugs were fabricated with minimal loss of drugs during the formulation, enabling extensive control of drug loading and establishing uniform drug distribution throughout the polymer matrix. OP is used in the formulation because of its anticancer drug properties targeting mammalian neuraminidase 1 (Neu1) involved in multistage tumorigenesis. OP and GEM encapsulated in inner/outer GEMin/OPout or OPin/GEMout implantable double-layered PLGA cylinders displayed sustained near linear release over 30 days. OP and GEM released from the double-layered PLGA cylinders effectively reduced cell viability in pancreatic cancer cell line PANC1 and its GEM-resistant variant for up to 15 days.