Peri-implant fibrosis (PIF) increases the postsurgical risks after implantation and limits the efficacy of the implantable drug delivery systems (IDDS). Pirfenidone (PF) is an oral anti-fibrotic drug with a short (<3 h) circulation half-life and strong adverse side effects. In the current study, disk-shaped IDDS prototype combining polylactic acid (PLA) and PF, PLA@PF, with prolonged (~3 days) PF release (in vitro) was prepared. The effects of the PLA@PF implants on PIF were examined in the rabbit ear skin pocket model on postoperative days (POD) 30 and 60. Matching blank PLA implants (PLA0) and PLA0 with an equivalent single-dose PF injection performed on POD0 (PLA0+injPF) served as control. On POD30, the intergroup differences were observed in α-SMA, iNOS and arginase-1 expressions in PLA@PF and PLA0+injPF groups vs. PLA0. On POD60, PIF was significantly reduced in PLA@PF group. The peri-implant tissue thickness decreased (532 ± 98 µm vs. >1100 µm in control groups) approaching the intact derma thickness value (302 ± 15 µm). In PLA@PF group, the implant biodegradation developed faster, while arginase-1 expression was suppressed in comparison with other groups. This study proves the feasibility of the local control of fibrotic response on implants via modulation of foreign body reaction with slowly biodegradable PF-loaded IDDS.
Insufficient vascular growth in the area of artificial-material implantation contributes to ischemia, fibrosis, the development of bacterial infections, and tissue necrosis around the graft. The purpose of this study was to evaluate angiogenesis after implantation of polycaprolactone microfiber scaffolds modified by a pCMV-VEGF165-plasmid in rats. Influence of vascularization on scaffold degradation was also examined. We investigated flat microfibrous scaffolds obtained by electrospinning polycaprolactone with incorporation of the pCMV-VEGF-165 plasmid into the microfibers at concentrations of 0.005 ng of plasmid per 1 mg of polycaprolactone (0.005 ng/mg) (LCGroup) and 0.05 ng/mg (HCGroup). The samples were subcutaneously implanted in the interscapular area of rats. On days 7, 16, 33, 46, and 64, the scaffolds were removed, and a histological study with a morphometric evaluation of the density and diameter of the vessels and microfiber diameter was performed. The number of vessels was increased in all groups, as well as the resorption of the scaffold. On day 33, the vascular density in the HCGroup was 42% higher compared to the control group (p = 0.0344). The dose-dependent effect of the pCMV-VEGF165-plasmid was confirmed by enhanced angiogenesis in the HCGroup compared to the LCGroup on day 33 (p-value = 0.0259). We did not find a statistically significant correlation between scaffold degradation rate and vessel growth (the Pearson correlation coefficient was ρ = 0.20, p-value = 0.6134). Functionalization of polycaprolactone by incorporation of the pCMV-VEGF165 plasmid provided improved vascularization within 33 days after implantation, however, vessel growth did not seem to correlate with scaffold degradation rate.
Mature hypertrophic scars (HSs) remain a challenging clinical problem, particularly due to the absence of biologically relevant experimental models as a standard rabbit ear HS model only reflects an early stage of scarring. The current study aims to adapt this animal model for simulation of mature HS by validating the time of the scar stabilization using qualitative and quantitative criteria. The full-thickness skin and perichondrium excision wounds were created on the ventral side of the rabbit ears. The tissue samples were studied on post-operation days (PODs) 30, 60, 90 and 120. The histopathological examination and morphometry were applied in parallel with biochemical analysis of protein and glycosaminoglycans (GAGs) content and amino acid composition. The supramolecular organization of collagen was explored by differential scanning calorimetry. Four stages of the rabbit ear HS maturation were delineated and attributed with the histolomorphometrical and physicochemical parameters of the tissue. The experimental scars formed in 30 days but stabilized structurally and biochemically only on POD 90–120. This evidence-based model can be used for the studies and testing of new treatments of the mature HSs.
Ïîäaeåëóäî÷íàÿ aeåëåçà / PancreasЦель. Изучить влияние конфигурации некроза поджелудочной железы на течение и исход наружных панкреатических свищей, сформировавшихся на этапе острого панкреатита. Материал и методы. Изучена динамика наружных панкреатических свищей, существующих от 2 до 143 мес после инвазивных вмешательств по поводу панкреонекроза, у 53 больных. Некроз поджелудочной железы, его глубина и конфигурация диагностированы с помощью КТ. Результаты. Панкреатический свищ закрылся у 30 из 53 больных: у всех 10 больных с 1-м типом конфигурации при неглубоком (<50%) некрозе и у всех 5 пациентов со 2-м типом конфигурации, даже при полном поперечном некрозе. При глубоком некрозе 1-го типа свищ закрылся у 15 из 38 больных. У 7 из 15 пациентов был восстановлен отток сока от жизнеспособной паренхимы, расположенной дистальнее некроза. Это осуществляли эндоскопической реканализацией протока через зону некроза на этапе острого панкреатита. В отдаленные сроки объем паренхимы дистальнее некроза не изменился: 50,4 ± 19,9 и 40,7 ± 14,4 см 3 (р > 0,05). У 8 пациентов в отдаленные сроки отмечено уменьшение объема функционирующей паренхимы дистальнее некроза с 20 ± 6,3 до 7,4 ± 2,7 см 3 (р < 0,001). При стойких панкреатических свищах 23 больным выполнили резекционно-дренирующие вмешательства. Заключение. Для прогноза динамики панкреатического свища после панкреонекроза целесообразно учитывать тип конфигурации некроза, его глубину и объем функционально активной паренхимы дистальнее зоны некроза. Глубокий некроз паренхимы поджелудочной железы при 1-м типе конфигурации и большой объем жизнеспособной паренхимы дистальнее некроза позволяют прогнозировать стойкий панкреатический свищ. Эндоскопическая транспапиллярная реканализация протока поджелудочной железы через зону глубокого некроза на этапе острого панкреатита способствует закрытию панкреатического свища и предотвращает атрофию дистально расположенной функционально активной паренхимы поджелудочной железы в отдаленные сроки. Неглубокий некроз при 1-м типе конфигурации и 2-й тип конфигурации некроза при остром панкреатите позволяют предполагать быстрое закрытие панкреатического свища.
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