Absorbable biomaterials are commonly used after endoscopic sinus surgery, both for hemostatic and wound healing considerations. Although removable nasal packing is the traditional method of controlling ongoing bleeding and modulating wound healing, it is uncomfortable for patients and associated with several complications. Currently available absorbable agents frequently incite an inflammatory reaction and have been shown in animal and human trials to adversely affect the wound healing process. Newer agents offer distinct advantages because of their unique composition and rapid clearance profiles. The selection of packing material used in any given sinus procedure should be based on surgeon preference and the details of the specific case.
Background: nasal packing in endoscopic sinus surgery
Endoscopic sinus surgery (ESS) is a continuously developing field that has had many exciting developments in the past 3 decades. Advances in the understanding of functional sinus surgery and mucosal-sparing techniques has driven an interest in the management of the post-ESS nasal and sinus cavity to achieve more rapid postoperative reepithelialization and reciliation. Many surgeons believe that the postoperative treatment regimen is as important as the surgery.
All sinus surgeons have the common objective of achieving excellent hemostasis and postoperative healing that avoids adhesion formation and lateralization of the middle turbinate; however, little agreement exists on how this is best achieved. The use of various interventions, from removable nasal packing, absorbable nasal packing, to no packing at all, is widely debated.
Nasal packing has been the traditional method of controlling ongoing bleeding after surgery to the paranasal sinuses. Additionally, nasal packing has been used to prevent adhesion formation, middle turbinate lateralization, and restenosis after surgery. Unfortunately, removable nasal packing has been rated by patients to be the most unpleasant aspect of the ESS surgical experience. Some surgeons advocate not packing the middle meatus, whereas others continue to use this technique to prevent middle turbinate lateralization. Controversy still exists about whether to pack or not. This article reviews the literature on the use of absorbable biomaterials and their effects on hemostasis and wound healing, evaluating experiences with 20th century agents and exploring developing trends and 21st century innovations.
Nasal packing was first described in the otorhinolaryngolic literature in 1951 and the use of absorbable biomaterials since 1969. Removable nasal packing has been designed to tamponade mucosal bleeding and act as a barrier to adhesion formation. Numerous packing agents are available, including Vaseline-soaked ribbon gauze, fingerstall packs, polyvinyl acetate sponge (Merocel, Medtronic Xomed, Jacksonville, Florida), and various balloon tamponade devices. However, these agents cause considerable discomfort for patients, both in terms of pain and bleeding on removal. Other complications associated with removable nasal packing include septal perforation, pack dislodgement, aspiration, toxic shock syndrome, foreign body granuloma, myospherulosis, obstructive sleep apnea secondary to nasal obstruction, and even death. Animal studies investigating the mucosal trauma caused by removable nasal packing have shown a 50% to 70% loss of the ciliated mucosal surface area in the region of the pack. Therefore, a transient impairment of the patient’s innate immune system, the mucociliary clearance, may be associated with the use of removable nasal packing.
These drawbacks of removable nasal packing have led to the ongoing development and application of absorbable biomaterials that do not require subsequent removal and still achieve positive effects on hemostasis, promote wound healing, and provide middle turbinate support. Absorbable biomaterials either provide clotting factors or a substrate to stimulate clotting. Other important characteristics of these agents include safety and efficacy, absorption kinetics, composition, usability (including form of the agent and delivery device), and cost. Biomaterials were extensively investigated and researched in the ear, nose, and throat literature well before the evolution of ESS, and this interest continues today. Both human and animal trials have contributed significantly to the understanding of these products and their role in ESS.
In an attempt to simplify the literature on biomaterials, this article is organized into effects on intraoperative hemostasis, postoperative hemostasis, and finally wound healing, in human studies and animal models. Table 1 summarizes the literature on 20th century biomaterials and lists observations on hemostasis and wound healing in humans.
| Biomaterial | Study | Study Design | Intraoperative Hemostasis | Postoperative Hemostasis | Adhesions/Wound Healing |
|---|---|---|---|---|---|
| Surgiflo/thrombin combination | 30 pts | Prospective (uncontrolled) | 29/30 in 10 min | 29/30 (1 req packing) | No adhesions |
| Epsilon–aminocaproic acid | 10 pts | DB RCT | Ineffective versus saline | 10/10 pts | — |
| Tranexamic acid | 10 pts | DB RCT | Better versus saline ( P <.05) | 10/10 pts | — |
| Sepragel sinus | 20 pts | RCT | Same as no treatment | — | — |
| Quixil (fibrin glue) | 158 pts | DB RCT | Same as Merocel | — | Same as Merocel |
| 64 pts | Prospective (controlled) | ||||
| Merocel | 16 pts | Cohort | — | 16/16 pts | No adhesions↓ Adhesions versus no packing ( P = .001) |
| 61 pts | SB RCT | ||||
| Surgicel Nu-knit | 60 pts | RCT | — | 60/60 pts, same as gauze and Merocel | — |
| MeroGel | 37 pts | DB RCT | — | — | Same as Merocel (3/37 adhesions) |
| 42 pts | SB RCT | — | — | Same as no pack | |
| 35 pts | RCT | — | — | Same as removable pack | |
| Gelfilm | 115 pts | Prospective (controlled) | — | — | ↑ adhesions verus MeroGel ( P <.05) |
| 51 pts | RCT | — | — | ↑ granulations versus no pack ( P <.05) | |
| Mitomycin C | 55 pts | 3 DB RCTs | — | — | All show same as no pack |
| 29 pts | |||||
| 38 pts |
Effect of 20th century biomaterials on hemostasis
Intraoperative Hemostasis
Absorbable porcine gelatin (Surgiflo, Ethicon Inc, Somerville, New Jersey) and thrombin combination; topical antifibrinolytics such as epsilon–aminocaproic acid (Amicar, Lederle Parenterals Inc, Carolina, Puerto Rico) and tranexamic acid (Cyklokapron, Pfizer, Puurs, Belgium); and hyaluronic acid have all been investigated in human studies for their intraoperative hemostatic properties after ESS. Surgiflo hemostatic matrix combined with thrombin is an absorbable porcine gelatin that was investigated by Woodworth and colleagues after sinus surgery in a prospective trial. Results showed that patients experienced rapid hemostasis within 10 minutes, with a median time of 1 minute; however, this study had no control arm.
Only one trial has studied topical antifibrinolytics after ESS. These agents prevent fibrinolysis and stabilize the blood clot. Results showed that topical epsilon–aminocaproic acid was ineffective at producing hemostasis compared with saline; however, tranexamic acid at low dose (100 mg) improved hemostasis significantly ( P <.05). This observed effect was reduced at higher doses. This study is only the second in the literature to use an objective surgical grade score to monitor hemostatic efficacy.
Fibrin glue (Quixil, Omrix Co., Brussels, Belgium) is a combination of human thrombin and fibrinogen mixed with amino acids and salts, which allows this compound to form an easily applied gel. It was first used in the rhinology literature in the early 1990s, largely for managing cerebrospinal fluid rhinorrhea or for endonasal/transsphenoidal pituitary surgery. Vaiman and colleagues showed that Quixil is effective in producing postoperative hemostasis, although they did not analyze how long it took to achieve.
Hyaluronic acid (Sepragel sinus, Genzyme Biosurgery, Cambridge, Massachusetts) is a viscoelastic gel containing polymers of highly purified forms of hyaluronic acid and has been investigated for immediate hemostasis by Frenkiel and colleagues. Results showed no significant difference in total blood loss between the Sepragel sinus side and the no treatment side; however, a subjective general improvement of hemostasis was noted with the intervention side.
Postoperative Hemostasis
Surgiflo/thrombin combination, Merocel, and oxidized regenerated cellulose (Surgicel Nu-knit, Ethicon Inc, Somerville, New Jersey) have been studied for their effects on hemostasis after ESS. The Surgiflo/thrombin combination caused postoperative bleeding, requiring nasal packing in 1 of 30 patients. Merocel was investigated in 16 patients after ESS, with no reported incidence of postoperative epistaxis. Shinkwin and colleagues compared Surgicel Nu-knit with Vaseline ribbon gauze and Merocel. All packing agents were equally effective with no incidence of postoperative epistaxis in any of the treatment arms.
Of particular interest is the number of patients experiencing postoperative epistaxis without any nasal packing or treatment at all. Athanasiadis and colleagues found no incidence of postoperative epistaxis in 30 patients undergoing ESS. Jameson and colleagues reported no incidence of postoperative epistaxis in 47 patients undergoing ESS without nasal packing. In a large retrospective review of patients after ESS, Orlandi and Lanza challenged the practice of placing any pack at all, both in the immediate perioperative period and postoperatively. Among 165 patients, only 11.2% required nasal packing at the conclusion of operating, and none experienced postoperative epistaxis over 4 years.
Conclusions on Hemostatics
Tranexamic acid is an effective hemostatic option compared with no treatment, and fibrin glue is as effective as Merocel packing on immediate hemostasis. Sepragel sinus does not significantly reduce intraoperative blood loss when compared with no treatment. Additionally, one uncontrolled prospective trial suggests that Surgiflo/thrombin combination is effective in the immediate intraoperative period. In terms of postoperative bleeding, no evidence shows that any agent was more effective than no treatment at all; however, one large retrospective analysis suggests that immediate postoperative and long-term packing are not necessary in more than 90% of patients.
Effect of 20th century biomaterials on hemostasis
Intraoperative Hemostasis
Absorbable porcine gelatin (Surgiflo, Ethicon Inc, Somerville, New Jersey) and thrombin combination; topical antifibrinolytics such as epsilon–aminocaproic acid (Amicar, Lederle Parenterals Inc, Carolina, Puerto Rico) and tranexamic acid (Cyklokapron, Pfizer, Puurs, Belgium); and hyaluronic acid have all been investigated in human studies for their intraoperative hemostatic properties after ESS. Surgiflo hemostatic matrix combined with thrombin is an absorbable porcine gelatin that was investigated by Woodworth and colleagues after sinus surgery in a prospective trial. Results showed that patients experienced rapid hemostasis within 10 minutes, with a median time of 1 minute; however, this study had no control arm.
Only one trial has studied topical antifibrinolytics after ESS. These agents prevent fibrinolysis and stabilize the blood clot. Results showed that topical epsilon–aminocaproic acid was ineffective at producing hemostasis compared with saline; however, tranexamic acid at low dose (100 mg) improved hemostasis significantly ( P <.05). This observed effect was reduced at higher doses. This study is only the second in the literature to use an objective surgical grade score to monitor hemostatic efficacy.
Fibrin glue (Quixil, Omrix Co., Brussels, Belgium) is a combination of human thrombin and fibrinogen mixed with amino acids and salts, which allows this compound to form an easily applied gel. It was first used in the rhinology literature in the early 1990s, largely for managing cerebrospinal fluid rhinorrhea or for endonasal/transsphenoidal pituitary surgery. Vaiman and colleagues showed that Quixil is effective in producing postoperative hemostasis, although they did not analyze how long it took to achieve.
Hyaluronic acid (Sepragel sinus, Genzyme Biosurgery, Cambridge, Massachusetts) is a viscoelastic gel containing polymers of highly purified forms of hyaluronic acid and has been investigated for immediate hemostasis by Frenkiel and colleagues. Results showed no significant difference in total blood loss between the Sepragel sinus side and the no treatment side; however, a subjective general improvement of hemostasis was noted with the intervention side.
Postoperative Hemostasis
Surgiflo/thrombin combination, Merocel, and oxidized regenerated cellulose (Surgicel Nu-knit, Ethicon Inc, Somerville, New Jersey) have been studied for their effects on hemostasis after ESS. The Surgiflo/thrombin combination caused postoperative bleeding, requiring nasal packing in 1 of 30 patients. Merocel was investigated in 16 patients after ESS, with no reported incidence of postoperative epistaxis. Shinkwin and colleagues compared Surgicel Nu-knit with Vaseline ribbon gauze and Merocel. All packing agents were equally effective with no incidence of postoperative epistaxis in any of the treatment arms.
Of particular interest is the number of patients experiencing postoperative epistaxis without any nasal packing or treatment at all. Athanasiadis and colleagues found no incidence of postoperative epistaxis in 30 patients undergoing ESS. Jameson and colleagues reported no incidence of postoperative epistaxis in 47 patients undergoing ESS without nasal packing. In a large retrospective review of patients after ESS, Orlandi and Lanza challenged the practice of placing any pack at all, both in the immediate perioperative period and postoperatively. Among 165 patients, only 11.2% required nasal packing at the conclusion of operating, and none experienced postoperative epistaxis over 4 years.
Conclusions on Hemostatics
Tranexamic acid is an effective hemostatic option compared with no treatment, and fibrin glue is as effective as Merocel packing on immediate hemostasis. Sepragel sinus does not significantly reduce intraoperative blood loss when compared with no treatment. Additionally, one uncontrolled prospective trial suggests that Surgiflo/thrombin combination is effective in the immediate intraoperative period. In terms of postoperative bleeding, no evidence shows that any agent was more effective than no treatment at all; however, one large retrospective analysis suggests that immediate postoperative and long-term packing are not necessary in more than 90% of patients.
Effect of 20th century biomaterials on adhesion formation
Adhesion formation is the most common complication encountered after ESS and can result in occlusion of the sinus drainage pathway. In addition, adhesions can result in recurrent symptoms and subsequent surgical failure. Studies have shown that up to 25% of patients who experience adhesion formation will require revision surgery in the future. The incidence of adhesion formation after ESS is reported to be between 1% and 36%. Therefore, a large body of literature is devoted to reducing the incidence of adhesion formation after ESS, with numerous biomaterials marketed for this effect.
When considering adhesion prevention, one must remember that agents that promote hemostasis through stimulation of the intrinsic coagulation cascade also stimulate inflammation. Inflammatory responses are linked to hemostatic activation through a network of humoral and cellular components, including protease factors involved in the clotting and fibrinolytic cascades. Thus, the potential exists for potent coagulation cascade activation, leading to adverse wound healing.
Animal trials have also contributed significantly to the understanding of paranasal sinus wound healing and a large number of trials reflect this. The predominant models used are those involving sheep, rabbits, and mice. Sheep are an ideal model because they are large animals in which routine sinus surgical techniques can be used, and histologically their mucosa is identical to that of humans.
Models of bacterial rhinosinusitis were developed using Merocel to block the maxillary sinus ostia, along with Bacteroides fragilis inoculation, resulting in a histologically confirmed, persistent, localized bacterial rhinosinusitis. Finally, rabbits have well-pneumatized sinus cavities, and both their sinonasal anatomy and immunologic reactions are very similar to those of humans, making them a useful animal model for the study of biomaterials.
Sheep Models
Shaw and colleagues examined the effects of ribbon gauze packing and cottonoids on the nasal mucosa in a single-blind randomized controlled trial involving sheep. Nasal packing was left in situ for 10 minutes, followed by removal of packing and the associated mucosa. Blinded histologic analysis was then performed. Results showed that both packing agents produced more than a 50% loss of ciliated mucosal surface area ( P <.005).
In a double-blind randomized controlled trial, McIntosh and colleagues compared the effects of Merocel (5 days) with no packing in the sheep model. Serial biopsies were taken at 4, 8, 12, and 16 weeks after treatment. Results showed no significant difference in the rate of reepithelialization, total surface ciliation, and overall maturity of cilia between the packed and non-packed sides at any point.
Another further study compared the effects of MeroGel (Medtronic Xomed, Jacksonville, Florida) with no treatment in a sheep model of chronic sinusitis. This study created standardized mucosal injuries after histologic analysis of healing mucosa at 1, 2, 3, and 4 months postoperatively. Results showed no significant difference in adhesion formation or histologic features of reepithelialization, cilial height, and reciliation between the arms.
The sheep model has also been used to examine the effects of drug delivery associated with nasal packing. Robinson and colleagues studied the effects of prednisolone-impregnated MeroGel and MeroGel alone and found no difference. Finally, growth factors have also been shown to be important in epithelialization and collagen deposition, including insulin-like growth factor. Insulin-like growth factor–impregnated MeroGel was analyzed in the same sheep model after ESS and found to have a positive effect on mucosal regrowth and maturity in healthy sheep. However, when introduced in a model of chronic sinusitis, this effect was negated.
Mice Models
Only one study used a murine model to examine the effects of biomaterials. Jacob and colleagues conducted a randomized controlled trial involving 20 mice to evaluate the histologic effects of MeroGel. Results showed induced bone formation within the sinonasal cavity, indicating that MeroGel may have osteogenic potential.
Rabbit Models
Maccabee and colleagues studied the effects of MeroGel in six self-controlled rabbits through denuding the maxillary sinuses and performing histologic analysis of the regenerating mucosa. At 2 weeks postoperatively, the MeroGel sinuses showed extensive fibrosis compared with control sinuses, with minimal reabsorption of the biomaterial along with incorporation of the biomaterial within the regenerating mucosa. Proctor and colleagues confirmed these findings, analyzing the effects of MeroGel in a rabbit model. Results showed that MeroGel caused significant stenosis of the ostia over a 2- to 3-week follow-up. Mitomycin C has also been investigated in the rabbit model, with one pilot study showing that increasing concentrations of Mitomycin C can delay healing of an intranasal antrostomy (0.4 mg/mL, 1.0 mg/mL).
Rahal and colleagues confirmed these results. However, these trials were conducted in healthy rabbits without chronic rhinosinusitis, which may explain the discrepancies between these findings and those seen in human studies. Two published studies have investigated the effect of mucosa treated with retinoic acid (DPT Laboratories, San Antonio, Texas) in rabbits. Maccabee and colleagues conducted a randomized controlled trial involving rabbits treated with retinoic acid, finding improved mucosal regeneration with less ciliary loss and fibrosis. These findings were also supported by Hwang and Chan, again involving the healthy rabbit model.
Human Studies
Table 1 summarizes the data on adhesions and wound healing. MeroGel is a hyaluronic acid, which is the major constituent of the extracellular matrix, and therefore acts as a scaffold for wound healing. It has been shown to be the key factor in eliminating scarring in fetal wounds. Franklin and Wright also conducted a single-blind, randomized controlled trial to compare the effects of MeroGel and a nonabsorbable nasal packing (2–3 days), showing a trend toward improved postoperative endoscopic scores; however, this failed to reach significance at all time points. Additionally, Wormald and colleagues investigated whether MeroGel had any effect on wound healing after ESS, showing no significant difference between the sides at 2, 4, and 8 weeks in the endoscopic features of adhesions, edema, or infection. Vaiman and colleagues compared Quixil and Merocel, showing comparable results in the incidence of adhesion formation between the arms.
Miller and colleagues compared Merocel pack (5–7 days) and hyaluronic acid (MeroGel). Patients underwent follow-up to 8 weeks postoperatively. Results showed both packing agents were associated with an 8% adhesion rate. This finding contrasts with those of Vaiman and colleagues and Pomerantz and Dutton, which showed no evidence of adhesion formation with Merocel packing. Discrepancies between these studies maybe related to the timing of pack removal. Bugten and colleagues investigated the effects of Merocel versus no nasal packing to determine whether removable nasal packing had any role after ESS. Video recordings taken 10 to 14 weeks after surgery showed 7 of 62 adhesions in the Merocel arm versus 29 of 54 adhesions in the no packing arm, a finding that was highly significant ( P = .001).
Only one published article investigated the effects on wound healing of a combination of Surgiflo (Ferrosan, Soeborg, Denmark) and thrombin. This uncontrolled prospective trial involving 30 patients after ESS showed no incidence of reported adhesion formation. However, as indicated by the authors, further randomized controlled trials are indicated.
Denatured porcine collagen (Gelfilm, Pharmacia and Upjohn Company, Kalamazoo, Michigan) has also been developed to reduce adhesion formation. It is an absorbable biomaterial manufactured from denatured porcine collagen. Results of two trials have shown adverse effects on wound healing, with one trial showing a significant increased in adhesions in patients implanted with Gelfilm compared with those implanted with MeroGel ( P <.05), and the second showing no significant difference in adhesion formation but a significant increase in granulation tissue formation in patients implanted with Gelfilm ( P <.05).
Mitomycin C is a topically applied agent that has been shown to reduce scar formation. Additionally, it has been shown to inhibit nasal fibroblast proliferation and increase apoptosis. It is isolated from the Streptomyces caespitosus strain of actinomyces, and used to crosslink DNA and inhibit cellular mitosis. Three human trials investigating the effects of mitomycin C against a saline control failed to show any significant findings regarding adhesion formation.
Conclusions on Antiadhesion Effects of Biomaterials
No studies show that absorbable packing has any antiadhesion advantage over removable nasal packing or no packing at all. However, the same cannot be said for removable nasal packing, one single-blind randomized controlled trial showing a highly significant reduction in adhesion formation when Merocel is used. Three double-blind randomized controlled trials in the sheep model of chronic rhinosinusitis (CRS) confirm that MeroGel alone and with prednisolone or insulin-like growth factor has no effect on adhesion formation or cilial recovery. Two prospective, controlled rabbit trials suggested that MeroGel increases fibrosis and is incorporated within regenerating mucosa, and another showed that MeroGel displayed osteogenic potential.
Mitomycin C has shown promising results on healing ostia in two randomized controlled trials in the healthy rabbit model. However, these effects were not translated to patients who had post-ESS CRS, a conclusion also supported by Tabaee and colleagues. Gelfilm stents have been shown to adversely affect the wound-healing process. One double-blind, randomized controlled trial shows that fibrin glue has no effect on adhesion formation, and one prospective trial suggests the same.
Finally, only one uncontrolled prospective trial has investigated the effects of the Surgiflo/thrombin combination, with no adhesions observed by the authors. Although the positive effects of vitamin A have been shown in healthy rabbit sinuses, further human trials are needed in patients who have CRS. Furthermore, although products containing oxidized regenerated cellulose (Surgicel) are widely known to have hemostatic properties, and advocated as an absorbable nasal dressing after ESS, no published literature has investigated their wound-healing properties after ESS.
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