Effect of tissue microenvironment on fibrous capsule formation to biomaterial-coated implants

The foreign body reaction (FBR) describes the host response towards material implants, including inflammation and the development of fibrotic scar tissue growth which encapsulates the biomaterial. This study sought to assess the contributions of microenvironment on the FBR, and specifically the fibrotic FBR in the uterine cavity, which is known to be immune privileged and naturally tolerant to foreign bodies. Here, we designed various materials using electrospinning to provoke fibrosis, which eluted sclerosing agents to cause inflammation. For this study, we screened the sclerosing agents doxycycline (Dox), silver nitrate (SN), and polidocanol (PD). We additionally investigated three polymer blends. First, we studied a blend of polyvinyl alcohol (PVA) and polyethylene oxide (PEO) to achieve burst release of the sclerosing agents to capture just the initial acute inflammatory phase of the FBR. Second, poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL) were studied to achieve sustained sclerosing agent release and persistent implant presence. Finally, we added gelatin (Gel) to the PLGA/PCL blend to assess the contribution of improved cell attachment to the material on fibrosis.

Materials were characterized for fiber diameter, drug release rates, and encapsulation efficiency. Electrospinning could formulate all the physicochemically diverse sclerosing agents into solid dosage forms. PVA/PEO materials fully dissolve within one hour and release all encapsulated drug. Polyester materials achieved drug release up to 10 days. In vitro, the materials were further studied for the capability to induce a fibrotic FBR via macrophage cytokine expression and fibroblast attachment. We hypothesized that a highly fibrotic FBR would require expression of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), as well as pro-healing interleukin 10 (IL-10). PVA/PEO blends induced some expression of TNF-α, but did not induce significant expression of IL-1β or IL-10. Some polyester fiber blends did achieve elevated TNF-α, IL-1β, as well as IL-10.

In vivo, we first measured the resulting FBR subcutaneously in mice to ensure a fibrotic response in a standard model for assessing the FBR. Masson's trichrome stained images show a collagen rich fibrotic capsule in response to the PLGA/PCL/Gel/SN implant, further supported by a scoring system of the FBR. This material blend was selected to be integrated onto an IUD for intrauterine study in a non-human primate baboon model. No abnormal tissue response was observed in the histology towards the materials or devices. These data suggest that the intrauterine fibrotic FBR is dampened in comparison to other tissue microenvironments, potentially due to immune privilege.