(615d) Sprayable Polymer Blends for the Prevention of Surgical Adhesions

Surgical adhesions are dense fibrous bands of tissue that connect body cavity surfaces. Their formation is traditionally spurred on by the disruption of the mesothelial tissue lining brought on by either internal injury or surgery itself. Generally associated with operations in the peritoneum, adhesions have staggering occurrence rates, with over 90% of laparotomic abdominal and gynecological surgeries and an estimated 95% overall occurrence in the United States. Adhesion formation can lead to additional complications of varying severity. They are the leading cause of small bowel obstruction, a condition that is fatal in 13% of untreated cases. Adhesions can also be fatal from complications such as internal bleeding as a result of vascularization and ventricular dysfunction in cardiac patients. In other cases, adhesions are the leading cause of secondary female infertility and cause chronic pain which can develop into psychological issues. From an economic standpoint, adhesions incur an estimated burden of almost $4 billion annually for patients and over $3 billion for the healthcare industry.

Although surgical intervention is possible in life-threatening cases through surgical severing of the bands in adhesiolysis procedures, these operations are often only performed for worst-case scenarios. Additionally, since adhesions traditionally form as a result of surgery, operations to remove them generally result in reformation with 80% of procedures targeting secondary adhesions, revealing a vicious cycle that plagues patients who undergo numerous procedures. In thoracic surgery, for patients with conditions such as congenital heart disease, adhesion formation can increase patient risk through decreased visibility and increased operation time, potentially rendering procedures impossible. Numerous FDA-approved products that aim to prevent adhesions exist, ranging from solid carboxymethyl cellulose films to liquid barriers that utilize hydroflotation to ensure organs and body tissues are never able to contact. Despite this, these products have demonstrated extremely inconsistent efficacy for a multitude of reasons including low mechanical integrity, rapid biodegradation, and a lack of easy application. There is an extraordinarily complex interplay of biological mechanisms that govern adhesions formation, principally between the coagulation cascade, angiogenesis, and the inflammatory response. All three of these mechanisms are imperative for proper wound healing following surgery and largely render therapeutic methods of prevention nonviable. Concerns of systemic toxicity further exasperate the improbability of therapeutic intervention.

With the failures of current medical products and an inability to use drug delivery mechanisms, the development of physical protective barriers to prevent adherence of tissue surfaces represents a crucial gap in the clinic. In this work, the use of solution blow-spinning (SBS), a fiber deposition technique that can generate mats that conform to rounded tissue surfaces as an adhesions barrier is explored. By utilizing a blend of polymers that offer varying properties, the surface chemistry and mechanical properties can be engineered to exhibit characteristics necessary for adhesions prevention. In particular, the blending of high and low molecular weight (HMW/LMW) polymers will result in segregation by chain length. Using this as an advantage, blending of a hydrophilic LMW polymer with a hydrophobic HMW polymer is hypothesized to create a hydrophilic surface while retaining robust mechanical properties via the HMW polymer chains. Importantly, a hydrophilic surface is necessary for optimal protective adhesions barriers, allowing water molecules within the aqueous internal environments within the body to bond to the material surface via hydrogen bonding. This is critical, as adhesion formation is spurred by an initial overabundance of proteins, macrophages, and other biological molecules that rush towards the site of injury. A hydrophilic protective surface results in spatial exclusion due to the water molecules, creating an anti-fouling layer that prevents proteins from adsorbing. Additionally, since reoperation only induce more adhesions, the material must be biodegradable and fully biocompatible to not create additional inflammation.

Mechanical characterization was performed through several methodologies, first by measuring adherence strength to wet porcine tissues. The improved surface conformation of formed fibers results in strong Van der Waals interactions but polymer blending parameters such as weight ratios, molecular weights, and solution concentration can lead to optimizations of the tissue adhesion strength. These studies were supplemented with mass loss degradation protocols in simulated biodegradation conditions in phosphate buffered saline at 37°C in a shaker incubator. The combination of these two studies eliminated blends that either degraded far too fast, mainly due to an overbalanced HMW:LMW ratio in the blends or failed to adhere strongly to wet tissue due to a lack of cohesive strength, resulting in fiber breakdown upon applied force.

Surface characterization was performed through water contact angle measurements and protein adsorption studies using bovine serum albumin. For the water contact angle measurements, the Sessile drop technique was used, revealing that blends containing the LMW hydrophilic polymer component exhibited not only hydrophilic surfaces, but dominance of the surface chemistry. To validate the hypothesis, protein adsorption studies showed a direct correlation of the surface hydrophilicity to prevented adsorption, where blends containing HMW polymer only adsorbed significant quantities of protein while blends containing the LMW component exhibited nearly zero adsorbed protein.

To assess safety and efficacy of the SBS polymer blends, preliminary investigations using in vivo mice abdominal adhesion models were performed. Initial results demonstrate that mice treated with the polymer blends exhibit a significant reduction in adhesions formation and severity compared to both negative and clinical controls. Additionally, analysis of the wound healing response through histology and reverse transcription PCR. It is critical that protective barriers do not impede surgical injuries from healing. Analysis of cellularity and key cytokine markers involved in inflammation revealed no change in the wound healing response, confirming the safety and biocompatibility of exposure. Additional studies on degradation of the polymer blends within the mice revealed complete biodegradation beyond relevant wound-healing timescales, ensuring the material remains present throughout the entire adhesions formation window.