Research Article: Adaptable Hydrogels Mediate Cofactor‐Assisted Activation of Biomarker‐Responsive Drug Delivery via Positive Feedback for Enhanced Tissue Regeneration

Date Published: October 22, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Kunyu Zhang, Zhaofeng Jia, Boguang Yang, Qian Feng, Xiao Xu, Weihao Yuan, Xingfu Li, Xiaoyu Chen, Li Duan, Daping Wang, Liming Bian.


The targeted and simultaneous delivery of diverse cargoes with vastly different properties by the same vehicle is highly appealing but challenging. Here, a bioactive nanocomposite hydrogel based on hyaluronic acid and self‐assembled pamidronate‐magnesium nanoparticles for the localized elution and on‐demand simultaneous release of bioactive ions and small molecule drugs is described. The obtained nanocomposite hydrogels exhibit excellent injectability and efficient stress relaxation, thereby allowing easy injection and consequent adaptation of hydrogels to bone defects with irregular shapes. Magnesium ions released from the hydrogels promote osteogenic differentiation of the encapsulated human mesenchymal stem cells (hMSCs) and activation of alkaline phosphatase (ALP). The activated ALP subsequently catalyzes the dephosphorylation (activation) of Dex phosphate, a pro‐drug of Dex, and expedites the release of Dex from hydrogels to further promote hMSC osteogenesis. This positive feedback circuit governing the activation and release of Dex significantly enhances bone regeneration at the hydrogel implantation sites. The findings suggest that these injectable nanocomposite hydrogels mediate optimized release of diverse therapeutic cargoes and effectively promote in situ bone regeneration via minimally invasive procedures.

Partial Text

The controlled and long‐term delivery of therapeutic agents including protein‐based growth factors, small molecule drugs, genes, and bioactive ions is critical to the effective and efficient treatment of many pathological conditions.1 However, the simultaneous delivery of these diverse cargoes with vastly different properties by the same vehicle remains challenging.2 Hydrogels have a unique 3D cross‐linked polymeric network encompassing a wide range of chemical compositions and bulk physical properties and have been widely used in drug delivery applications.3 However, due to the intrinsic permeability and limited network interactions with cargo molecules in hydrogels, the sustained delivery is usually achieved on macromolecules like protein‐based growth factors, and the delivery of small‐molecule drugs and bioactive ions is still a challenge.

Taken together, we have presented a self‐assembled HA‐Pam‐Mg nanocomposite hydrogel with tunable mechanical properties, excellent injectability, rapid stress relaxation, and unique bioactivities. Owing to the interaction between Mg2+ and DexP, this small molecular prodrug can be stably loaded into the hydrogels with low basal release and become activated and initiate expedited release in response to a regeneration marker, ALP. The Mg2+ released from the hydrogels can promote osteogenic differentiation of the encapsulated hMSCs and activation of ALP. Meanwhile, the elevated ALP expression and activity promoted the activation and release of Dex from the hydrogels, thereby further enhancing the osteogenesis of hMSCs. Therefore, this positive feedback circuit of drug release regulation from hydrogels can significantly enhance bone regeneration at the intended sites. Our findings demonstrated the promising potential of our HA‐Pam‐Mg nanocomposite hydrogels as carriers of therapeutic cells and drugs for bone repair by minimally invasive procedures.

Materials: Sodium hyaluronate (MW = 80 kDa) was purchased from Bloomage Freda Biopharm (China). Pamidronate disodium salt (Pam) was purchased from Dalian Meilun Biology Technology (China). Magnesium chloride hexahydrate and sodium hydroxide were obtained from Aladdin Reagent (China). Methacrylic anhydride, propidium iodide (PI), paraformaldehyde, Triton X‐100, 4′,6‐diamidino‐2‐phenylindole (DAPI), sliver nitrate, and sodium thiosulfate were ordered from Sigma‐Aldrich (USA). Deuterium oxide (D2O), N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide hydrochloride (EDC), and N‐hydroxysuccinimide (NHS) were obtained from the J&K Scientific (China). All chemicals were used as received without further purification. PBS, α‐minimum essential medium (α‐MEM), penicillin/streptomycin (pen/strep), l‐glutamine, calcein AM, and fetal bovine serum (FBS) were obtained from Gibco (USA). Alkaline phosphatase was purchased from Baomanbio (China). Magnesium colorimetric assay kit and calcium colorimetric assay kit were purchased from Bio Vision (USA). BCA protein assay kit and revertAid First strand cDNA synthesis kit were obtained from Thermo (USA). Peroxidase substrate kit DAB and vectastain ABC kit were purchased from Vector Lab (USA). Human mesenchymal stem cells (hMSCs) were obtained from Lonza. The water used in all the experiments was purified by Millipore system.

The authors declare no conflict of interest.




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