Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates

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From: Nature Biotechnology(Vol. 34, Issue 3)
Publisher: Nature Publishing Group
Document Type: Report
Length: 11,968 words
Lexile Measure: 1450L

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The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient (1-6). There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.

The foreign body response to implanted biomaterials consists of inflammatory events and wound-healing processes (1) that lead to fibrosis. The cellular and collagenous deposition isolate the device from the host (1,7,8). This can interfere with sensing of the host environment, lead to painful tissue distortion, cut off nourishment (for implants containing living, cellular components) and ultimately lead to device failure (1,3). Overcoming the foreign body response to implanted devices could pave the way for implementing new medical advances, making the development of materials with both anti-inflammatory and antifibrotic properties a critical medical need (1,2,4). Macrophages are a key component of material recognition and actively adhere to the surface of foreign objects (1,3,5,9,10). Objects too large for macrophage phagocytosis initiate processes that result in the fusion of macrophages into foreign-body giant cells (1,3). These multinucleated bodies amplify the immune response by secreting cytokines and chemokines that result in the recruitment of fibroblasts that actively deposit matrix to isolate the foreign material (1,3,11,12). This response has been described for materials that encompass a wide range of physicochemical properties, from naturally occurring polymers to synthetic materials (3,9,13).

Alginate is a unique and versatile biomaterial that forms hydrogels in di-cationic aqueous solutions ([Ca.sup.2+], [Ba.sup.2+]) and has been used in numerous biomedical applications including drug delivery, tissue regeneration, implantable sensors and cell encapsulation (14,15). Its low cost, low toxicity, mild gelation (harmless to cells) and tunability has made alginate a popular coating in biomedical device research and the most commonly used material for encapsulation technologies (14). The immune recognition of alginate microspheres results in even empty microspheres eliciting a foreign body response, and the presence of encapsulated allogeneic or xenogeneic donor tissue can further stimulate this response (16-25). The fibrotic response to alginate has been observed in non-human primate (NHP) models, and the fibrosis of alginate microspheres in rodents has been shown to be strain dependent (26,27). Implantation of alginate microcapsules in the intraperitoneal space of rodent models characterized as immune compliant (e.g., BALB/c) yields implants relatively free of fibrous deposition (26,27), but in C57BL/6J mice, microcapsules are covered with fibrous overgrowth, mimicking the foreign body response observed in humans and non-human primates...

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Gale Document Number: GALE|A448568443