Papers & Patents

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Adherus Dural and Spinal Sealant as Adjuncts to Sutured Dural Repair in a Canine Lumbar Durotomy Repair Model

The objective of this GLP study was to evaluate the safety and effectiveness of Adherus Dural Sealant and Adherus Spinal Sealant when used to achieve watertight dural closure in a canine lumbar durotomy repair model. Another important objective of this study was to determine whether Adherus Dural and Adherus Spinal Sealants would inhibit the formation of peridural fibrosis and dural adhesions as normal healing occurred. The formulations were easy to apply, setting in the expected time frame to form an approximate 2 mm hydrogel film over the durotomy site. Application of Adherus Dural Sealant or Adherus Spinal Sealant provided 100% water-tight closure at time of surgery, as well as at four or five days, two months and four months post-operatively. There were no adverse test article-related effects in clinical observations, body weight, food consumption, physical or neurological parameters, clinical pathology parameters, CSF total cell count or chemistry parameters during this study. In addition, there was no histopathological evidence that application of Adherus Dural Sealant or Adherus Spinal Sealant had any adverse effects on the adjacent tissues, including the spinal cord and spinal nerve roots. Furthermore, the formulations did not appear to impede healing of the surgical site. Adherus Dural and Adherus Spinal Sealant, in general, significantly limited dura adhesions at both the two month and four month necropsy intervals. Peridural fibrosis and dura thickening/fibrosis was also reduced in animals that received Adherus Dural or Spinal treatment over that in control animals which did not receive either of the test articles.
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In-Vitro Properties of Adherus Dural Sealant

The physical and mechanical properties of Adherus Dural Sealant were evaluated through in vitro testing which included set time, water uptake, Young's modulus and burst strength. Using product up to two years old, Adherus Dural Sealant repeatedly set in one second, remained dimensionally stable, swelling only 8% in any one axis when exposed to an excess of solution, and was able to provide a firm barrier to fluid leaks for three to four weeks when exposed to pressures corresponding to spinal CSF pressures and five to six weeks when exposed to cranial physiological pressures.
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First Human Clinical Experience with Adherus Dural Sealant for Watertight Dural Closure

This preliminary short term trial was performed to confirm the safety and effectiveness of Adherus Dural Sealant when used in lieu of or in conjunction with standard methods of dura repair to prevent cerebrospinal fluid (CSF) leaks. The PEG-based hydrogel sealant was used in 25 patients with confirmed CSF leaks in the cranial or spinal dura using either an open or transsphenoidal approach. Adherus Dural Sealant was 100% effective (17/17) at achieving intraoperative watertight dural closure when used as an adjunct to suture and 88% effective (7/8) in creating watertight closures when used as a method of primary dural closure. In this fourteen (14) day follow up study, no device related events or surgical site infections were observed.
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The Safety of Adherus Dural Sealant When the Hydrogel or its Extracts are Placed in Direct Contact with Neurological Tissue

To demonstrate the safety of Adherus Dural Sealant when in direct contact with neurological tissue, two neuro-compatibility evaluations were performed. During the first portion of the assessment, Adherus Dural Sealant was evaluated for the potential to cause local irritation or toxicity when implanted within the brain parenchyma. A cannula was used to implant pieces of Adherus Dural Sealant or a comparative control article into the brain parenchyma in test animals. Examinations for clinical signs of disease or abnormality were performed daily and neurological assessments were conducted prior to treatment and at days 4, 14, and biweekly thereafter for up to three months. At 1 week and three months after implantation, four animals per treatment group were euthanized. The brain and proximal portion of the cervical spinal cord were dissected and removed. No neurologic deficits were noted and no adverse reactions were observed for any of the test sites at explant. There was no histological evidence of local (implant site) or distant neurotoxicity associated with the test article implanted within the parenchyma. In the second portion of the assessment, extracts of Adherus Dural Sealant were also evaluated following injection of the prepared extracts or control solutions into the lateral ventricle (ICV) and the cisterna magna (CM) of the brain of a rat. Detailed health examinations and neurologic assessments were conducted at pre-specified intervals. At 4 days and 2 weeks following injection, half of the animals from each cannulation type and treatment group were euthanized and necropsy performed. The microscopic evaluation of the tissues revealed no evidence of a treatment related toxicity. In conclusion, under the conditions of this study, there was no evidence of inflammation or neurotoxicity from Adherus Dural Sealant or its extracts when placed in direct contact with neurological tissues of the rat.
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Adherus Dural Sealant as an Adjunct to Sutured Dural Repair in a Canine Cranial Durotomy Repair Model

The objective of this study was to evaluate the safety and effectiveness of Adherus Dural Sealant when used as an adjunct to sutured closure in a canine durotomy repair model. The effectiveness of dural repair was evaluated at time of surgery, one week post surgery and again at approximately six months post surgery by pressure testing. The safety and endurance of the test article was evaluated over approximately six months using magnetic resonance imaging, clinical evaluations, clinical pathology, and histopathology. During pressure testing at all specified time points, Adherus Dural Sealant provided 100% water-tight closure. None of the Adherus Dural Sealant-treated incisions leaked at intracranial pressures up to 50 mmHg. MRI scans obtained at two to four days post surgery and monthly thereafter showed the test material to be clearly visible in all imaging sequences (T2, FLAIR, T1, and T1 with contrast). The test article continued to be visible, although clearly degrading, through the three month scan, was barely discernible in a portion of the scans at four months, and not present in the five and six month scans (T2 images). Adherus Dural Sealant was well-tolerated and none of the treated animals experienced test article related clinical signs after surgery. There were no test article related changes in body weight, food consumption, neurological/physical examination parameters, and clinical pathology parameters. Histopathologic evaluations indicate that there were no unanticipated morphologic changes associated with a single topical administration of Adherus Dural Sealant to a durotomy site in beagle dogs at eight days or six months post surgery.
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Patents

Crosslinked Polyalkyleneimine Hydrogels with Tunable Degradation Rates

One aspect of the present invention relates to methods of sealing a wound or tissue plane or filling a void space, or securing meshes, films or other devices within the body. In certain embodiments, the wound is an ophthalmic, pleural or dural wound, or a hernia repair mesh. Remarkably, disclosed herein is the discovery that the use of certain crosslinkers in combination with polyalkyleneimines at specific concentrations can result in hydrogels with tunable degradation properties.
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Applicators for Multiple Component Formulations and the Like, and Methods of Use Thereof

One aspect of the invention relates to an applicator system, and methods of use thereof, that can be used to house separately one or more liquids and one or more solids (e.g., components of a polymerizable hydrogel). In certain embodiments, the applicator systems are further designed to facilitate the mixing of the solids and liquids inside the applicator. In addition, in certain embodiments, the applicator systems are also designed to facilitate the application of the mixture to a surface.
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Self-contained Medical Applicators for Multiple Component Formulations, and Methods of Use Thereof

Certain aspects of the invention relate to an applicator, and methods of use thereof, which can house multiple component formulations in separate material receptacles, which can then be easily reconstituted at time of use without any assembly by the user. A device of the invention can be used for, but is not limited to, applying hydrogel formulations to dura mater, abdominal tissue in hernia repair, tissues near the spine, lung tissue, intestinal tissue, and any of the internal tissues. A device of the invention can be configured to apply a spray or a stream of liquid formulation onto a surface to be treated. A device of the invention can be configured to deliver the formulation through an endoscope or laparoscope.
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Self-Contained Medical Applicators for Surgical Sealants, and Methods of Use Thereof

Aspects of the invention relate to an applicator, and methods of use thereof, which can house multiple component formulations in separate material receptacles, which components can then be easily combined at the time of use without assembly by the user. In certain embodiments, a device of the invention can be used for, but is not limited to, applying hydrogel formulations to dura mater, abdominal tissue in hernia repair, tissues near the spine, lung tissue, intestinal tissue, or any of the internal tissues. In certain embodiments, a device of the invention can be configured to apply a spray or a stream of a liquid formulation to a surface. In certain embodiments, a device of the invention can be configured to deliver the formulation through an endoscope or laparoscope.
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