Calcium-Based Nanoparticles Accelerate Skin Wound Healing

INTRODUCTION: Nanoparticles (NPs) are small entities that consist of a hydroxyapatite core, which can bind ions, proteins, and other organic molecules from the surrounding environment. These small conglomerations can influence environmental calcium levels and have the potential to modulate calcium homeostasis in vivo. Nanoparticles have been associated with various calcium-mediated disease processes, such as atherosclerosis and kidney stone formation. We hypothesized that nanoparticles could have an effect on other calcium-regulated processes, such as wound healing. In the present study, we synthesized pH-sensitive calcium-based nanoparticles and investigated their ability to enhance cutaneous wound repair. METHODS: Different populations of nanoparticles were synthesized on collagen-coated plates under various growth conditions. Bilateral dorsal cutaneous wounds were made on 8-week-old female Balb/c mice. Nanoparticles were then either administered intravenously or applied topically to the wound bed. The rate of wound closure was quantified. Intravenously injected nanoparticles were tracked using a FLAG detection system. The effect of nanoparticles on fibroblast contraction and proliferation was assessed. RESULTS: A population of pH-sensitive calcium-based nanoparticles was identified. When intravenously administered, these nanoparticles acutely increased the rate of wound healing. Intravenously administered nanoparticles were localized to the wound site, as evidenced by FLAG staining. Nanoparticles increased fibroblast calcium uptake in vitro and caused contracture of a fibroblast populated collagen lattice in a dose-dependent manner. Nanoparticles also increased the rate of fibroblast proliferation. CONCLUSION: Intravenously administered, calcium-based nanoparticles can acutely decrease open wound size via contracture. We hypothesize that their contraction effect is mediated by the release of ionized calcium into the wound bed, which occurs when the pH-sensitive nanoparticles disintegrate in the acidic wound microenvironment. This is the first study to demonstrate that calcium-based nanoparticles can have a therapeutic benefit, which has important implications for the treatment of wounds

Calcium-based nanoparticles increase fibroblast proliferation and contraction.

<p>(A) BrdU incorporation after 12 hrs of growth with calcium-based nanoparticles (CNP) in NIH3T3 fibroblasts. CNP-treatment increased fibroblast proliferation rate, which was dependent on CNP concentration in a dose-dependent manner. (B) Fibroblasts were added to a collagen lattice to form a fibroblast populated lattice complex. The surface area of the FPCL reduced over time depending on CNP concentration. The amount of contractility is inversely proportional to FPCL size. CNP-treatment increased FPCL contraction. P-values were calculated using the Dunnett's test. The data is expressed as the mean ± SD.</p

Effects of prior contractions on muscle microvascular oxygen pressure at onset of subsequent contractions

In humans, pulmonary oxygen uptake (V̇(O2)) kinetics may be speeded by prior exercise in the heavy domain. This ‘speeding’ arises potentially as the result of an increased muscle O(2) delivery (Q̇(O2)) and/or a more rapid elevation of oxidative phosphorylation. We adapted phosphorescence quenching techniques to determine the Q(O2)-to-O(2) utilization (Q̇(O2)/V̇(O2)) characteristics via microvascular O(2) pressure (P(O2,m)) measurements across sequential bouts of contractions in rat spinotrapezius muscle. Spinotrapezius muscles from female Sprague-Dawley rats (n = 6) were electrically stimulated (1 Hz twitch, 3–5 V) for two 3 min bouts (ST(1) and ST(2)) separated by 10 min rest. P(O2,m) responses were analysed using an exponential + time delay (TD) model. There was no significant difference in baseline and ΔP(O2,m) between ST(1) and ST(2) (28.5 ± 2.6 vs. 27.9 ± 2.4 mmHg, and 13.9 ± 1.8 vs. 14.1 ± 1.3 mmHg, respectively). The TD was reduced significantly in the second contraction bout (ST(1), 12.2 ± 1.9; ST(2), 5.7 ± 2.2 s, P < 0.05), whereas the time constant of the exponential P(O2,m) decrease was unchanged (ST(1), 16.3 ± 2.6; ST(2), 17.6 ± 2.7 s, P > 0.1). The shortened TD found in ST(2) led to a reduced time to reach 63 % of the final response of ST(2) compared to ST(1) (ST(1), 28.3 ± 3.0; ST(2), 20.2 ± 1.8 s, P < 0.05). The speeding of the overall response in the absence of an elevated P(O2,m) baseline (which had it occurred would indicate an elevated Q(O2)/V̇(O2)) or muscle blood flow suggests that some intracellular process(es) (e.g. more rapid increase in oxidative phosphorylation) may be responsible for the increased speed of P(O2,m) kinetics after prior contractions under these conditions