A biomimetic and bioactive scaffold with intelligently pulsatile teriparatide delivery for local and systemic osteoporosis regeneration

Abstract

Osteoporosis is one of the most disabling consequences of aging, osteoporotic fractures and higher risk of the subsequent fractures leading to substantial disability and deaths, indicating both local fractures healing and the early anti-osteoporosis therapy are of great significance. Teriparatide is strong bone formation promoter effective in treating osteoporosis, while side effects limit clinical applications. Traditional drug delivery is lack of sensitive and short-term release, finding a new non-invasive and easily controllable drug delivery to not only repair the local fractures but also improve total bone mass has remained a great challenge. Thus, bioinspired by the natural bone components, we develop appropriate interactions between inorganic biological scaffolds and organic drug molecules, achieving both loaded with the teriparatide in the scaffold and capable of releasing on demand. Herein, biomimetic bone microstructure of mesoporous bioglass, a near-infrared ray triggered switch, thermosensitive liposomes based on a valve, and polydopamine coated as a heater is developed rationally for osteoporotic bone regeneration. Teriparatide is pulsatile released from intelligent delivery, not only rejuvenating osteoporotic bone defect, but also presenting strong systemic anti-osteoporosis therapy. This biomimetic bone carrying novel drug delivery platform is well worth expecting to be a new promising strategy and clinically commercialized to help patients survive from the osteoporotic fracture.

Keywords: Osteoporotic bone regeneration; Precise pulsatile release; Smart delivery; Teriparatide.

Graphical abstract

Fig. 1

Schematic illustration of the preparation process of the teriparatide delivery devices and the treatment of local bone defects and systemic osteoporosis.

Fig. 2

Characterization of liposomes and scaffolds. a) Cryo-TEM image of DEPC liposomes and DSC spectra showing the T_m at 17 °C; the scale bar is 100 nm. b) Cryo-TEM image of DPPC liposomes and DSC spectra showing the T_m at 41.6 °C; the scale bar is 100 nm. c) Fluorescence intensity of calcein released from DPPC liposomes at room temperature (RT), 37 °C and 42 °C, or in 1% Triton X solution. d, e) Morphology of the MBG scaffolds and PDA-MBG scaffolds at different scales by camera and SEM, respectively; the scale bars are 200 μm (left) and 1 μm (right). f) SEM images of PDA-MBG scaffolds loaded with teriparatide-encapsulated DPPC liposomes after freeze-drying; the scale bars are 500 μm (top) and 3 μm (down).

Fig. 3

The photothermal effect of scaffolds and the controllable release of payloads from liposomes or platforms in vitro and in vivo. a,b) Infrared images of scaffolds with or without coating upon irradiation, and the typical plot of the time-dependent temperature increase as well as their cooling behaviors in vitro. c, d) Infrared images of scaffolds with or without coating upon irradiation and the typical plot of the time-dependent temperature increase as well as their cooling behaviors in vivo. e) In vitro release of calcein from the Pulsatile group scaffold by laser scanning confocal microscopy. The scaffold was irradiated by NIR light for 0 s (NIR-0 s), 20 s (NIR-20 s), and 30 s (NIR-30 s) and then irradiated for 30 s after 5 min (re-NIR); the scale bar is 1 mm. f) Fluorescence images of calcein released from Pulsatile group scaffolds in vivo, indicating that the release amount increases as the irradiation time increases. g) Fluorescence images showing the long-term release effect in vivo. h) Quantitative analysis of mean fluorescence intensity indicating that the release amount of payloads is controllable and persistent.

Fig. 4

a) Continuous and pulsatile release profiles of teriparatide occurred on Continuous and Pulsatile group scaffolds in vitro, respectively (n = 3). Orange curves represent the amount of single release, while the black curves represent the cumulative release profiles. b) Cell viability of BMSCs on different platforms after 1, 4, and 7 days showing the proliferation ability. c) Cell morphology observation showed that the PDA coating was also suitable for cell spreading; the scale bar is 200 μm. d, e) ALP activity of BMSCs on different platforms after 7 and 14 days; the scale bar is 1 mm **p < 0.01, ***p < 0.001. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 5

a) Coronal-view micro-CT 3D reconstructed images of the femur in Sham and OVX rats; the scale bar is 500 μm; b) Micro-CT 3D reconstructed images of transaxial view of the femur in Sham and OVX rats; the scale bar is 1 mm; c) Morphological parameters BV/TV quantified by CTAn software; d) Representative images of H&E staining of the femur in Sham and OVX rats; the scale bar is 400 μm; e) Micro-CT 3D reconstructed images of the defect site after 4 weeks and 8 weeks of regeneration; the scale bar is 1 mm. f) Micro-CT 2D images of coronary (i), sagittal (ii), and transaxial (iii) sections of the defect area with surrounding tissue after 4 weeks and 8 weeks of regeneration; the scale bar is 1 mm. g) Morphological parameters BV quantified by CTAn software. h) Morphological parameters Tb.Th quantified by CTAn software. i) Morphological parameters BS quantified by CTAn software. j) Morphological parameters Tb.N quantified by CTAn software. k) Morphological parameters BV/TV quantified by CTAn software. l) Morphological parameters Tb.Sp quantified by CTAn software. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 6

a) Optical photographs and their magnified images for H&E staining in different platforms for 4 and 8 weeks. b) Optical photographs and their magnified images for MT staining in different platforms for 4 and 8 weeks. c) Optical photographs and their magnified images for TRAP staining in different platforms for 4 and 8 weeks. The scale bar is 200 μm.

Fig. 7

a) Micro-CT 2D images of coronary and sagittal sections of the femur at 8 weeks; the scale bar is 1 mm. b) Micro-CT 3D reconstructed images of the femoral cortical bone at 8 weeks; the scale bar is 1 mm. c) Micro-CT 3D reconstructed images of the femoral cancellous bone at 8 weeks; the scale bar is 1 mm. d) Micro-CT 3D reconstructed images of the lumbar vertebra at 8 weeks; the scale bar is 1 mm. e) Morphological parameters BV/TV quantified by CTAn software. f) Morphological parameters Tb.Th quantified by CTAn software. g) Morphological parameters Tb.N quantified by CTAn software. h) Morphological parameters Tb.Sp quantified by CTAn software. i) Morphological parameters SMI quantified by CTAn software. j) Morphological parameters BV quantified by CTAn software. *p < 0.05, **p < 0.01, ***p < 0.001.