Dual growth factor-loaded core-shell polymer microcapsules can promote osteogenesis and angiogenesis

Abstract

Growth factors (GFs) are very critical in stem cell differentiation and tissue regeneration. Therefore GF delivery carriers have been a major subject in tissue engineering research. In this study, we prepare and optimize core-shell microcapsules (C-S MCs) for dual GF delivery. The C-S MCs, composed of an alginate shell and poly(lactic-co-glycolic) acid (PLGA) core, are fabricated using an electrodropping method via custom-made coaxial needles. They are 198±38 µm in diameter with an average core size of 90±13 µm, and they are fabricated using an alginate concentration of 1% (w/v), an electrical voltage of 11 kV, and an inner syringe flow rate of 50 µL/min. Using this platform, dual GFs, bone morphogenetic protein (BMP-2) and vascular endothelial growth factor (VEGF) are encapsulated in the alginate shell and PLGA core, respectively. In vitro release tests of dual GF-loaded C-S MCs reveal early release of BMP-2, followed by VEGF on a temporal release profile of 28 days. In vitro study of the dual GF-loaded MCs demonstrates their osteogenic activity with preosteoblasts; osteogenic markers (osteocalcin and type I collagen) are upregulated and both calcium content and alkaline phosphatase (ALP) activity also increased. In addition, C-S MCs combined with collagen and preosteoblasts were subcutaneously transplanted to the dorsal region of nude mice for 3 weeks. Analysis of the retrieved constructs exhibits that both osteogenesis and angiogenesis were more active in the group containing dual GF-loaded MCs, along with deep penetration of blood vessels inside the construct, compared to blank MCs or single GF (BMP-2)-loaded MCs. This study proposes a dual GF delivery carrier using C-S MCs and demonstrates the feasibility of C-S MCs in the induction of osteogenesis and angiogenesis.

Osteogenic/Angiogenic Dual Growth Factor Delivery Microcapsules for Regeneration of Vascularized Bone Tissue

“…A GF delivery system of core–shell MCs was proposed in the previous study . However, fabrication of homogeneous core–shell MCs using electrodropping method depends on various parameters including physicochemical properties of polymers, coaxial needle set up, electrostatic repulsion, and flow rate . Herein, a new MC design is attempted via PLGA NPs and alginate for dual GF delivery.…”

“…Therapies using genes, stem cells, and growth factors (GFs) are major strategies employed by researchers to induce vascularization during new bone formation and to overcome some drawbacks associated with conventional treatment modalities, such as the use of autografts, allografts, and xenografts. Since a report of dual GF‐mediated angiogenesis by Richardson et al, several groups have examined the effect of dual GF delivery on the regeneration of complex tissues such as angiogenesis, chondrogenesis, myogenesis, osteogenesis, and neurogenesis . In particular, studies regarding dual GF‐mediated osteogenesis have yet to provide any conclusive findings; while several works reported on an augmented level of osteogenesis via dual GFs delivery, others reported on an insignificant level of osteogenesis .…”

Materials Science and Design Principles of Growth Factor Delivery Systems in Tissue Engineering and Regenerative Medicine

“…[101b] PLGA has been prepared as nanoparticles/microcapsules ( Figure A–C), films, and electrospun fibers for tissue engineering applications and tested for the delivery of BMP‐2, VEGF, GDNF, PDGF, and FGF‐2. [33a,34,72,101b] PLGA nanoparticles offer the effective loading and spatiotemporal release of GFs with high relevant bioactivity. The loading efficiency of GFs with PLGA is low, but it can be increased by stabilizing agents such as bovine serum albumin (BSA) and GAGs.…”

“…PLGA nanoparticles can be incorporated into microcapsules, hydrogels, or prepared as core–shell microcapsules to achieve sequential delivery of multiple GFs for synergistic tissue regeneration. [33a,72] GFs in PLGA delivery systems have generally been loaded by direct entrapment or indirect adsorption method, that results in a burst followed by a sustained release (Figure E). PLGA is tested for the delivery of BMP‐2 and VEGF .…”

“…Covalent‐based loading achieves long‐term sustained release and prevents burst release (Figure H). [33a,34,72] However, chemical cross‐linking affects GF bioactivity after chemical coupling. Each of the aforementioned loading strategies can be applied individually or in combination to load dual GFs separately and to achieve tunable release kinetics.…”