FasL-engineered biomaterials with immunomodulatory function
Described herein are FasL-engineered biomaterials, as well as methods of making and using such FasL-engineered biomaterials, such as for immunomodulation, such as for inducing immunosuppression and specific immune tolerance, such as for preventing or reducing the risks of rejection of cellular or tissue grafts and/or the treatment of autoimmune disorders such as Type I diabetes. In specific embodiments, the FasL-engineered biomaterials are biotinylated microgels bound to SA-FasL.
1 . A biomaterial comprising:
a) a hydrogel comprising maleimide-terminated four-arm polyethylene glycol (PEG-4MAL);
b) a biotin moiety displayed on the hydrogel; and
c) a chimeric FasL protein comprising a FasL moiety and a streptavidin moiety conjugated to the hydrogel via the biotin moiety; wherein,
the FasL moiety comprises an extracellular domain that lacks matrix metalloproteinase sensitive sites.
2 . The biomaterial of claim 1 , wherein the hydrogel is a microgel.
3 . The biomaterial of claim 2 , wherein the microgel has a 150 μm diameter.
4 . The biomaterial of claim 1 , wherein the biotin moiety comprises biotin-PEG-thiol.
5 . The biomaterial of claim 4 , wherein the hydrogel is a microgel.
6 . The biomaterial of claim 5 , wherein the microgel has a 150 μm diameter.
7 . The biomaterial of claim 4 , wherein the microgel is formed by reacting biotin-PEG-thiol with PEG-4MAL via microfluidics polymerization.
8 . A method of treating type 1 diabetes in a human subject in need thereof, comprising transplanting into the subject the biomaterial of claim 7 and pancreatic islet cells.
9 . The method of claim 8 , further comprising administering to the subject an immunosuppressive drug.
10 . The method of claim 9 , wherein the immunosuppressive drug is rapamycin.
11 . A method of treating type 1 diabetes in a human subject in need thereof, comprising transplanting into the subject the biomaterial of claim 4 and pancreatic islet cells.
12 . The method of claim 11 , further comprising administering to the subject an immunosuppressive drug.
13 . The method of claim 12 , wherein the immunosuppressive drug is rapamycin.
14 . A method of treating type 1 diabetes in a human subject in need thereof, comprising transplanting into the subject the biomaterial of claim 1 and pancreatic islet cells.
15 . The method of claim 14 , further comprising administering to the subject an immunosuppressive drug.
16 . The method of claim 15 , wherein the immunosuppressive drug is rapamycin.
17 . A method of inducing immune tolerance to a graft cell to a patient in need thereof, comprising transplanting into the subject the biomaterial of claim 1 and a graft cell.
18 . A method of making a biomaterial displaying a fusion protein comprising streptavidin and a FasL moiety, the method comprising reacting biotin-PEG-thiol with PEG-4MAL macromere to generate a microgel crosslinked with dithiothreitol (DTT) via microfluidics polymerization and capturing a chimeric protein comprising streptavidin and a FasL moiety via the biotin.
19 . The method of claim 18 , wherein the microgel has a 150 μm diameter.
20 . A biomaterial displaying a fusion protein comprising streptavidin and a FasL moiety produced by a method comprising reacting biotin-PEG-thiol with PEG-4MAL macromere to generate a microgel crosslinked with dithiothreitol (DTT) via microfluidics polymerization and capturing a chimeric protein comprising streptavidin and a FasL moiety via the biotin, wherein the microgel has a 150 μm diameter.