Hydrolysis and sulfation pattern effects on release of bioactive bone morphogenetic protein-2 from heparin-based microparticles

Tellier, Liane E.; Miller, Tobias; McDevitt, Todd C.; Temenoff, Johnna S.

doi:10.1039/c5tb00933b

Cited by 29 publications

(36 citation statements)

References 53 publications

(121 reference statements)

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“…Heparin is a glycosaminoglycan that binds cationic proteins such as SDF-1α and protects them from denaturing conditions. 23–25 We have previously demonstrated that matrices functionalized with a heparin derivative protect proteins against denaturation to maximize bioactivity and lower the payload requirement for in vivo efficacy. 24,26 To reduce the anticoagulant activity of heparin for safe use in vivo, we incorporated a cross-linkable heparin derivative that was selectively desulfated at the -N position (Hep −N ) 24 within a poly(ethylene glycol) diacrylate (PEG-DA) network.…”

Section: Introductionmentioning

confidence: 99%

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

Ogle

Krieger

Tellier

et al. 2017

ACS Biomater. Sci. Eng.

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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.

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Section: Introductionmentioning

confidence: 99%

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

Ogle

Krieger

Tellier

et al. 2017

ACS Biomater. Sci. Eng.

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“…34 Furthermore, 1 H NMR indicated that the heparin derivatives were MAm-functionalized with 13, 11, 8, and 8% functionalization per saccharide unit for Hep, Hep −N , Hep −N,−6O , and Hep-, respectively (Figure S1). …”

Section: Resultsmentioning

confidence: 99%

“…It is important to note, however, that there are likely several factors at play that may affect gel degradation, including the overall charge of the heparin derivative utilized. 34 Overall, while these results suggest that to achieve a desired degradation time, DTT amounts may need to be selected based on the particular heparin derivative used, overall, varying the DTT concentration within hydrogels allowed for the fabrication of hydrogels that fully degraded over a range of 3 to 13 days. In contrast, a small molecule-releasing hydrogel composed of chondroitin 4-sulphate, which is a GAG similar to heparin, 44 was non-degradable, 19 which is usually undesirable when implanting such drug delivery vehicles in vivo .…”

Section: Discussionmentioning

confidence: 98%

Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery

2016

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Sustained release of anti-inflammatory agents remains challenging for small molecule drugs due to their low molecular weight and hydrophobicity. Therefore, the goal of this study was to control the release of a small molecule anti-inflammatory agent, crystal violet (CV), from hydrogels fabricated with heparin, a highly sulfated glycosaminoglycan capable of binding positively-charged molecules such as CV. In this system, both electrostatic interactions between heparin and CV and hydrogel degradation were tuned simultaneously by varying the level of heparin sulfation and varying the amount of dithiothreitol within hydrogels, respectively. It was found that heparin sulfation significantly affected CV release, whereby more sulfated heparin hydrogels (Hep and Hep−N) released CV with near zero-order release kinetics (R-squared values between 0.96-0.99). Furthermore, CV was released more quickly from fast-degrading hydrogels than slow-degrading hydrogels, providing a method to tune total CV release between 5-15 days while maintaining linear release kinetics. In particular, N-desulfated heparin hydrogels exhibited efficient CV loading (~90% of originally included CV), near zero-order CV release kinetics, and maintenance of CV bioactivity after release, making this hydrogel formulation a promising CV delivery vehicle for a wide range of inflammatory diseases.

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“…Combining these two ideas, a protein undesirable at one point in time might be captured and temporarily eliminated from the microenvironment until it is released at a second point in time, when its expression is desirable for tissue regeneration [1]. The sequestration and release of the protein of interest would be controlled both by conditions in the cellular microenvironment, such as concentration gradients [1], as well as by biomaterial properties, such as affinity of the protein to the material [11–13]. By designing materials with a specific application and protein in mind, it may be possible to precisely tune the timing of protein sequestration and release.…”

Section: Introductionmentioning

confidence: 99%

“…Heparin is a highly sulfated glycosaminoglycan, often used in tissue engineering scaffolds due to its ability to bind positively charged proteins [4, 11, 13, 23–25]. Importantly, heparin can bind many growth factors involved in tissue formation, including bone morphogenetic protein-2 (BMP-2), Indian hedgehog (IHH), basic fibroblast growth factor (FGF-2), WNT, and transforming growth factor-β (TGF-β) [26].…”

Section: Introductionmentioning

confidence: 99%

Core-shell microparticles for protein sequestration and controlled release of a protein-laden core

2017

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Development of multifunctional biomaterials that sequester, isolate, and redeliver cell-secreted proteins at a specific timepoint may be required to achieve the level of temporal control needed to more fully regulate tissue regeneration and repair. In response, we fabricated core-shell heparin-poly(ethylene-glycol) (PEG) microparticles (MPs) with a degradable PEG-based shell that can temporally control delivery of protein-laden heparin MPs. Core-shell MPs were fabricated via a re-emulsification technique and the number of heparin MPs per PEG-based shell could be tuned by varying the mass of heparin MPs in the precursor PEG phase. When heparin MPs were loaded with bone morphogenetic protein-2 (BMP-2) and then encapsulated into core-shell MPs, degradable core-shell MPs initiated similar C2C12 cell alkaline phosphatase (ALP) activity as the soluble control, while non-degradable core-shell MPs initiated a significantly lower response (85±19% vs. 9.0±4.8% of the soluble control, respectively). Similarly, when degradable core-shell MPs were formed and then loaded with BMP-2, they induced a ~7-fold higher C2C12 ALP activity than the soluble control. As C2C12 ALP activity was enhanced by BMP-2, these studies indicated that degradable core-shell MPs were able to deliver a bioactive, BMP-2-laden heparin MP core. Overall, these dynamic core-shell MPs have the potential to sequester, isolate, and then redeliver proteins attached to a heparin core to initiate a cell response, which could be of great benefit to tissue regeneration applications requiring tight temporal control over protein presentation.

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Hydrolysis and sulfation pattern effects on release of bioactive bone morphogenetic protein-2 from heparin-based microparticles

Cited by 29 publications

References 53 publications

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

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

Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery

Core-shell microparticles for protein sequestration and controlled release of a protein-laden core

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