Biomimetic delivery of signals for bone tissue engineering

Abstract

Bone tissue engineering is an exciting approach to directly repair bone defects or engineer bone tissue for transplantation. Biomaterials play a pivotal role in providing a template and extracellular environment to support regenerative cells and promote tissue regeneration. A variety of signaling cues have been identified to regulate cellular activity, tissue development, and the healing process. Numerous studies and trials have shown the promise of tissue engineering, but successful translations of bone tissue engineering research into clinical applications have been limited, due in part to a lack of optimal delivery systems for these signals. Biomedical engineers are therefore highly motivated to develop biomimetic drug delivery systems, which benefit from mimicking signaling molecule release or presentation by the native extracellular matrix during development or the natural healing process. Engineered biomimetic drug delivery systems aim to provide control over the location, timing, and release kinetics of the signal molecules according to the drug's physiochemical properties and specific biological mechanisms. This article reviews biomimetic strategies in signaling delivery for bone tissue engineering, with a focus on delivery systems rather than specific molecules. Both fundamental considerations and specific design strategies are discussed with examples of recent research progress, demonstrating the significance and potential of biomimetic delivery systems for bone tissue engineering.

Fig. 1

Various drug delivery strategies for signal molecules. Different types of signal molecules require different delivery systems to achieve optimal therapeutic effects. Delivery systems that have been developed and are currently used and/or are under investigation for bone tissue engineering applications include surface presentation, controlled sustained release, preprogrammed release, responsive release, and gene transfection. Copyright © 2016 by Nature Publishing Group, reprinted with permission of Nature Publishing Group, from Zhang et al.

Fig. 2

Surface modified nanofibrous microspheres with BMP-2-mimicking peptide induced stem cell osteogenesis and bone regeneration. a SEM images of surface modified nanofibrous microspheres. b A cross-sectional confocal image of nanofibrous microspheres after fluorescent labeling at the conjugation site, indicating that the microspheres’ surface has been functionalized with reactive groups for peptide conjugation. H&E analysis of BMP-2-mimic peptide conjugated microspheres (c) control microspheres (d) microspheres seeded with rabbit bone marrow stromal cells (BMSCs) after 5 weeks subcutaneous implantation. The BMP-2-mimicking peptide surface presentation strategy significantly induced osteogenic differentiation and promoted bone regeneration. Scale bars: 100 µm unless otherwise noted. Copyright © 2014 by John Wiley and Sons, reprinted with permission of John Wiley and Sons, from Zhang et al.

Fig. 3

BMP-7-releasing nanofibrous scaffold. a SEM images of BMP-7-encapsulated PLGA nanospheres prepared via double emulsion method. b In vitro BMP-7 release profiles. The release kinetics were modulated by tailoring the chemical and physical properties of the polymer matrix. SEM micrographs of PLGA nanospheres-immobilized on porous NF scaffolds at (c) lower magnification, ×100 and (d) higher magnification, ×10 000. The drug-releasing nanospheres were immobilized onto the internal surface of the scaffold pores. H&E staining of tissue formation in the BMP-7 absorbed scaffold (e) and the BMP-7 controlled releasing scaffold (f) in mouse subcutaneous implantation model, showing that significant bone was regenerated in the BMP-7 controlled release group. Scale bar: 100 µm in (e and f). Copyright © 2006 by Elsevier, reprinted with permission of Elsevier, from Wei et al.

Fig. 4

Preprogrammed PTH delivery system for local bone defect repair. a Schematic illustration of PTH delivery device (pulsatile and continuous). Two types of devices made with the same biodegradable materials and loaded with the same amount of PTH but delivered PTH in distinct manners, pulsatile or continuous, for 21 days. b Representative µCT characterization of mouse calvarial defect (top panel) and intact tibiae (bottom panel) in response to the different PTH delivery systems in vivo. PTH delivery device (pulsatile or continuous) was implanted in the calvarial defect locally. A subset of control mice received standard PTH subcutaneous injection (40 µg/kg/day) for 21 days. The PTH pulsatile device significantly enhanced the PTH anabolic effects in regenerating bone compared to the standard PTH injection, whereas the PTH continuous device resulted in bone resorption; PTH local delivery (pulsatile or continuous) resulted in negligible systemic effect compared to the PTH injection treatment. Copyright © 2016 by Elsevier, reprinted with permission of Elsevier, from Dang et al.

Fig. 5

Two-stage delivery of miRNA-26a from scaffold repaired critical bone defects. a Schematic illustration of the two-stage miRNA delivery system. The miRNA and gene vector formed polyplexes in water, which were encapsulated into PLGA microspheres, followed by immobilization onto the PLLA scaffold. The implanted scaffold filled in the mouse calvarial defect. The PLGA microspheres released miRNA–vector complex or polyplexes in vivo and the polyplexes were taken into cells through endocytosis. Once inside the cell, the intracellular release of miRNA regulated subsequent gene expression. b Release profiles of miRNA from different PLGA (6.5 or 64 kDa) microspheres containing different gene/vector complexes (LP or HP). The release durations (short and long) were controlled by tuning the polymer matrix. c Representative µCT and H&E analysis of scaffolds in the mouse critical defect model. (a) Cell-free scaffold with the NC polyplexes (miR-26a-bolus or NC-bolus) or miRNA-26a/HP vector polyplexes bolus; (b) cell-free scaffold with short-term releasing PLGA microspheres that contains the NC polyplexes (miR-26a-bolus or NC-bolus) or miRNA-26a/HP vector polyplexes; (c) cell-free scaffold with long-term releasing PLGA microspheres that contains the NC polyplexes (miR-26a-bolus or NC-bolus) or miRNA-26a/HP vector polyplexes. Results showed that the two-stage delivery of miRNA-26a repaired the critical calvarial bone defect in vivo and the long-term sustained release was much more advantageous than the short-term release. Scale bars, 5 mm (in μCT images), 2.0 mm (in H&E images at right), 200 mm (in higher-mag H&E images at far right). Copyright © 2016 by Nature Publishing Group, reprinted with permission of Nature Publishing Group, from Zhang et al.