creates a defect that intra-abdominal contents may protrude through. [1] The most common types of hernias are incisional, inguinal, femoral, umbilical and hiatal hernias. [2] Hernia repair for many defects is performed by the surgical implantation of a prosthetic mesh to firmly support and reinforce the damaged abdominal wall and facilitate the healing process (Figure 1A,B). Each year, over 400 000 incisional hernia repair surgeries are performed with a cost of ≈$15 billion in US healthcare expenditures. [3-5] Prosthetic hernia mesh implants are developed using synthetic, biologic, and coated materials. [6,7] Despite their specific advantages, these mesh implants are not very effective in minimizing potential adverse postsurgical complications. [8] Surgical hernia repair with mesh implants mostly fail due to the formation of visceral adhesions, hardening, and shrinking of the mesh after its implantation. Visceral adhesions are fibrous tissues developed from the underlying serosal membrane of stomach, intestine or colon, that attach to the implanted mesh. [9] These adhesions are mainly composed of collagen and fibroblasts that grow on the mesh and adhere to the nearby tissue, nerves and organs. [10] The mesh shrinks as the adhesions grow and scar tissue hardens, thus forming a hard, fibrous mass that may cause chronic pain, bowel obstruction, enteric fistula, infertility, poor quality of life, and failure of the surgical hernia repair. [11-13] To remove the failed hernia mesh, a complicated surgery needs to be performed, wherein the mesh must be peeled off bladder, stomach, intestine, colon, or a major blood vessel, that may adversely affect the clinical outcomes. [14] To minimize adhesions formation, graft contraction, and foreign body reactions, absorbable and biological meshes have been developed. However, these meshes are not significantly effective because of very high hernia recurrence rates. [15-17] Causative factors for adverse complications arising due to surgical mesh implantation are chronic inflammatory responses, poor mesh-tissue integration, rapid degradation of the materials, surface chemistry and topochemical design of the mesh. [18,19] We herein present the development of an intrinsically inflammation modulating 3D-fabricated biomaterial scaffold (bioscaffold) for soft tissue repair and demonstrate its in vivo efficacy in a rat ventral hernia Development of inflammation modulating polymer scaffolds for soft tissue repair with minimal postsurgical complications is a compelling clinical need. However, the current standard of care soft tissue repair meshes for hernia repair is highly inflammatory and initiates a dysregulated inflammatory process causing visceral adhesions and postsurgical complications. Herein, the development of an inflammation modulating biomaterial scaffold (bioscaffold) for soft tissue repair is presented. The bioscaffold design is based on the idea that, if the excess proinflammatory cytokines are sequestered from the site of injury by the surgical implantation of a bioscaffold,...

Background and Purpose: Delayed neurological deficits are a devastating consequence of subarachnoid hemorrhage (SAH), which affects about 30% of surviving patients. Although a very serious concern, delayed deficits are understudied in experimental SAH models; it is not known whether rodents recapitulate the delayed clinical decline seen in SAH patients. We hypothesized that mice with SAH develop delayed functional deficits and that microthrombi and infarction correlate with delayed decline. Methods: Adult C57BL/6J mice of both sexes were subjected to endovascular perforation to induce SAH. Mice were allowed to survive for up to 1 week post-ictus and behavioral performance was assessed daily. Postmortem microthrombi, large artery diameters (to assess vasospasm), and infarct volume were measured. These measures were analyzed for differences between SAH mice that developed delayed deficits and SAH mice that did not get delayed deficits. Correlation analyses were performed to identify which measures correlated with delayed neurological deficits, sex, and infarction. Results: Twenty-three percent of males and 47% of females developed delayed deficits 3 to 6 days post-SAH. Female mice subjected to SAH had a significantly higher incidence of delayed deficits than male mice with SAH. Mice that developed delayed deficits had significantly more microthrombi and larger infarct volumes than SAH mice that did not get delayed deficits. Microthrombi positively correlated with infarct volume, and both microthrombi and infarction correlated with delayed functional deficits. Vasospasm did not correlate with either infarction delayed functional deficits. Conclusions: We discovered that delayed functional deficits occur in mice following SAH. Sex differences were seen in the prevalence of delayed deficits. The mechanism by which microthrombi cause delayed deficits may be via formation of infarcts.

Diseases affecting the retina, such as age-related macular degeneration (AMD), diabetic retinopathy, macular edema, and retinal vein occlusions, are currently treated by the intravitreal injection of drug formulations. These disease pathologies are driven by oxidative damage due to chronic high concentrations of reactive oxygen species (ROS) in the retina. Intravitreal injections often induce retinal detachment, intraocular hemorrhage, and endophthalmitis. Furthermore, the severe eye pain associated with these injections lead to patient noncompliance and treatment discontinuation. Hence, there is a critical need for the development of a noninvasive therapy that is effective for a prolonged period for treating retinal diseases. In this study, we developed a noninvasive cerium oxide nanoparticle (CNP) delivery wafer (Cerawafer) for the modulation of ROS in the retina. We fabricated Cerawafer loaded with CNP and determined its SOD-like enzyme-mimetic activity and ability to neutralize ROS generated in vitro. We demonstrated Cerawafer's ability to deliver CNP in a noninvasive fashion to the retina in healthy mouse eyes and the CNP retention in the retina for more than a week. Our studies have demonstrated the in vivo efficacy of the Cerawafer to modulate ROS and associated downregulation of VEGF expression in the retinas of very-low-density lipoprotein receptor knockout (vldlr−/−) mouse model. The development of a Cerawafer nanotherapeutic will fulfill a hitherto unmet need. Currently, there is no such therapeutic available, and the development of a Cerawafer nanotherapeutic will be a major advancement in the treatment of retinal diseases.

Subarachnoid hemorrhage induces neuronal apoptosis which causes acute and long-term memory deficits. Ourhypothesis is that agonism of α7-acetylcholine receptors attenuates neuronal apoptosis and improves memorydeficits in SAH mice. Mice were randomly assigned into the experimental groups. One cohort was euthanizedone day after SAH to assess neuronal apoptosis and signaling pathways. A second cohort survived for 30 dayspost-SAH to test long-term memory function. Inhibitors and an α7-acetylcholine receptor knockout mouse wereused. Neurobehavioral performance was assessed on days 1-3, 5, 7, and 23-28. All outcomes were performedand all data was analyzed by a blinded investigator. The α7-acetylcholine receptor agonist prevented neuronalapoptosis and improved acute memory deficits caused by SAH via activation of the PI3K/Akt pathway in neurons.Agonism of the α7-acetylcholine receptor was beneficial in both male and female mice, although the protectionin females was significantly better than in male mice. α7-acetylcholine receptor agonism did not provide anybenefit in α7-acetylcholine receptor knockout mice subjected to SAH. Treatment with the α7-acetylcholinereceptor agonist for 3 days after SAH led to improved working memory one month after SAH suggesting thatacutely improving neuronal survival can have long-lasting benefits. The α7-acetylcholine receptor may be atherapeutic target for SAH which can promote neuronal survival acutely after SAH, but also confer long-lastingmemory benefits. The findings of this study support the α7-acetylcholine receptor as a treatment target whichmay attenuate the long-term memory deficits which SAH patients suffer from.

Aneurysmal subarachnoid hemorrhage (aSAH) causes a robust inflammatory response which leads worse brain injury and poor outcomes. We investigated if stimulation of nicotinic acetylcholine α 7 receptors (α 7 -AChR) (receptors shown to have anti-inflammatory effects) would reduce inflammation and improve outcomes. To investigate the level of peripheral inflammation after aSAH, inflammatory markers were measured in plasma samples collected in a cohort of aSAH patients. To study the effect of α 7 -AChR stimulation, SAH was induced in adult mice which were then treated with a α 7 -AChR agonist, galantamine, or vehicle. A battery of motor and cognitive tests were performed 24 h after subarachnoid hemorrhage. Mice were euthanized and tissue collected for analysis of markers of inflammation or activation of α 7 -AChR-mediated transduction cascades. A separate cohort of mice was allowed to survive for 28 days to assess long-term neurological deficits and histological outcome. Microglia cell culture subjected to hemoglobin toxicity was used to assess the effects of α 7 -AChR agonism. Analysis of eighty-two patient plasma samples confirmed enhanced systemic inflammation after aSAH. α 7 -AChR agonism reduced neuroinflammation at 24 h after SAH in male and female mice, which was associated with improved outcomes. This coincided with JAK2/STAT3 and IRAK-M activity modulations and a robust improvement in neurological/cognitive status that was effectively reversed by interfering with various components of these signaling pathways. Pharmacologic inhibition partially reversed the α 7 -AChR agonist's benefits, supporting α 7 -AChR as a target of the agonist's therapeutic effect. The cell culture experiment showed that α 7 -AChR agonism is directly beneficial to microglia. Our results demonstrate that activation of α 7 -AChR represents an attractive target for treatment of SAH. Our findings suggest that α 7 -AChR agonists, and specifically galantamine, might provide therapeutic benefit to aSAH patients.