Prevention strategies of postoperative adhesion in soft tissues by applying biomaterials: Based on the mechanisms of occurrence and development of adhesions

Abstract

Postoperative adhesion (POA) widely occurs in soft tissues and usually leads to chronic pain, dysfunction of adjacent organs and some acute complications, seriously reducing patients' quality of life and even being life-threatening. Except for adhesiolysis, there are few effective methods to release existing adhesion. However, it requires a second operation and inpatient care and usually triggers recurrent adhesion in a great incidence. Hence, preventing POA formation has been regarded as the most effective clinical strategy. Biomaterials have attracted great attention in preventing POA because they can act as both barriers and drug carriers. Nevertheless, even though much reported research has been demonstrated their efficacy on POA inhibition to a certain extent, thoroughly preventing POA formation is still challenging. Meanwhile, most biomaterials for POA prevention were designed based on limited experiences, not a solid theoretical basis, showing blindness. Hence, we aimed to provide guidance for designing anti-adhesion materials applied in different soft tissues based on the mechanisms of POA occurrence and development. We first classified the postoperative adhesions into four categories according to the different components of diverse adhesion tissues, and named them as "membranous adhesion", "vascular adhesion", "adhesive adhesion" and "scarred adhesion", respectively. Then, the process of the occurrence and development of POA were analyzed, and the main influencing factors in different stages were clarified. Further, we proposed seven strategies for POA prevention by using biomaterials according to these influencing factors. Meanwhile, the relevant practices were summarized according to the corresponding strategies and the future perspectives were analyzed.

Keywords: Biomaterials; Mechanisms of occurrence and development; Prevention of postoperative adhesions (POA); Soft tissues.

Graphical abstract

Fig. 1

The occurrence and development of POA. Foreign-body, infection or vulnus trigger the subsequent inflammatory response, hematoma or cavity macrophages aggregation in different tissues. Among them, acute inflammations, especially fibrinous inflammation and serous inflammation, are easily occur in mucosa (e.g., pharynx, larynx, trachea, intestine) and serosa (e.g., pleura, peritoneum, and pericardium); Hematoma caused by damage to great vessels usually takes place in highly vascular tissues such as dura mater; Cavity macrophages easily aggregate in injured serosal membranes (e.g., peritoneum and pericardium) in case of sterile injury. The excessive deposited fibrin, hematoma or macrophage-fibrin clot then play the role of cell scaffolds to attract cell invasion, excessive extracellular matrix (ECM) deposition and vascularization, as well as ECM remodeling, performing as “adhesion tissues” to interconnect the adjacent tissues or organs. According to the specific composition of adhesion tissues, we classified POA into four categories and named them as “membranous adhesion”, “vascular adhesion”, “adhesive adhesion” and “scarred adhesion”, respectively. The severity of injury and inflammatory response, as well as specific tissue characteristics together decide the occurrence, development and ending of POA in different tissues.

Fig. 2

Schematic diagrams of some mechanisms during POA formation. (A) The formation of fibrin. (B) The degradation of fibrinogen/fibrin. (C) The resources of myofibroblast.

Fig. 3

Strategies for preventing POA by using biomaterials based on mechanisms of adhesion formation. Six strategies could be proposed according to the corresponding determinants during the occurrence and development of POA. In addition, the combination of several strategies to construct multi-functional materials could be effective.

Fig. 4

Constructing ideal surfaces to reduce the adhesion and deposition of fibrin and cells, including constructing (A) superhydrophobic surface, (B) applying antifouling materials. (A) Superhydrophobic surface fabricated by combining the hydrophobic fumed silica and electrospray deposition showed inhibiting effect on protein adsorption and cell adhesion; (B) Illustration of mechanisms how (a) poly-hydrophilic, (b) poly-zwitterionic polymers and (c) long-chain polymers prevent the protein and cell adhesion. Reproduced with permission: (A) [163] copyright 2020, Elsevier; (C) [188], copyright 2014, ACS.

Fig. 5

Preventing adhesion by applying antifouling materials. (A) Applying Poly-zwitterionic materials to achieve antiadhesive effectiveness. (a) Constructing PMPC coating on PLA membrane through subsurface-initiated approach; (b) The SEM images of PLA/I2959 nanofibers before and after coating. (c) Photos, H&E staining and Masson staining images of the harvested cecum and abdominal wall, as well as tendon on 14 d following implantation. Scale bar: 500 μm. The black arrows pointed to adhesion site; M membrane; NA no adhesion; CE cecum; AW abdominal wall; T tendon. The membranes performed antiadhesion effectiveness in both rat tendon adhesion model and abdominal adhesion model. (B) Introducing ultra-hydrophilic structure to promote antifouling capability and efficiency of postsurgical adhesions prevention; (C) Fabricating self-deactivating bio-adhesives to prevent postoperative adhesion. Reproduced with permission: (A) [219], copyright 2022, NPG; (B) [222], copyright 2022, Elsevier; (C) [200], copyright 2022, ACS.

Fig. 6

Preventing adhesion by constructing biomaterials with performance of preventing abnormal remodeling of ECM including providing (A) chemical clues and (B) mechanical clues. (A) Constructing biomaterials with chemical clues to inhibit fibrosis. The PEBP hydrogel group had the least fibrotic tissue and expressed least TGF-β and Muc-4 in the uterine stromal layer 10 d postsurgery compared to the sham-operated group (OS), the control uterine tube (Model) group and the cross-linked hyaluronic acid hydrogel (CLHA) group (usually applied in IUA prevention clinically) (a). Hence, it significantly decreased the degree of fibrosis might through regulating the expression and interactions of TGF-β1 and Muc-4 (b). (B) Regulating cell behavior by constructing electrospun fiber scaffolds with different microstructures and chemical cues (a). Morphology of fibroblasts and immunofluorescence staining of integrin β1, α-SMA and COL-I in fibroblasts cultured on ASCF and RSCF containing varying COL-I content (5, 20, and 50%) (b) indicated that the anisotropic scaffold could inhibit integrin clustering, reorganize cytoskeleton and reduce cell tension, inhibit YAP nuclear localization, and down-regulate α-SMA expression. Histopathological characterization of spinal dura mater and epidural tissues 8 weeks after operation (c) further showed an apparent inhibition effect of the anisotropic scaffold on COL-I and α-SMA expression, thereby to effectively prevent epidural scar adhesion. Reproduced with permission: (A) [281], copyright 2021, ACS; (B) [283], copyright 2020, AAAS.

Fig. 7

Constructing multifunctional biomaterials to prevent POA. (A) Engineering a multifunctional hydrogel with functions of antioxidation, anti-inflammation, and antifibrosis to prevent epidural fibrosis and adhesion after laminectomy (a). Macroscopic observation, H&E and Masson staining results, the quantified epidural fibrosis (EF) scores, fibroblast infiltration grades, and percentages of fibrotic areas after 3 weeks of treatment in rats (b) showed that PXNT hydrogel had a more beneficial anti-adhesion efficacy than that of the commercial adhesion barrier Interceed. Data are presented as mean ± SD (n = 6). *P < 0.05, **P < 0.005, ***P < 0.0005. (B) Constructing a multi-function J-1-ADP hydrogel with hemostatic and antimicrobial activity to prevent abdominal adhesion (a). The outstanding antimicrobial activity of J-1-ADP hydrogel was demonstrated from the results of colony formation of S. aureus, MRSA, E. coli, and C. albicans from the suspensions of bacteria/fungi after incubation with hydrogel for 24 h (b). And, the prominent hemostatic activity of the hydrogel was indicated in the photographs of the bleeding liver with no treated, PBS treated, and the J-1-ADP hydrogel treated groups at the indicated time interval (c). Lastly, the obvious anti-adhesion efficacy of the hydrogel could be found in the results of formation of the abdominal adhesions between the abdominal wall and cecum in the control group, J-1-ADP hydrogel treatment group, and film treatment group at day 0 and day 14 post-operation (d), and the histopathological analysis of specimens in the three groups on day 14 post-operation (e). AW: surface of the abdominal wall. CE: surface of the cecum. Reproduced with permission: (A) [7], copyright 2020, ACS; (B) [8], copyright 2022, ACS.