RNA interfering molecule delivery from in situ forming biodegradable hydrogels for enhancement of bone formation in rat calvarial bone defects

Nguyen, Minh Khanh; Jeon, Oju; Dang, Phuong N.; Huynh, Cong Truc; Varghai, Davood; Riazi, Hooman; McMillan, Alexandra; Herberg, Samuel

doi:10.1016/j.actbio.2018.06.007

Cited by 97 publications

(75 citation statements)

References 67 publications

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“…[11,12] Although nanoparticles have been utilized to deliver miRs, [13,14] repeated administrations were almost always required to achieve long-term gene silencing in vivo. [16][17][18] However, hydrogels are often isotropic in architecture and hence lack the ability to direct tissue regrowth. [16][17][18] However, hydrogels are often isotropic in architecture and hence lack the ability to direct tissue regrowth.…”

Section: Introductionmentioning

confidence: 99%

Biomimicking Fiber Scaffold as an Effective In Vitro and In Vivo MicroRNA Screening Platform for Directing Tissue Regeneration

et al. 2019

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MicroRNAs effectively modulate protein expression and cellular response. Unfortunately, the lack of robust nonviral delivery platforms has limited the therapeutic application of microRNAs. Additionally, there is a shortage of drug‐screening platforms that are directly translatable from in vitro to in vivo. Here, a fiber substrate that provides nonviral delivery of microRNAs for in vitro and in vivo microRNA screening is introduced. As a proof of concept, difficult‐to‐transfect primary neurons are targeted and the efficacy of this system is evaluated in a rat spinal cord injury model. With this platform, enhanced gene‐silencing is achieved in neurons as compared to conventional bolus delivery ( p < 0.05). Thereafter, four well‐recognized microRNAs (miR‐21, miR‐222, miR‐132, and miR‐431) and their cocktails are screened systematically. Regardless of age and origin of the neurons, similar trends are observed. Next, this fiber substrate is translated into a 3D system for direct in vivo microRNA screening. Robust nerve ingrowth is observed as early as two weeks after scaffold implantation. Nerve regeneration in response to the microRNA cocktails is similar to in vitro experiments. Altogether, the potential of the fiber platform is demonstrated in providing effective microRNA screening and direct translation into in vivo applications.

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Section: Introductionmentioning

confidence: 99%

Biomimicking Fiber Scaffold as an Effective In Vitro and In Vivo MicroRNA Screening Platform for Directing Tissue Regeneration

et al. 2019

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“…We have previously demonstrated that miR-100-5p and miR-143-3p can promote MSC osteogenesis, but the future applicability of this approach was limited by the complexity of the system which required multiple stages of manipulation to transfect and then encapsulate the cells. In recent years, a handful of studies have probed the use of in situ hydrogel transfections for therapeutic application ranging from siRNA delivery in vitro to miRNA delivery in vivo [21,24,25,26,6,27]. Interestingly however, these studies are limited to the use of either a single transfection agent or a limited range in mechanical properties for the base hydrogels.…”

Section: Discussionmentioning

confidence: 99%

In situ miRNA delivery from a hydrogel promotes osteogenesis of encapsulated mesenchymal stromal cells

Carthew

Donderwinkel

Shrestha

et al. 2019

Preprint

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Hydrogels have many properties that emulate biological tissues and are therefore attractive candidates for use in tissue engineering. In particular the encapsulation and subsequent differentiation of mesenchymal stem/stromal cells (MSCs) is a strategy that holds great promise for the repair and regeneration of bone and cartilage. However, MSCs are well-known for their sensitivity to mechanical cues, particularly substrate stiffness, and so the inherent softness of hydrogels is poorly matched to the mechanical cues that drive efficient osteogenesis. This limits the success of bone tissue engineering using MSCs encapsulated in a hydrogel. One approach to overcome this limitation is to harness mechanotransductive signalling pathways and override the signals cells receive from their environment. Previous reports have shown that the mechanosensitive miRNAs, miR-100-5p and miR-143-3p can enhance MSC osteogenesis, but this required a complex multi-step procedure to transfect, encapsulate and differentiate the cells. In this study, we develop and characterise a facile system for in situ transfection of MSCs encapsulated within a light-crosslinkable gelatin-PEG hydrogel. Comparing the influence of different transfection agents and hydrogel compositions, we determine the factors affecting transfection agent release and MSC transfection, showing that it is possible to transfect MSCs with miRNAs in situ. We then compare the efficacy of both pretransfection and in situ transfection on the osteogenic capacity of hydrogel-encapsulated MSCs, demonstrating superior mineralisation and osteogenic gene expression for in situ transfected samples. Our platform therefore demonstrates a simple, one-pot system for delivery of pro-osteogenic miRNAs and in situ transfection that is able to enhance MSC osteogenic potential without the need of multi-step transfection procedures, thus demonstrating significant promise for bone tissue engineering.

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“…Hydrogels are polymer networks with hydrophilic properties. Researchers have demonstrated that PEGylation hydrogels constantly release siRNA against noggin and miRNA-20a mimics and promote encapsulated human bone marrow-derived mesenchymal stem cells (hMSCs) to differentiate into osteoblasts [116]. In another study, scientists from the Massachusetts Institute of Technology (MIT) showed that a novel self-assembled dual-color RNA-triple-helix hydrogel composed of miRNA-225 mimics and miRNA-221 antagomirs facilitated nearly 90% tumor shrinkage in a triple-negative breast cancer mouse model [117].…”

Section: D Scaffold-based Delivery Systemsmentioning

confidence: 99%

Recent progress in microRNA-based delivery systems for the treatment of human disease

Chen

Huang

2019

ExRNA

159

118

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MicroRNAs (miRNAs) are naturally occurring, small non-coding RNAs that mediate posttranscriptional regulation. Based on the level of sequence complementarity, miRNAs lead to the degradation of target mRNAs or the suppression of mRNA translation, thereby inhibiting the synthesis of proteins and achieving the regulation of genes. miRNAs, which exhibit tissue-and temporal-specific expression, are important negative regulatory RNAs that decrease the levels of other functional genes. miRNAs play a crucial role in disease progression and prognosis and thus exhibit potential for developing novel therapeutics. Due to the instability of miRNAs and their complex environment, including degradation by nucleases in vivo, the safety and effectiveness of miRNA delivery has become the focus of recent attention. Therefore, we discuss some representative advances related to the application of viral-and nonviral-mediated miRNA delivery systems and provide a new perspective on the future of miRNA-based therapeutic strategies.

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RNA interfering molecule delivery from in situ forming biodegradable hydrogels for enhancement of bone formation in rat calvarial bone defects

Cited by 97 publications

References 67 publications

Biomimicking Fiber Scaffold as an Effective In Vitro and In Vivo MicroRNA Screening Platform for Directing Tissue Regeneration

Biomimicking Fiber Scaffold as an Effective In Vitro and In Vivo MicroRNA Screening Platform for Directing Tissue Regeneration

In situ miRNA delivery from a hydrogel promotes osteogenesis of encapsulated mesenchymal stromal cells

Recent progress in microRNA-based delivery systems for the treatment of human disease

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