Dural sealants for the management of cerebrospinal fluid leakage after intradural surgery: current status and future perspectives

ABSTRACT

Introduction: Cerebrospinal fluid leakage is a complication after intradural surgery and is associated with severe secondary complications like compromised wound healing and meningitis. Dural sealants are meant to augment the primary dural closure in order to achieve a watertight closure.

Areas covered: This review summarizes the efficacy of currently available dural sealants. Potential future improvements and biomaterials are discussed.

Expert opinion: The use of a dural sealant seems to be the logical method to prevent CSF leakage. However, based on the efficacy of currently available dural sealants according to systematic reviews and in vitro studies, a significant effective dural sealant seems is still lacking. A new dural sealant has to be thoroughly assessed before clinical application in in vitro, in vivo and clinical trials. A new research area within sealant development might be the introduction of dural sealants with both antimicrobial and analgesic properties.

KEYWORDS:

• Cerebrospinal fluid leakage
• craniotomy
• spinal surgery
• biomaterials

1. Introduction

Postoperative cerebrospinal fluid (CSF) leakage after intradural surgery or an unintended dural tear is a severe complication because of its association with complications such as compromised wound healing and meningitis [1]. The most obvious step in preventing CSF leakage is watertight closure of the dura. Although in supratentorial craniotomy watertight closure became subject of debate, this is a widely accepted adage within neurosurgery [2].

The classical dural closure technique consists of suturing the two sides of incised dura together. Watertight dural closure is thereby difficult due to the biomechanical characteristics of the dura. The dura is fragile, has minimal elasticity and even the needle of the suture creates leaking pinholes. Moreover, the dura is very prone to shrink due to dehydration during surgery. The warm light of the microscope often accelerates this process. These limitations have led to the introduction of sealants with the purpose to prevent CSF leakage. Most of the first sealants were adopted from trauma, gastrointestinal and thoracic surgery [3–5]. In the past decades, sealants specifically for dural use have been developed. Biotechnological improvements will lead to next generation dural sealants in the upcoming years. In this review, we evaluated the efficacy of currently available dural sealants and provided briefly an overview of current potential biomaterials. Also, expected developments in the near future are discussed.

2. Dural sealant biomaterials

Current and potential biomaterials for dural sealing can be divided into two categories: biopolymers and synthetic polymers. Biopolymers are natural available polymers that are collected from human, animals, plants or microorganisms. Biopolymers could be further classified in protein-based, polysaccharide-based biopolymers and biomimetic polymers [6–8]. Since there is a wide variety of synthetic polymer adhesives available, we focused on the most important synthetic polymer groups consisting of Polycyanoacrylates, Polyethylene glycol (PEG), aliphatic Polyesters and Polyurethanes (PU).

2.1. Biopolymers

2.1.1. Protein based adhesives

Currently, protein-based polymers are mainly human and animal derived biopolymers that are characterized by their close resemblance to human tissue. Protein-based polymers have the capacity to induce desirable biological response such as clot formation, which is an essential property in hemostasis [7]. They are in general biodegradable and biocompatible. Protein-based adhesives have sealing properties by direct clot formation with the underlying tissue. The major disadvantages of protein-based adhesives are that they are produced from human or animal derived materials which form a potential risk for viral or prion transmission. Thereby, animal derived biomaterials carry the risk of inducing immunogenic reaction. Another disadvantage of certain protein-based adhesives is that they often have to be crosslinked with toxic components like aldehydes or acrylates for sealing properties. These groups are associated with neurotoxicity [7]. Moreover, protein-based tissue adhesives usually require specific conditions like dry surfaces or presence of blood [6,7]. In the absence of these conditions, protein-based sealants tends to fail. Another disadvantage of protein-based tissue adhesives is that they degrade enzymatically, in which the rate of degradation varies significantly depending on the site of implantation, availability, and concentration of the enzymes [8].

2.1.2. Polysaccharide adhesives

Polysaccharides are sugar built polymers derived from natural resources, like human, animals, plants, and microorganisms and are therefore widely available. Available polysaccharides for tissue adhesive materials are chitosan, chitin, dextran and chondroitin sulfate. Polysaccharides have excellent biodegradable, biocompatible and non-immunogenic features. They can often be modified by chemical and physical methods. The effectiveness of a methacrylate-functionalized hyaluronic acid, a polysaccharides-based adhesive, has been described in a study in which corneal laceration in rabbits was sealed. This resulted in 97% sealing after photopolymerization [9]. The major disadvantages of most of these polysaccharide-based biomaterials are that they have to be crosslinked with methacrylate and acrylate groups for functionalization that needs photo-polymerization to achieve gel formation in situ. Photo-polymerization generates free radicals that damage the surrounding tissue and the material obtained is non-degradable [7]. As protein-based biomaterials, Polysaccharides degrades enzymatically which have downsides as mentioned previously.

2.1.3. Biomimetic adhesives

Biomimetic adhesives such as mussel adhesive protein, gecko-inspired adhesives, and endoparasitic worm inspired adhesives, are currently gaining more interest. These adhesives are natural products with adhesive properties (mussel adhesive protein) or naturally inspired adhesives (gecko-inspired adhesives and endoparasitic worm inspired adhesives) whereas the last group forms mechanical adhesion to the underlying tissue. First results of mussel adhesive protein performed excellently in both dry and wet conditions. However, this protein needs between 12 and 24 h for full strength adhesion. Currently, there are no biomimetic biopolymers clinically available for dural sealing [7,10].

2.2. Synthetic polymers

2.2.1. Polycyanoacrylates

Cyanoacrylates have excellent adhesive properties in wet conditions. Cyanoacrylate monomers rapidly polymerize in the presence of blood and water and form a covalent bond with the underlying tissue proteins. Cyanoacrylates do not need functionalization, preparation or any additions like catalyst, heat or pressure to seal [6,7]. Their biodegradability and adhesive strength can be adjusted by changing the chain length [11]. Moreover, polycyanoacrylates have antimicrobial properties by forming a barrier [12]. The major disadvantage of polycyanoacrylates is that they degrade into cytotoxic degradation products, cyanoacrylate and formaldehyde [13]. The internal use of cyanoacrylates remains controversial because the inflammatory response is associated with pancreatic tumor development [14]. Besides, polycyanoacrylates become brittle after polymerization leading to less tensile strength [11].

2.2.2. Poly(ethylene glycol) (PEG) polymers

PEG is a synthetic, water soluble, biocompatible and non-immunogenic polymer. Although the first generation of PEG adhesives required photopolymerization for an adhesive property, current PEG-based sealants are functionalized with N-hydroxysuccinimide (NHS)-esters. These sealants consist of two components which form an adhesive hydrogel by a covalent reaction of the NHS-esters with the amines in the mixture and in the underlying humid tissue [15]. The hydrogels also form mechanical interlocking by filling the cavities in the surface of underlying tissue [7]. Degradation of the hydrogel occurs via hydrolysis which has minimal site-to-site and patient-to-patient variation [16]. A major drawback of PEG polymers is the water uptake, leading to a degree of swelling of the sealants of 87–558% [17]. Another downside for most PEG polymers is the weak cohesive (internal) strength of liquid PEG sealants. CE and FDA approved liquid sealants based on PEG polymers for dural sealing are Duraseal® (Integra LifeScience, Plainsboro USA) and Adherus® (Hyperbranch Medical Technology, Durham USA) [18–20].

2.2.3. Aliphatic polyesters

Aliphatic polyesters are one of the most extensively investigated synthetic polymers. Since the successful development of the first synthetic sutures based on polyesters (polyglycolic acid), the biomedical application of polyesters broadened in medical use. The most commonly used biomedical polyesters are based on lactic acid, glycolic acid, and caprolactone. The biodegradation of these polyesters such as poly(caprolactone) can be shortened by, for example; copolymerization of lactide with caprolactone. Although very difficult and not common, the stiffness of poly(glycolic acid) can be reduced by copolymerization of glycolide with lactide [21]. An example of a CE approved polyester copolymerized dural sealant is TissuePatchDural® (Tissuemed, Leeds UK) [18].

2.2.4. Polyurethanes

Polyurethanes are synthetic polymers in which the mechanical properties, biocompatibility, and biodegradability are determined by its composition. Polyurethanes are formed via a reaction between a diisocyanate and a diol. Isocyanates adhesives adhere covalently to the underlying tissue in the presence of water through the formation of urea bond with amines available in the underlying tissue [8]. The major disadvantage of the commonly used polyurethanes is that they are toxic and not readily biodegradable. However, the use of aliphatic isocyanates instead of aromatic isocyanates eliminates toxicity. By incorporating hydrolytically degradable esters bonds by using monomers such as lactic acid or caprolactone enables the development of biodegradable polyurethanes  [22,23].

2.3. Dural sealant efficacy

Based on the currently available literature, it can be stated that the use of currently available sealant has not reduced CSF leakage in general. Meta-analysis of 2321 intradural cranial cases showed no significant difference in CSF leakage between the use of a dural sealant (leakage rate, 8.2%) and primary closure (leakage rate, 8.4%) [24]. Significant difference was found regarding surgical side infection, which was less seen in cases with sealants (RR 0.25, CI 0.13–0.48) [24]. Meta-analysis of 883 spinal cases showed that the CSF leakage rate did not significantly differ between the group with sealant (9.1%) and the group treated with sutures only (13.8%) [25]. In vitro studies provided an explanation for these results, which showed that most currently dural sealants do not seal the dura sufficiently. Hereto, our group tested nine commonly used dural sealants on fresh porcine dura in a standardized in vitro cranial burst pressure model [26]. The maximum acute pressure sealants could resist and the chronic resistance of the sealants in physiological conditions (humid environment, the continuous temperature at 37 ◦C and triphasic intracranial pressure between 6 and 16 mmHg) for 72 h were tested in two different setups. Out of nine different sealants tested, three could resist physiological intracranial pressure (16 mmHg), of which only two could resist prolonged physiological conditions for 72 h [26]. These two sealants were both liquid PEG sealants, which are associated with swelling and are contraindicated in confined anatomical spaces [27,28]. Comparable burst pressure results were shown in another in vitro study [29].

3. Expert opinion

There is still an unmet need for an effective method to prevent CSF leakage. Various different alternative suturing techniques were assessed to prevent CSF leakage through the dura, but none of these techniques was successful to prevent CSF leakage [30]. Other techniques as non-penetrating clips have not reached the clinical practice [31,32]. These techniques are probably less effective in neurosurgery due to the biomechanical characteristics of the dura. External CSF drainage is an effective method to treat percutaneous CSF leakage and can be also used prophylactically. However, the method is invasive, and the associated consequences are unattractive, such as hospitalization, immobilization and infection risk. A promising area to prevent CSF leakage is minimal invasive surgery. Analysis showed that (endoscopic) minimal invasive surgery had lower CSF leakage rates than open surgery regardless of the use of sealants [25]. This surgical technique is still evolving and its indication is broadening, but it will not completely replace open surgery in the near future. Another method to prevent CSF leakage is watertight closure of the cutaneous tissue. This will obviously only prevent incisional leakage, not pseudomeningocele. However, it seems too impossible to prevent incisional leakage by only primary cutaneous closure. Skin sealants may augment cutaneous closure, but external factors such as wound manipulation, friction and sweat will compromise sealant adhesion. Conclusively, dural sealants application in combination with or without dural graft seems still potential the most logical method to prevent CSF leakage and a key area for improvement. Dural grafts have the advantage to cover large dural defects, but could never replace dural sealants. Dural grafts do only adhere to the dura with a sealant. Moreover, suturing the dural graft to the dura will create new needle holes, which could potentially leak CSF. Therefore, a dural graft alone will not result in watertight closure. An ideal sealant should be easy to use, adhere strongly to the dura, remain attached until the dura is regenerated, be biocompatible and be biodegradable. Synthetic polymers tend to be preferred rather than biopolymers. Synthetic polymers offer the immense possibility to tailor the features of the biomaterial. Although several synthetic polymers such as polycyanoacrylates have biocompatibility issues, numerous synthetic polymers such as aliphatic and PEG polymers are available with excellent biocompatibility. Besides, degradation of synthetic polymers via hydrolysis devoid the patient and implant-side variation. The degradation time of synthetic polymers supposed to be adjustable by combining different polymers.

To achieve easy closure, patch sealants might be preferred above liquid sealants. A major disadvantage of current liquid sealants, often composed of two components, is application issues such as; preparation time, suboptimal mixture, under or overdosing of the solution and risk of clogging of the application device. Moreover, liquid sealants have low cohesive (internal) strength [7]. In contrast, patch sealants are in general ready to use, need no or minimal preparation and are easy to handle.

Any new sealant should be thoroughly assessed before clinical application, not only safety but also efficacy. However, results of individual sealants and objective evaluation of dural sealants are rare in the literature. This is also caused by FDA and CE approval mechanisms. These institutions mainly judge the safety and biocompatibility of medical devices and not on its efficacy. This necessitates a critical attitude of health-care providers toward dural sealants and evaluation in a more standardized in vitro, in vivo and clinical trials of new dural sealants before clinical application. Ideally, the effectiveness of a new dural sealant should be evaluated separately for each region of application (i.e. spinal, cranial and transsphenoidal) since the requirements per region differ. For example, transsphenoidal use of a sealant requires the ability to apply the sealant through the narrow nasal cavity, while for cranial use the sealant should be flexible to follow the cranial curvature. For spinal use, the sealant should have the ability to resist friction due to the mobility of the spine, while eventually needed compression can only be applied very gently.

Although there is no straightforward method of CSF leakage prevention management, the cornerstone of preventing CSF leakage seems to be watertight closure, especially after infratentorial surgery. Sufficient time, attention and effort have to be paid to suture the dura watertight. Also, small dural defects should be prevented. Overstretching of the dura to close it has to be avoided because tension by stitches will cause micro-ruptures that can result in CSF leakage. If a dural defect appears, grafts and/or sealants can be used to achieve watertightness. In general, we prefer the use of a sealant over the total dural surface (not only the suture line) to close defects smaller than 3 mm. Larger dural defects need a dural graft. We consider autologous tissue such as pericranium or fascia ideal grafts. For small defects sometimes fat or muscle can be used. In case autologous tissue is not easily available in sufficient quantity an allograft is also an option. Preventive external lumbar drain placement is usually not considered due to its disadvantages such as hospitalization, immobilization, and risk of infection. We consider preventive external drain placement only in case of obvious CSF leakage during transsphenoidal surgery. In case of postoperative leakage, first, an external lumbar drain is applied under local anesthesia. If there is no immediate effect and the wound is not fully dry during 3 days of immobilization and CSF drainage, the wound should be surgically revised.

Increasing population, aging and advances in diagnostic and treatment increased the number of procedures performed [33,34], meaning that the absolute numbers of CSF leakage will also increase. The unmet need for a dural sealant in combination with the growing number of procedures will persuade researchers to develop a more effective dural sealant. The next generation sealants will be extensively compared with currents sealants to prove their effectiveness. Numerous currently approved and used sealants will disappear in the near future due to lack of effectiveness. As dural sealants are also preventively used, a profound cost-utility analysis will have to be performed to assess the benefits per dural sealant. We suppose that CSF leakage will never be completely banned, but it should be possible to significantly reduce the leakage rate in the future using effective sealants developed in this suggested way.

A new research area within sealant development might be the introduction of dural sealants with antimicrobial and analgesic properties. These properties have been already emerged in surgical sutures and wound dressings [35–37]. The first in vivo studies about sutures with analgesic properties and fibrin sealants blended with an antibiotic has already been performed [38,39]. The first clinical trials will be probably presented in the near future. The key factor in drug containing dural sealants will be the controlled release of a drug without neurotoxic overdose.

Article Highlights

• Postoperative cerebrospinal fluid (CSF) leakage after intradural surgery or an unintended dural tear is a severe complication because of its association with complications such as compromised wound healing and meningitis. The most obvious step in preventing CSF leakage is watertight closure of the dura.

• Two systematic reviews, cranial and spinal, showed no significant effect of dural sealants on CSF leakage rate if primary closure is augmented by a dural sealant.

• In vitro studies showed that most currently available sealants cannot resist physiological intracranial pressure.

• There is still an unmet need for a biocompatible, biodegradable and effective dural sealant. A variety of synthetic- and biopolymers are available to develop such a dural sealant. Thorough assessment in order of in vitro, in vivo and clinical trials is necessary to evaluate the usefulness of new dural sealants.

• Thorough assessment in order of in vitro, in vivo and clinical trials is necessary to evaluate the usefulness of new dural sealants.

Declaration of interest

A Kinaci’s PhD position is partly funded by Polyganics BV. TPC van Doormaal is a consultant for Polyganics BV. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.