Immune‐responsive biodegradable scaffolds for enhancing neutrophil regeneration

Abstract

Neutrophils are essential effector cells for mediating rapid host defense and their insufficiency arising from therapy‐induced side‐effects, termed neutropenia, can lead to immunodeficiency‐associated complications. In autologous hematopoietic stem cell transplantation (HSCT), neutropenia is a complication that limits therapeutic efficacy. Here, we report the development and in vivo evaluation of an injectable, biodegradable hyaluronic acid (HA)‐based scaffold, termed HA cryogel, with myeloid responsive degradation behavior. In mouse models of immune deficiency, we show that the infiltration of functional myeloid‐lineage cells, specifically neutrophils, is essential to mediate HA cryogel degradation. Post‐HSCT neutropenia in recipient mice delayed degradation of HA cryogels by up to 3 weeks. We harnessed the neutrophil‐responsive degradation to sustain the release of granulocyte colony stimulating factor (G‐CSF) from HA cryogels. Sustained release of G‐CSF from HA cryogels enhanced post‐HSCT neutrophil recovery, comparable to pegylated G‐CSF, which, in turn, accelerated cryogel degradation. HA cryogels are a potential approach for enhancing neutrophils and concurrently assessing immune recovery in neutropenic hosts.

Biodegradable scaffolds for enhancing vaccine delivery

“…CpG‐OVA‐HAC2 was administered in immunodeficient mice to assess the mechanism and potential enhancement of vaccine efficacy. Consistent with our previous work, the degradation of HA cryogels in gp91 phox− mice was impaired 12 . Moreover, the induction of anti‐OVA IgG1 antibody titers in the gp91 phox− were significantly delayed, supporting the need for release of vaccine components.…”

“…Sample sizes for animal studies were based on prior work without use of additional statistical estimations 12 . Results were analyzed where indicated using Student t ‐test, one‐way ANOVA with Dunnett multiple comparison, Kruskal–Wallis test with Dunnett multiple comparison, two‐way ANOVA with Bonferroni test, and log‐rank test using Graphpad Prism software.…”

“…After dialysis, solutions containing HA-Tz or HA-Nb were frozen overnight and lyophilized (Labconco Freezone 4.5) for 48 h. Cy5 conjugated HA-Nb (Cy5-HA-Nb) was synthesized following a previously described technique. 12 A total of 0.8 mg of Cy5-Tz was reacted with 100 mg of HA-Nb at 0.2 wt/vol in DI water for 24 h at 37 C and purified by dialysis in DI water using a 12,000 Da MW cutoff dialysis sack for 48 h.…”

“…Hyaluronic acid (HA) is a polysaccharide‐based polymer that is abundant in tissues including skin, cartilage, and synovial fluid. It has been widely studied in biomedical applications including drug delivery as HA can be modified to form a matrix to encapsulate drugs, such as growth factors and chemotherapeutic agents, and release them in a sustained manner via controlled degradation 12 . We have previously demonstrated that the degradation of HA can be immune‐responsive, mediated by oxidative burst of neutrophils, 12 and is also processed by endogenous hyaluronidases 13,14 (HYAL).…”

“…It has been widely studied in biomedical applications including drug delivery as HA can be modified to form a matrix to encapsulate drugs, such as growth factors and chemotherapeutic agents, and release them in a sustained manner via controlled degradation 12 . We have previously demonstrated that the degradation of HA can be immune‐responsive, mediated by oxidative burst of neutrophils, 12 and is also processed by endogenous hyaluronidases 13,14 (HYAL). The degradation generates low molecular weight HA fragments which have been shown to activate toll‐like receptors (TLRs) and act as adjuvants in vaccine formulations 4–6 …”