Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
  • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
  • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/1841—Transforming growth factor [TGF]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/1858—Platelet-derived growth factor [PDGF]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/21—Interferons [IFN]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
  • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
  • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
  • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
  • A61L27/3813—Epithelial cells, e.g. keratinocytes, urothelial cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
  • A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
  • A61L27/3843—Connective tissue
  • A61L27/386—Ligaments, tendons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
  • A61L27/3895—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells using specific culture conditions, e.g. stimulating differentiation of stem cells, pulsatile flow conditions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the piesent invention is directed to methods for controlling cellulai contraction and to medical treatments that rely upon this conti ol
• the methods are important in the treatment of ligament damage, osteopoiosis, wound healing, tissue engineering, drug delivery, and the pievention of tumor cell metastasis
• Cellulai contraction also plays an important 1 ole in wound healing Although contraction may initially piomote healing, it can also lead to significant scarring and a loss of physiological function (see U S 5,741,777) The adverse effects of contraction are particularly severe in surgical and burn patients In addition, scarring may cause secondary damage to patients that have incurred damage to the spmal cord oi othei sevei e trauma
• an agent that promoted endothehal cell contraction might be include in mtranasal oi lntramusculai vehicles to aid m the passage of drug through the walls of capillaries Such agents may also aid substances already in the bloodstream in exiting mto tissue
• Alpha smooth muscle actm (SMA) ⁇ s a particular isoform of actm that may cause the contraction of vascular smooth muscle cells (Saga, et al , Exp Cell Res 249 279-292 ( 1999)) It is known to be expressed m myofibroblasts during wound healing and in tissues undergoing fibrosis (Zhang, et al , Am J Pathol 148 527-537 (1996), Jestei, et al , Opthal Vis Sci 36 809-819 (1995), Darby, et al , Lab Invest 63 21-28 (1990)) The complete nucleotide and ammo acid sequences of the human form of the gene have been i eported (Herrman, Curr Opin
• the present invention is based upon the discovery that SMA is responsible for the contraction of a variety of cells other than fibroblasts and for which such activity was not previously known Agents that inhibit SMA activity prevent these cells from contracting, whereas agents that induce SMA
• SMA activity promote conti action examples include platelet derived growth factor (PDGF), staurosporm and mterferons
• PDGF platelet derived growth factor
• TGF- ⁇ transforming growth facto ⁇ - ⁇
• the piesent invention is directed to methods of repairing musculoskeletal tissue (including bone, articulai cartilage, meniscus, tendon mtervertebral disk and especially damaged ligaments), and epithelial tissue
• musculoskeletal tissue including bone, articulai cartilage, meniscus, tendon mtervertebral disk and especially damaged ligaments
• epithelial tissue One procedure foi accomplishing this involves removing cells from a patient's body, growing them on a matrix, and then implanting the matrix/cell combination at the site of the damage, e g at the site of atom ligament
• tissue engineering The cells used may be any of the musculoskeletal, or epithelial cells mentioned above Alternatively, marrow stromal stem cells may be used and have the advantage of being relatively easy to obtain Matnces may be made out of several different types of biologically compatible material, but type I collagen and synthetic polymers, such as polylactic acid and polyglycohc acid, will typically be employed
• the invention is directed to an improvement in this
• agents that may be used for inhibiting contraction are PDGF and interferon.
• the activity of SMA may also be reduced by preventing its expression using an antisense oligonucleotide, particularly an oligonucleotide complementary to the promoter region of the human SMA gene.
• agents that may be used to promote contraction is TGF- ⁇ .
• the invention is also directed to a method of treating a patient for damaged musculoskeletal tissue (particularly a damaged ligament) or epithelial tissue by sequentially administering, at the site of injury, an SMA inhibitor followed by an SMA inducer.
• the inhibitor should be given at a dosage and for a duration sufficient to promote tissue attachment.
• the time necessary for attachment to occur will vary from patient to patient, but will typically be between 1 and 10 weeks .
• the extent to which attachment has occurred may be determined by clinical examination and by diagnostic imaging techniques well known in the art.
• the inducer should be administered for the purpose of causing the tissue to contract and thereby assume a more natural conformation.
• TGF-beta at a concentration of between 100 ng/ml and 500 ug/ml at the site of ligament damage, e.g., the knee. After a period of, for example, 4 weeks, injections are made using a comparable concentration of PDGF or an interferon until healing is complete.
• the invention is directed to a procedure for promoting the healing of wounded musculoskeletal tissue in a patient.
• an SMA inducer TGF-beta
• an SMA inhibitor e.g., PDGF or an interferon in the concentration ranges recited above
• PDGF vascular endothelial growth factor
• an interferon in the concentration ranges recited above
• Inducers of SMA may also be administered to a patient for the purpose of enhancing drug absorption.
• a sufficient dosage should be given to induce endothehal cell contraction.
• TGF- ⁇ at a concentration of 100 ng/ml - 500ug/ml can be co-administered with a second drug either parenterally or intranasally.
• the invention is also directed to a method of preventing tumor cell metastasis in a cancer patient. This may be accomplished by administering an agent that inhibits SMA in the endothehal cells of the vasculature. Because the endothehal cells do not contract, cancer cells shed from a main tumor mass is prevented from entering into the patient's bloodstream and those in the bloodstream are prevented from invading tissue.
• Replacement ligaments may be prepared by removing cells from a patient's body and growing them on matrices containing collagen and similar materials. The contraction of the cells in vitro creates matrix distortions that complicate this procedure. It has now been discovered that agents modulating the activity of alpha-smooth muscle actin can be used to control cell contraction.
• the invention is compatible with any method of growing cells in vitro and involves simply adding an inhibitory agent to growth medium and/or to the matrix prior to the seeding of cells.
• PDGF may be added to DMEM culture medium used for the growth of fibroblasts on a collagen/ glycosaminoglycan matrix.
• the concentration of PDGF should generally be between 1 and 500 ng/ml and preferably between 10 and 50 ng/ml. This therapeutic approach to the treatment of ligament injuries also applies in the same way to injuries in bone, articular cartilage, meniscus, tendon, mtervertebral disk, and for liver or other epithelial tissue engineering.
• an SMA inhibitor e.g., a pharmaceutical preparation of PDGF at a concentration of between 100 ng/ml and 500 ug/ml
• Administration should be repeated on a regular basis, e.g., twice a week, until standard clinical procedures and imaging techniques indicate that attachment is complete.
• An inducer of SMA may then be injected at the site of injury to cause the ligament to contract and thereby assume a more normal conformation. For example,
• TGF- ⁇ may be injected at a concentration of between 100 ng/ml and 500 ug/ml.
• the injections of the SMA inhibitor should be performed on a regular basis with results followed by periodic clinical evaluation.
• the in vivo procedures used for damaged ligaments can be applied in exactly the same way to the repair of bone, articular cartilage, meniscus, tendon and mtervertebral disk.
• Cellulai- contraction also plays an important role in wound repair (see, e.g., Mast, in Wound Healing: Biochemical and Clinical Aspects, Cohen et al, ed., WB Saunders Co. (1992)).
• Myo fibroblasts expressing alpha-smooth muscle actin pull together the open margins of skin wounds to promote healing (Eddy et al, Am. J. Pathol 130:252-260 (1988); Welch et al, J. Cell. Biol 70: 133-145 (1990)) .
• an inducer of SMA may be administered at the wound site.
• TGF-beta may be administered in a topical preparation at a concentration of between 100 ng/ml and 500 ug/ml.
• the preparation should be changed periodically over a period of days until wound closure has been accomplished.
• a preparation containing one or more inhibitors of alpha-smooth muscle actin should then be administered either topically or by local injection.
• a preparation containing PDGF at a concentration of between 100 ng/ml and 500 ug/ml may be injected. Injections should be repeated periodically until healing has been completed.
• alpha-smooth muscle actin in endothehal cells may be used to enhance drug delivery.
• inducers of SMA may be used to promote the contraction of endothehal cells, thereby making it easier for drug to be absorbed into the vasculature of a patient.
• an agent such as TGF- ⁇ may be combined with a drug injected intramuscularly to aid in its absorption.
• an SMA inducer may be included in intranasal drug compositions to promote the absorption of therapeutic agents into the capillaries of the lung.
• TGF- ⁇ it is expected that a concentration in the range of 100 ng/ml- 500 ug/ml would be used in preparations.
• SMA inhibitors may be used as a treatment for patients with solid tumors.
• An inhibitor may be injected either systemically or it may be administered directly at the site of tumor occurrence.
• Topical preparations of inhibitor may also prove useful in certain instances, e.g. in the treatment of various types of skin cancer.
• Agents inhibiting alpha-smooth muscle actin may also be used as a therapy for patients with osteoporosis.
• Systemic injections of agents such as PDGF or an interferon may be used to inhibit osteoblast retraction and thereby block osteoclast access to the bone surface for the purpose of calcium resorption. It is expected that this treatment will be used in conjunction with other established methods of treating osteoporosis involving the administration of agents such as calcium, vitamin D and parathyroid hormone.
• PDGF or interferon is used as the inhibitor, it is expected that they will typically be injected in a pharmaceutical composition in a concentration range of between 100 ng/ml and 500 ug/ml. Sustained release preparations are also appropriate for the treatment of osteoporosis patients and may be more convenient for patients than repeated parenteral administration.
• the total dosage of alpha-smooth muscle inhibitor or inducer administered to a patient will be determined based upon the particular condition being treated, the route of administration and the treatment of objective.
• a typical daily dose of inhibitor or inducer administered to a patient will, depending upon the agent used, be between 1 ug and 10 mg.
• Topical, intranasal and locally injected preparations will, typically, also fall within this range.
• Agents may be provided in either a single or multiple dosage regimen and may be given either alone or in conjunction with other therapeutic agents. Dosage Forms and Route of Administration
• the present invention is compatible with any 1 oute of administration and any dosage form
• certain dosage forms will tend to be more convenient or more effective than others
• local injection will be the prefened route of administration for accomplishing in vivo ligament repair whereas topical admmistration will generally be preferred in treating skm cancers
• agents may be administered orally, perorally, internally, mtra nasally, rectally, vaginally, lmgually, and transdermally
• Specific dosage forms include tablets, pills, capsules, powders, aerosols, suppositones, skm patches, parenterals and oral liquids including suspensions, solutions and emulsions Sustained release dosage forms may also be used All dosage forms may be prepared usmg metho ds that are standard mthe art (see e g , Remington's Pharmaceutical Sciences, 16th, Ed A Oslo Editoi, Easton, PA (1980)
• Inhibitors and mducers of alpha-smooth muscle actm may be used m conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e g , talc, gum arable, lactose, starch, magnesium sterate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc Coloring and flavonng agents may also be added to preparations, particulaily those for oral admmistration Solutions can be prepared usmg water or physiologically compatible organic solvents such as ethanol, 1 ,2-propylene glycol, polyglycols, dimethyl sulfoxide, fatty alcohols, tnglycendes, partial esters of glycerine and the like
• Parenteial compositions may be used foi intravenous, mtraartal, intramuscular, intraperitoneal, mti acutaneous or subcutaneous delivery These pi eparations can be made usmg conventional techniques and may include sten
• Inhibitors and mducers of cell contraction can also be used m conjunction with matnces employed as implants to facilitate tissue healing and as scaffolds to be seeded with cells in vitro for subsequent implantation
• the inhibitors and inducers can be adsorbed by the matrix and, some cases, chemically coupled to the matnx Advantages of Treatment Methods
• fibroblasts that have assumed a contractile phenotype (myofibroblasts) have been found to play an important role in healing and in pathological conditions This phenotype, if expressed in meniscal cells, may affect their behavior in cells seeded matrices developed for tissue engineering
• alpha-SM actin alpha-smooth muscle
• Calf meniscus cells were seeded in type I and type II collagen-glycosaminoglycan (GAG) matrices The diameter of the matrices was measured every two-three days Immunohistochemical staining of the 2-dimensional cultures for alpha-SM actin was performed after 1, 3, and 7 days, and of the seeded matrices at 1 , 7, 14, and 21 days Transmission electron microscopy (TEM) was performed on selected samples

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