Delivering Nucleic‐Acid Based Nanomedicines on Biomaterial Scaffolds for Orthopedic Tissue Repair: Challenges, Progress and Future Perspectives

Abstract

As well as acting to fill defects and allow for cell infiltration and proliferation in regenerative medicine, biomaterial scaffolds can also act as carriers for therapeutics, further enhancing their efficacy. Drug and protein delivery on scaffolds have shown potential, however, supraphysiological quantities of therapeutic are often released at the defect site, causing off-target side effects and cytotoxicity. Gene therapy involves the introduction of foreign genes into a cell in order to exert an effect; either replacing a missing gene or modulating expression of a protein. State of the art gene therapy also encompasses manipulation of the transcriptome by harnessing RNA interference (RNAi) therapy. The delivery of nucleic acid nanomedicines on biomaterial scaffolds - gene-activated scaffolds -has shown potential for use in a variety of tissue engineering applications, but as of yet, have not reached clinical use. The current state of the art in terms of biomaterial scaffolds and delivery vector materials for gene therapy is reviewed, and the limitations of current procedures discussed. Future directions in the clinical translation of gene-activated scaffolds are also considered, with a particular focus on bone and cartilage tissue regeneration.

3D Bioprinting of Developmentally Inspired Templates for Whole Bone Organ Engineering

“…The approach could also be adapted to other biofabrication methods such as inkjet printing and electrospinning where cellular and extra cellular material can be arranged in complex patterns [31] . Future work will look at recapitulating biomolecule gradients that occur during skeletal developmental processes using bioprinted patterns of plasmid DNA encoding for vascular, chondrogenic and osteogenic factors such as VEGF, PDGF, TGF-β3 and BMP-2 [32][33][34][35] . We will also explore the spatial and temporal control of these and other factors [3,36] to help engineer the micro-environment of developing bones.…”

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

“…[37,38] The numerous options available within both categories have been reviewed extensively in recent publications, [39,40] yet there is still no consensus in an optimal system. [38] This section focuses on miRNA delivery vectors which have been considered for the development of scaffold-based miRNA delivery systems, their design and characteristics.…”

“…Other nonviral synthetic vectors that generally feature low cytotoxicity have garnered significant attention in pDNA and siRNA delivery, such as dendrimers, [40] cyclodextrins, [74,75] and cell penetrating peptides (CPP). [76,77] However, all of these are to-date minimally explored in RM applications of miRNA therapeutics.…”

“…[96,124] Studies on scaffold-based gene delivery in the lab originally began with the delivery of pDNA including BMP2 [95] and combinations of BMP2 and VEGF [155] utilizing the nHA particles [94] and coll-nHA scaffolds [94,156] developed in-house specifically for bone repair. Having demonstrated the dramatically enhanced therapeutic potential of such systems not only for bone but also cartilage and nerve repair, we also progressed to investigating the utility of alternative gene delivery vectors including PEI, [85,155,157] chitosan, [40,158] Lipofectamine 2000, [75] and cyclodextrin, [75,159] different genetic cargo such as pDNA, [85,95,155,157] miRNA, [96,124] and siRNA, [75,159] and various scaffold types including collagen alone, [85,95] collagennHA, [75,95,96,124,155,159] collagen-HA [85] and collagen hyaluronic acid (coll-HyA) [85] to tailor our systems depending on the final application required. [158] Delivery of the miR-mimics and miR-inhibitors from porous collagen-nHA scaffolds yielded very promising results demonstrating silencing functionality of ≈20% and 88.4%, respectively.…”

“…Having demonstrated the dramatically enhanced therapeutic potential of such systems not only for bone but also cartilage and nerve repair, we also progressed to investigating the utility of alternative gene delivery vectors including PEI, [85,155,157] chitosan, [40,158] Lipofectamine 2000, [75] and cyclodextrin, [75,159] different genetic cargo such as pDNA, [85,95,155,157] miRNA, [96,124] and siRNA, [75,159] and various scaffold types including collagen alone, [85,95] collagennHA, [75,95,96,124,155,159] collagen-HA [85] and collagen hyaluronic acid (coll-HyA) [85] to tailor our systems depending on the final application required. [158] Delivery of the miR-mimics and miR-inhibitors from porous collagen-nHA scaffolds yielded very promising results demonstrating silencing functionality of ≈20% and 88.4%, respectively. The antagomiR-functionality levels achieved in our "coll-nHA-nanomiR" system were improved over miR-mimic silencing, although 20% silencing can still trigger therapeutic improvements in vivo, [108] providing evidence suggestive of the potential benefit of the TERG system.…”