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Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations
Open accessAbstract
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 anti-inflammatory 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 sites-subcutaneous, intraperitoneal and intramuscular. In particular, incorporation of GW2580, a colony stimulating factor 1 receptor inhibitor, into a range of devices, including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and muscle-stimulating 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.
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“Several FBR-targeting compounds are already progressing toward use in humans (King et al., 2014; Farah et al., 2019), and as our understanding of FBR continues to evolve this repertoire will likely continue to expand.”
From Foreign Body Reaction to Implanted Biomaterials and Its Impact in Nerve Neuroprosthetics (2021) · cites this paper as Farah et al., 2019
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“CSF1 receptor has been recently identified as playing a unique role in FBR-associated inflammation, with its inhibition using both implant-encapsulated and systemically-delivered small molecule compounds leading to a decrease in macrophage activity and fibrosis around implanted materials without impacting wound healing (Doloff et al., 2017; Farah et al., 2019).”
From Foreign Body Reaction to Implanted Biomaterials and Its Impact in Nerve Neuroprosthetics (2021) · cites this paper as Farah et al., 2019
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“The incorporation of the CSF1R inhibitor GW2580 in its crystallized form within alginate microcapsules allowed for its controlled release overtime, resulting in long-term reduction of fibrosis and significant improvements in islet transplantation outcomes in mice, even within the subcutaneous space.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [110]
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Metadata
- Authors
- Farah, S., Doloff, J. C., Müller, P., Sadraei, A., Han, H. J., Olafson, K., Vyas, K., Tam, H. H., Hollister-Lock, J., Kowalski, P. S., Griffin, M., Meng, A., McAvoy, M., Graham, A. C., McGarrigle, J., Oberholzer, J., Weir, G. C., Greiner, D. L., Langer, R., & Anderson, D. G.
- Affiliations
- Boston Children's Hospital (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Harvard University (US)
- University of Illinois Chicago (US)
- Joslin Diabetes Center (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Anderson, Daniel G.
- ORCID
- Venue
- Nature Materials
- Published
- 2019-06-24
- Volume
- 18
- Issue
- 8
- Pages
- 892-904
- ISSN
- 1476-1122 (ISSN-L)
- 1476-4660
- PMC
- PMC7184801
- OpenAlex
- W2949742175
- Cited by
- 181
- References
- 61
- Citations by year
- 2026: 20 · 2025: 23 · 2024: 25 · 2023: 27 · 2022: 20 · 2021: 38 · 2020: 23 · 2019: 5
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Materials (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- National Institutes of Health (4r37eb000244-34, 1uc4dk104218-01)
- National Cancer Institute (U54CA151884)
- National Institute of Diabetes and Digestive and Kidney Diseases (UC4-DK-104218, R01DK091526, P30DK036836)
- National Institute of Biomedical Imaging and Bioengineering (R01EB000244, R37-EB000244, R01EB000351)
- National Institute of Dental and Craniofacial Research (R01DE013023)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- foreign body reaction, controlled drug release, GW2580, anti-inflammatory drug delivery, biomedical implants, islet microencapsulation, continuous glucose monitoring
- MeSH terms
- Animals, Delayed-Action Preparations, Drug Compounding, Fibrosis, Macrophages, Rodentia, Prostheses and Implants
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