Dual Affinity Heparin-Based Hydrogels Achieve Pro-Regenerative Immunomodulation and Microvascular Remodeling

Abstract

The immune response to biomaterial implants critically regulates functional outcomes such as vascularization, transplant integration/survival, and fibrosis. To create “immunologically smart” materials, the host-material response may be engineered to optimize the recruitment of pro-regenerative leukocyte subsets which mature into corresponding wound-healing macrophages. We have recently identified a unique feature of pro-regenerative Ly6Clow monocytes that is a higher expression of both the bioactive lipid receptor sphingosine-1-phosphate receptor 3 (S1PR3) and the stromal derived factor-1α (SDF-1α) receptor CXCR4. Therefore, we designed a bifunctional hydrogel to harnesses a mechanistic synergy between these signaling axes to enhance the recruitment of endogenous pro-regenerative monocytes. To overcome the challenge of codelivering two physiochemically distinct molecules—a large hydrophilic protein and hydrophobic small molecule—we engineered a dual affinity hydrogel that exploits the growth factor affinity of a heparin derivative (Hep−N) and lipid chaperone activity of albumin. The sphingosine analog FTY720 and SDF-1α are successfully loaded and coreleased from the Hep−N-functionalized PEG-DA hydrogels while maintaining bioactivity. Placement of these hydrogels into a murine partial thickness skin wound demonstrates that corelease of FTY720 and SDF-1α yields superior recruitment of myeloid cells to the implant interface compared to either factor alone. Although in vivo delivery of FTY720 or SDF-1α individually promotes the enhanced recruitment of Ly-6Clow anti-inflammatory monocytes, codelivery enhances the early accumulation and persistence of the differentiated wound healing CD206+ macrophages in the tissue surrounding the gel. Co-delivery similarly promoted the synergistic expansion of vasculature adjacent to the implant, a key step in tissue healing. Taken together, these findings suggest that the combination of chemotactic molecules may provide additional maturation signals to the infiltrating leukocytes to facilitate macrophage transition and vascular network expansion, thus, ultimately, potentiating tissue repair. The coupling of multiple pro-regenerative biological cues provides a foundation for more fine-tuned immunoregenerative modulation to facilitate tissue repair.

Solar Energy Storage via Thermochemical Metal Oxide/Metal Sulfate Water Splitting Cycle

“…Inability of local delivery of FTY720 to induce pro-regenerative monocyte and macrophage recruitment and protein production after murine RCT contrasts with prior studies indicating such effects in the murine dorsal skin window model [9,10,21]. The disparity may suggest that the effects of FTY720 on inflammation are highly context-dependent.…”

Engineering immunomodulatory biomaterials for type 1 diabetes

“…Of note, this problem was not observed for systemic FTY-720 delivery 160,162 , indicating that the route of delivery impacts its islet toxicity. Coupling FTY-720 with chemotactic stromal derived 162 factor-1α (SDF-1α/CXCL12) can mitigate these negative impacts by the recruitment of woundresolving macrophages 163 , but this has not yet been tested in islet transplants. 160,161 Material-based intranodal drug delivery or sphingosine-1-phosphate analogues with better receptor selectivity, such as KRP203 164 , could be investigated to overcome this challenge.…”

Bioactive Molecules for Skin Repair and Regeneration: Progress and Perspectives

“…Recently, it has reported that a bifunctional hydrogel loaded with the sphingosine analogs, FTY720 and SDF-1α, enhances the recruitment of anti-inflammatory monocytes and promotes microvascular remodeling, thus promoting of tissue repair. This dualaffinity hydrogel overcomes the challenge of codelivering two physiochemically distinct molecules, and the corelease of FTY720 and SDF-1α yields superior proregenerative biological effects over either factor alone [117].…”