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Bone repair and regeneration processes are markedly impaired in diabetes mellitus (DM). Intervening approaches similar to those developed for normal healing conditions have been adopted to combat DM-associated bone regeneration. However, limited outcomes were achieved for these approaches. Hence, together with osteoconductive hydroxyapatite (HA) nanocrystals, osteoinductive magnesium oxide (MgO) nanocrystals were uniformly mounted into the network matrix of an organic hydrogel composed of cysteine-modified γ-polyglutamic acid (PGA-Cys) to construct a hybrid and rough hydrogel scaffold. It was hypothesized that the HA/MgO nanocrystal hybrid hydrogel (HA/MgO-H) scaffold can significantly promote bone repair in DM rats via the controlled release of Mg2+. The HA/MgO-H scaffold exhibited a sponge-like morphology with porous 3D networks inside it and displayed higher mechanical strength than a PGA-Cys scaffold. Meanwhile, the HA/MgO-H scaffold gradually formed a tough hydrogel with G′ of more than 1000 Pa after hydration, and its high hydration swelling ratio was still retained. Moreover, after the chemical degradation of the dispersed MgO nanocrystals, slow release of Mg2+ from the hydrogel matrix was achieved for up to 8 weeks because of the chelation between Mg2+ and the carboxyl groups of PGA-Cys. In vitro cell studies showed that the HA/MgO-H scaffold could not only effectively promote the migration and proliferation of BMSCs but could also induce osteogenic differentiation. Moreover, in the 8th week after implanting the HA/MgO-H scaffold into femur bone defect zones of DM rats, more effective bone repair was presented by micro-CT imaging. The bone mineral density (397.22 ± 16.36 mg cm−3), trabecular thickness (0.48 ± 0.07 mm), and bone tissue volume/total tissue volume (79.37 ± 7.96%) in the HA/MgO-H group were significantly higher than those in the other groups. Moreover, higher expression of COL-I and OCN after treatment with HA/MgO-H was also displayed. The bone repair mechanism of the HA/MgO-H scaffold was highly associated with reduced infiltration of pro-inflammatory macrophages (CD80+) and higher angiogenesis (CD31+). Collectively, the HA/MgO-H scaffold without the usage of bioactive factors may be a promising biomaterial to accelerate bone defect healing under diabetes mellitus. [ABSTRACT FROM AUTHOR]

Keratinocyte growth factor (KGF) has a good therapeutic effect on injured corneas. However, due to the washout of tears and blinking, locally administrated KGF usually has a short residence time on the surface of an injured cornea, resulting in its poor bioavailability. Herein, a bioadhesive hydrogel is described produced using cysteine-modified γ-polyglutamic acid (PGA-Cys) as the hydrogel-forming material to locally deliver KGF. A series of PGA-Cys polymers with different graft ratios of cysteine were firstly synthesized and carefully characterized. Thereafter, the PGA-Cys hydrogel was screened by changing the graft ratio of cysteine and polymer concentration, and the apparent viscosities and bioadhesive force were also carefully investigated. It was found that PGA-Cys polymers with different graft ratios of cysteine exhibited tunable apparent viscosity and bioadhesive properties at the same polymer concentration. When PGA-Cys with a graft ratio of 1.5 mmol g-1 of cysteine (PGA-Cys-1.5) was used as hydrogel-forming material, the hydrogel exhibited a good gelation property with an apparent viscosity of 5.2 Pa s and strong bioadhesive force of 167 ± 0.5 mN. In vitro release study showed that KGF was slowly released from PGA-Cys-1.5 hydrogel over a longer time in comparison to PGA solution alone. Moreover, PGA-Cys-1.5 hydrogel enabled most of the encapsulated KGF to be retained on the cornea and conjunctiva after local administration. Meanwhile, the morphology of the corneal epithelium in the alkali-injured cornea of mice was well repaired after 7 days of treatment with KGF-PGA-Cys-1.5 hydrogel. The therapeutic mechanism was strongly associated with inhibiting corneal inflammation and neovascularization, promoting proliferation of the corneal epithelium and inhibiting apoptosis. Overall, the use of the bioadhesive PGA-Cys hydrogel with a suitable KGF release profile may be a more promising approach than using PGA solution alone and KGF to repair injured corneas.