Nano-structured, drug-eluting medical devices for improved clinical outcomes

The biological response to implanted medical devices is critical to the success of surgical procedures. Implantation of foreign devices into the body increases infection risk and may cause inflammation, both of which can result in surgical/device failure. Electrospinning is a promising manufacturing technology due to its capacity to form medical devices composed of nano- and micro-fibers from almost any polymer or polymer/drug combination. This versatility allows for tuning of fiber size and selection of polymer and/or drug to locally modulate the biological response to devices. Here, we investigate the use of electrospinning to manufacture devices with added functionality to improve clinical outcomes. Although they are associated with vision-threatening eye infections, more than 12 million nylon sutures are used in ocular procedures each year. We demonstrate manufacture, via wet electrospinning, of biocompatible sutures capable of sustained antibiotic release for more than 60 days in vitro and activity against Staphylococcus epidermidis for at least 1 week in vitro. Next, we engineered a novel system to manufacture and twist together hundreds of drug-loaded nanofibers into a single multifilament suture. To our knowledge, this is the first demonstration of a drug-loaded suture capable of surpassing United States Pharmacopeia strength specifications. Multifilament sutures delivered antibiotic at detectable levels in rat eyes for at least 14 days, and prevented ocular infection against consecutive bacterial inoculations over 1 week in a rat model of bacterial keratitis. Millions of vascular anastomosis procedures are performed yearly. The inflammatory response to the surgical procedure using sutures leads to neointimal hyperplasia, and resulting vessel stenosis. We demonstrate manufacture of nanofiber-coated sutures capable of sustained anti-proliferative drug release and reduction of neointimal hyperplasia, in comparison to standard nylon sutures, following anastomosis of the rat abdominal aorta. Finally, we describe the adaptation of our manufacturing platform to glaucoma, which affects over 60 million people, and in which fibrosis is the major cause of surgical treatment failure. We demonstrate manufacture of nanostructured, small lumen glaucoma shunts that are biocompatible and significantly reduce intraocular pressure in normotensive rabbits for at least 27 days. Collectively, these results demonstrate the clinical potential of nano-structured, drug-eluting medical devices

Hydrogel–Electrospun Fiber Mat Composite Coatings for Neural Prostheses

Achieving stable, long-term performance of implanted neural prosthetic devices has been challenging because of implantation related neuron loss and a foreign body response that results in encapsulating glial scar formation. To improve neuron–prosthesis integration and form chronic, stable interfaces, we investigated the potential of neurotrophin-eluting hydrogel–electrospun fiber mat (EFM) composite coatings. In particular, poly(ethylene glycol)-poly(ε-caprolactone) (PEGPCL) hydrogel–poly(ε-caprolactone) EFM composites were applied as coatings for multielectrode arrays. Coatings were stable and persisted on electrode surfaces for over 1 month under an agarose gel tissue phantom and over 9 months in a PBS immersion bath. To demonstrate drug release, a neurotrophin, nerve growth factor (NGF), was loaded in the PEGPCL hydrogel layer, and coating cytotoxicity and sustained NGF release were evaluated using a PC12 cell culture model. Quantitative MTT assays showed that these coatings had no significant toxicity toward PC12 cells, and neurite extension at day 7 and 14 confirmed sustained release of NGF at biologically significant concentrations for at least 2 weeks. Our results demonstrate that hydrogel–EFM composite materials can be applied to neural prostheses to improve neuron–electrode proximity and enhance long-term device performance and function

Cell Attachment to Hydrogel-Electrospun Fiber Mat Composite Materials

Hydrogels, electrospun fiber mats (EFMs), and their composites have been extensively studied for tissue engineering because of their physical and chemical similarity to native biological systems. However, while chemically similar, hydrogels and electrospun fiber mats display very different topographical features. Here, we examine the influence of surface topography and composition of hydrogels, EFMs, and hydrogel-EFM composites on cell behavior. Materials studied were composed of synthetic poly(ethylene glycol) (PEG) and poly(ethylene glycol)-poly(ε-caprolactone) (PEGPCL) hydrogels and electrospun poly(caprolactone) (PCL) and core/shell PCL/PEGPCL constituent materials. The number of adherent cells and cell circularity were most strongly influenced by the fibrous nature of materials (e.g., topography), whereas cell spreading was more strongly influenced by material composition (e.g., chemistry). These results suggest that cell attachment and proliferation to hydrogel-EFM composites can be tuned by varying these properties to provide important insights for the future design of such composite materials

Nanofiber-coated, tacrolimus-eluting sutures inhibit post-operative neointimal hyperplasia in rats

Post-operative complications of vascular anastomosis procedures remain a significant clinical challenge and health burden globally. Each year, millions of anastomosis procedures connect arteries and/or veins in vascular bypass, vascular access, organ transplant, and reconstructive surgeries, generally via suturing. Dysfunction of these anastomoses, primarily due to neointimal hyperplasia and the resulting narrowing of the vessel lumen, results in failure rates of up to 50% and billions of dollars in costs to the healthcare system. Non-absorbable sutures are the gold standard for vessel anastomosis; however, damage from the surgical procedure and closure itself causes an inflammatory cascade that leads to neointimal hyperplasia at the anastomosis site. Here, we demonstrate the development of a novel, scalable manufacturing system for fabrication of high strength sutures with nanofiber-based coatings composed of generally regarded as safe (GRAS) polymers and either sirolimus, tacrolimus, everolimus, or pimecrolimus. These sutures provided sufficient tensile strength for maintenance of the vascular anastomosis and sustained drug delivery at the site of the anastomosis. Tacrolimus-eluting sutures provided a significant reduction in neointimal hyperplasia in rats over a period of 14 days with similar vessel endothelialization in comparison to conventional nylon sutures. In contrast, systemically delivered tacrolimus caused significant weight loss and mortality due to toxicity. Thus, drug-eluting sutures provide a promising platform to improve the outcomes of vascular interventions without modifying the clinical workflow and without the risks associated with systemic drug delivery