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Intervertebral disc (IVD) degeneration is one of the primary causes of low back pain, causing disability; hence, there is no regenerative nature of the current treatments. Hyaluronic acid (HA) was reported to facilitate tissue repair and alleviate pain. Herein, we determined the therapeutic effect of HA and type II collagen (COLII) hydrogel for tissue repair targeting pain in IVD degeneration. We implanted HA/COLII hydrogel following surgically induced disc injury at coccygeal levels in the rat tail model of pain. We assessed the efficacy of the HA/COLII hydrogel in reducing pain behaviour by using the von Frey assessment, protein expression of growth-associated protein (GAP) 43 for sensory nerve innervation, and disc hydration by magnetic resonance imaging (MRI). We observed the anti-nociceptive effect of the HA/COLII hydrogel in alleviating mechanical allodynia in rats. There was an inhibition of sensory hyperinnervation indicated by the GAP43 protein in the treatment group. We revealed an increase in T1ρ mapping of MRI, indicating that the hydrogel restored disc hydration in vivo. Our findings suggest the HA/COLII hydrogel alleviates pain behaviour, inhibits hyperinnervation and promotes disc hydration for tissue repair, implying that it is a potential candidate for the treatment of degenerative disc-associated low back pain. [ABSTRACT FROM AUTHOR]

Oxidative stress is a contributing factor that leads to the vascular complications of diabetes mellitus. Diabetic peripheral neuropathy (DPN) is one of the microvascular complications with rising concern as the disease progresses despite strict glucose control and monitoring. Thus, there is an ongoing need for an early intervention that is effective in halting or slowing the progression of DPN where antioxidants have been proposed as potential therapeutic agents. This systematic review aims to evaluate the existing evidence on the antioxidant effect in DPN and provide insight on the role of antioxidants in the progression of DPN in a rat model. A comprehensive literature search was conducted on Web of Science, EBSCOhost, and Scopus to identify the effects and role of antioxidants in DPN. Data extraction was performed and SYRCLE's risk of bias (RoB) tool was used for risk assessment. This systematic review was written following the PRISMA 2020 statements. From the literature search, 1268 articles were screened, and a total of 101 full-text articles were further screened before 33 were analyzed. These findings collectively suggest that antioxidants can play a crucial role in managing and potentially reversing the effects of diabetic neuropathy by targeting oxidative stress and improving nerve function. [ABSTRACT FROM AUTHOR]

Therapeutic factors secreted by mesenchymal stem cells (MSCs) promote angiogenesis in vivo. However, delivery of MSCs in the absence of a cytoprotective environment offers limited efficacy due to low cell retention, poor graft survival, and the nonmaintenance of a physiologically relevant dose of growth factors at the injury site. The delivery of stem cells on an extracellular matrix (ECM)-based platform alters cell behavior, including migration, proliferation, and paracrine activity, which are essential for angiogenesis. We demonstrate the biophysical and biochemical effects of preconditioning human MSCs (hMSCs) for 96 h on a three-dimensional (3D) ECM-based microgel platform. By altering the macromolecular concentration surrounding cells in the microgels, the proangiogenic phenotype of hMSCs can be tuned in a controlled manner through cell-driven changes in extracellular stiffness and “outside-in” integrin signaling. The softest microgels were tested at a low cell dose (5 × 104 cells) in a preclinical hindlimb ischemia model showing accelerated formation of new blood vessels with a reduced inflammatory response impeding progression of tissue damage. Molecular analysis revealed that several key mediators of angiogenesis were up-regulated in the low-cell-dose microgel group, providing a mechanistic insight of pathways modulated in vivo. Our research adds to current knowledge in cell-encapsulation strategies by highlighting the importance of preconditioning or priming the capacity of biomaterials through cell–material interactions. Obtaining therapeutic efficacy at a low cell dose in the microgel platform is a promising clinical route that would aid faster tissue repair and reperfusion in “no-option” patients suffering from peripheral arterial diseases, such as critical limb ischemia (CLI). [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) can improve chronic wound healing; however, recent studies suggest that the therapeutic effect of MSCs is mediated mainly through the growth factors and cytokines secreted by these cells, referred to as the MSC secretome. To overcome difficulties related to the translation of cell therapy into clinical use such as efficacy, safety and cost, we propose a hydrogel loaded with a secretome from the recently established human adipose tissue mesenchymal stem cell line (HATMSC2) as a potential treatment for chronic wounds. Biocompatibility and biological activity of hydrogel-released HATMSC2 supernatant were investigated in vitro by assessing the proliferation and metabolic activity of human fibroblast, endothelial cells and keratinocytes. Hydrogel degradation was measured using hydroxyproline assay while protein released from the hydrogel was assessed by interleukin-8 (IL-8) and macrophage chemoattractant protein-1 (MCP-1) ELISAs. Pro-angiogenic activity of the developed treatment was assessed by tube formation assay while the presence of pro-angiogenic miRNAs in the HATMSC2 supernatant was investigated using real-time RT-PCR. The results demonstrated that the therapeutic effect of the HATMSC2-produced factors is maintained following incorporation into collagen hydrogel as confirmed by increased proliferation of skin-origin cells and improved angiogenic properties of endothelial cells. In addition, HATMSC2 supernatant revealed antimicrobial activity, and which therefore, in combination with the hydrogel has a potential to be used as advanced wound-healing dressing. [ABSTRACT FROM AUTHOR]

The diatom's frustule, characterized by its rugged and porous exterior, exhibits a remarkable biomimetic morphology attributable to its highly ordered pores, extensive surface area, and unique architecture. Despite these advantages, the toxicity and nonbiodegradable nature of silica-based organisms pose a significant challenge when attempting to utilize these organisms as nanotopographically functionalized microparticles in the realm of biomedicine. In this study, we addressed this limitation by modulating the chemical composition of diatom microparticles by modulating the active silica metabolic uptake mechanism while maintaining their intricate three-dimensional architecture through calcium incorporation into living diatoms. Here, the diatom Thalassiosira weissflogii was chemically modified to replace its silica composition with a biodegradable calcium template, while simultaneously preserving the unique three-dimensional (3D) frustule structure with hierarchical patterns of pores and nanoscale architectural features, which was evident by the deposition of calcium as calcium carbonate. Calcium hydroxide is incorporated into the exoskeleton through the active mechanism of calcium uptake via a carbon-concentrating mechanism, without altering the microstructure. Our findings suggest that calcium-modified diatoms hold potential as a nature-inspired delivery system for immunotherapy through antibody-specific binding.

Introduction: A regenerative strategy employing extracellular matrix (ECM)-based biomaterials and stem cells provide a better approach to mimicking the three-dimensional (3D) microenvironment of intervertebral disc for endogenous tissue regeneration. However, there is currently limited understanding regarding the human Wharton Jelly derived-mesenchymal stem cells (hWJ-MSCs) towards nucleus pulposus (NP)-like cells. Our study focused on the development of 3D bioengineered hydrogel based on the predominant ECM of native NP, including type II collagen (COLII) and hyaluronic acid (HA), which aims to tailor the needs of the microenvironment in NP. Methods: We have fabricated a 3D hydrogel using from COLII enriched with HA by varying the biomacromolecule concentration and characterised it for degradation, stability and swelling properties. The WJ-MSC was then encapsulated in the hydrogel system to guide the cell differentiation into NP-like cells. Results: We successfully fabricated COLII hydrogel (2 mg/ml) and HA 10 mg/ml at a weight ratio of HA and COLII at 1:9 and 4.5:9, and both hydrogels physically maintained their 3D sphere-shaped structure after complete gelation. The higher composition of HA in the hydrogel system indicated a higher water intake capacity in the hydrogel with a higher amount of HA. All hydrogels showed over 60% hydrolytic stability over a month. The hydrogel showed an increase in degradation on day 14. The hWJ-MSCs encapsulated in hydrogel showed a round morphology shape that was homogenously distributed within the hydrogel of both groups. The viability study indicated a higher cell growth of hWJ-MSCs encapsulated in all hydrogel groups until day 14. Discussion: Overall, our findings demonstrate that HA/COLII hydrogel provides an optimal swelling capacity, stability, degradability, and non-cytotoxic, thus mimics the NP microenvironment in guiding hWJ-MSCs towards NP phenotype, which is potentially used as an advanced cell delivery system for intervertebral disc regeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mohd Isa, Zulkiflee, Ogaili, Mohd Yusoff, Sahruddin, Sapri, Mohd Ramli, Fauzi and Mokhtar.)

Painful intervertebral disc degeneration is mediated by inflammation that modulates glycosylation and induces hyperinnervation and sensory sensitization, which result in discogenic pain. Hyaluronic acid (HA) used as a therapeutic biomaterial can reduce inflammation and pain, but the effects of HA therapy on glycosylation and pain associated with disc degeneration have not been previously determined. We describe a novel rat model of pain induced by intervertebral disc injury, with validation of the pain phenotype by morphine treatment. Using this model, we assessed the efficacy of HA hydrogel for the alleviation of pain, demonstrating that it reduced nociceptive behavior, an effect associated with down-regulation of nociception markers and inhibition of hyperinnervation. Furthermore, HA hydrogel altered glycosylation and modulated key inflammatory and regulatory signaling pathways, resulting in attenuation of inflammation and regulation of matrix components. Our results suggest that HA hydrogel is a promising clinical candidate for the treatment of back pain caused by degenerated discs.