A Developmental Roadmap Toward Abdominal Adhesions Prevention Technologies

Abdominal adhesions are networks of fibrotic tissues that form between organs postoperatively. Current prophylactic strategies do not reproducibly prevent adhesive small bowel obstruction across the entire abdomen. Human placental-derived stem cells produce an anti-inflammatory secretome that has been applied to multiple fibrosing diseases. The purpose of this project is to test human placental stem cell (hPSC)-based therapies for prevention of abdominal adhesions in a clinically relevant rat model. Fifty-four (n = 54, n = 6/group) male Sprague-Dawley rats (250-350 g) underwent model creation and treatment randomization under anesthesia. Experimental groups included human placental-derived stem cells (hPSC, 5 × 106 cells/10 mL Plasmalyte A), human placental-derived stem cells in a hyaluronic acid (HA-Mal-hPSC) hydrogel, the human placental-derived stem cell secretome from conditioned media in 10 mL Plasmalyte A, human placental-derived stem cells' conditioned media in a hyaluronic acid (HA-Mal-CM) hydrogel, Plasmalyte A (media alone, 10 mL), hyaluronic acid hydrogel alone (HA-Mal), Seprafilm (Baxter, Deerfield, IL), and the control groups, model with no treatment (MNT) and sham animals. Treatments were administered intraperitoneally, and the study period was 14 days postoperation. Adhesions were scored at necropsy and analyzed as the difference between means of an index statistic (Animal Index Score) versus MNT. Underlying molecular mechanisms were explored by functional genomic analysis and histology of peritoneal tissues. Hyaluronic acid hydrogel alone, HA-Mal-CM hydrogel, and Seprafilm significantly reduced the overall appearance of abdominal adhesions by mean Animal Index Score at 14 days versus MNT. Human placental stem cell, HA-Mal-hPSC hydrogel, HA-Mal-CM hydrogel, HA-Mal hydrogel alone, and Seprafilm significantly reduced the collagen content of injured peritoneal tissues. Human placental stem cell and HA-Mal-hPSC hydrogel suppressed expression of the most profibrotic genes. Conditioned media, HA-Mal hydrogel alone, and media alone significantly altered the expression of proteins associated with peritoneal fibrotic pathways. Human placental stem cell-based therapies reduce abdominal adhesions in a prospective randomized preclinical trial. This effect is supported by suppression of profibrotic genomic and proteomic pathways.

Regenerative Medicine Therapies for Prevention of Abdominal Adhesions: A Scoping Review.

Innate immunity, coagulation and placenta-related adverse pregnancy outcomes

Fabrication of a modified bacterial cellulose with different alkyl chains and its prevention of abdominal adhesion

Background: Abdominal adhesions are considered as an important problem in abdominal surgery. In this study we compared the effectiveness of atorvastatin, hyaluronic acid and interceed (oxidized cellulose) in prevention of postoperative intestinal adhesions. Material and Methods: A total of 40 Wistar-albino rats were randomly divided into 5 groups: Group 1 (Sham); Group 2 (Control or Adhesion induction); Group 3 (Adhesion induction + hyaluronic acid); Group 4 (Adhesion induction + oxidized cellulose); and Group 5 (Adhesion induction + atorvastatin). A same experimental method of cecal abrasion and ligature was used to produce adhesions in all rats. Fourteen days after adhesions formation, animals were killed and adhesions were scored according to macromorphological characteristics and adhesion-carrying tissues under standard histologic examination. Inflammation, vascularization and fibrosis in granulation sites were graded in all samples. Results: Adhesion scores in all experimental groups were slightly lower than control group. Group 3 had the lowest mean adhesions score (1.18 ± 1.24) based on surgeon observation. The mean of adhesion score in Group 3 (1.18 ± 1.24) was significantly lower than that in Group 4 (3.43 ± 0.53) (p=0.004). Group 5 showed the lowest mean adhesions score on pathological examination (5.62 ± 3.73). The mean of adhesion total score in Group 3 was slightly lower than that in other groups; however, this difference was not significant. Conclusion: Hyaluronic acid, oxidized cellulose, and atorvastatin are effective in treatment and prevention of intestinal adhesions during open abdominal surgery. Although hyaluronic acid was slightly more effective, further studies are needed to evaluate the effect of combination therapy with these agents.

ABSTRACTPostoperative adhesions represent a prevalent complication following surgical interventions, commonly forming between soft tissue surfaces within body cavities. These adhesions can give rise to severe consequences, such as chronic pain, organ dysfunction, intestinal obstruction, and infertility. Notwithstanding substantial progress in the prevention of postoperative adhesions, their underlying formation mechanisms remain intricate, and there is currently no fully effective approach to preclude their development. Hydrogels, characterized by their highly hydrophilic three‐dimensional network structure, tissue‐mimetic mechanical properties, and porous architecture, have demonstrated considerable promise as anti‐adhesion barriers and as controlled‐release carriers for therapeutic agents. In recent years, hydrogel materials have emerged as a focal point in the prevention and treatment of postoperative adhesions, owing to their excellent biocompatibility, tunable degradability, and injectability. Hydrogels have exhibited remarkable anti‐adhesive and tissue‐regenerative effects through multiple mechanisms, including physical isolation, anti‐inflammatory and anti‐fibrotic actions, and controlled drug delivery. This review summarizes the key properties and recent advancements in hydrogel‐based anti‐adhesion materials, outlines the types and functional characteristics of hydrogels currently utilized for adhesion prevention, and discusses the challenges encountered in clinical translation. Additionally, we explore future directions for the development of multifunctional composite hydrogels, offering novel perspectives and potential strategies for the effective prevention of postoperative adhesions and promotion of tissue regeneration.

Fibrin sealants have recently been approved for clinical use in the US by the FDA and have been available for clinical use in Europe for years. The indication for use in the US is haemostasis. Nevertheless, both commercial and non-commercial fibrin sealant preparations are also for wound healing and for prevention of abdominal adhesions in the US and Europe. To the non-cognoscenti of fibrin sealants, their use to promote wound repair and to prevent abdominal adhesions appears contradictory since an agent that promotes connective tissue repair might be expected to promote abdominal adhesion rather than prevent them. In this systematic survey of the animal and clinical data evidence is presented that supports both off-label uses. However there is much inconsistency in the data secondary to the use of various fibrin sealant preparations, different animal models and clinical situations and different application techniques. It is clear from this survey that standard preparation and application of fibrin sealant for a particular surgical setting are needed to resolve the many apparent discrepancies in the literature. A corollary to this is the likelihood that different fibrin sealant preparations may be preferred for different clinical situations.

Role of a hyaluronate-based membrane in the prevention of peritonitis-induced adhesions

OBJECTIVES/SPECIFIC AIMS: INTRODUCTION: Many of the innovative therapies used in regenerative medicine, such as additive manufacturing and stem cell engineering, rely on novel technologies and techniques for which standards for safety, efficacy, and quality have not been fully explored and established. As these therapies and technologies develop at a rapid pace, there is a need for the development of scientifically-based metrics to assess whether new treatments are effective and safe for clinical translation. Research and development of such standards is known as “regulatory science,” and is needed by the United States Food and Drug Administration (FDA) to support the creation of the evidence-based guidances and regulations that are used in review of product submissions. As outlined by the FDA’s description of their Centers for Excellence in Regulatory Science and Innovation (CERSIs) and the Association for Clinical and Translational Science’s (ACTS) Regulatory Science Working Group, here is a need to train investigators and clinicians to conduct regulatory science research to support successful clinical translation of regenerative treatments. OBJECTIVE: To develop a course to expose scholars to regulatory science concepts, to empower them to apply these concepts to their personal areas of research, and to challenge them to engage in the dialogue surrounding regulatory science on a national level. METHODS/STUDY POPULATION: METHODS: The “Introduction to Regulatory Science” course was developed jointly by the Yale-Mayo CERSI and the Mayo Clinic Center for Clinical and Translational Science (CCaTS) in 2017 as a didactic in-person survey course. The course objectives included exposing scholars to the ideas of regulatory science and affairs; reviewing the FDA’s Priority Areas for Advancing Regulatory Science; and determining what safety, quality, and efficacy concerns may need to be addressed when using new technologies, such as those used in regenerative medicine research. To meet these intended learning objectives, the course addressed one FDA Priority area each week, with a team of experts providing one-hour of lecture and discussion each class session. Regenerative medicine-related topics included a bioethics of stem cell therapy development, evaluation of additive manufacturing as an emerging technology, and the application of cGMPs to the manufacture of new therapies. Assignments and assessments included a quiz each week, which served as a knowledge check of that week’s lecture content, and a final paper analyzing regulatory concerns associated with a technology or product of the scholar’s choosing. RESULTS/ANTICIPATED RESULTS: RESULTS: The course was first delivered as an elective in 2017, with an enrollment of 8 scholars and 3 auditors. Scholars enrolled included 7 trainees and established investigators from Mayo Clinic Rochester and one from Arizona. Of the 8 scholars enrolled, 7 completed the post-course survey. Scholars strongly agreed that the “course objectives were met” (7/7) and that the “course was well worth the effort I put into it” (7/7). Five scholars stated that they learned “a lot” during the course; two said they learned “an incredible amount.” Scholars unanimously gave the course a grade of “A.” Qualitative feedback was positive, indicating that the team-taught and in-person course design choices were highlights for trainees. The course is currently in its second delivery (2018), with an enrollment of 16 scholars across Mayo Clinic Rochester, Arizona, and Florida. DISCUSSION/SIGNIFICANCE OF IMPACT: CONCLUSIONS: The developed course was successfully piloted and well-received. Scholars reported that they agreed that the course aims were achieved, and indicated that they would like to see additional coursework to continue to learn how to engage in regulatory science. Next steps include utilizing course feedback to iterate on the current course, expanding course delivery to include scholars at the Yale site of the Yale-Mayo CERSI, and the creation of a second course.

Objective To explore the clinical effect of sodium hyaluronic acid on prevention of post-surgical pelvic and abdominal adhesion in gynecology. Methods 336 patients with pelvic and abdominal operation, using the double blind method for the patients and doctors, were randomly divided into the observation group(172 cases) and control group(164 cases). The experimental group was given hyaluronic acid in corresponding regions of the peritoneum, and the control group was not given any tissue adhesion prevention measures. Postoperative adhesions incidence and the change of serum CRP level of two groups were recorded. Results There was significant difference between the two groups in postoperative adhesions incidence(47.5% vs 19.8%,χ2= 13.10,P<0.01).The CRP level of the observation group changed significantly as compared with the control group after operation[(24.5±3.4)mg/L vs(12.7±3.9)mg/L(t= 20.86,P< 0.01)]. Conclusion Hyaluronic acid in prevention of postoperative adhesion of pelvic and abdominal operation is effective on improving the serum level of inflammatory factors. Key words: Adhesions; Hyaluronic acid

Objective: To evaluate the effectiveness of poly (lactic-co-glycolic acid) (PLGA) nanofiber membrane on prevention of postoperative abdominal adhesion. Methods: PLGA nanofiber membrane was prepared by high-voltage electrospinning technique. The effectiveness of the membrane in prevention of postoperative abdominal adhesions was characterized with rat abdominal adhesion models. Results: PLGA nanofiber membrane was prepared successfully by electrospinning technique. Scanning electron microscopy (SEM) observation showed that the average diameter of PLGA fibers was approximately 800 nm, and the membrane had microporous structures. Mechanical tests showed that the tensile strength of PLGA nanofiber membrane was 6.36 ± 0.39 MPa, which was significantly higher than the tensile strength of DIKANG absorbable medical film. The results of in vivo experiments showed that PLGA nanofiber membrane and DIKANG absorbable medical film could both reduce the degree of abdominal adhesions. The histological results showed that there was only a small extent of inflammatory cell infiltration in the PLGA group and the control group. The proliferation of connective tissue was reduced, and so was the degree of adhesion. Conclusion: PLGA nanofiber membrane can significantly reduce the incidence and severity of postoperative adhesions, and bodes well for future clinical applications.

A combination of hybrid polydopamine-human keratinocyte growth factor nanoparticles and sodium hyaluronate for the efficient prevention of postoperative abdominal adhesion formation

Summary Efficacy of a 1% solution of sodium carboxymethylcellulose (cmc) infused into the peritoneal cavity of ewes was evaluated for prevention of intraperitoneal adhesions resulting from surgery of the reproductive tract. Six ewes were assigned to each of 4 groups. Group-1 ewes were controls that underwent ventral midline celiotomy and exploration of the abdominal viscera. Group-2 ewes were treated similarly to group-1 ewes, except that a 1% solution of cmc (14 ml/kg of body weight) was infused into the peritoneal cavity. This group was studied to determine whether cmc would cause changes in the peritoneal cavity. Group-3 comprised ewes representing a uterine trauma model. Ewes underwent abdominal exploration, but in addition had a standard embryo collection technique performed on 1 uterine horn and hysterotomy performed on the opposite uterine horn. Group-4 ewes were treated like group-3 ewes, except that, similar to treatment of group-2 ewes, cmc was infused into the peritoneal cavity. All ewes were euthanatized and necropsied 12 to 14 days after surgery. Abdominal adhesions were evaluated, and an adhesion severity score was assigned to each ewe on the basis of number and severity of the adhesions. Ewes of all groups had abdominal adhesions. Significantly (P &lt; 0.05) lower adhesion score was observed in ewes given cmc (groups 2 and 4) than in the adhesion model (group 3). Significant difference was not observed in adhesion score when groups 1, 2, or 4 were compared. Though not statistically significant, fewer adhesions were observed in ewes of groups 2 and 4 than in group-1 ewes.

pH-responsive nanocomposite hydrogel for simultaneous prevention of postoperative adhesion and tumor recurrence.

Adhesions commonly occur after abdominal surgery and can cause bowel obstruction, chronic abdominal pain, and infertility. Their prevention remains a challenge. To evaluate the effects of the application of low-level lasers on the prevention of adhesions and scarring of the skin after peritoniectomia. Twenty-four New Zealand breed male rabbits, approximately 2 months of age, were randomly divided into 3 groups (n = 8): GC-control group not subjected to laser, GL1-group with laser application at a dose of 0.2 J, and GL2-group with laser application at a dose of 3.6 J. All animals received a longitudinal midline incision and a bilateral resection of the peritoneal fragment, measuring 3 × 1 cm(2) . The animals received a laser treatment of one application every 24 hours, beginning at the time of surgery and lasting for a period of 4 days. After 14 days post-surgery, the animals were killed and adhesion formation was evaluated qualitatively and quantitatively by means of a laparotomy shaped inverted "U", which allowed for the verification of the broad wall of the abdominal cavity and organs. Differences were considered significant at P < 0.05. The adhesion formation was observed in 100% of the rabbits from groups GC and GL1, as compared to 37.5% of the rabbits from group GL2 (P < 0.01). The evaluation of the vascularization and tenacity of adhesions among the groups showed no significant difference. In groups CG and GL1, 72% and 83% of adhesions were verified between visceras, respectively whereas in GL2 occurred among abdominal wall. The tensile strength of the skin between the groups was not significant (P = 0.3106). The resistance of abdominal wall segments without skin he resistance of skin segments between groups GL2 and GC were higher than in GL1 (P = 0.01). Low-level LASER is effective in preventing intra-abdominal adhesions in rabbits without compromising strength and healing of the abdominal wall.