Preventing post-operative adhesions with a sprayable viscoelastic hydrogel
Gels with the appropriate mixture of tissue adherence and soft viscoelastic properties dramatically inhibit adhesion formation in a large animal model of cardiopulmonary bypass surgery
Over 20 million Americans undergo invasive surgeries each year, more than 95% of whom develop fibrous bands of scar tissue called adhesions, independent of the type of procedure or location in the body. These adhesions form as a result of normal wound healing processes following surgery, but cause internal organs and tissues to adhere together, which can result in severe complications ranging from pain to organ dysfunction. Often, follow-up operations are required to release adhesions with the hope of alleviating these complications. Furthermore, if a patient requires a secondary operation as part of their treatment plan, the presence of adhesions can obstruct the field of view or restrict access to the surgical site, requiring that the adhesions be released before the planned surgery can begin, increasing the risk of organ injury, blood loss, and mortality.
While post-operative adhesions represent a long-standing and ever-growing surgical challenge, current technologies for preventing adhesions exhibit poor efficacy and are infrequently used. These commercially-available adhesion barrier systems generally rely on solid polymer films or fabrics to physically separate organs and tissues in an attempt to prevent adhesions from forming. Many researchers have attempted to address these limitations by creating sprayable materials that form into soft, albeit solid-like, gels with static crosslinks once in the body. However, while these materials are easier to use in the operating room, they behave similarly to current commercial products in the body since they are also stationary barriers. We hypothesized that a sprayable and viscoelastic (meaning that it has both solid-like and liquid-like properties) gel with dynamic crosslinks would allow for easy application and highly effective adhesion prevention by creating a lubricious barrier between organs and tissues. In a collaborative effort between Dr. Eric Appel, Assistant Professor of Material Science & Engineering, and Dr. Joseph Woo, Norman E. Shumway Professor and Chair of Cardiothoracic Surgery, at Stanford University, we investigated polymer-nanoparticle (PNP) gels that exhibit tunable shear-thinning, yield-stress, and self-healing properties. These mechanical behaviors enable the gels to be easily sprayed for simple use in the operating room, while also imbuing dynamic properties that prevent the barrier from dislodging from the application site during natural movement of the tissues.
The lead author Lyndsay Stapleton, a PhD candidate in Bioengineering at Stanford, and the team demonstrate these PNP gel materials have desirable viscoelastic and flow properties permitting simple spray delivery, robust tissue adherence, local retention in vivo for several weeks, and ability to prevent pericardial adhesion formation. We initially investigated a rodent model of severe cardiac adhesions, and while current commercial products fared no better than simply not treating the animals, our PNP gels almost completely inhibited adhesion formation. We tested numerous PNP gel formulations and found that only the materials exhibiting an appropriate mixture of tissue adherence and soft viscoelastic properties dramatically inhibited post-operative adhesion formation. These findings were very encouraging and prompted us to validate our adhesion barrier system in a large animal pre-clinical model of cardiac surgery where sheep underwent aortic valve surgery with cardiopulmonary bypass to simulate an actual human cardiac operation and the resulting adhesion formation. Again, we saw a dramatic decrease in the incidence and severity of adhesions in animals treated with PNP gels compared to control animals, confirming the clinical translatability of this therapy.
Moving forward, we are investigating our gel materials in other surgical indications, particularly in the abdomen, as they have the potential to be applied during any type of surgery anywhere in the body. As we continue to optimize our adhesion barrier system, we are developing the necessary processes for large-scale manufacturing of our materials under Good Manufacturing Practice guidelines to hopefully translate this technology from the bench to the bedside.