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  • Importantly lactate and H exert some of

    2022-08-12

    Importantly, lactate and H+ exert some of their biological effects independently of each other, though sometimes through redundant pathways leading to a same biological effect, as for angiogenesis. In other cases, they can have antagonist effects: lactate was shown to stimulate extracellular matrix synthesis by chondrocytes, whereas extracellular acidification inhibited extracellular matrix synthesis and chondrocyte proliferation [37]. As a polymer controlling the release of lactate and H+, PLGA could thus be considered as an active ingredient when lactate and H+ exert a biological effect that can influence the bazedoxifene of a specific disease.
    In 2003, Trabold et al. used for the first time a PLGA mesh as a lactate-releasing polymer on purpose in the fluid of a wound cylinder implanted in rats in order to create lactate rich microenvironment [38]. PLGA was shown to significantly elevate lactate level of 2–3 mM at steady-state in the wound fluid whereas higher levels of VEGF and collagen deposition were concomitantly observed in the cylinder. Based on this work and on the hypothesis that the application of exogenous lactate would accelerate angiogenesis and wound healing processes, Porporato et al. reported a pre-clinical study using a PLGA implant to supply lactate sustainably. In situ microdialysis revealed a local 3-fold elevation of lactate concentration as compared to control at day 7 post-implantation of PLGA, which is consistent with the signaling functions of lactate released upon PLGA hydrolysis. Compared to that of control group, the PLGA implanted group showed nearly 60% more healing in wounded area after 10 days post-injury and a dependence of this effect on angiogenesis and VEGF signaling [39]. In our previous works, we have tested three types of drug loaded PLGA nanoparticles for wound healing properties in both normal and diabetic mice. In all the three cases, we have included empty PLGA nanoparticles as a control group, which showed faster wound closure, better re-epithelialization, collagen deposition and angiogenesis than that of untreated group, thereby highlighting the intrinsic properties of PLGA. Those biological effects were associated with a local 3.5-fold increase of lactate concentration as compared to untreated animals at day 7 post-injection. When used as drug-loaded formulation, PLGA-drug combination showed the best result compared with the untreated and the other treated (drug alone and PLGA alone) groups [[40], [41], [42]]. We also evaluated dose dependent responses of PLGA and pure lactic acid. PLGA showed increasing healing effects up to 5 mg dose in the tested model whereas wounds treated with lactic acid showed delayed healing and necrosis at higher doses. PLGA appeared therefore as a realistic way to supply lactate therapeutically and locally over time, at a level relevant for regenerative effects and avoiding any toxicity i.a., linked to local excessive acidification [41,43]. In wound healing, other groups also observed a beneficial effect of PLGA per se, though it has not been linked to lactate release. Lee et al. used a PLGA nanofibrous membrane for the local delivery of metformin in a rat model of cutaneous wound [44]. In their study, they also included an unloaded PLGA nanofibrous membrane group, which showed a faster wound closure and re-epithelialization than the classical gauze sponge group. Although described by the authors, this effect has not been discussed. However, they are consistent with a local delivery of lactate upon hydrolysis of the PLGA membrane. Similarly, Wang et al. compared the effect of a collagen-chitosan +/− PLGA mesh in a rat model of cutaneous wound [45]. Although the pro-angiogenic and re-epithelializing effects of PLGA have been attributed to its impact on the mechanical properties and on the structure of the collagen-chitosan mesh, we cannot exclude the benefits of a local lactate release based on the results of other studies.