3D Gradient and Linearly Aligned Magnetic Microcapsules in Nerve Guidance Conduits with Remotely Spatiotemporally Controlled Release to Enhance Peripheral Nerve Repair

Although numerous strategies have been implemented to develop nerve guidance conduits (NGCs) to treat peripheral nerve injury (PNI), functionalization of an NGC to make it remotely controllable for providing spatiotemporal modulation on in situ nerve tissues remains a challenge. In this study, a gelatin/silk (GS) hydrogel was used to develop an NGC based on its self-owned reversible thermoresponsive sol-to-gel phase transformation ability that permitted rapid three-dimensional (3D) micropatterning of the incorporated nerve growth factor (NGF)-loaded magnetic poly(lactic-co-glycolic acid) (PLGA) microcapsules (called NGF@MPs) via multiple magnetic guidance. The thermally controllable viscosity of GS enabled the rapid formation of a 3D gradient and linearly aligned distribution of NGF@MPs, leading to magnetically controlled 3D gradient release of NGF to enhance topographical nerve guidance and wound healing in PNIs. Particularly, the as-formed micropatterned hydrogel, called NGF@MPs-GS, showed corrugation topography with a pattern height H of 15 μm, which resulted in the linear axon alignment of more than 90% of cells. In addition, by an external magnetic field, spatiotemporal controllability of NGF release was obtained and permitted neurite elongation that was almost 2-fold longer than that in the group with external addition of NGF. Finally, an NGC prototype was fabricated and implanted into the injured sciatic nerve. The patterned implant, assisted by magnetic stimulation, demonstrated accelerated restoration of motor function within 14 days after implantation. It further contributed to the enhancement of axon outgrowth and remyelination after 28 days. This NGC, with controllable mechanical, biochemical, and topographical cues, is a promising platform for the enhancement of nerve regeneration

Characteristics of patients grouped by change in left ventricular ejection fraction 6 months after percutaneous coronary interventions for acute myocardial infarction.

<p>*<i>P</i><0.05, Mann–Whitney U test.</p><p>6 M, six months; BMI, body mass index; CPK, creatine- phosphor-kinase; CKMB, creatine phosphokinase-MB; HbA1C, glycohemoglobin; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; hsCRP, high sensitivity C reactive protein; IL-6, interleukin 6; WMSI, wall motion score index; TIMI, thrombolysis in myocardial infarction; LVMI, left ventricular mass index; LVEF, left ventricular ejection fraction; E/A ratio, the ratio of the peak velocities of early (E wave) and late (A wave) diastolic filling; DT, the deceleration time of the E wave; EDV, left ventricular end diastolic volume; ESV, left ventricular end systolic volume; Hb, hemoglobin; RDW, red blood cell distribution width; LAD, left anterior descending artery; RCA, right coronary artery; LCX, left circumflex artery; D2B, door to balloon; PCI, percutaneous coronary interventions; TIMI, thrombolysis in myocardial infarction.</p

The relationship between serum iron and interleukin-6 levels in all subjects.

<p>(Dependent variable: serum iron concentration).</p><p>*<i>P</i><0.05 and **<i>P</i><0.001, general linear model. AMI, acute myocardial infarction; IL-6, interleukin 6; SE, standardized error. The intercept is the predicted value of serum iron concentration in AMI group. The predicted value is 71.872 µg/dl. The serum iron concentration in the control group was, on average, 35.494 µg/dl higher than that in the AMI group. For every one unit increase in IL-6 concentration, there was a decrease of 0.625 units in serum iron concentration.</p

Univariate correlation between serum iron concentration and patient characteristics after acute myocardial infarction.

<p>*<i>P</i><0.05, Spearman’s rho correlation.6 M, six months; TIMI, thrombolysis in myocardial infarction; EF 6 M, left ventricular ejection fraction at 6–month follow-up.</p

The relationship between serum iron concentration and IL-6 levels in all enrolled subjects.

<p>The result indicated that the serum iron concentration was negatively correlated with circulating IL-6 concentration in all study subjects. The linear relationship was well described by Serum iron = 95.994−1.246 (IL-6), R² = 0.133 and <i>P</i><0.001.</p

Lower serum iron concentration is associated with higher inflammatory markers and TIMI risk score after acute myocardial infarction.

<p>*<i>P</i><0.05, Mann–Whitney U test. TIMI, thrombolysis in myocardial infarction; IL-6, interleukin 6.</p

The relationships between serum iron concentration and TIMI risk scores after primary angioplasty for AMI.

<p>The AMI patients were divided into four subgroups according to TIMI risk score for STEMI: Group 1 (TIMI risk score 1, n = 8); Group 2 (TIMI risk score 2, n = 15); Group 3 (TIMI risk score 3, n = 19); and Group 4 (TIMI risk score ≥4, n = 13). Trend analysis with Jonckheere-Terpstra test found that serum iron concentration significantly decreased as TIMI risk score rose (<i>P</i> = 0.002).</p

Trend analysis showed serum iron concentration was inversely proportional to IL-6 concentration in STEMI patients.

<p>AMI patients were divided into three subgroups according to circulating IL-6 concentration tertile: group 1, IL-6 concentration ≤10.48 pg/ml (n = 19); group 2, IL-6 concentration between 10.49–19.67 pg/ml (n = 20); group 3, IL-6 concentration ≥19.68 pg/ml (n = 16). Trend analysis showed serum iron concentration was inversely proportional to IL-6 concentration. (Jonckheere-Terpstra test, <i>P</i> = 0.043).</p

Multiple linear regression analysis of variables associated with ejection fraction 6 months after primary angioplasty for acute myocardial infarction.

<p>(Dependent variable: ejection fraction at 6 months).</p><p><i>R²</i> = 0.620.</p><p>*<i>P</i><0.05 and **<i>P</i><0.001.</p><p>CPK MB, creatine phosphokinase-MB; IL-6, interleukin 6; WMSI, wall motion score index; IRA, infarct related artery; LAD, left anterior descending artery; RCA, right coronary artery; LCX, left circumflex artery.</p