Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations

Abstract

Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled release formulations for local antiinflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sitessubcutaneous, intraperitoneal and intramuscular. In particular incorporation of GW2580, a Colony Stimulating Factor 1 Receptor (CSF1R) inhibitor, into a range of devices including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and musclestimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials. Implanted biomedical devices are an integral part of modern therapeutics, playing key roles in many clinical applications including neural interfacing 1 , monitoring vital signs 2 , pacemakers 3 , controlled drug release 4 , scaffolds for tissue reconstruction 5 , vascular stenting, cell encapsulation and transplantation 6. While the immunological response to materials can be therapeutic, for example with particulate vaccines 7 , some device materials, including polysaccharides, polymers, ceramics, and metals 8 , can induce host immune-mediated foreign body and rejection responses This response can lead to fibrotic encapsulation, and in some cases, reduced efficacy or failure 8-12. Current approaches for long-term maintenance of biomedical device implant biocompatibility often involve broad-spectrum antiinflammatories 13. Short-term steroid or anti-fibrotic drug delivery can transiently inhibit inflammatory cell recruitment as well as improve protein secretion of immuno-isolated cellular grafts 14,15. However, many anti-inflammatory drugs have multiple targets and differential effects in vivo, and associated toxicity 13,16. In particular, macrophages are known to be key mediators of the immune response to implanted biomaterials 8-10. Recently it was shown that the implant-induced foreign body response can be inhibited through selective targeting of the monocyte/macrophage-expressed colony stimulating factor-1 (CSF1R) receptor 10. Importantly, while macrophage numbers in the IP space as well as Farah et al.

An implant for long-term cervical vagus nerve stimulation in mice

“…Future studies will include higher resolution images with same side noncuffed controls. Fibrotic encapsulation is another process that not only leads to reduced efficacy but can also lead to implant failure [57,76,81]. Consistent with previous reports [57,76,80], we observed moderate implant fibrosis in all explanted electrodes ( Fig 4A).…”

Selection for CD49A+ and CD26- cells in pancreatic islet-like clusters differentiated from human pluripotent stem cells improves their therapeutic activity in diabetic mice

“…Recently developed multistage protocols of differentiation produce pancreatic islet cell populations including insulin-producing beta cells that function in reducing glycemia in animal models of diabetes (4)(5)(6). New methods for microencapsulation in modified alginate support long term function after implantation in diabetic animals (7)(8)(9).…”

Nitric Oxide Release Device for Remote‐Controlled Cancer Therapy by Wireless Charging

“…[ 30 ] Typically, the implantable devices are encapsulated with various soft materials to prevent short‐circuit, while avoiding mechanical damage or immune rejection caused by the devices. [ 31,32 ] Therefore, we propose a remote‐controlled implantable gas therapy system to integrate NO donor and the encapsulated materials into a device for improved stability of NO donor and increased controllability of NO release.…”