Controlled Release of a Therapeutic Peptide in Sprayable Surgical Sealant for Prevention of Postoperative Abdominal Adhesions

Abstract

Formation of asymmetric, rigid scar tissue known as surgical adhesions is caused by traumatic disruption of mesothelial-lined surfaces in surgery. A widely adopted prophylactic barrier material (Seprafilm) for the treatment of intra-abdominal adhesions is applied operatively as a pre-dried hydrogel sheet but has reduced translational efficacy due its brittle mechanical properties. Topically administered peritoneal dialysate (Icodextrin) and anti-inflammatory drugs have failed to prevent adhesions due to an uncontrolled release profile. Hence, inclusion of a targeted therapeutic into a solid barrier host matrix with improved mechanical properties could provide dual utility in adhesion prevention and as a surgical sealant. Spray deposition of poly(lactide-co-caprolactone) (PLCL) polymer fibers through solution blow spinning has yielded a tissue-adherent barrier material with previously reported adhesion prevention efficacy due to a surface erosion mechanism that inhibits deposition of inflamed tissue. However, such an approach uniquely presents an avenue for controlled therapeutic release through mechanisms of diffusion and degradation. Such a rate is kinetically tuned via facile blending of "high" molecular weight (HMW) and "low" molecular weight (LMW) PLCL with slow and fast biodegradation rates, respectively. Here, we explore viscoelastic blends of HMW PLCL (70% w/v) and LMW PLCL (30% w/v) as a host matrix for anti-inflammatory drug delivery. In this work, COG133, an apolipoprotein E (ApoE) mimetic peptide with potent anti-inflammatory properties was selected and tested. In vitro studies with PLCL blends presented low (∼30%) and high (∼80%) percent release profiles over a 14-day period based on the nominal molecular weight of the HMW PLCL component. Two independent mouse models of cecal ligation and cecal anastomosis significantly reduced adhesion severity versus Seprafilm, COG133 liquid suspension, and no treatment control. The synergy of physical and chemical methods in a barrier material with proven preclinical studies highlights the value of COG133-loaded PLCL fiber mats in effectively dampening the formation of severe abdominal adhesions.

Real-time fluorescence-guided adhesiolysis with indocyanine green in intra-abdominal surgery (with video)

“…The dissection of intra-abdominal adhesions is a challenge faced by every abdominal surgeon 12 , as severe adhesions can result in inadvertent organ injuries during the process. Despite various methods available for the prevention and treatment of postoperative intra-abdominal adhesions 3 , 13 – 16 , there is a relative paucity of research reports focusing on the safe and efficient dissection of these adhesions.…”

Amphiphilic Janus Nanoparticles with Enhanced Sealing Properties as Follower Sealants

“…To construct the amorphous cell, the target density is set to 0.85 g/cm 3 . The density of the amorphous cell was kept 0.78 g/cm 3 , lower than the target density. The periodic cell length parameters were then decreased gradually following local energy minimization for each frame.…”

“…The simulation box contains 4PDMS, 2PPG, and 1SA-N-SiO 2 in the 5% system; 2PDMS, 1PPG, and 1SA-N-SiO 2 in the 10% system; and 4PDMS + 2PPG + 3SA-N-SiO 2 in the 15% system. To construct the amorphous cell, the target density is set to 0.85 g/cm 3 . The density of the amorphous cell was kept 0.78 g/cm 3 , lower than the target density.…”

“…Follower sealants can be widely used in aerospace, biomedicine, , wound hemostasis, , etc., due to their liquid sealing properties. Follower sealants prepared by adding a single thickener to the base oil are thermodynamically unstable due to the components’ inherent low entropy of mixing, resulting in a coarsened morphology, resulting in shorter sealing cycles and poorer thermal stability of the follower sealants.…”

Antifouling and Injectable Granular Hydrogel for the Prevention of Postoperative Intrauterine Adhesion

“…Currently, the FDA-approved products for antiadhesion are mainly physical films, such as Seprafilm, Interceed, and Gore-tex. , Although with a certain therapeutic effect, these strategies still face their own problems. Due to the lower strength of Seprafilm in hysteroscopic surgery, it is more suitable for open surgery with more complexity and more severe wounds. − The adhesion of Interceed to the tissue is significantly reduced due to the residual blood or tissue fluid on the surface of the tissue; thus, thorough hemostasis and cleaning are required during the operation. , Due to its nonadhesive properties, Gore-tex requires an effective suturing to be positioned on the injured tissue surface, which also increases the complexity of surgery, especially hysteroscopic surgery. , Moreover, unlike the other two products that can be cleared or degraded, Gore-tex needs to be removed through a second surgery, which also increases the suffering of the patient. , In addition, the current film products are difficult to form conformal barriers on irregular surfaces of the human uterine cavity.…”