Biology subjects

Dobricic, M.

Publications and source records attributed to Dobricic, M..

4 recordsLinked to original sources

bioRxiv2026

Scaffold-mediated delivery of a miRNA-29b mimic mitigates excessive extracellular matrix deposition and matrix contraction in wound healing applications

Disruption of the wound healing cascade can result in pathological outcomes, including fibrosis due to myofibroblast-mediated contraction and collagen deposition. Despite the clinical significance, effective treatments for fibrosis remain limited as current therapies often show inconsistent efficacy, adverse effects, and patient discomfort. Combinatorial therapeutic strategies integrating biomaterial scaffolds with gene delivery have shown promise in regenerative healing. MicroRNAs (miRNAs) are key regulators of fibrotic signalling in cells, including fibroblasts and myofibroblasts. Specifically, miRNA-29b is notable for downregulating pro-fibrotic genes, including collagen type I, reducing ECM accumulation, and limiting fibroblast/myofibroblast overactivation. In this context, the present work develops a collagen-GAG (CG) scaffold platform for delivery of miRNA-29b complexed GET nanoparticles to inhibit fibrosis. Initially, bioinformatic analysis of miRNA-29b validated its involvement in ECM-associated pathways and processes, followed by successful nanoparticle internationalisation in primary dermal fibroblasts. The anti-fibrotic efficacy of the optimised miRNA-29b nanoparticles was subsequently demonstrated by significant reductions in collagen deposition and -SMA expression, both key indicators of myofibroblast differentiation and fibrosis. The optimised miRNA-29b formulation was then incorporated into 3D porous collagen-GAG (CG) scaffolds, which modulated fibrotic gene expression while preserving scaffold structure conducive to fibroblast/myofibroblast infiltration and proliferation. Finally, functional outcomes of seeded TGF-{beta}-stimulated fibroblasts, including reduced matrix contraction, -SMA expression, and ECM deposition, were comparable to those observed in non-fibrotic conditions, thereby confirming the therapeutic potential of scaffold-mediated miRNA-29b delivery. Together, these findings demonstrate that scaffold-mediated miRNA-29b delivery represents a promising anti-fibrotic strategy for wound healing by mitigating myofibroblast activation, limiting matrix contraction, and preventing pathological ECM accumulation.

bioengineering↗

bioRxiv2026

Biomimetic miR-133a inhibitor activated scaffolds optimised for spinal cord repair promote neurite outgrowth and angiogenesis via neuronal cytoskeletal remodelling

Significant challenges in spinal cord injury include the loss of neural tissue, disruption of local vasculature, and intrinsic suppression of actin mobilisation in neurons, together preventing axonal regrowth. Here, we develop an implantable biomimetic microRNA (miR) inhibitor-activated scaffold that combines optimised matrix cues with transcriptomically defined RNA-based modulation of intrinsic neuronal pathways as a platform to support neuronal cell delivery and promote neurovascular repair. First, hyaluronic acid macroporous scaffolds functionalized with collagen-IV and fibronectin supported iPSC-derived neuronal spheroid formation and neurite extension. To identify a neurotrophic target, we performed analysis of public miRNA-mRNA interaction datasets, revealing that miR-133a regulates pathways involved in neuronal actin cytoskeletal organisation. MiR-133a inhibitors were complexed with the cell-penetrating peptide RALA to form nanoparticles, demonstrated >95% scaffold loading efficiency, sustained localised release over 28 days and enhanced neurite outgrowth from motor neurons and iPSC neurons. Bulk RNA-sequencing and transcriptomic analysis of iPSC neurons within the scaffolds demonstrated coordinated upregulation of actin-remodelling, cell-matrix adhesion and metabolic pathways, indicative of a cytoskeletally adaptable neuron. When employed in an ex vivo dorsal root ganglia model, scaffold-mediated miR-133a inhibition promoted neurite extension and integration of delivered iPSC neurons with injured neural tissue. Finally, miR-133a-inhibitor-activated scaffolds upregulated neurovascular genes, increased endothelial cell migration and enhanced blood vessel formation in vivo in a chick embryo assay. These findings identify miR-133a as a neurotrophic target, elucidate the underlying mechanisms of action through transcriptomic analysis and demonstrate that biomimetic scaffold-mediated inhibition of miR-133a can enhance neuronal delivery for multifaceted spinal cord repair applications. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/719922v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@13fcb26org.highwire.dtl.DTLVardef@13239c3org.highwire.dtl.DTLVardef@6e6f5eorg.highwire.dtl.DTLVardef@51ad93_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Scaffold-mediated miRNA-155 inhibition promotes regenerative macrophage polarisation leading to anti-inflammatory, angiogenic, and neurogenic responses for wound healing

Chronic wounds represent a significant clinical challenge due to persistent inflammation and impaired nerve regeneration, both of which delay healing. Conventional treatments often yield limited success and inconsistent outcomes, especially in complex and recurring wounds. Combinatorial strategies that integrate biomaterial scaffolds with gene delivery offer a promising approach to promote tissue repair. MicroRNAs (miRNAs), particularly miRNA-155, have emerged as crucial regulators of wound healing. MiRNA-155 is highly expressed in inflammatory conditions and plays a key role in macrophage activation, polarisation, and nerve regeneration. In this context, this study introduces a miRNA-155 inhibitor-activated scaffold designed to modulate the chronic wound environment by inhibiting miRNA-155. MiRNA-155 inhibitor complexed GET nanoparticles were characterised and incorporated into collagen-glycosaminoglycan (CG) scaffolds. These supported dermal fibroblast and endothelial cell growth while enabling controlled inhibitor release. Scaffold-mediated miRNA-155 inhibition in both non-polarised (M0) and pro-inflammatory (M1) macrophages promoted anti-inflammatory (M2) polarisation. Macrophage secretome analysis showed reduced inflammatory cytokines and increased angiogenic growth factor secretion in both conditions. The regenerative potential of the miRNA-i-activated scaffold via macrophage polarisation was validated through inflammatory and angiogenic functional assays with endothelial cells. In parallel, scaffold-mediated miRNA-155 delivery to dorsal root ganglia (DRG) promoted neurogenic outcomes through enhanced axonal regrowth, essential for the synergistic repair of chronic wounds across the skin-nerve axis. In vivo implantation of miRNA-155 inhibitor-activated scaffolds in chicks demonstrated successful integration without disrupting vascular network formation. Collectively, these findings establish the miRNA-155 inhibitor-activated scaffold as a regenerative platform with anti-inflammatory, pro-angiogenic, and neurogenic outcomes, offering a multifaceted solution for chronic wound healing applications. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/682055v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1c6a6b6org.highwire.dtl.DTLVardef@eb04f9org.highwire.dtl.DTLVardef@1937f15org.highwire.dtl.DTLVardef@7c70d3_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Mechanically activated bone cell derived extracellular vesicles regulate angiogenesis in a manner that is dependent on the stage of lineage commitment

Bone regeneration requires a finely tuned interplay between osteogenesis and angiogenesis. While current treatments such as auto/allografts, provide support, they often fail to promote adequate vascularisation necessary for complete repair. Extracellular vesicles (EVs), as mediators of intercellular communication, have emerged as promising acellular nanotechnologies for tissue regeneration due to their bioactive cargo and low immunogenicity. Mechanical stimulation, a known enhancer of bone cell function, can modulate EV cargo and potentially improve regenerative efficacy. In this study, we investigated how mechanical stimulation, and the stage of mesenchymal lineage commitment influence the angiogenic potential of secretomes and EVs derived from mesenchymal stromal/stem cells, osteoblasts, and osteocytes. Our findings reveal that both cell mechanical stimulation and their differentiation stage significantly modulate the angiogenic properties of the resulting EVs. Among the tested conditions, mechanically-stimulated osteocyte-derived EVs demonstrate superior angiogenesis, promoting endothelial cell migration, tube formation, and CD31 expression. These effects were further validated in a pre-clinical ex ovo chick chorioallantoic membrane assay, where robust neovascularisation was observed. This work highlights the critical role of both mechanical cues and cell differentiation stage in regulating the angiogenic capacity of EVs and proposes mechanically activated osteocyte-derived EVs as a novel pro-angiogenic nanotherapeutic for bone repair.

bioengineering↗