Micromolded honeycomb scaffold design to support the generation of a bilayered RPE and photoreceptor cell construct

Age-related macular degeneration(AMD)causes blindness due to loss of retinal pigment epithelium(RPE)and photoreceptors(PRs),which comprise the two outermost layers of the retina.Given the small size of the macula and the importance of direct contact between RPE and PRs,the use of scaffolds for targeted reconstruction of the outer retina in later stage AMD and other macular dystrophies is particularly attractive.We developed microfabricated,honeycomb-patterned,biodegradable poly(glycerol sebacate)(PGS)scaffolds to deliver organized,adjacent layers of RPE and PRs to the subretinal space.Furthermore,an optimized process was developed to photocure PGS,shortening scaffold production time from days to minutes.The resulting scaffolds robustly supported the seeding of human pluripotent stem cell-derived RPE and PRs,either separately or as a dual celllayered construct.These advanced,economical,and versatile scaffolds can accelerate retinal cell transplantation efforts and benefit patients with AMD and other retinal degenerative diseases.

Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms

Abdominal aortic aneurysm(AAA)is a progressive aortic dilatation,causing~80%mortality upon rupture.Currently,there is no approved drug therapy for AAA.Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which,however,account for~90%of the newly diagnosed cases.It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression.We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods.There is substantial evidence that degenerative smooth muscle cells(SMCs)orchestrate AAA pathogenesis and progression.In this study,we made an exciting finding that PERK,the endoplasmic reticulum(ER)stress Protein Kinase R-like ER Kinase,is a potent driver of SMC degeneration and hence a potential therapeutic target.Indeed,local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo.In parallel,we also conceived a biomimetic nanocluster(NC)design uniquely tailored to AAA-targeting drug delivery.This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating;and when loaded with a selective PERK inhibitor(PERKi,GSK2656157),the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA.In summary,our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis,but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.