CN118302175A

CN118302175A - Fucan and modified fucan compositions for treating conditions associated with capsular contracture and inhibiting fiber growth around or on implants

Info

Publication number: CN118302175A
Application number: CN202280064842.6A
Authority: CN
Inventors: H·孙; I·米莱特; C·M·K·斯普林加特
Original assignee: Arc Medical Co ltd
Current assignee: Arc Medical Co ltd
Priority date: 2021-08-20
Filing date: 2022-08-18
Publication date: 2024-07-05

Abstract

Compositions and methods comprising medically acceptable fucans suitable for use in medical and surgical applications, including the treatment of capsular contracture and other Foreign Body Response (FBR) disorders, as well as medical and surgical applications associated with implants and transplantation procedures, such as GVHD and fiber growth around or on implants or implants after implantation/transplantation, and related diseases, infections, and wounds.

Description

Fucan and modified fucan compositions for treating conditions associated with capsular contracture and inhibiting fiber growth around or on implants

Background

Fucan (Fucans), including fucoidan, is a sulfated polysaccharide. In general, this means that they are molecules composed of a number of sugar groups and also have sulfur atoms attached to the sugar groups. The main sugar group is called "fucose", which is a sugar having 6 carbon atoms, and has the chemical formula C ₆H₁₂O₅. "fucoidan" (or fucoidan (fucoidin)) means fucoidan derived from brown algae (seaweed). Fucans may be present alone or in mixtures of other sugars, for example in mixtures of sugars such as xylose, galactose, glucose, glucuronic acid and/or mannose. These other sugars may be extracted with fucans from seaweed or other sources. Although fucans are currently derived from natural sources, such as brown algae (seaweed), sea cucumber, etc., as mentioned herein, "fucan" includes polymer molecules having the chemical and structural motifs of fucans discussed herein, regardless of the final source or sources of fucans.

Fucoidan may be obtained from a variety of brown algae, including but not limited to: the plant growth regulator comprises the components of chlorella (Adenocystis utricularis), ascophyllum nodosum (Ascophyllum nodosum), rope alga (Chorda filum), cystoseirabies marina, antarctic bull alga (Durvillaea antarctica), phaeophyta kelp (Ecklonia kurome), kelp (Ecklonia maxima), esculenta (Eisenia bicyclis), fucus (Fucus evanescens), fucus vesiculosus (Fucus vesiculosis), cyrtymenia Sparsa (Hizikia fusiforme), sargassum elongatum (HIMANTHALIA ELONGATA), kelp (Kjellmaniella crassifolia), LAMINARIA BRASILIENSIS, chicory kelp (LAMINARIA CICHORIOIDES), north kelp (Laminariahyperborea), japanese sea tangle (LAMINARIA JAPONICA), sugar kelp (LAMINARIA SACCHARINA), lessonia trabeculata, kelp (Macrocystis pyrifera), PELVETIA FASTIGIATA, deer antler (Pelvetia Canaliculata), SACCHARINA JAPONICA, SACCHARINA LATISSIMA, sargassum stenophylum, sargassum thunbergii (Sargassum thunbergii), sea fleabane (Sargassum confusum), cyrtymenia (Sargassum fusiforme) and undaria pinnatifida (Undaria pinnatifida). These exemplary species are all from the class Phaeophyceae (Phaeophyceae) and most of these species belong to the following families: fucales (Fucales) and kelp (LAMINARIACEAE).

As used herein, "transplantation" refers to a surgical procedure for transplanting an organ or tissue into or onto a body, i.e., inserting an organ or tissue from one body into another body (typically within a species) or from one location within the body to another location within the same body by surgery. "grafts" are organic whole organs or tissues and are therefore distinguished from implants and the like, such as replacement knee joints or replacement intraocular lenses (oculars), which are generally non-organic items, although implants may include organically derived components such as biological elements derived from blood, vaccines, allergens, tissues, cells, and cell and gene therapies.

The present disclosure provides compositions and methods comprising fucans for treating capsular contractures or Graft and Graft surgery related disorders such as Graft versus host disease (GVHD, https:// en. Wikipedia. Org/wiki/Graft-versus-host_disease) and inhibiting fiber growth on or around implants or grafts, the need for compounds, compositions, methods, and the like (including delivery regimens) for treating such capsular contractures, grafts, or implant disorders has not been met, including providing therapeutic methods with fewer side effects. The systems and methods of the present invention, etc., provide these and/or other advantages.

Incorporated by reference

The present application is incorporated by reference in its entirety into the following publications: PCT/CA2019/051025 submitted at 24, 7, 2019; PCT/CA2019/051026 submitted 24 at 7/2019; PCT/CA2019/051027 submitted 24 in 7 in 2019, PCT/CA2019/051030 submitted 24 in 7 in 2019; PCT/CA2019/051028 submitted 24 at 7/2019; PCT/CA2020/050294 submitted on 3/5 of 2020; PCT/CA2020/050295 submitted 3/5/2020; and PCT/CA2019/051029 submitted 24 at 7/2019.

SUMMARY

As indicated above, the present application relates to compositions and methods comprising medically acceptable fucans suitable for use in medical and surgical applications, including the treatment of capsular contracture and other Foreign Body Response (FBR) disorders. The present application also relates to compositions and methods comprising medically acceptable fucans suitable for use in medical and surgical applications associated with implants and transplant surgery, such as GVHD and fiber growth around or on implants or implants after implantation/transplantation, as well as related diseases, infections and wounds. Such graft-related GVHD, fibrogenesis problems, and the like are collectively referred to herein as "graft disorders". The compositions and methods of the present application include medically acceptable fucans that can be effective in treating problems such as FBR and transplant disorders in a therapeutically effective medical composition. In certain embodiments, the pharmaceutically acceptable fucan is fucoidan. The medically acceptable fucans of the present application can be, or can be included on or in, medical compositions, including, for example, medical acceptable medical devices, biologicals (biologicals herein include products derived from living sources such as animals (including humans) and microorganisms, e.g., blood, vaccines, allergens, tissues, cells, and cell and gene therapies), pharmaceuticals, combinations, pharmaceutical compositions, biopharmaceuticals, and other medically acceptable, therapeutically, and/or medically effective compositions, all of which are collectively referred to herein as "medical compositions".

In certain embodiments, the patient receives a medical composition comprising a medically acceptable fucan as discussed herein to treat capsular contracture, fiber growth around the implant, and the like as discussed herein. In certain embodiments, the patient receives a transplant disorder medical composition comprising a medically acceptable fucan as discussed herein to treat the transplant disorder. Treatment herein includes inhibition, prevention, removal, reduction, or other treatment of capsular contracture or fibrous growth around the implant as discussed herein. The medical compositions discussed herein may comprise a medically acceptable fucan with suitably low endotoxin levels for use in medical and/or surgical applications. The compositions herein may further comprise a medically acceptable fucan having a desired molecular weight distribution and/or sulfate level. The treatment may comprise administering the medical composition at a suspected site, wherein the suspected indicates that the site is considered by the practitioner to have been affected by capsular contracture or fiber growth around the foreign body and/or graft, or is at a higher risk than the level of risk before implantation/implantation of a capsular contracture or fiber growth or graft disorder occurring around the implant.

The systems, devices, methods, and the like of the present invention provide methods of treating certain capsular contracture or fiber growth or transplantation conditions surrounding a graft, for example, signaling activities such as cytokine or chemokine activity are part of the condition. In certain embodiments, the treatment comprises inhibiting the presence or formation of such capsular contracture or fibrous growth around the implant/graft at a specific site in the patient. For example, the method comprises administering a therapeutically effective amount of a medically acceptable fucan composition to a site of capsular contracture or fiber growth around an implant/graft in a patient suspected of having capsular contracture or fiber growth around the implant or graft.

In certain embodiments, the method further comprises, prior to administering the medically acceptable fucan composition to the patient, identifying a need to inhibit capsular contracture or fiber growth around the implant in the patient, and then selecting the medically acceptable fucan composition for administration to the patient in particular to effect inhibition or other treatment. In certain embodiments, the administering, treating and/or inhibiting comprises flushing a particular treatment site suspected of having capsular contracture or fiber growth around the implant, or otherwise administering a medically acceptable fucan composition directly to the site having or suspected of having capsular contracture or fiber growth around the implant. Flushing the target area with a composition comprising the fucan composition herein may be particularly advantageous as a means of administration and/or treatment/inhibition.

In certain aspects of the systems, devices, methods, etc., of the invention, administration comprises delivering a medically acceptable fucan composition directly to a site having or suspected of having capsular contracture or fiber growth around the implant, for example, by instillation, rinsing, gelling, or powder; this does not include systemic administration, such as by oral drug therapy. The medically acceptable fucan composition may be applied substantially continuously by controlled release from a polymer or other acceptable controlled release dosage form to a site having or suspected of having capsular contracture or fiber growth around the implant. The pharmaceutically acceptable fucan composition may be administered intravenously, intra-articular, intra-focal, intravaginally, rectally, intramuscularly, intraperitoneally, subcutaneously, topically, intranasally, intraocularly or orally.

In other aspects, the systems, devices, methods, and the like of the present invention provide methods of treating capsular contracture or fibrous growth around an implant in a patient, the methods comprising coating at least one surface of the implant with a therapeutically effective amount of a medically acceptable fucan composition, and then delivering the implant to the patient. Such methods may further comprise, prior to coating the surface of the implant with the medically acceptable fucan composition, identifying a need to treat capsular contracture or fiber growth around the implant in the patient, and then selecting the medically acceptable fucan composition for coating the surface of the implant with the medically acceptable fucan composition to effect treatment.

The pharmaceutically acceptable fucan composition may further comprise at least one pharmaceutically acceptable excipient selected from gelatin, hypromellose, lactose, water for injection (united states pharmacopeia), sodium chloride, sodium phosphate, sodium citrate, sodium ascorbate, phosphate buffer, citrate buffer, phosphate-citrate buffer, pramipexole (pluronic), cellulose, alginate, acrylate, hyaluronic acid, polyethylene glycol, poly (lactic acid), poly (lactic acid-co-glycolic acid), carrageenan, polyurethane, polyethylene, polypropylene, polytetrafluoroethylene, chitosan, and lactated ringer's injection (united states pharmacopeia). The patient may be an animal, including a human in some cases. The medically acceptable fucan composition may comprise fucan, and embodiments and the like herein include the use of the medically acceptable fucan composition to treat (including inhibit) capsular contracture or fiber growth around an implant as discussed herein. Also included herein are compositions comprising a medically acceptable modified fucan for use in treating (including inhibiting) at least one of capsular contracture or fibrous growth, including, for example, capsular contracture, around an implant herein; a foreign body response; forming a fibrous capsule; and biofilm infection.

In certain embodiments, the composition comprises a medically acceptable modified fucan having less than about 0.2EU/mg, 0.1EU/mg, 0.05EU/mg, 0.02EU/mg, 0.01EU/mg, 0.005EU/mg, 0.002 EU/mg. In other embodiments, the composition may comprise less than about 0.40% w/w total nitrogen, less than about 0.20% w/w total nitrogen, less than about 0.15% w/w total nitrogen, or less than about 0.10% w/w total nitrogen. The medically acceptable modified fucan may comprise between about 10% w/w and 60% w/w of sulfate or between about 30% w/w and 60% w/w of sulfate. The medically acceptable modified fucan may comprise a molar ratio of total sulfate to total fucose between 0.5 and 3.0.

The medically acceptable modified fucan may comprise a molar ratio of total sulfate to total fucose between 1.1 and 3.0. The medically acceptable modified fucan may comprise a molar ratio of total sulfate to total fucose and galactose of between about 0.5 and 3.0 or between about 1.1 and 3.0. The medically acceptable modified fucan may comprise a total carbohydrate content between about 27% w/w and 80% w/w, or between about 30% w/w and 70% w/w. The medically acceptable modified fucan may comprise a fucose content as a percentage of total carbohydrates of more than about 30% w/w, 40% w/w, 50% w/w, 70% w/w, 80% w/w or 90% w/w. The medically acceptable modified fucan may comprise a galactose content as a percentage of total carbohydrates of less than about 60% w/w, 30% w/w, 20% w/w or 10% w/w. The medically acceptable modified fucan may comprise less than about 30% w/w, 20% w/w, 10% w/w or 5% w/w total glucuronic acid, mannose, rhamnose and xylose content as a percentage of total carbohydrate content.

The systems, devices, methods, etc. of the present invention are also provided herein:

a method of treating fibrocystic formation in a patient at an implant site on or in the body surface of the patient, which method may comprise treating fibrocystic formation with a therapeutically effective amount of a medically acceptable fucan composition in certain embodiments.

A method of treating a foreign body response in a patient at an implant site on or in the body surface of the patient, the method may comprise treating the foreign body response with a therapeutically effective amount of a medically acceptable fucan composition.

A method of treating capsular contracture in a patient at an implant site on or in the body surface of the patient, the method may comprise treating capsular contracture with a therapeutically effective amount of a medically acceptable fucan composition. A method of treating a biofilm infection in a patient at an implant site on or in the body surface of the patient, the method may comprise treating biofilm formation with a therapeutically effective amount of a medically acceptable fucan composition.

The treatment may include inhibition and the implant may include at least one of a medical device, a drug, or a combination product. The implant may be constructed of at least one of a non-synthetic material, a biological material, a naturally derived material, and a synthetic material. The implant may include at least one of a bone plate, a fracture fixation device, a hip prosthesis, a knee prosthesis, a shoulder prosthesis, an ankle prosthesis, an elbow prosthesis, an artificial ligament, an artificial tendon, a cell therapy, a gene therapy, a pacemaker package, a catheter, a stent, an artificial heart valve, an artificial artery, a drug reservoir device for sustained release, a diabetes monitor, an insulin pump, a skin repair device, a breast implant, a cochlear replacement, an intraocular lens (artificial lens), a vascular graft, a nerve conduit, a surgical mesh, an organ, a tissue, and a cell. The implant may be composed of at least one of: autograft, allograft, fibrin, poly (lactic acid), poly (lactic-co-glycolic acid), alginate, carrageenan, hyaluronic acid, heparin, synthetic polyurethane, polyester, silicone, aluminum, steel, titanium, cobalt, chromium, nickel, gold, silver, platinum, metal alloys, calcium phosphate, hydroxyapatite, inorganic salt derivatives, alumina, zirconia, bioactive glass, porcelain, carbon, cyclic olefin copolymers, polycarbonate, polyetherimide, polyvinylchloride, polyethersulfone, polyethylene, polytetrafluoroethylene, polyetheretherketone, polypropylene, silicone, hydrogels, cellulose, starch, proteins, peptides, DNA, RNA, collagen, gelatin, silk, chitin, chitosan, glucose, heart valves, blood vessels, and liver tissue.

Treatment with a therapeutically effective amount of a medically acceptable fucan composition may include coating at least one surface of the implant with a therapeutically effective amount of a medically acceptable fucan composition prior to delivering the implant to a patient. Treatment with a therapeutically effective amount of a medically acceptable fucan composition may include coating at least one surface of the implant with a therapeutically effective amount of a medically acceptable fucan composition after delivery of the implant to a patient. Treatment with a therapeutically effective amount of a medically acceptable fucan composition may include embedding the therapeutically effective amount of the medically acceptable fucan composition within the implant prior to delivering the implant to the patient.

Treatment with a therapeutically effective amount of a medically acceptable fucan composition may include embedding the therapeutically effective amount of the medically acceptable fucan composition within the implant after delivery of the implant to the patient. Treatment with a therapeutically effective amount of a medically acceptable fucan composition may include co-administering a therapeutically effective amount of a medically acceptable fucan composition with the implant. Treatment with a therapeutically effective amount of a medically acceptable fucan composition may include administering the therapeutically effective amount of the medically acceptable fucan composition prior to delivering the implant to the patient. Treatment with a therapeutically effective amount of a medically acceptable fucan composition may include, after delivering the implant to the patient, administering a therapeutically effective amount of a medically acceptable fucan composition.

The administration may occur at the site of the implant and the patient may be an animal.

The pharmaceutically acceptable fucan composition may comprise at least one of a paste, gel, patch, film, spray, liquid, lotion, cream, solution, suspension, solid, implant, powder, and microsphere. The pharmaceutically acceptable fucan composition may further comprise at least one pharmaceutically acceptable excipient selected from gelatin, hypromellose, lactose, water for injection (united states pharmacopeia), sodium chloride, sodium phosphate, sodium citrate, sodium ascorbate, phosphate buffer, citrate buffer, phosphate-citrate buffer, pramipexole, cellulose, alginate, acrylate, hyaluronic acid, polyethylene glycol, poly (lactic acid), poly (lactic acid-co-glycolic acid), alginate, carrageenan, polyurethane, polyethylene, polypropylene, polytetrafluoroethylene, chitosan, and lactated ringer's injection (united states pharmacopeia). The pharmaceutically acceptable fucan composition may comprise less than about 200 Endotoxin Units (EU), 100 Endotoxin Units (EU), 50 Endotoxin Units (EU), 20 Endotoxin Units (EU), 10 Endotoxin Units (EU), 5 Endotoxin Units (EU), or 2 Endotoxin Units (EU).

Methods and the like herein include the use of a medically acceptable fucan composition to treat fibrocystic formation, foreign body response, treating capsular contracture, biofilm infection, implant disorders, or graft disorders.

The composition may comprise an implant or graft and a medically acceptable fucan composition. The implant may include at least one of a medical device, a drug, and a combination product, and may be composed of at least one of a non-synthetic material, a biological material, a naturally derived material, and a synthetic material. The implant may include bone plates, fracture fixation devices, hip prostheses, knee prostheses, shoulder prostheses, ankle prostheses, elbow prostheses, artificial ligaments, artificial tendons, cell therapies, gene therapies, pacemaker packaging, catheters, stents, prosthetic heart valves, artificial arteries, drug reservoir devices for sustained release, diabetes monitors, insulin pumps, skin repair devices, breast implants, cochlear implants, intraocular lenses, vascular grafts, nerve conduits, surgical meshes, organs, tissues and cells. The implant may be composed of at least one of: autograft, allograft, fibrin, poly (lactic acid), poly (lactic-co-glycolic acid), alginate, carrageenan, hyaluronic acid, heparin, synthetic polyurethane, polyester, silicone, aluminum, steel, titanium, cobalt, chromium, nickel, gold, silver, platinum, metal alloys, calcium phosphate, hydroxyapatite, inorganic salt derivatives, alumina, zirconia, bioactive glass, porcelain, carbon, cyclic olefin copolymers, polycarbonate, polyetherimide, polyvinylchloride, polyethersulfone, polyethylene, polytetrafluoroethylene, polyetheretherketone, polypropylene, silicone, hydrogels, cellulose, starch, proteins, peptides, DNA, RNA, collagen, gelatin, silk, chitin, chitosan, glucose, heart valves, blood vessels, and liver tissue.

In certain aspects, the methods comprise treating a transplant condition of a patient at a transplant site on or in a body surface of the patient, which methods may comprise treating the transplant condition with a therapeutically effective amount of a medically acceptable fucan composition. The treatment may include inhibiting a transplant disorder. The grafts may include at least one of heart, kidney, liver, lung, pancreas, intestine, thymus, uterus, bone and tendon, cornea, skin, heart valve, nerve or vein grafts.

Treatment with a therapeutically effective amount of a medically acceptable fucan composition can include coating at least one surface of the implant with a therapeutically effective amount of a medically acceptable fucan composition prior to, during, or after delivery of the implant to the patient. Treatment with a therapeutically effective amount of a medically acceptable fucan composition may include embedding the therapeutically effective amount of the medically acceptable fucan composition within the implant prior to, during, or after delivery of the implant to the patient. Treatment with a therapeutically effective amount of a medically acceptable fucan composition may include co-administering a therapeutically effective amount of a medically acceptable fucan composition with the implant or before or after delivering the implant to the patient.

The administration may occur at the site of implantation and the patient may be an animal. The pharmaceutically acceptable fucan composition may comprise at least one of a paste, gel, patch, film, spray, liquid, lotion, cream, solution, suspension, solid, implant, powder, and microsphere. The pharmaceutically acceptable fucan composition may further comprise at least one pharmaceutically acceptable excipient selected from gelatin, hypromellose, lactose, water for injection (united states pharmacopeia), sodium chloride, sodium phosphate, sodium citrate, sodium ascorbate, phosphate buffer, citrate buffer, phosphate-citrate buffer, pramipexole, cellulose, alginate, acrylate, hyaluronic acid, polyethylene glycol, poly (lactic acid), poly (lactic acid-co-glycolic acid), alginate, carrageenan, polyurethane, polyethylene, polypropylene, polytetrafluoroethylene, chitosan, and lactated ringer's injection (united states pharmacopeia).

Methods and the like herein include the use of a medically acceptable fucan composition to treat a transplant condition. The compositions herein may comprise an implant and a medically acceptable fucan composition suitable for treating an implant disorder.

These and other aspects, features and embodiments are set forth within the present application, including the detailed description that follows. All embodiments, aspects, features, etc. may be mixed and matched, combined, and arranged in any desired manner unless explicitly stated otherwise.

Detailed Description

The compositions, systems, methods, etc. of the invention discussed herein comprise a medically acceptable fucan configured to be effective for medical treatment, which may be, for example, during or after surgery. In certain embodiments, the signaling protein activity contributes to initiation, progression, severity, prognosis, etc. of such capsular contracture or fiber growth around the implant or graft. In certain embodiments, such treatment comprises inhibiting or isolating a medically acceptable fucan of such signaling proteins. Signaling proteins include proteins such as cytokines and chemokines.

In certain embodiments, the pharmaceutically acceptable fucan is fucoidan. The medically acceptable fucan of the present invention may be a medical device, a combination product, a biologic itself, or may be contained on or within a medical device, a combination product, a biologic, or on or within a pharmaceutically or medically acceptable, therapeutically and/or medically effective composition. The compositions discussed herein may comprise a medically acceptable modified fucan having a desired, specific low endotoxin level for use in medical and/or surgical applications. The compositions herein may further comprise a medically acceptable modified fucan having a desired, specific molecular weight distribution and/or sulfate level.

The following paragraphs briefly discuss some of the capsular contracture or fibrous growth around an implant or graft that may be treated with the medically acceptable fucans discussed herein.

Foreign body response and fibrocyst formation

Implantation or introduction of materials or implants, including biological materials, medical devices, prosthetic tissue engineered constructs and/or combination products, at a target site (e.g., a surgical cavity) can lead to the development of an inflammatory/fibrotic healing process response known as the Foreign Body Response (FBR). The final stage of the healing process may result in fibrous encapsulation, wherein fibroblasts produce fibrous vesicles, which may be vascularized and/or collagen, that prevent or reduce the ability of the implant material to interact with surrounding tissue. Fibroblasts involved in inflammation respond to signaling proteins (including TGFb1, IL-1b, IL-6, IL-13, IL-33, prostaglandins, and leukotrienes) at foreign body sites in the body.

Implants capable of causing FBR and fibrous capsule formation include, but are not limited to: orthopedic implant devices such as bone plates, fracture fixation devices, hip, knee, shoulder, ankle and elbow joint prostheses, artificial ligaments and tendons, cardiovascular implants such as pacemaker packaging, defibrillators, catheters, stents, prosthetic heart valves and arteries, drug delivery systems such as drug reservoir devices for sustained release, monitoring devices such as diabetes monitors, insulin pumps, artificial tissue such as skin repair devices, breast implants, cochlear implants, intraocular lenses, vascular grafts, cerebrospinal fluid (CSF) shunt systems, permanent fertility control, tissue engineered constructs, nerve conduits, surgical meshes and organs, tissues and cells. Such implants may be non-synthetic, biological (derived from animals such as humans), naturally derived or synthetic, or a combination of non-synthetic, naturally derived, and biological materials. Examples of materials that may be used to fabricate the implant include, but are not limited to: autograft, allograft, organic polymers such as natural collagen, fibrin, chitosan, poly (lactic acid), poly (lactic-co-glycolic acid), alginate, carrageenan, hyaluronic acid, heparin, cellulose and synthetic Polyurethane (PU), polyesters, silicones, metals such as aluminum, steel, titanium, cobalt, chromium, nickel, gold, silver, platinum and alloys thereof, inorganic salts such as calcium phosphate, hydroxyapatite and compounds or derivatives thereof, ceramic articles such as alumina, zirconia, bioactive glass, porcelain, carbon, biocompatible plastics and polymers such as cyclic olefin copolymers, polycarbonates, polyetherimides, medical grade polyvinylchloride, polyethersulfones, polyethylene, polyetheretherketones, polytetrafluoroethylene and polypropylene, silicones, hydrogels, biopolymers such as cellulose, starch, proteins, peptides, DNA, RNA, protein-based biomaterials such as collagen, gelatin, silk, polysaccharide-based biomaterials such as chitin, chitosan, glucose, decellularized tissue derived biomaterials such as heart valves, blood vessels, liver tissue and other composites and/or combinations of these materials.

There is a lack of compositions capable of producing therapeutic effects at the implantation site or at the surgical cavity. The compositions herein may be used to treat FBR and fibrocystic formation and/or provide significant therapeutic benefits to patients suffering from these conditions. The compositions herein may be used to coat the surface of an implant, co-administer with or after an implant, or be embedded within an implant. The compositions herein may be configured to release over time (delayed release) to achieve a desired therapeutic effect.

Envelope contracture

Capsular contracture is an example of fibrocystic formation and is an adverse reaction after breast implantation surgery and one of the reasons for re-surgery after breast implantation surgery. Envelope contractures occur when fibrous sacs or internal scar tissue form a tight or contracted sac around the implant to form a physical barrier between the foreign object and other parts of the body. As a result, the breast may feel pain and stiffness, and the envelope may affect the appearance or shape of the breast. This complication most often requires invasive intervention, where the fibrous capsule and breast implant must be surgically excised.

Mast cells within the envelope tissue have been found to contain the signaling protein Tumor Growth Factor (TGF) b1. In addition to TGFb1, other signaling proteins associated with capsular contracture include tumor necrosis factor TNFa, matrix metalloproteinase MMP-2, metalloproteinase Tissue Inhibitor (TIMP) 1, and TIMP-2. The presence of TNFa and MMP-2 is particularly associated with an increased degree of capsular contracture, as graded by the Baker scale for capsular contracture.

Attempts to prevent capsular contracture include antibiotic washout, but these attempts have not been very successful in reducing the occurrence of capsular contracture. Traditionally, capsular contractures have been treated surgically, but this increases the risk of contracture recurrence. Thus, there is an unmet need for a safe and effective treatment of capsular contracture during breast implantation surgery.

The compositions herein may be used to treat capsular contracture. The compositions herein may be used, for example, to coat the surface of an implant, co-administered prior to, simultaneously with, or after implantation of an implant, or embedded within an implant, and may be configured to release (provide controlled or delayed release) over time to achieve a desired therapeutic effect, for example, an average coating thickness reduction of about 20% to 100% as compared to the absence of such a fucan composition, or an average coating thickness reduction of about 60 microns to 230 microns as compared to the absence of such a composition. The use of the fucan composition herein may also reduce the maximum coating thickness by about 20% to 100% as compared to the use of no such composition, or by 100 microns to 1000 microns as compared to the use of no such composition. The use of the Wen Yanzao glycan composition can also provide an average envelope thickness of no more than about 228 microns, about 200 microns, or about 190 microns after implantation, or a maximum envelope thickness of no more than about 442 microns, about 450 microns, or about 540 microns after implantation.

Implantable and patient-contact medical device

The surfaces of implantable and patient-contacted medical devices often attract proteins, bacteria, cells and tissues, resulting in the formation of a biofilm layer on the surface of the medical device. Such a biofilm layer can in turn lead to infection. Biofilm infection presents clinical challenges due to resistance to immune defense mechanisms and antimicrobial agents. Most implantable and patient-contacted medical devices are susceptible to microbial colonization and infection, which can lead to malfunction, serious disease or death of the device.

Attempts to treat biofilm infections with traditional compounds (e.g., antibiotics) that inhibit the growth of or kill the microbial infection have met with limited success due to the prevalence of resistance development in biofilm infections. Removal of the infected implanted medical device is possible, but it is largely invasive and therefore harmful to the patient and potentially dangerous to the patient. Furthermore, removal of implanted medical devices often still requires long-term antimicrobial inhibition therapy.

One strategy to reduce biofilm formation and thus reduce the incidence of biofilm infection is to render the surfaces of medical devices and implants anti-adhesive, but such a solution has met with limited success. The compositions herein may be used, for example, to coat the surface of an implant, co-administered before, simultaneously with, or after the implant, or embedded within the implant. The compositions, systems, etc. herein may be configured to release (provide controlled or delayed release) over time to achieve a desired therapeutic effect.

Transplantation disorder

The surface of implantable organs, tissues, etc. (e.g., heart, kidney, liver, lung, pancreas, intestine, thymus, uterus, musculoskeletal grafts such as bones and tendons, cornea, skin, heart valves, nerves and veins) can often attract proteins, bacteria, cells, tissues, antibodies, and other immunological responses, etc. Such responses can in turn lead to infection, fibrosis, fibrous adhesions and GVHD.

Attempts to treat graft disorders with traditional compounds (such as antibiotics) have met with limited success because of the ubiquity of resistance development in graft disorders or the inapplicability of such compounds to certain graft disorders such as GVHD or fibrous adhesions. In some cases, the removal of the problematic graft may be possible, but even if possible, it is very invasive and therefore harmful to the patient and may be dangerous to the patient. Furthermore, removal of implanted medical devices often still requires long-term antimicrobial or immunosuppressive therapy.

One strategy to reduce biofilm formation and thus reduce the incidence of graft disorders is to provide the graft surface with anti-blocking properties, but such approaches have met with limited success in the past. The fucan composition herein may be used, for example, to coat the surface of the implant, co-administered before, simultaneously with or after the implant, or embedded within the implant. The compositions, systems, etc. herein may be configured to release (provide controlled or delayed release) over time to achieve a desired therapeutic effect.

Medical devices, combinations, biological products and pharmaceutical products

The discussion herein also provides medical devices, combinations, biological products, and pharmaceutical products comprising the compositions discussed herein in a medical device, combination product, biocontainer, or pharmaceutically acceptable container. The product may also include an announcement associated with the container, typically in a form prescribed by a regulatory agency that governs the manufacture, use or sale of the medical device, combination and medicament or biopharmaceutical, whereby the announcement reflects approval of the composition by the agency, such as an announcement that medically acceptable fucans have been approved for human or veterinary administration to treat, for example, capsular contracture or fibrous growth around an implant or implant as discussed herein. Instructions for use of fucans herein may also be included. Such instructions may include information regarding the patient's dosage and mode of administration.

The application further relates to methods of preparing the various components of the medically acceptable fucans, systems, and the like discussed herein, including preparing the medically acceptable medical compositions themselves, and methods of use thereof, including, for example, treatment of capsular contracture or fibrogenesis, disease, and the like, about an implant or graft, as described herein.

Fucan

The medically acceptable fucan composition discussed herein may be modified to obtain a medically acceptable modified fucan composition having a low endotoxin level. The medically acceptable modified fucan composition discussed herein can have an endotoxin level of less than about 0.2, 0.18, 0.12, 0.1, 0.09, 0.02, 0.01, 0.007, 0.005, 0.002, or 0.001 Endotoxin Units (EU)/milligrams (mg) of fucan (EU/mg).

The medically acceptable fucan discussed herein may be modified by removing nitrogen-containing compounds that may adhere to the medically acceptable fucan to obtain a medically acceptable modified fucan with low total nitrogen levels. The medically acceptable modified fucan and compositions comprising a medically acceptable modified fucan discussed herein can have a total nitrogen level of less than 0.2, 0.1, 0.08, 0.05, 0.03, or 0.02% w/w.

The medically acceptable fucan and medically acceptable modified fucan discussed herein may be incorporated into a composition further comprising any number of pharmaceutically acceptable excipients, for example, gelatin, hypromellose, lactose, water for injection (U.S. pharmacopoeia), sodium chloride, sodium phosphate, sodium citrate, sodium ascorbate, phosphate buffers, citrate buffers, phosphate-citrate buffers, pramipexole, cellulose, alginate, acrylate, hyaluronic acid, polyethylene glycol, poly (lactic acid), poly (lactic-co-glycolic acid), carrageenan, polyurethane, polyethylene, polypropylene, polytetrafluoroethylene, chitosan, injectable excipients, and ringer's injection containing lactate (U.S. pharmacopoeia).

The medically acceptable fucan and medically acceptable modified fucan discussed herein may be administered in a composition comprising at least one of a paste, gel, patch, film, spray, liquid, lotion, cream, solution, suspension, solid, implant, microsphere, powder, or other desired form. The medically acceptable fucan and the medically acceptable modified fucan may be administered by intravenous, intra-articular, intra-focal, intravaginal, rectal, intramuscular, intraperitoneal, subcutaneous, topical, intranasal, intraocular, or oral routes of administration. The medically acceptable fucan and medically acceptable modified fucan may be delivered directly to the site of capsular contracture or fiber growth around the implant or the graft disorder. The medically acceptable fucan and medically acceptable modified fucan may be continuously released by controlled release from a polymer or other acceptable controlled release dosage form to sites of capsular contracture or fiber growth around the implant or graft. Solutions or sprays comprising the medically acceptable fucan and/or medically acceptable modified fucan herein can be used to flush, rinse or wash the site of capsular contracture or fiber growth around the implant or graft disorder. The medically acceptable fucan and medically acceptable modified fucan may be applied as a coating on an implant or graft delivered to a target site, such as a surgical cavity.

The medically acceptable fucan and medically acceptable modified fucan discussed herein may be administered as a component of a pharmaceutical or biological product or combination product or medical composition comprising medically acceptable fucan/medically acceptable modified fucan and at least one other drug. The drug may be at least one of paclitaxel, doxorubicin, camptothecin, etoposide, mitoxantrone, methotrexate, menaquinone, pinocembrin, juglone, β -laperchone cyclosporin, sulfasalazine, steroids, rapamycin, retinoids, docetaxel, colchicine, antisense oligonucleotides, ribozymes, and vaccines.

The medically acceptable fucan and medically acceptable modified fucan discussed herein may be administered as a component of a pharmaceutical or biological product or a combination product or a medical composition comprising medically acceptable fucan/medically acceptable modified fucan and at least one binder, adjuvant, excipient, etc.

The medically acceptable fucan composition can be coated onto an implant or graft (including hydrophobic or hydrophilic implants) by a variety of methods, such as: the method may include the steps of immersing the implant or graft in or spraying the implant or graft with a medically acceptable fucan composition, ionically, covalently or otherwise bonding the medically acceptable fucan composition to the implant or graft, mixing the medically acceptable fucan composition with a material used to manufacture the implant or graft prior to manufacturing the implant or graft, and ionically, covalently or otherwise bonding the medically acceptable fucan composition within the implant or graft.

The medically acceptable fucan and medically acceptable modified fucan discussed herein can have a sulfation level of between about 10% w/w to 60% w/w, between about 20% w/w to 55% w/w, between about 30% w/w to 50% w/w, or between about 40% w/w to 45% w/w.

The medically acceptable fucan and medically acceptable modified fucan discussed herein can have a molar ratio of total fucose to total sulfate of between 1:0.5 to 1:4, between about 1:0.8 to 1:3.5, between about 1:1 to 1:2.5, between about 1:1.2 to 1:2.0, or between about 1:1.5 to 1:3.

The medically acceptable fucan and medically acceptable modified fucan discussed herein can have a molar ratio of total fucose to galactose to total sulfate of between about 1:0.5 to 1:4, between about 1:0.8 to 1:3.5, between about 1:1 to 1:2.5, between about 1:1.2 to 1:2.0, or between about 1:1.5 to 1:3.

The medically acceptable fucan discussed herein can be modified to obtain a medically acceptable modified fucan having an increased or decreased weight average molecular weight, number average molecular weight, and/or peak molecular weight. The medically acceptable fucan having a broad molecular weight distribution discussed herein may be modified to obtain a medically acceptable modified fucan having a molecular weight distribution of: wherein the fucan moiety at the low molecular weight end or the high molecular weight end of the broad molecular weight distribution has been reduced or eliminated.

The molecular weight distribution of the medically acceptable modified fucan may be measured using any desired, suitable measurement system. Different systems may produce different readings or results from different compositions having substantially the same composition, or even from the same batch when measured in different ways. One suitable measurement system is an aqueous gel permeation chromatography device consisting essentially of the following columns: a 7.8mm inner diameter 300mm analytical gel permeation chromatography column packed with a gel based on hydroxylated polymethacrylate having an effective molecular weight range of between about 50kDa to about 5,000 kDa; a 7.8mm inside diameter 300mm analytical gel permeation chromatography column packed with a gel based on hydroxylated polymethacrylate having an effective molecular weight range between about 1kDa to about 6,000kDa, and a 6mm inside diameter 40mm guard column packed with a gel based on hydroxylated polymethacrylate, said two analytical gel permeation chromatography columns and said one guard column being contained in a column compartment at about 30 ℃; a refractive index detector at about 30 ℃; a 0.1M sodium nitrate mobile phase running at 0.6 mL/min; and quantifying with respect to a peak molecular weight standard curve consisting essentially of: a first dextran standard having a peak molecular weight of about 2,200 kda; a second dextran standard having a peak molecular weight of about 720kDa to about 760 kDa; a third dextran standard having a peak molecular weight of about 470kDa to about 510 kDa; a fourth dextran standard having a peak molecular weight of about 370kDa to about 410 kDa; a fifth dextran standard having a peak molecular weight of about 180kDa to about 220 kDa; and a sixth dextran standard having a peak molecular weight of about 40kDa to 55 kDa. The peak molecular weight standard curve may further comprise dextran standards having a peak molecular weight between 3kDa and 5 kDa.

The medically acceptable modified fucans discussed herein may have a weight average molecular weight of greater than 300kDa, for example, between about 300kDa and 2000kDa, between about 350kDa and 1500kDa, or between about 375kDa and 1300 kDa.

The medically acceptable modified fucans discussed herein may have a number average molecular weight of greater than 100kDa, for example, between about 100kDa and 800kDa, between about 150kDa and about 800kDa, or between about 170kDa and 700 kDa.

The medically acceptable modified fucans discussed herein may have a peak molecular weight of greater than 200kDa, for example, between about 200kDa and 800kDa, between about 250kDa and 750kDa, or between about 300kDa and 700 kDa.

The medically acceptable modified fucans discussed herein may have a molecular weight distribution such that: wherein at least about 80% w/w or 90% w/w of the distribution is greater than 100kDa. The medically acceptable modified fucans discussed herein may have a molecular weight distribution such that: wherein at least about 60% w/w, 70% w/w, 80% w/w, or 90% w/w of the distribution is greater than 200kDa. The medically acceptable modified fucans discussed herein may have a molecular weight distribution such that: wherein at least 20%, 40%, 50% or 70% of the distribution is greater than 500kDa.

The medically acceptable fucan and medically acceptable modified fucan discussed herein may have a total carbohydrate content of between 27% w/w and 80% w/w, between about 30% w/w and 70% w/w, between about 40% w/w and 90% w/w, or between about 50% w/w and 100% w/w.

The medically acceptable fucan and medically acceptable modified fucan discussed herein may have a fucose content as a percentage of total carbohydrates between about 30% w/w and 100% w/w, between about 40% w/w and 95% w/w, or between about 50% w/w and 90% w/w.

The medically acceptable fucan and medically acceptable modified fucan discussed herein may have a galactose content as a percentage of total carbohydrates between about 0% w/w and 60% w/w, between about 3% w/w and 30% w/w, or between about 0% w/w and 10% w/w.

The medically acceptable fucan and medically acceptable modified fucan discussed herein can have a total glucuronic acid, mannose, rhamnose and xylose content as a percentage of the total carbohydrate content of less than about 30% w/w.

Examples

Examples of methods that may be used to modify fucans and fucan compositions to obtain medically acceptable modified fucans and medically acceptable modified fucan compositions are discussed, for example, in the following publications, all of which are owned by the owner/applicant of the present application: PCT/CA2019/051025 submitted at 24, 7, 2019; PCT/CA2019/051026 submitted 24 at 7/2019; PCT/CA2019/051027 submitted 24 at 7.2019; PCT/CA2019/051030 submitted 24 days 7, 2019; PCT/CA2019/051028 submitted 24 at 7/2019; PCT/CA2020/050294 submitted on 3/5 of 2020; PCT/CA2020/050295 submitted 3/5/2020; and PCT/CA2019/051029 submitted 24 at 7/2019. These methods can be used to obtain a medically acceptable modified fucan composition having low endotoxin levels and/or other desirable characteristics. For example, a medically acceptable modified fucan composition may have low levels of nitrogen-containing compounds that may interfere with the immunoassays discussed in this example section as well as the patient treatments and other methods discussed herein.

Example 1: analysis of sulfate, fucose, galactose, total Nitrogen content and molecular weight distribution of three medically acceptable modified fucose

Three medically acceptable modified fucans in the medically acceptable modified fucan compositions used in the following examples were analyzed by the following methods to determine physicochemical properties thereof.

Three medically acceptable modified fucans (hereinafter referred to as modified fucan 1, modified fucan 2 and modified fucan 3) were dissolved at 40mg/mL in 72% w/w sulfuric acid and incubated in a 45 ℃ water bath for 30 minutes. The resulting acid hydrolysate was then diluted to 4% w/w sulfuric acid in a high pressure tube and incubated at 120℃for 60 minutes. The resulting second acid hydrolysate was diluted to a concentration of 1/333 with distilled water and run on a high performance anion exchange column chromatography device equipped with a pulsed current detector (HPAE-PAD). Analyte separation was accomplished by running 10mM NaOH eluent at 1.0 mL/min using an isocratic pump.

The fucose content of three medically acceptable modified fucoses was determined by interpolation on the fucose standard curve. The galactose content of the three medically acceptable modified fucans was determined by standard additions.

The medically acceptable modified fucan was dissolved in deionized water, hydrolyzed under acidic conditions and analyzed by ICP-MS for% w/w total sulfur content. The sulfur content is converted to a sulfate content by multiplying the sulfur content by the sulfate to sulfur molar ratio to obtain the% w/w sulfate content in the modified fucan.

Three medically acceptable modified fucans were subjected to total nitrogen analysis by igniting the sample in a combustion analyzer and analyzing the nitrogen in the generated nitrous oxide gas using a thermal conductivity detector.

The molecular weight distribution obtained for three medically acceptable modified fucans was evaluated using gel permeation chromatography. Gel Permeation Chromatography (GPC) has a wide variety of parameters, columns and standards available, and therefore the instrumentation available for molecular weight analysis is diverse. For molecular weight determinations herein, GPC was performed using the following parameters: the mobile phase was 0.1M sodium nitrate, running at 0.6 mL/min. The column oven and detector were at 30 ℃. Detection was performed using a Waters 2414 refractive index detector.

Suitable GPC columns include GPC columns compatible with aqueous solvents, for example columns packed with at least one of sulfonated styrene-divinylbenzene, NH-functionalized acrylate copolymer networks, modified silica gels, and hydroxylated polymethacrylate-based gels. For the analysis herein, three columns were used in series, including one 40mm long guard column of 6mm Inside Diameter (ID) packed with a 6 μm particle size hydroxylated polymethacrylate-based gel, followed by a 300mm analytical GPC column of 7.8mm inside diameter packed with a 12 μm particle size hydroxylated polymethacrylate-based gel having an exclusion limit of between about 7,000kDa and an effective molecular weight range of about 50kDa to about 5,000kDa, followed by a second 300mm analytical GPC column of 7.8mm inside diameter packed with a 10 μm particle size hydroxylated polymethacrylate-based gel having an exclusion limit of between about 7,000kDa and an effective molecular weight range of about 1kDa to about 6,000 kDa. The total effective molecular weight of the column device ranges between about 1kDa and about 6,000 kDa. An example of such a column arrangement may be a series connectionGuard-2000-A linear chromatographic column.

Three samples of medically acceptable modified fucans run were quantified according to a standard curve containing a traceable standard from american polymer standards company (American Polymer Standards Corporation): DXT3755K (peak molecular weight=2164 kDa), DXT820K (peak molecular weight=745 kDa), DXT760K (peak molecular weight=621 kDa), DXT670K (peak molecular weight=401 kDa), DXT530K (peak molecular weight=490 kDa), DXT500K (peak molecular weight=390 kDa), DXT270K (peak molecular weight=196 kDa), DXT225K (peak molecular weight=213 kDa), DXT150K (peak molecular weight=124 kDa), DXT55K (peak molecular weight=50 kDa), DXT50K (peak molecular weight=44 kDa) and DXT5K (peak molecular weight=4 kDa), the peak molecular weights of these standards being between about 4kDa and about 2,200 kDa. The standard curve used may, for example, comprise at least one of dextran 3755kDa, dextran 50kDa and dextran 55kDa, and 3 to 6 additional traceable standards discussed herein, the calibration point being the peak molecular weight of the calibrator used. An example calibration curve may consist of DXT3755K, DXT820K, DXT530K, DXT500K, DXT225K and DXT 55K. The column used herein has a total effective molecular weight range that encompasses and extends beyond the peak molecular weight range of standards for quantitating three medically acceptable modified fucans.

It is well known that the identification of molecular weights of polymers comprising fucans/fucoidans generally has a distribution of individual molecules, which have a variety of molecular weights. For a given molecular weight determined within the distribution: there is a distribution of individual molecules of higher and lower molecular weight. The amount or percentage of each polymer of a particular molecular weight increases or decreases as the molecular weight increases or decreases away from the specified molecular weight. The distribution may, but need not, have a generally gaussian shape or a distorted gaussian shape.

The results of the total fucose, total galactose, total sulfate and molecular weight distribution of modified fucan 1, modified fucan 2 and modified fucan 3 are shown in table 1 below.

The results in the following table contain abbreviations for certain features of the molecular weight distribution. The peak molecular weight is indicated by PMW, the weight average molecular weight is indicated by "WAMW", the number average molecular weight is indicated by "NAMW", and the percentage distribution is indicated by "% dist".

Tables 1-3 different physicochemical properties of modified fucans that are medically acceptable. "mod" = modified and pharmaceutically acceptable.

Example 2 endotoxin measurement of modified fucan 1

Use Associates of Cape Cod according to manufacturer's instructionsT lysate assay modified endotoxin of fucan 1. Using BiotekThe HTX plate reader performs turbidity measurements. The results were quantified according to the manufacturer CSE (control standard endotoxin) calibration curve. Modified fucan 1 was determined to have about 0.001EU/mg.

Example 3: in vitro immunoassay of fucans bound to signaling proteins

The binding of the following three medically acceptable modified fucans to a variety of signaling proteins (including cytokines and chemokines) was studied herein by in vitro immunoassays to demonstrate the potential of fucans to inhibit or sequester these signaling proteins and thus treat capsular contracture or fiber growth around the implant associated with the corresponding signaling proteins: modified fucan 1, modified fucan 2 and modified fucan 3.

The following human antibody array immunoassay procedure was performed:

Three different medically acceptable modified fucans discussed in table 1 were dissolved in deionized water at 100mg/mL, 10mg/mL, 1mg/mL and 0.1mg/mL to provide fucan stock solution. Applying each separate fucan stock solution Sample dilutions (RayBiotech QA-SDB, rayBiotech, georgia, U.S.A.) were diluted 1:1. The fucan solution-diluent mixture was incubated at room temperature for about 1 hour. Each individual fucan solution-diluent mixture was then filtered through a 0.22 μm PVDF filter to obtain 50mg/mL, 5mg/mL, 0.5mg/mL and 0.05mg/mL fucan solution-diluent mixture for each individual fucan.

A signaling protein standard mixture comprising a plurality of signaling protein standards is serially diluted to obtain a concentration series of signaling protein standards.

Each fucan solution-diluent mixture was further diluted 1:1 with the most concentrated signal transfer protein standard. A 1:1 mixture of deionized water and the most concentrated signal transfer protein standard was used as a blank. The resulting fucan solution-diluent-signaling protein standard mixtures were each incubated for 1 hour at room temperature.

A plurality of slides are provided (human Kiloplex quantitative proteomic arrays,QAH-CAA-X00-1) each slide contained 40 different antibodies in wells arranged in a microarray, each antibody specific for one of the signaling proteins in the signaling protein standard. Antibodies were used by incubation for 30 minutes followed by decantationSample dilutionQA-SDB) closure. Then 95 μl of each fucan solution-diluent-signaling protein standard mixture was added to each well. The mixture was incubated in the wells for 2.5 hours. The same blocking and incubation procedure was followed for the concentration series of signaling protein standards. After incubation, all samples and signaling protein standards were poured from each well. The wells were washed with 150. Mu.L of 1 Xwashing buffer 1 (washing buffer 1 from 20XAA-WB1-30 ML) dilution) was washed 5 times at room temperature, the washing solution was removed from the wells after each wash. The wells were then washed with 150. Mu.L of 1 Xwashing buffer 2 (from 20 Xwashing buffer 2 #AA-WB2-30 ML) dilution) was washed 2 times at room temperature, the washing solution was removed from the wells after each wash.

80 Mu L ofSample dilutionQA-SDB) (which contains multiple biotinylated antibodies, each specific for a signaling protein in a signaling protein standard) was added to each well and incubated for 1 to 2 hours. The solution was poured out of the wells and the wells were again washed in the same way with 1X wash buffer 1 and 1X wash buffer 2.

80 Mu L ofSample dilutionQA-SDB) (which contained Cy3 equivalent dye-conjugated streptavidin) was added to each well and incubated in the dark for about 1 hour. The diluent solution was poured from the wells and the wells were again washed a total of 5 times with 150 μl of 1X wash buffer 1, after each wash the wash solution was removed from the wells.

Slides were further washed on a slide washer/dryer with 30ml of 1x wash buffer 1, then 30ml of 1x wash buffer 2, after which the wash solution was poured out. Residual droplets were removed by drying with a stream of N ₂.

The slides were then imaged using a Cy3 wavelength laser scanner. Results were obtained and converted to a signal reduction relative to the blank sample.

Table 2 below shows the immunoassay results reported as percent signal reduction of each signaling protein compared to the blank in the presence of a medically acceptable modified fucan.

Table 2-immunoassay results for signaling proteins reported as percent reduction in signal compared to blank signal in the presence of a medically acceptable modified fucan. The 3 different medically acceptable modified fucans presented in the table are discussed in example 1.

The results in table 2 demonstrate that the medically acceptable modified fucans discussed herein inhibit a wide variety of signaling proteins, typically in significant and even highly significant amounts.

For certain signaling proteins, the medically acceptable modified fucans discussed herein are capable of inhibiting or isolating signaling protein activity by at least about 50%. For other signaling proteins, the medically acceptable modified fucans are capable of inhibiting or isolating signaling protein activity by at least about 60%. For yet other signaling proteins, the medically acceptable modified fucan is capable of inhibiting signaling protein activity by at least about 70%. For yet other signaling proteins, the medically acceptable modified fucans are capable of inhibiting signaling protein activity by at least about 80%. For yet other signaling proteins, the medically acceptable modified fucan is capable of inhibiting signaling protein activity by at least about 90%. For yet other signaling proteins, the medically acceptable modified fucans are capable of inhibiting signaling protein activity by at least about 95%. For yet other signaling proteins, the medically acceptable modified fucan is capable of inhibiting signaling protein activity by at least about 98%.

The results in table 2 also demonstrate that the medically acceptable modified fucans discussed herein (including the medically acceptable modified fucans shown in table 2) can inhibit or sequester a wide variety of signaling proteins at a target site in vivo and thus can effectively inhibit or treat capsular contracture or fiber growth around an implant as discussed herein.

Modified fucan 1, modified fucan 2 and modified fucan 3 are all capable of inhibiting or sequestering TGFb1 activity between 64 and 87%, TNFa activity between 1 and 53%, MMP-2 activity between 17 and 73%, TIMP-1 activity between 7 and 86% and TIMP-2 activity between 14 and 99%. This suggests that the medically acceptable modified fucans discussed herein inhibit or sequester chemokines involved in the development of capsular contractures.

Modified fucan 1, modified fucan 2 and modified fucan 3 are all capable of inhibiting or sequestering TGFb1 activity between 64 and 87%, TNFa activity between 1 and 53%, IL-1b activity between 8 and 74%, IL-13 activity between 27 and 61% and IL-33 activity between 60 and 86%. This suggests that the medically acceptable modified fucans discussed herein inhibit or sequester chemokines involved in the occurrence of FBR and fibrocyst formation.

Example 4: treatment of in vivo fibrocystic and capsular contractures with fucoidan

About 3kg of female New Zealand white rabbits were pre-administered with 22.5mg/kg ketamine and 2.5mg/kg of xylazine. Anesthesia induction was performed using 5% isoflurane and oxygen, and rabbits were maintained at about 2% isoflurane and cannulated for LRS intravenous infusion (3 mL/kg/h) to complete the remainder of the procedure. The area around the back and one hind limb of the rabbit was shaved. The doppler cuff was placed on the hindleg shaved area and the animal was transferred to the operating table.

A 3 cm lateral skin incision was made at the level of the XII rib (13 th rib) in the medial lumbosacral region. A 3 cm long transverse incision was made in the meat wrapping film (panniculus carnosum) (avoiding cutting through the muscular fascia). A tunnel was formed by dissection of the meat envelope over the right rib down to the level of the right scapula by the blunt instrument. A 2.5cm diameter pocket was made at the end of the tunnel. The envelope forming method described in table 3 below was applied to the pocket site. The fucoidan solution was applied to one pocket at a dose of <10mL/kg body weight (about 4.5mL of 3mg/mL fucoidan solution), ensuring that the entire pocket was coated. For the control group, no fucoidan solution was applied. A silicone implant (2 cm diameter x 1cm height) was inserted into the pocket. All bleeding was controlled prior to closing the incision. The meat wrapping incision was closed in a continuous mode using 4-0 Vicryl. The subsurface layers were sutured using 4-0 Monocryl. The skin incision layer was sutured in a continuous subcuticular mode using 4-0 Monocryl. The same procedure was repeated for the region above the left rib to the left of the scapula level, the right lumbosacral region at the right iliac crest level, and the left lumbosacral region at the left iliac crest level for a total of 4 implants. Surgical glue is used after suturing if necessary.

The fibrous capsule thickness was quantitatively measured by selecting 4 different regions from bisected capsular tissue sections, and then taking 3 linear measurements perpendicular to the capsular surface within each of these regions. The average of these 3 measurements for each region was recorded by location. The average of the 4 areas was then again averaged to determine the average capsule thickness for each implantation site, and then the average capsule thickness for the 4 sites was averaged to obtain the average capsule thickness for each rabbit. The results are shown in Table 3 below.

Table 3: average and maximum coating thickness of fucoidan solution and control group using different coating formation methods

The results of the study show that fucoidan solutions are effective in treating fibrocystic and capsular contractures at the surgical site caused by various methods. The use of fucoidan solution at the implantation site reduced the average capsule thickness by 21% to 65% and the maximum capsule thickness by 23% to 70% compared to untreated samples.

Example 14: treatment of in vivo FBR and fibrocysts with fucoidan

A 5mm thick x12 mm diameter polyether-polyurethane sponge disc implant (Vitafoam Ltd, manchester, u.k.) was used to induce foreign body reactions in the abdominal cavity. Four different treatment groups were used in the study, as shown in table 4. Sterilizing the implant, and then a) coating the implant by immersing the implant in a 50% w/v fucoidan solution overnight; b) Embedding with fucoidan by injecting a 50% w/v fucoidan solution into the implant; or c) no treatment prior to implantation surgery-for these untreated implants, in one group the implants were implanted without fucoidan to provide a control implant, and in another group the implants were implanted with co-administration of fucoidan solution (0.05% w/v,5 mL) co-administered with the implant in the abdominal cavity by instillation. Male Wistar rats of 300-350g body weight were anesthetized with a mixture of ketamine and xylazine (60 mg/kg and 10mg/kg, respectively). The abdominal hair was shaved and the skin was rubbed with chlorhexidine and 70% ethanol. The implant was aseptically implanted into the abdominal cavity through a1 cm long ventral midline incision in the abdominal white line.

The incision is closed with a non-absorbable suture woven from silk. At 10 days post implantation, animals were anesthetized with ketamine and xylazine and subsequently euthanized by cervical dislocation. The implant was carefully detached from the adherent tissue, removed and weighed. They are then subjected to histological staining, immunohistochemical and morphometric analysis.

The implants of both groups (control and treatment) were fixed in 10% buffered formalin (pH 7.4) and paraffin embedded. Sections 5mm thick were stained with hematoxylin/eosin (H & E) and treated for light microscopy studies. Collagen fibers were observed and determined using sirius scarlet staining followed by polarized microscopy. Monoclonal antibody clone CD31 (Fitzgerald MA, usa) was used for Immunohistochemical (IHC) reactions for detection of endothelial cells/vessels. Tissue sections (5 μm) were deparaffinized and antigen retrieval was performed in citrate buffer (pH 6). Slides were boiled in citrate buffer at 95 ℃ for 25 minutes and then cooled in the same buffer for 1 hour. Sections were incubated in 3% hydrogen peroxide for 5 minutes to quench endogenous tissue peroxidases. Non-specific binding was blocked for 10 minutes using normal goat serum (1:10 in phosphate buffered saline) and 1% bovine serum albumin (in phosphate buffered saline). The sections were then immunostained with monoclonal antibody directed against CD31 (1:40 dilution, dako Corporation, carpinteria, calif., U.S.A.) at room temperature for 60 minutes, followed by washing in Tris-HCl buffer. The sections were incubated with biotinylated Link Universal Streptavidin-HRP (Dako; carpinteria, calif., USA) for 30 minutes at room temperature. The reaction was revealed by using 3,3' -diaminobenzidine (Dako; carpinteria, calif., USA) in a chromogen solution (DAB). Sections were counterstained with hematoxylin and mounted in permaunt (FISHER SCIENTIFIC; NJ, usa). Immunostaining was performed manually and protein expression was assessed according to the extent of cytoplasmic immunolabeling in endothelial cells forming a lumen in six high power fields, regardless of staining intensity (x 400). Total collagen area, envelope thickness and blood vessels were measured by morphometric measurements to assess fibrocystic formation.

For morphometric analysis of vessel numbers, cross-sectional images were taken from 35 fields of view and captured in a 400-magnification optical microscope. For collagen analysis and wall thickness, images were obtained from three representative regions at 200 x magnification. The results of the morphometric analysis were used to assess fibrocystic thickness and fibrovascular tissue infiltration.

Rats that received fucoidan-coated, fucoidan-embedded, and fucoidan-co-administered implants had reduced fibrotic capsule thickness and fibrovascular tissue infiltration compared to rats that received only any fucoidan-free implant device.

Example 15: treatment of in vivo FBR and fibrocysts with fucoidan

Cells are implanted into a system (e.g., cell Pouch System, semova, corp., london, ON, canada) for inducing a foreign body response in the abdominal cavity. Four different treatment groups were used in the study. Sterilizing the implant, and then a) coating the implant by immersing the implant in a 50% w/v fucoidan solution overnight; b) Embedding with fucoidan by injecting a 50% w/v fucoidan solution into the implant; or c) no treatment prior to implantation surgery-for these untreated implants, in one group the implants were implanted without fucoidan to provide a control implant, and in another group the implants were implanted with co-administration of fucoidan solution (0.05% w/v,5 mL) co-administered with the implant in the abdominal cavity by instillation. Male Wistar rats of 300-350g body weight were anesthetized with a mixture of ketamine and xylazine (60 mg/kg and 10mg/kg, respectively). The abdominal hair was shaved and the skin was rubbed with chlorhexidine and 70% ethanol. The implant was aseptically implanted into the abdominal cavity through a1 cm long ventral midline incision in the abdominal white line. The incision is closed with a non-absorbable suture woven from silk. At 10 days post implantation, animals were anesthetized with ketamine and xylazine and subsequently euthanized by cervical dislocation. The implant was carefully detached from the adherent tissue, removed and weighed. They are then subjected to histological staining, immunohistochemical and morphometric analysis.

Rats that received fucoidan-coated, fucoidan-embedded, and fucoidan-co-administered implants had reduced fibrotic capsule thickness and less fibrovascular tissue infiltration than rats that received only any fucoidan-free implant device.

Example 16: in vivo FBR treatment with fucoidan

Each of the 30 mice was surgically implanted with 5 silicone catheters intraperitoneally: an 8-mm midline incision was made in the abdomen and 5 catheters were placed in the abdomen. 15 mice received a catheter prior to surgery, which was coated with fucoidan solution (5 mg/mL) by immersing the catheter in the fucoidan solution for 4 hours. 15 mice received uncoated catheters. Antibiotics (0.5 mg cefazolin and 1mg gentamicin) were injected intraperitoneally just prior to closure. The muscles are closed with absorbable sutures and the covered skin is closed with wound clips. Catheters were recovered from 5 mice at week 1, week 3 and week 5: animals were anesthetized and the catheter and adherent cell layer were carefully removed from the abdomen.

Tissue samples of the abdominal wall were imaged using trichromatography to measure the thickness of the intraperitoneal subcutaneous layer of implanted catheter. Mice that received fucoidan-coated catheters exhibited a thinning of the subcutaneous layer thickness of between 50-90% compared to mice with untreated catheters, indicating a lower foreign body response.

EXAMPLE 17 treatment of in vivo GVHD with fucoidan

Ten pairs of 6-8 week old donor matched mice were sub-lethally irradiated with 2Gy, anesthetized, and 1mm fragments of human fetal thymus and liver were implanted under bilateral kidney capsule. Subsequently, one mouse of each donor matched pair was administered 0.5mL fucoidan solution (2.5 mg/mL) prior to closure, and the other mouse of the pair did not receive any further treatment prior to closure. In addition, cd34+ cells were isolated from fetal liver by anti-CD 34 microbeads and 1×10 ⁵ cells were injected intravenously within 6 hours after surgery.

Histologically, the skin involvement in GVHD is characterized by lymphocyte infiltration at the epidermis, hair follicles, and dermis/subcutaneous interface, with corresponding hair follicle shedding, loss of subcutaneous fat, epidermal hyperplasia, and dermal collagen-like changes, similar to those observed in human GVHD or scleroderma. GVHD in donor-matched mice was characterized by 40 weeks blindness scoring (0-4) of four components of skin histology (inflammation, epidermal hyperplasia, fibrosis and subcutaneous lipoatrophy). Mice that received fucoidan solution prior to occlusion exhibited a 50-90% reduction in inflammation, epidermal hyperplasia, fibrosis, and subcutaneous lipoatrophy scores compared to mice that did not receive fucoidan solution.

Example 18: treatment of in vivo fibrosis and graft fibrous adhesions with fucoidan

Ten pairs of 25-30g mice were used in this study, half of which were donors and half were recipients.

Donor grafting surgery: through a long midline incision into the abdomen. The left kidney is exposed by moving the intestine laterally to the right and retracting the stomach using the mosquito clamp. The left kidney was isolated by ligating and separating adrenal and testicular vessels with 8-0 silk. After ligating and separating the lumbar branches, the aorta and Inferior Vena Cava (IVC) are active at their junctions with the left renal artery and vein. Four sutures were tied around the aorta and IVC above and below the renal arteries and veins. Left ureter was excised from the hilum to the bladder; the distal 3-5mm of the donor ureter is cleared of surrounding adipose tissue. The aorta was ligated above the renal arteries, a 30 gauge needle was inserted into the infrarenal aorta, and the graft was slowly perfused in situ with 0.5-1ml cold heparinized ringer's lactate solution (heparin concentration = 100U/ml). The renal vein is transected at its junction with the IVC. The aorta is inclined apart about 2mm below the renal arteries. This was taken out of the kidneys and their vascular supply and connected ureters as a whole and stored in ringer's lactate solution at 4 ℃ (n=5 contained 2.5mg/mL fucoidan solution, and n=5 did not contain 2.5mg/mL fucoidan solution).

Recipient grafting surgery: a midline incision was made, the intestinal tract covered with wet gauze and retracted to the left. The native right kidney of the recipient is first resected. After ligating the lumbar support, the infrarenal aorta and IVC were carefully separated and cross-clamped with two 4mm micro vascular clamps. An oval aortic dissection (approximately one fifth of the vessel diameter) was performed using 11-0 nylon suture retracted through the entire thickness of the aorta, with a single cut using iris scissors. Longitudinal phlebotomy (0.18 mm) was performed in IVC by first puncturing the IVC with a 30 gauge needle and then cutting with iris scissors at a level slightly below the aortic dissection (0.08 mm). The aorta and IVC were thoroughly washed with heparinized saline. Two indwelling sutures were placed at the two apices of the phlebotomy. The donor kidneys were then removed from the ice and placed in the right flank of the mice. End-to-side anastomosis between donor renal vein and recipient IVC was performed using a continuous 10-0 suture. The posterior wall is sutured within the vessel lumen without repositioning the graft. The anterior wall is then closed from the outside using the same suture. After the venous anastomosis is completed, the suture is tied. Arterial anastomosis is performed in the same manner as venous anastomosis described herein. After revascularization, the anastomotic site is gently pressed with a dry cotton swab for 1-2 minutes. A 25 gauge needle or a pair of microsurgical forceps is used to pierce the bladder sidewall to create two small holes. The ureter tip is grasped and pulled through the two holes. The donor ureter was fixed to the proximal end of the outer bladder wall by three needles using 10-0 nylon through the periureteral connective tissue. The distal ureter was cut and the remaining 1mm ureter was retracted into the bladder lumen. The second bladder hole was closed and secured using a 10-0 suture. Prior to closing the kidney lumen, another group received 1mL of LRS at the surgical site by administering an additional 1mL of 5mg/mL fucoidan in LRS to mice receiving fucoidan-soaked donor kidney grafts.

After 4 weeks, mice were euthanized and the strength and number of kidney luminal adhesions were scored (0-4). Mice that received transplanted kidney stored in fucoidan-LRS solution prior to surgery and mice that received 5mg/mL fucoidan solution prior to surgery at the site of the closure procedure exhibited 70-90% reduced graft adhesions and 50-90% reduced strength compared to mice that received untreated transplanted kidney and LRS at the surgical site prior to closure.

All terms used herein are used according to their ordinary meaning unless the context or definition clearly indicates otherwise. In addition, unless explicitly indicated otherwise, in this disclosure the use of "or" includes "and vice versa. Non-limiting terms are not to be construed as limiting unless expressly stated otherwise, or the context clearly indicates otherwise (e.g., "comprising," "having," and "including" generally indicate "including but not limited to"). Included in the claims are singular forms such as "a," "an," and "the" including plural referents unless the context clearly dictates otherwise.

Unless otherwise indicated, adjectives (such as "substantially" and "about") modifying a condition or relational feature of one or more features of an embodiment herein are indicative of that condition or feature being defined for its intended application within the operationally acceptable tolerances of that embodiment.

The scope of the methods, compositions, systems, etc. of the present invention includes both apparatus plus function and step plus function concepts. The claims should not be read as indicating a "means-plus-function" relationship unless the word "means" is specifically recited in the claims, and the claims should be read as indicating a "means-plus-function" relationship where the word "means" is specifically recited in the claims. Similarly, the claims should not be interpreted as indicating a "step plus function" relationship, unless the term "step" is specifically recited in the claims, and where the term "step" is specifically recited in the claims, the claims should be interpreted as indicating a "step plus function" relationship.

From the foregoing, it will be appreciated that, although specific embodiments have been discussed herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the discussion herein. Accordingly, systems and methods, etc. include such modifications as well as all permutations and combinations of the subject matter set forth herein, and are not limited except by the appended claims or other claims which have sufficient support in the discussion and figures herein.

Claims

1. A method of treating fibrocystic formation in a patient at an implant site on or in the body surface of the patient, the method comprising treating fibrocystic formation with a therapeutically effective amount of a medically acceptable fucan composition.

2. A method of treating a foreign body response in a patient at an implant site on or in the body surface of the patient, the method comprising treating the foreign body response with a therapeutically effective amount of a medically acceptable fucan composition.

3. A method of treating capsular contracture in a patient at an implant site on or in the body surface of the patient, the method comprising treating capsular contracture with a therapeutically effective amount of a medically acceptable fucan composition.

4. A method of treating a biofilm infection in a patient at an implant site on or in the body surface of the patient, the method comprising treating biofilm formation with a therapeutically effective amount of a medically acceptable fucan composition.

5. The method of any one of claims 1 to 4, wherein the treatment comprises inhibition.

6. The method of any one of claims 1 to 5, wherein the implant comprises at least one of a medical device, a drug, or a combination product.

7. The method of any one of claims 1 to 6, wherein the implant is composed of at least one of a non-synthetic material, a biological material, a naturally derived material, and a synthetic material.

8. The method of any one of claims 1 to 7, wherein the implant comprises at least one of a bone plate, a fracture fixation device, a hip prosthesis, a knee prosthesis, a shoulder prosthesis, an ankle prosthesis, an elbow prosthesis, an artificial ligament, an artificial tendon, cell therapy, gene therapy, a pacemaker package, a catheter, a stent, an artificial heart valve, an artificial artery, a drug reservoir device for sustained release, a diabetes monitor, an insulin pump, a skin repair device, a breast implant, a cochlear replacement, an intraocular lens, a vascular graft, a nerve catheter, a surgical mesh, an organ, a tissue, and a cell.

9. The method of any one of claims 1 to 8, wherein the implant consists of at least one of: autograft, allograft, fibrin, poly (lactic acid), poly (lactic-co-glycolic acid), alginate, carrageenan, hyaluronic acid, heparin, synthetic polyurethane, polyester, silicone, aluminum, steel, titanium, cobalt, chromium, nickel, gold, silver, platinum, metal alloys, calcium phosphate, hydroxyapatite, inorganic salt derivatives, alumina, zirconia, bioactive glass, porcelain, carbon, cyclic olefin copolymers, polycarbonate, polyetherimide, polyvinylchloride, polyethersulfone, polyethylene, polytetrafluoroethylene, polyetheretherketone, polypropylene, silicone, hydrogels, cellulose, starch, proteins, peptides, DNA, RNA, collagen, gelatin, silk, chitin, chitosan, glucose, heart valves, blood vessels, and liver tissue.

10. The method of any one of claims 1 to 9, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises coating at least one surface of the implant with a therapeutically effective amount of a medically acceptable fucan composition prior to delivering the implant to the patient.

11. The method of any one of claims 1 to 9, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises, after delivering the implant to the patient, coating at least one surface of the implant with a therapeutically effective amount of a medically acceptable fucan composition.

12. The method of any one of claims 1 to 9, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises embedding the therapeutically effective amount of the medically acceptable fucan composition within an implant prior to delivering the implant to a patient.

13. The method of any one of claims 1 to 9, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises embedding the therapeutically effective amount of the medically acceptable fucan composition within an implant after delivering the implant to a patient.

14. The method of any one of claims 1 to 9, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises co-administering a therapeutically effective amount of a medically acceptable fucan composition with an implant.

15. The method of any one of claims 1 to 9, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises administering a therapeutically effective amount of a medically acceptable fucan composition prior to delivering the implant to the patient.

16. The method of any one of claims 1 to 9, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises, after delivering the implant to the patient, administering a therapeutically effective amount of a medically acceptable fucan composition.

17. The method of any one of claims 14 to 16, wherein the administering occurs at the site of an implant.

18. The method of any one of claims 1 to 17, wherein the patient is an animal.

19. The method of any one of claims 1 to 18, wherein the medically acceptable fucan composition comprises at least one of a paste, gel, patch, film, spray, liquid, lotion, cream, solution, suspension, solid, implant, powder, and microsphere.

20. The method of any one of claims 1to 19, wherein the medically acceptable fucan composition further comprises at least one medically acceptable excipient selected from the group consisting of gelatin, hypromellose, lactose, water for injection (united states pharmacopeia), sodium chloride, sodium phosphate, sodium citrate, sodium ascorbate, phosphate buffer, citrate buffer, phosphate-citrate buffer, pramipexole, cellulose, alginate, acrylate, hyaluronic acid, polyethylene glycol, poly (lactic acid), poly (lactic-co-glycolic acid), alginate, carrageenan, polyurethane, polyethylene, polypropylene, polytetrafluoroethylene, chitosan, and ringer's injection containing lactate (united states pharmacopeia).

21. The method of any one of claims 1 to 20, wherein the medically acceptable fucan composition comprises less than about 200 Endotoxin Units (EU).

22. The method of any one of claims 1 to 20, wherein the medically acceptable fucan composition comprises less than about 100 Endotoxin Units (EU).

23. The method of any one of claims 1 to 20, wherein the medically acceptable fucan composition comprises less than about 50 Endotoxin Units (EU).

24. The method of any one of claims 1 to 20, wherein the medically acceptable fucan composition comprises less than about 20 Endotoxin Units (EU).

25. The method of any one of claims 1 to 20, wherein the medically acceptable fucan composition comprises less than about 10 Endotoxin Units (EU).

26. The method of any one of claims 1 to 20, wherein the medically acceptable fucan composition comprises less than about 5 Endotoxin Units (EU).

27. The method of any one of claims 1 to 20, wherein the medically acceptable fucan composition comprises less than about 2 Endotoxin Units (EU).

28. Use of a medically acceptable fucan composition for the treatment of fibrocystic formation.

29. Use of a medically acceptable fucan composition for treating a foreign body response.

30. Use of a medically acceptable fucan composition for treating capsular contracture.

31. Use of a medically acceptable fucan composition for the treatment of a biofilm infection.

32. A composition comprising an implant and a medically acceptable fucan composition.

33. The composition of claim 32, wherein the implant comprises at least one of a medical device, a drug, and a combination product.

34. The composition of any one of claims 32 or 33, wherein the implant is comprised of at least one of a non-synthetic material, a biological material, a naturally derived material, and a synthetic material.

35. The composition of any one of claims 32 to 34, wherein the implant comprises a bone plate, a fracture fixation device, a hip prosthesis, a knee prosthesis, a shoulder prosthesis, an ankle prosthesis, an elbow prosthesis, an artificial ligament, an artificial tendon, cell therapy, gene therapy, pacemaker packaging, a catheter, a stent, an artificial heart valve, an artificial artery, a drug reservoir device for sustained release, a diabetes monitor, an insulin pump, a skin repair device, a breast implant, a cochlear replacement, an intraocular lens, a vascular graft, a nerve conduit, a surgical mesh, an organ, a tissue, and cells.

36. The composition of any one of claims 32 to 35, wherein the implant consists of at least one of: autograft, allograft, fibrin, poly (lactic acid), poly (lactic-co-glycolic acid), alginate, carrageenan, hyaluronic acid, heparin, synthetic polyurethane, polyester, silicone, aluminum, steel, titanium, cobalt, chromium, nickel, gold, silver, platinum, metal alloys, calcium phosphate, hydroxyapatite, inorganic salt derivatives, alumina, zirconia, bioactive glass, porcelain, carbon, cyclic olefin copolymers, polycarbonate, polyetherimide, polyvinylchloride, polyethersulfone, polyethylene, polytetrafluoroethylene, polyetheretherketone, polypropylene, silicone, hydrogels, cellulose, starch, proteins, peptides, DNA, RNA, collagen, gelatin, silk, chitin, chitosan, glucose, heart valves, blood vessels, and liver tissue.

37. The composition of any one of claims 32 to 36, wherein the composition comprises less than about 200 Endotoxin Units (EU).

38. The composition of any one of claims 32 to 36, wherein the composition comprises less than about 100 Endotoxin Units (EU).

39. The composition of any one of claims 32 to 36, wherein the composition comprises less than about 50 Endotoxin Units (EU).

40. The composition of any one of claims 32 to 36, wherein the composition comprises less than about 20 Endotoxin Units (EU).

41. The composition of any one of claims 32 to 36, wherein the composition comprises less than about 10 Endotoxin Units (EU).

42. The composition of any one of claims 32 to 36, wherein the composition comprises less than about 5 Endotoxin Units (EU).

43. The composition of any one of claims 32 to 36, wherein the composition comprises less than about 2 Endotoxin Units (EU).

44. A method of treating a graft disorder in a patient at a site of implantation in the body surface or body of the patient, the method comprising treating the graft disorder with a therapeutically effective amount of a medically acceptable fucan composition.

45. The method of claim 44, wherein the treatment comprises inhibiting a transplant condition.

46. The method of any one of claims 44 to 45, wherein the graft comprises at least one of a heart, kidney, liver, lung, pancreas, intestine, thymus, uterus, bone and tendon, cornea, skin, heart valve, nerve or vein graft.

47. The method of any one of claims 44 to 46, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises coating at least one surface of the implant with a therapeutically effective amount of a medically acceptable fucan composition prior to delivering the implant to the patient.

48. The method of any one of claims 44 to 46, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises, after delivering the implant to the patient, coating at least one surface of the implant with a therapeutically effective amount of a medically acceptable fucan composition.

49. The method of any one of claims 44 to 46, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises embedding the therapeutically effective amount of the medically acceptable fucan composition within the implant prior to delivering the implant to the patient.

50. The method of any one of claims 44 to 46, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises embedding the therapeutically effective amount of the medically acceptable fucan composition within the implant after delivering the implant to the patient.

51. The method of any one of claims 44 to 46, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises coadministering a therapeutically effective amount of a medically acceptable fucan composition with the implant.

52. The method of any one of claims 44 to 46, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises administering a therapeutically effective amount of a medically acceptable fucan composition prior to delivering the graft to the patient.

53. The method of any one of claims 44 to 46, wherein treating with a therapeutically effective amount of a medically acceptable fucan composition comprises, after delivering the graft to the patient, administering a therapeutically effective amount of a medically acceptable fucan composition.

54. The method of any one of claims 44 to 53, wherein the administration occurs at a site of implantation.

55. The method of any one of claims 44 to 54, wherein the patient is an animal.

56. The method of any one of claims 44 to 55, wherein the pharmaceutically acceptable fucan composition comprises at least one of a paste, gel, patch, film, spray, liquid, lotion, cream, solution, suspension, solid, implant, powder, and microsphere.

57. The method of any one of claims 44 to 56, wherein the medically acceptable fucan composition further comprises at least one medically acceptable excipient selected from the group consisting of gelatin, hypromellose, lactose, water for injection (U.S. pharmacopoeia), sodium chloride, sodium phosphate, sodium citrate, sodium ascorbate, phosphate buffer, citrate buffer, phosphate-citrate buffer, pramipexole, cellulose, alginate, acrylate, hyaluronic acid, polyethylene glycol, poly (lactic acid), poly (lactic-co-glycolic acid), alginate, carrageenan, polyurethane, polyethylene, polypropylene, polytetrafluoroethylene, chitosan, and ringer's injection containing lactate (U.S. pharmacopoeia).

58. The method of any one of claims 44 to 57, wherein said medically acceptable fucan composition comprises less than about 200 Endotoxin Units (EU).

59. The method of any one of claims 44 to 57, wherein said medically acceptable fucan composition comprises less than about 100 Endotoxin Units (EU).

60. The method of any one of claims 44 to 57, wherein said medically acceptable fucan composition comprises less than about 50 Endotoxin Units (EU).

61. The method of any one of claims 44 to 57, wherein said medically acceptable fucan composition comprises less than about 20 Endotoxin Units (EU).

62. The method of any one of claims 44 to 57, wherein said medically acceptable fucan composition comprises less than about 10 Endotoxin Units (EU).

63. The method of any one of claims 44 to 57, wherein said medically acceptable fucan composition comprises less than about 5 Endotoxin Units (EU).

64. The method of any one of claims 44 to 57, wherein said medically acceptable fucan composition comprises less than about 2 Endotoxin Units (EU).

65. Use of a medically acceptable fucan composition for treating a transplant condition.

66. A composition comprising a graft and a medically acceptable fucan composition suitable for treating a graft disorder.

67. The composition of any one of claims 44 to 66, wherein said composition comprises less than about 200 Endotoxin Units (EU).

68. The composition of any one of claims 44 to 66, wherein said composition comprises less than about 100 Endotoxin Units (EU).

69. The composition of any one of claims 44 to 66, wherein said composition comprises less than about 50 Endotoxin Units (EU).

70. The composition of any one of claims 44 to 66, wherein said composition comprises less than about 20 Endotoxin Units (EU).

71. The composition of any one of claims 44 to 66, wherein said composition comprises less than about 10 Endotoxin Units (EU).

72. The composition of any one of claims 44 to 66, wherein said composition comprises less than about 5 Endotoxin Units (EU).

73. The composition of any one of claims 44 to 66, wherein said composition comprises less than about 2 Endotoxin Units (EU).