Search

US-12616771-B2 - Tissue adherent chitosan material that resists dissolution

US12616771B2US 12616771 B2US12616771 B2US 12616771B2US-12616771-B2

Abstract

The present invention relates to a biocompatible, foldable, thin profile, low mass and high surface area, chitosan dressing, optionally modified with catechol, and suitable for treating bleeding in a physiological environment, e.g., gastrointestinal tract, bladder (in particular in connection with the TURP procedure). The characteristics and structures of the chitosan dressing are provided. Methods of making and using the chitosan dressing are also provided.

Inventors

  • Simon J. McCarthy
  • Cole Gannett
  • Mattie R. JONES
  • Ervelyn Winata

Assignees

  • TRICOL BIOMEDICAL, INC.

Dates

Publication Date
20260505
Application Date
20181228

Claims (17)

  1. 1 . A modified chitosan material, wherein the chitosan has a degree of polymerization of greater than 60 and is modified with a compound comprising a catechol group selected from a group consisting of at least one of a 3,4-dihydroxyhydrocinnamic acid; 3,4-dihydroxycinnamic acid; trans-3,4-dihydroxycinnamic acid; and a 3,4-dihydroxyphenylacetic acid; wherein at least a portion of the catechol groups is oxidized to o-quinone and cross-linked to form at least one of compound (A) or (B), wherein ‘m’ represents o-quinone modified chitosan polymer and ‘l’ represents chitosan cross-linked with the o-quinone modified chitosan polymer, wherein the modified chitosan has a catechol group degree of substitution of from 7% to 29%; and wherein the material is in a dry solid form that comprises an acid salt content of from about 2% to about 15% (w/w) and that is resistant to dissolution in water, saline solution, blood, gastrointestinal (GI) fluid or urine at about 37° C. for at least about 6 hours and adherent to wet tissue.
  2. 2 . The modified chitosan material according to claim 1 , wherein the material has at least one of: (i) a thickness that is 500 microns or less; (ii) a density that is in the range of from about 0.03 g/cm 3 to about 0.7 g/cm 3 ; (iii) is compressed; (iv) is square shaped, rectangular shaped, circular shaped, or circular petal shaped; and (a) measures for each of the length and width for a square or rectangular shape may range from about 10 mm to about 70 mm; and (b) diameter measures for each of the circular or circular petal shape range from about 10 mm to about 70 mm; (v) has a moisture content of 15% or less by weight (w/w); (vi) has an adhesive side and a non-adhesive side and, optionally, wherein the adhesive side is provided on a first layer and the non-adhesive side is provided on a second layer, or wherein the adhesive side adheres to a tissue surface when the material is wet, or wherein the non-adhesive side does not adhere to a delivery device when the material is wet; (vii) adheres to a gastrointestinal mucosa in 1 minute or less, or adheres to a bladder mucosa in 3 minutes or less, or both; (viii) forms a quaternary ammonium cation at the chitosan glucosamine C-2 amine at a tissue site; (ix) has a coloration of: 1) a brown coloration including a dark brown coloration; or 2) a pink to pinkish brown coloration.
  3. 3 . The modified chitosan material according to claim 1 , wherein said material is freeze-dried in the form of a lamella and, optionally, wherein the freeze-dried structure has a thickness of 100 microns or less, or wherein the freeze-dried structure comprises more than one freeze-dried layer.
  4. 4 . The modified chitosan material according to claim 1 , further comprising spun fibers.
  5. 5 . The modified chitosan material according to claim 1 , further comprising a porous surface providing one or more of: (i) an absorbent surface; or (ii) channels to redirect moisture away from a target tissue surface site.
  6. 6 . The modified chitosan material according to claim 1 , wherein the material adherence strength is greater than or equal to about 1 kPa.
  7. 7 . The modified chitosan material according to claim 1 , wherein the material: (i) when folded or furled does not crack or tear; (ii) when, in an open, unfurled, or unfolded condition, has an outward facing surface area that may range from about four to about eight times greater than the outward facing surface area of that same material when it is in a closed, furled, or folded condition; (iii) has a ratio of the outward facing surface area of an open, unfurled, or unfolded condition relative to a closed, furled, or folded condition that may range from about 15:1 to about 2:1; or (iv) when punctured or sewn does not crack or tear.
  8. 8 . The modified chitosan material according to claim 1 , wherein the material is deliverable intact by a balloon device, a wire device, or an endoscopic device and, optionally, wherein the balloon device or the wire device, or the endoscopic device comprises a working channel having a diameter of 7.0 mm or less, and wherein the material is delivered through the working channel, and wherein the material when wet adheres intact to either gastric mucosa in less than 30 seconds with application of a pressure of 50 kPa or less, or to bladder mucosa in less than three minutes.
  9. 9 . The modified chitosan material of claim 8 , wherein the pressure is from about 20 kPa to about 30 kPa, or the material adheres intact to bladder mucosa in less than two minutes, or both.
  10. 10 . The modified chitosan material according to claim 1 , wherein the material: (i) removes hydrophilic and hydrophobic biological fluids that interfere with adhesion; or (ii) stays in place intact and stops moderate to oozing bleeding ranging from about 1 ml/min to about 150 ml/min, and wherein the material readily detaches from a delivery device after adherence to a target tissue site.
  11. 11 . The modified chitosan material according to claim 1 , wherein the material resists dissolution for at least six hours after adhering to an injury site in presence of corrosive enzymes and acid environment of about pH 3, or in presence of urine, or both; or wherein the material seals and protects a target tissue site for at least 12 hours; or wherein the material achieves a controlled, slow dissolution from the attachment site over a period of time not exceeding seven (7) days; or wherein the material is folded and unfolded; or wherein the material is able to be furled and unfurled; or wherein the material does not dissolve fully at pH from about 4.5 to 8 at about 37° C. for at least 12 hours following application.
  12. 12 . The modified chitosan material according to claim 1 , wherein the material does not dissolve fully in water, saline solution, blood, or GI fluid or bladder fluid, or urine at about 37° C. for at least 12 hours following an application.
  13. 13 . The modified chitosan material according to claim 2 , wherein the material does not adhere to a delivery device; does not increase or decrease in size by more than about 25% in length and width, or more than about 50% in thickness in the presence of water, saline solution, blood, or GI fluid or bladder fluid, or urine at about 37° C.; comprises an adhesive side that interacts with an injury site, and wherein the chitosan material comprises a non-adhesive side that interacts with one of a delivery device or the adhesive side when the material is in a dry and folded or a dry and furled condition; is sterilized without affecting material characteristics; and is stored under controlled conditions over time without affecting material characteristics.
  14. 14 . The modified chitosan material according to claim 1 for use in a treatment of an injury by directly adhering the material at an injury site upon wetting, and applying pressure to the material for about 30 seconds and allowing the material to remain at the injury site for at least 24 hours.
  15. 15 . The modified chitosan material according to claim 14 for use in a treatment of an injury, wherein the material dissolves completely from the injury site without human intervention in seven days or less.
  16. 16 . The modified chitosan material according to claim 1 for use in combination with transurethral resection of a prostate by directly adhering the material to an injury site.
  17. 17 . The modified chitosan material according to claim 1 , wherein the dry solid form is selected from the group consisting of a powder, a matrix, a membrane, a thin foil, a pleget, a fiber, or a coating.

Description

GOVERNMENT LICENSE RIGHTS This invention was made with Government support under R42DK078400 and R44DK104564 awarded by National Institute of Diabetes and Digestive and Kidney Disease. The Government has certain right in the invention. BACKGROUND Technical Field Safe, reliable and effective delivery of bioactive chitosan material within the body remains a major problem. In use, the bioactive chitosan material must remain intact for a period of at least 12 hours in the presence of biological fluids such as gastric fluid, blood, bile and urine and it must be able to adhere to tissue including mucosa of the gastrointestinal tract and the internal elastic lamina of the vascular system for a period longer than 24 hours. Bioactive chitosan has many applications in the body not limited to drug delivery, hemostasis, wound healing, tissue regeneration, and embolotherapy. Current chitosan materials and compositions of chitosan material used on, or within the body are limited in their application as they are unable to resist dissolution and rapid loss in harsh environments such as the stomach and they cannot be maintained in place by their adhesion to tissue. This disclosure relates to the field of chitosan materials comprising catechol modified chitosan and uses thereof. Description of the Related Art There are many surgeries on vascularized organs and tissue such as heart, liver, pancreas, stomach, intestine, colon, prostate, tonsils, ear, nose, throat and brain that often continue to bleed following injury and through wound healing. The initial injury may continue to bleed for days unless standard hemostasis is applied and the bleeding may also recur at a later time. Standard of care initial hemostasis for treatment of bleeding following surgery is varied depending on the type of surgery. Ligature, gauze packing, biologic dressings, cautery, and banding may be applied to locally address the issue. Packing may be applied for up to 24 hours in the case of protracted bleeding. If the bleeding is uncontrollable after the period of conservational management, the patient may have to return to surgical unit promptly to stop the hemorrhaging with either open or endoscopic procedures. Although there have been advances in bleeding control using advanced dressings none of these advances have yet translated into reliable treatment options under unique surgical conditions where delivery, tissue adhesion, and continuous bleeding intermingled with other biological fluid considerations are highly challenging. Rapid bleeding control under all circumstances is highly desirable. Minimally invasive surgical procedures are becoming the preferred means of interventional access due to ability to access areas of the body with significantly reduced risk (compared to open surgery) with lower morbidity, lower hospital cost and lower patient discomfort. Advanced biomaterials are at the forefront of addressing current limitations and enabling improvements in safety, reliability and increased practice and application of minimally invasive surgical procedures. Current limitations in minimally invasive surgical practice include control of bleeding (especially hemorrhage), sutureless closure of delicate soft tissue sites, local promotion of healing, local treatment of pathogenic conditions, and local placement with anchoring or adhesion to a surgical/interventional site. More recently minimally invasive interventions are being used to address vascular pathogenesis including vascular malformations, aneurysms, and vascular tumors. A preferred procedure to address vascular malformations, aneurysms, and vascular tumors is the use of embolotherapy to occlude abnormal blood vessels. Embolotherapy involves the local delivery of an occlusion device such as a stent or a coil of material or an anchored biomaterial which remain in place over an extended time to promote the formation of a lot clot with subsequent permanent closure of the vessel. A biocompatible, tissue adhesive, chitosan material that remains intact for a prolonged time with promotion of local clot formation and normal tissue healing presents advanced material attributes that will enable significant development in surgical practice. In addition, prolonged bleeding, with its associated risks in mortality and morbidity, remains a serious problem in the gastrointestinal (GI) tract. Techniques and devices that could provide for rapid bleeding control in gastrointestinal bleeding (GIB) for both upper gastrointestinal bleeding (UGIB) and lower gastrointestinal bleeding (LGIB) are needed. Current bleeding control in and after transurethral resection of the prostate (TURP) relies on cautery for small vessel arterial bleeding and application of balloon pressure to address venous oozing. The bladder neck and prostrate are both highly vascularized tissue that often continue to bleed following injury and through wound healing. The initial injury site may continue to bleed for days unless standard hemostas