Enhanced tendon healing by a tough hydrogel with an adhesive side and high drug-loading capacity.

Hydrogels that provide mechanical support and sustainably release therapeutics have been used to treat tendon injuries. However, most hydrogels are insufficiently tough, release drugs in bursts, and require cell infiltration or suturing to integrate with surrounding tissue. Here we report that a hydrogel serving as a high-capacity drug depot and combining a dissipative tough matrix on one side and a chitosan adhesive surface on the other side supports tendon gliding and strong adhesion (larger than 1,000 J m-2) to tendon on opposite surfaces of the hydrogel, as we show with porcine and human tendon preparations during cyclic-friction loadings. The hydrogel is biocompatible, strongly adheres to patellar, supraspinatus and Achilles tendons of live rats, boosted healing and reduced scar formation in a rat model of Achilles-tendon rupture, and sustainably released the corticosteroid triamcinolone acetonide in a rat model of patellar tendon injury, reducing inflammation, modulating chemokine secretion, recruiting tendon stem and progenitor cells, and promoting macrophage polarization to the M2 phenotype. Hydrogels with 'Janus' surfaces and sustained-drug-release functionality could be designed for a range of biomedical applications.

Degradable and Removable Tough Adhesive Hydrogels.

The development of tough adhesive hydrogels has enabled unprecedented adhesion to wet and moving tissue surfaces throughout the body, but they are typically composed of nondegradable components. Here, a family of degradable tough adhesive hydrogels containing ≈90% water by incorporating covalently networked degradable crosslinkers and hydrolyzable ionically crosslinked main-chain polymers is developed. Mechanical toughness, adhesion, and degradation of these new formulations are tested in both accelerated in vitro conditions and up to 16 weeks in vivo. These degradable tough adhesives are engineered with equivalent mechanical and adhesive properties to nondegradable tough adhesives, capable of achieving stretches >20 times their initial length, fracture energies >6 kJ m-2 , and adhesion energies >1000 J m-2 . All degradable systems show complete degradation within 2 weeks under accelerated aging conditions in vitro and weeks to months in vivo depending on the degradable crosslinker selected. Excellent biocompatibility is observed for all groups after 1, 2, 4, 8, and 16 weeks of implantation, with minimal fibrous encapsulation and no signs of organ toxicity. On-demand removal of the adhesive is achieved with treatment of chemical agents which do not cause damage to underlying skin tissue in mice. The broad versatility of this family of adhesives provides the foundation for numerous in vivo indications.

Novelty preferences and cocaine-associated cues influence regions associated with the salience network in juvenile female rats.

Preferences for novel environments (novelty-seeking) is a risk factor for addiction, with little known about its underlying circuitry. Exposure to drug cues facilitates addiction maintenance, leading us to hypothesize that exposure to a novel environment activates a shared neural circuitry. Stimulation of the D1 receptor in the prelimbic cortex increases responsivity to drug-associated environments. Here, we use D1 receptor overexpression in the prelimbic cortex to probe brain responses to novelty-preferences (in a free-choice paradigm) and cocaine-associated odors following place conditioning. These same cocaine-conditioned odors were used to study neural circuitry with Blood Oxygen Level Dependent (BOLD) activity. D1 overexpressing females had deactivated BOLD signals related to novelty-preferences within the insula cortex and amygdala and activation in the frontal cortex and dopamine cell bodies. BOLD responses to cocaine cues were also sensitive to D1. Control females demonstrated a place preference for cocaine environments with no significant BOLD response, while D1 overexpressing females demonstrated a place aversion and weak BOLD responses to cocaine-conditioned odor cues within the insula cortex. For comparison, we provide data from an earlier study with juvenile males overexpressing D1 that show a strong preference for cocaine and elevated BOLD responses. The results support the use of a pharmacological manipulation (e.g., D1 overexpression) to probe the neural circuitry downstream from the prelimbic cortex.

A novel two-component, expandable bioadhesive for exposed defect coverage: Applicability to prenatal procedures.

BACKGROUND/PURPOSE: We sought to test select properties of a novel, expandable bioadhesive composite that allows for enhanced adhesion control in liquid environments. METHODS: Rabbit fetuses (n = 23) underwent surgical creation of spina bifida on gestational day 22-25 (term 32-33 days). Defects were immediately covered with a two-component tough adhesive consisting of a hydrogel made of a double network of ionically crosslinked alginate and covalently crosslinked polyacrylamide linked to a bridging chitosan polymer adhesive. Animals were euthanized prior to term for different analyses, including hydraulic pressure testing. RESULTS: Hydrogels remained adherent in 70% (16/23) of the recovered fetuses and in all of the last 14 fetuses as the procedure was optimized. Adherent hydrogels showed a median two-fold (IQR: 1.7-2.4) increase in area at euthanasia, with defect coverage confirmed by ultrasound and histology. The median maximum pressure to repair failure was 15 mmHg (IQR: 7.8-55.3), exceeding reported neonatal cerebrospinal fluid pressures. CONCLUSIONS: This novel bioadhesive composite allows for selective, stable attachment of an alginate-polyacrylamide hydrogel to specific areas of the spina bifida defect in a fetal rabbit model, while the hydrogel expands with the defect over time. It could become a valuable alternative for the prenatal repair of spina bifida and possibly other congenital anomalies. TYPE OF STUDY: N/A (animal and laboratory study). LEVEL OF EVIDENCE: N/A (animal and laboratory study).

Essential and sex-specific effects of mGluR5 in ventromedial hypothalamus regulating estrogen signaling and glucose balance.

The ventromedial hypothalamus (VMH) plays chief roles regulating energy and glucose homeostasis and is sexually dimorphic. We discovered that expression of metabotropic glutamate receptor subtype 5 (mGluR5) in the VMH is regulated by caloric status in normal mice and reduced in brain-derived neurotrophic factor (BDNF) mutants, which are severely obese and have diminished glucose balance control. These findings led us to investigate whether mGluR5 might act downstream of BDNF to critically regulate VMH neuronal activity and metabolic function. We found that mGluR5 depletion in VMH SF1 neurons did not affect energy balance regulation. However, it significantly impaired insulin sensitivity, glycemic control, lipid metabolism, and sympathetic output in females but not in males. These sex-specific deficits are linked to reductions in intrinsic excitability and firing rate of SF1 neurons. Abnormal excitatory and inhibitory synapse assembly and elevated expression of the GABAergic synthetic enzyme GAD67 also cooperate to decrease and potentiate the synaptic excitatory and inhibitory tone onto mutant SF1 neurons, respectively. Notably, these alterations arise from disrupted functional interactions of mGluR5 with estrogen receptors that switch the normally positive effects of estrogen on SF1 neuronal activity and glucose balance control to paradoxical and detrimental. The collective data inform an essential central mechanism regulating metabolic function in females and underlying the protective effects of estrogen against metabolic disease.