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Abstract
Postoperative abdominal adhesion (PAA) causes significant long-term postoperative morbidity. Although numerous physical anti-adhesion barriers (AAB) are used as therapeutical interventions, none of them has achieved sustained success. As a potential strategy to overcome the limitations, drug-eluting AAB have attracted scientific attention. Here, we produced agar films (AF) chemically cross-linked with different concentrations of citric acid (CA) and we measured the physicochemical properties such as crosslinking strength, swelling ratio, hydrophilicity, and biodegradability of the yielded CA-AFs. Next, Metformin (MET), an anti-diabetic drug with anti-proliferative and anti-inflammatory properties, was loaded in the CA-AFs yielding the MET-loaded CA-AF (MET@CA-AF) and the time-dependent MET release was monitored. Based on their physicochemical properties, MET@CA-AF containing 20% CA appeared a promising AAB candidate and was further used in an in vivo study. Mouse models of PAA were established with cecum abrasion and the MET@CA-AF and CA-AF were applied between the injured interfaces. At postoperative day 14, the therapeutic efficacies were analyzed by using clinical adhesion scoring and quantification of collagen-I and fibroblasts in adhesion interfaces. The results showed that applications of MET@CA-AF or CA-AF for 14 days significantly attenuated the clinical adhesion score and thickness of adhesion interface. Furthermore, when compared with the group with operation, the groups with MET@CA-AF or CA-AF exhibited the significant attenuation in PAA-associated myofibroblast activation in adhesion interface. Importantly, these attenuations were significantly more intensified in the group with MET@CA-AF than in the group with CA-AF. Based on our data, we anticipate that MET@CA-AF, a novel synthesized drug-eluting AAB, can protect against PAA by exerting the dual role of physical barrier and MET-based pharmaceutic.
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Fig. 1.
The novel synthesized MET@CA-AF. (A) The macroscopic appearance of MET@CA-AF. (B) Chemical formula of MET@CA-AFs after cross-linking reaction and the predicted releasing dynamics of MET from MET@CA-AF.
Fig. 2.
Physicochemical properties of the CA-AFs with different concentrations of CA and MET@CA-AF. (A) FT-IR spectra with indicat-ed esterification, (B) swelling properties, (C) in vitro degradation properties, (D) hydrophilicity, and (E) in vitro MET-releasing properties of CA-AFs cross-linked with different concentrations of CA. In graphs of (B) and (D), data were represented as mean±S.D (p∗∗∗<0.001 between the indicated samples).
Fig. 3.
Attenuation of gross findings associated with postoperative abdominal adhesion by MET@CA-AF. (A) Representative laparoscopic images obtained at POD 14. The wide and well-developed adhesions are indicated with black arrowheads, the abdominal wall is indicated as AW, and the cecum is indicated as C. (B) H-E stained tissue samples involving the adhesive lesion. Scale bar = 100 μm.
Fig. 4.
Inhibition of the adhesion interface formation and myofibroblast activation by MET@CA-AF. (A) Representative Masson's tri-chrome-stained tissue samples involving the adhesive lesion. Scale bar = 100 μm. (B) Quantitative graphs showing the averaged thicknesses of adhesion interface of different groups. Data are represented as mean± S.D (p∗∗∗<0.001 vs. OP group. p†††<0.001 vs. CA-AF group). (C) Representative images of immunofluorescence for detecting activated myofibroblast, which is depicted as DAPI+ vimentin+ cells surround-ed by collagen-I+ fluorescence (indicated with white arrows). Scale bar = 50 μm. (D) Quantitative graphs showing the average number of activated myofibroblasts of different groups. Data are represented as mean± S.D (p∗∗<0.01 and p∗∗∗<0.001 vs. OP group; p††<0.01 vs. CA-AF group).
Table 1.
Attenuation of PAA severity by MET@CA-AF. Adhesions are graded from 0 to 5: 0, no adhesion; 1, one thin filmy adhesion; 2, more than one thin adhesion; 3, thick adhesion with focal point; 4, thick adhesion with planar attachment or more than one thick adhesion with focal point; and 5, very thick vascularized adhesion or more than one planar adhesion. Data are represented as a mean± S.D.
| Adhesion | CTRL | OP | CA-AF | MET@CA-AF |
|---|---|---|---|---|
| 0 | 8 | 0 | 0 | 4 |
| 1 | 0 | 0 | 1 | 2 |
| 2 | 0 | 0 | 2 | 0 |
| 3 | 0 | 0 | 3 | 0 |
| 4 | 0 | 3 | 0 | 0 |
| 5 | 0 | 2 | 0 | 0 |
| Death | 0 | 3 | 2 | 2 |
| Mean±S.D | 0 | 4.4±0.55 | 2.3±0.82∗∗∗ | 0.33±0.52∗∗∗,††† |
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