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. 2019 Apr 19;17(4):236.
doi: 10.3390/md17040236.

Development of Injectable Fucoidan and Biological Macromolecules Hybrid Hydrogels for Intra-Articular Delivery of Platelet-Rich Plasma

Hsien-Tsung Lu  1   2 , Wan-Ting Chang  3 , Min-Lang Tsai  4 , Chien-Ho Chen  5 , Wei-Yu Chen  6   7 , Fwu-Long Mi  8   9   10
Affiliations

Development of Injectable Fucoidan and Biological Macromolecules Hybrid Hydrogels for Intra-Articular Delivery of Platelet-Rich Plasma

Hsien-Tsung Lu et al. Mar Drugs. .

Abstract

Platelet-rich plasma (PRP) is rich in growth factors and has commonly been utilized in the repair and regeneration of damaged articular cartilage. However, the major drawbacks of direct PRP injection are unstable biological fixation and fast or burst release of growth factors. Fucoidan is a heparinoid compound that can bind growth factors to control their release rate. Furthermore, fucoidan can reduce arthritis through suppressing inflammatory responses and thus it has been reported to prevent the progression of osteoarthritis, promote bone regeneration and accelerate healing of cartilage injury. Injectable hydrogels can be used to deliver cells and growth factors for an alternative, less invasive treatment of cartilage defects. In this study, hyaluronic acid (HA) and fucoidan (FD) was blended with gelatin (GLT) and the GLT/HA/FD hybrid was further cross-linked with genipin (GP) to prepare injectable GP-GLT/HA/FD hydrogels. The gelation rate was affected by the GP, GLT, HA and FD concentrations, as well as the pH values. The addition of HA and FD to GLT networks improved the mechanical strength of the hydrogels and facilitated the sustained release of PRP growth factors. The GP-GLT/HA/FD hydrogel showed adequate injectability, shape-persistent property and strong adhesive ability, and was more resistant to enzymatic degradation. The PRP-loaded GP-GLT/HA/FD hydrogel promoted cartilage regeneration in rabbits, which may lead to an advanced PRP therapy for enhancing cartilage repair.

Keywords: drug delivery; fucoidan; genipin; growth factors; hydrogels; platelet-rich plasma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Weight-average molecular weights (Mw) and polydispersity index (PDI) of the original and depolymerized fucoidan, (B) Fourier Transform-Infrared (FTIR) spectra of the original and depolymerized fucoidan.
Figure 2
Figure 2
Anti-inflammatory activity of depolymerized fucoidan against lipopolysaccharides (LPS) (1 μg/mL) induced cytotoxicity in RAW 264.7 macrophages: (A) Nitrogen oxide (NO) production, (B) cell viability, (C) IL-6 production, (D) reactive oxygen species (ROS) production.
Figure 3
Figure 3
Absorption spectra of genipin (GP)-crosslinked gelatin (GLT), GLT/hyaluronic acid (HA) and GLT/HA/ fucoidan (FD) at 37 °C: (A) 8% GLT cross-linked with different concentrations of GP at pH 7.4, (B) different concentrations of GLT cross-linked with 0.075% GP at pH 7.4, (C) 8% GLT cross-linked with 0.075% GP at different pH values, (D) 8% GLT cross-linked with 0.075% GP at pH 7.4 in the presence of 1% HA and FD.
Figure 4
Figure 4
(A) Color changes and inverted tube test of the GP-crosslinked GLT samples, (B–E) gelation times of GP-crosslinked GLT, GLT/HA and GLT/HA/FD at 37 °C: (B) 8% GLT cross-linked with different concentrations of GP at pH 7.4, (C) different concentrations of GLT cross-linked with 0.075% GP at pH 7.4, (D) 8% GLT cross-linked with 0.075% GP at different pH values, (E) 8% GLT cross-linked with 0.075% GP at pH 7.4 in the presence of different concentrations of HA, (F) 8% GLT cross-linked with 0.075% GP at pH 7.4 in the presence of 1% HA and different concentrations of FD.
Figure 5
Figure 5
Injectability, stability, degradability and FD release property of GP-crosslinked GLT/HA and GLT/HA/FD hybrid hydrogels (GP-GLT/HA and GP-GLT/HA/FD) prepared at 37 °C: (A) injectability of the hydrogels through a 23-gauge needle, (B) stability of the hydrogels after injection into phosphate buffered saline (PBS) with (w/) and without (w/o) enzyme, (C) weight loss of the hydrogels in PBS with (w/) and without enzyme, (D) FD release from the hydrogels in PBS with (w/) and without enzymes.
Figure 6
Figure 6
Chemical and physical properties of GP-crosslinked GLT/HA and GLT/HA/FD hybrid hydrogels (GP-GLT/HA and GP-GLT/HA/FD): (A) FTIR spectra of GP, GLT, HA and GP-GLT/HA, (B) FTIR spectra of FD, GP-GLT/HA and GP-GLT/HA/FD, (C) rheological behavior, (D) compressive strength.
Figure 7
Figure 7
(A) Cytotoxicity of GP-crosslinked GLT/HA and GLT/HA/FD hybrid hydrogels, (B) PDGF release behavior of GP-crosslinked GLT/HA and GLT/HA/FD hybrid hydrogels.
Figure 8
Figure 8
Histological examinations of cartilage at the femoral condyles after treatments by intra-articular injection of: (A) normal saline (control), (B) GP-GLT hydrogel, (C) GP-GLT/HA/FD hydrogel, (D) PRP-loaded GP-GLT/HA/FD hydrogel.
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