Editors' ChoiceBIOMATERIALS

Opening borders for foreign bodies

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Science Translational Medicine  12 Apr 2017:
Vol. 9, Issue 385, eaan2775
DOI: 10.1126/scitranslmed.aan2775

Abstract

Targeting macrophage-specific receptors involved in host immune response against foreign bodies eliminates the fibrotic processes responsible for failure of many implantable biomedical devices.

Google “border” and the definition returned is “a line separating two political or geographical areas.” In biology, “borders” create cell structure, delineate tissue organization, and provide defensive immunological boundaries. Just like the complexities in our world, crossing boundaries of the immune system is complicated, whether it is skin protecting us from bacteria or the destruction of foreign bodies. The host foreign body response is critical for limiting infection, but many biomedical technologies—replacement joints, prostheses, pacemakers, transplants, encapsulated cells—are hindered by this process. When macrophages detect matter too large for engulfment, they recruit cells that surround the implant in a fibrotic capsule. This walling off often leads to device failure.

Doloff and colleagues have tackled this problem by dissecting the innate and adaptive immune pathways involved in fibrotic responses after injection of beads made of a common biomaterial, alginate. In B cell knockout mice, the team discovered that the fibrotic response to the beads was reduced; in mice lacking B and T cells, fibrosis increased. Intriguingly, in mice with impaired macrophage function that also lack B and T cells, fibrosis was absent. Macrophages were identified as key players in these vastly different fibrotic levels. Gene expression analysis revealed colony stimulatory factor 1 receptor (CSF-1R) as an important macrophage-specific gene up-regulated during the fibrotic response. Strikingly, inactivating CSF-1R eliminated fibrosis, but other important macrophage functions were maintained, including wound healing and phagocytosis. Similar outcomes were confirmed with additional common biomaterials, including polystyrene and ceramics. When monkeys were implanted with alginate beads, CSF-1R expression also increased and correlated with fibrosis, along with other similarities to mouse studies both in cell composition and phenotype.

Existing implant technologies rely on nonspecific systemic immunosuppression or replacement to deal with the foreign body response. Questions remain that must be addressed to overcome this challenge: Does targeting CSF1R in monkeys eliminate fibrosis? Are there side effects? Why does fibrosis increase in mice lacking B and T cells? Even so, this work creates a tantalizing possibility for safely relaxing border security by selectively targeting macrophage functions vital to fibrosis but not to useful functions such as wound healing.

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