EP2675491A2 - Compositions et procédés améliorés de remplacement de tissu mou - Google Patents

Compositions et procédés améliorés de remplacement de tissu mou

Info

Publication number
EP2675491A2
EP2675491A2 EP12708198.2A EP12708198A EP2675491A2 EP 2675491 A2 EP2675491 A2 EP 2675491A2 EP 12708198 A EP12708198 A EP 12708198A EP 2675491 A2 EP2675491 A2 EP 2675491A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
compound
alkyl
optionally substituted
mpa
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12708198.2A
Other languages
German (de)
English (en)
Inventor
Dennis E. Van Epps
Guang-Liang Jiang
Wha-Bin Im
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Inc
Original Assignee
Allergan Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US13/193,744 external-priority patent/US8697056B2/en
Application filed by Allergan Inc filed Critical Allergan Inc
Publication of EP2675491A2 publication Critical patent/EP2675491A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/3641—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 characterised by the site of application in the body
    • A61L27/3666—Epithelial tissues other than skin
    • 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
    • A61L27/3869—Epithelial tissues other than skin
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances

Definitions

  • Soft tissue replacement methods are commonly used for a wide variety of clinical and cosmetic purposes.
  • One use involves reconstructive applications that rebuild and restore a body part or structure to correct deformities from congenital anomalies, trauma, cancer, infections, disease, or medication side effects.
  • the replacement tissue serves to support surrounding tissue and to maintain the normal appearance of the body.
  • the restoration of this normal appearance has an extremely beneficial psychological effect on post-operative patients, alleviating much of the shock and depression that often follows extensive surgical procedures.
  • Another use involves augmentation applications that alter a body part or structure usually to improve its cosmetic or aesthetic appearance. Augmentation of the appearance also has beneficial psychological effects that improve self-esteem, well-being, and confidence of an individual.
  • a third use involves structural applications that provide support to a body part or structure to improve its function, thereby alleviating a symptom associated with a disorder involving soft tissue loss.
  • disorders include, without limitation, stress urinary incontinence, fecal incontinence, vocal cord paralysis, vocal atrophy, vocal implantation, intubation trauma, post-hemilaryngectomy defects, irradiation damage, lumbar disc repair, and plantar footpad repair.
  • Soft tissue replacement methods currently rely on two general approaches: 1 ) implantation of artificial or alloplastic fillers like soft tissue implants, and injectable polymers and hydrogels; and 2) transplantation of tissue like tissue flaps and autologous tissue transfers.
  • a drawback to the use of artificial or alloplastic fillers it that these inorganic materials lack any metabolic activity, do not become physiologically incorporated into the body, and as such, surrounding tissue and blood supply does not develop within the implanted material.
  • artificial or alloplastic fillers risk migration and/or extrusion from the implant site. Furthermore, many of these fillers produce only temporary effects because the body rapidly reabsorbs them.
  • transplantation of adipose tissue generally results in a loss of 20% to 90% of its volume within the first year.
  • This tissue loss is unpredictable and is a result of poor survival and/or regeneration from progenitor cells in the transplanted tissue due to necrosis and a lack of vascular formation.
  • tissue breakdown is associated with traumatic rupture of the cells, avascular necrosis, apoptosis of the adipocytes, inflammation secondary to apoptosis, fibrosis and contraction of the graft, and/or delipidation of the adipocytes with subsequent volume loss.
  • Failed tissue grafts sometime produce stellate and irregular nodules with calcifications.
  • transplanted tissue methods are usually performed two or three times to obtain the desired effect, resulting in massive time and cost.
  • tissue breakdown seen in transplanted tissue methods is the lack of a blood supply sufficient to support the transplanted tissue.
  • alleviation of tissue ischemia is critically dependent upon formation of new blood vessels.
  • the growth of new blood vessels and associated vasculature or repair or remodeling of existing blood vessels and associated vasculature provides collateral circulation in and around an ischemic area, improves blood flow, and alleviates the symptoms caused by the ischemia.
  • compositions and methods that promote new blood vessel formation within a transplanted tissue are needed as this will improve the survival rate of such tissues, thereby achieving reliable long-term survival of grafted tissues.
  • compositions and soft tissue replacement methods using compositions that reduce tissue volume loss by increasing the survival rate of the transplanted tissue.
  • This improved survival rate is achieved by administering a compound that promotes new blood vessel formation, thereby ensuring that a blood supply adequate to support the transplanted tissue is established.
  • compositions comprising adipose tissue, a hydrogel material, and a compound having the structure of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof,
  • each dashed line represents the presence or absence of a bond
  • R , R 2 and R 3 are each independently selected from H or d_ 6 alkyl
  • R 6 is C0 2 H, C0 2 R 7 , CON(R 7 ) 2 , CONHCH 2 CH 2 OH, CON(CH 2 CH 2 OH) 2 , CH 2 OR 7 , P(0)(OR 7 ) 2 , or
  • R 7 is H or Ci_ 6 hydrocarbyl
  • Z and Z 2 are each independently selected from CH or N
  • W and W 2 are each independently selected from CH, CH 2 , optionally substituted aryl, or optionally substituted heteroaryl
  • m is 0, 1 , 2, 3, 4, 5, or 6
  • o is 0, 1 , 2, 3, 4
  • p is 0 or 1
  • V is Ci -6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • compositions comprising adipose tissue, a hydrogel material, and a compound having the structure of formula VI, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof
  • each dashed line represents the presence or absence of a bond
  • Z 2 and Z 3 are independently CH or N
  • Z Z 4 , Z 5 , and Z 6 are each independently CR 9 , CHR 9 , NH, O, or S
  • A is -(CH 2 ) m -Ar-(CH 2 ) 0 - wherein Ar is optionally substituted aryl or optionally substituted heteroaryl, the sum of m and o is from 1 , 2, 3, or 4, and wherein one CH 2 may be substituted with S or O
  • R 8 is H, hydrocarbyl, or hydrocarbyl-OH
  • R 9 is independently H, Ci -6 alkyl, OH, F, CI, Br, I, or O
  • J is Ci -6 alkyl, Ci -6 -O
  • composition comprising adipose tissue, a hydrogel material, and a compound having the structure of formula IX
  • compositions comprising adipose tissue, a hydrogel material, and a compound having the structure of compound 24, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.
  • Yet other aspects of the present specification disclose a method of treating a soft tissue condition of an individual, the method comprising the step of administering a composition disclosed herein to a site of the soft tissue condition, wherein administration of the composition promotes formation of a blood supply sufficient to support the transplanted tissue, thereby treating the soft tissue site.
  • a soft tissue condition include breast imperfection, defect, disease and/or disorder, such as, e.g.
  • a breast augmentation a breast reconstruction micromastia, thoracic hypoplasia, Tru's syndrome, defects due to implant complications like capsular contraction and/or rupture
  • a facial imperfection, defect, disease or disorder such as, e.g., a facial augmentation, a facial reconstruction, Parry-Romberg syndrome, lupus erythematosus profundus, dermal divots, sunken cheeks, thin lips, nasal imperfections or defects, retro-orbital imperfections or defects, a facial fold, line and/or wrinkle like a glabellar line, a nasolabial line, a perioral line, and/or a marionette line, and/or other contour deformities or imperfections of the face; a neck imperfection, defect, disease or disorder; a skin imperfection, defect, disease and/or disorder; other soft tissue imperfections, defects, diseases and/or disorders, such as, e.g.
  • torso including abdomen, buttocks, upper leg, lower leg including calves, foot including plantar fat pad, eye, genitals, or other body part, region or area, or a disease or disorder affecting these body parts, regions or areas
  • urinary incontinence, fecal incontinence, other forms of incontinence and gastroesophageal reflux disease (GERD).
  • GSD gastroesophageal reflux disease
  • Still other aspects of the present specification disclose a method of treating a soft tissue condition of an individual, the method comprising the steps of a) administering the adipose tissue to a site of the soft tissue condition; b) administering a composition comprising a compound as disclosed herein to the site of the soft tissue condition; and c) administering a hydrogel material to the site of the soft tissue condition, wherein administration of the compound promotes formation of a blood supply sufficient to support the transplanted tissue, thereby treating the soft tissue site.
  • a soft tissue condition include those described above.
  • angiogenesis refers to a physiological process involving the growth of new blood vessels from pre-existing vessels and includes sprouting angiogenesis, the formation of new blood vessel by sprouting off existing ones, and splitting angiogenesis (intussusception), the formation of new blood vessel by splitting off existing ones.
  • vasculogenesis refers to a physiological process involving the cfe novo production of new blood-vessels by proliferating endothelial stem cells, and as such, the formation of new blood vessels when there were no pre-existing ones.
  • Blood vessel formation requires signals from growth factors and other proteins that direct and control the process, such as, e.g., fibroblast growth factors (like FGF-1 and FGF-2), vascular endothelial growth factors (like VEGF-A and VEGF-C), angiopoietins (like Ang-1 and Ang-2), platelet derived growth factor (PDGF), monocyte chemotactic protein-1 (MCP-1 ) (also known as chemokine (C-C motif) ligand 2 (CCL-2)), transformation growth factor betas (TGF- ⁇ , TGF ⁇ 2, TGF- ⁇ , and TGF ⁇ 4), vascular cell adhesion molecules (like VCAM-1 ), matrix metalloproteinases (like MMP-2 and MPP-9), integrins, cadherins, plasminogen activators, plasminogen activator inhibitors, and ephrin.
  • growth factors and other proteins that direct and control the process, such as, e.g., fibroblast growth factors
  • FGF-2 FGF-2
  • VEGF vascular endothelial growth factor
  • FGF-2 is a more potent factor in new blood vessel formation than VEGF or PDGF.
  • FGF-2 is an important factor in wound healing. This factor stimulates proliferation of fibroblasts and endothelial cells that give rise to new vessel formation and developing granulation tissue; both increase blood supply and fill up a wound space/cavity early in the wound-healing process.
  • VEGF is another major contributor to new blood vessel formation.
  • VEGF causes a massive signaling cascade in endothelial cells resulting in the release of many other factors known to be responsible for new blood vessel formation.
  • binding to VEGF receptor-2 VEGFR-2 (VEGFR-2) starts a tyrosine kinase signaling cascade that stimulates the production of factors that variously stimulate vessel permeability (eNOS, producing NO), proliferation/survival (FGF-2), migration (ICAMs/VCAMs/MMPs) and finally differentiation into mature blood vessels.
  • eNOS vessel permeability
  • FGF-2 proliferation/survival
  • ICMs/VCAMs/MMPs migration
  • endothelial cells would proliferate, migrate, and eventually form tube structures resembling capillaries.
  • the compounds, compositions and methods disclosed herein increase the survival rate of transplanted tissue by promoting new blood vessel formation within the transplanted tissue.
  • Administration of a compound either as a composition with the transplanted tissue or as a prior or subsequent administration to the transplantation procedure, upregulate factors essential to new blood vessel formation, like FGF-2 and VEGF.
  • This upregulation initiates the signaling cascade in endothelial cells responsible for the formation of new blood vessel.
  • This initiation results in the formation of new blood vessels that, in turn, provide oxygen, nutrients, and other substances necessary to establish essential physiological functions to the transplanted tissue.
  • This adequate blood supply supports the establishment, growth and survival of the transplanted tissue.
  • the compounds, compositions and methods disclosed herein ameliorate or prevent one of the major underlying causes for the tissue breakdown of transplanted tissue, namely the lack of a blood supply sufficient to support the transplanted tissue.
  • the compounds and compositions disclosed herein are superior to the mere addition of factors critical to new blood vessel formation, like FGF-2 and VEGF, because these small molecules are more stable and less costly then these protein-based therapies.
  • formation of new blood vessels can soften scar tissue, capsular contracture by facilitating the remolding of fibrous tissue into normal soft tissue typical of the affected region.
  • adipose tissue is synonymous with “fat” or “fatty tissue” and refers to a loose fibrous connective tissue comprising fat cells (adipocytes) and multiple types of regenerative cells.
  • Adipose tissue may comprise brown and/or white adipose tissue taken from any body site, such as, e.g. , subcutaneous, omental/visceral, interscapular, or mediastinal. It may be obtained from any organism having adipose tissue, or the adipose tissue used may be from a primary cell culture or an immortalized cell line.
  • Adipose tissue may be collected from the same individual who is undergoing the soft tissue replacement procedure (autograft), from a donor individual who is not the same individual as the one undergoing the soft tissue replacement procedure (allograft), or from an animal source (xenograft).
  • autograft refers to the transplantation of organs, tissues, or cells from one part of the body to another part in the same individual, i.e. , the donor and recipient are the same individual. Tissue transplanted by such "autologous" procedures is referred to as an autograft or autotransplant.
  • allotransplantation refers to the transplantation of organs, tissues, or cells from a donor to a recipient, where the donor and recipient are different individuals, but of the same species. Tissue transplanted by such "allologous" procedures is referred to as an allograft or allotransplant.
  • xenotransplantation refers to the transplantation of organs, tissues, or cells from a donor to a recipient, where the donor is of a different species as the recipient. Tissue transplanted by such "xenologous" procedures is referred to as a xenoograft or xenotransplant.
  • Adipose tissue can be collected by any procedure that can harvest adipose tissue useful for the compositions and methods disclosed herein, including, without limitation a liposuction (lipoplasty) procedure or a lipectomy procedure. Procedures useful for collecting adipose tissue should minimize the trauma and manipulation associated with adipose tissue removed. Adipose tissue may be harvested from any suitable region, including, without limitation, a mammary region, an abdominal region, a thigh region, a flank region, a gluteal region, a trochanter region, or a gonadal region. Procedures useful for collecting adipose tissue are well known to a person of ordinary skill in the art. The selected procedures may be performed concomitantly with liposculpture.
  • a liposuction procedure harvests adipose tissue by aspirating the tissue using a cannula.
  • the cannula may be connected to a syringe for manual aspiration or to a power assisted suction device, like an aspirator, adapted to collect the adipose tissue into a vacuum bottle.
  • a liposuction procedure does not maintain an intact blood supply of the harvested tissue.
  • the syringe may be a 10, 20 or 60 mL syringe fitted with a 12 or 14 gauge cannula.
  • Non-limiting examples of liposuction procedures include suction- assisted liposuction (SAL), ultrasound-assisted liposuction (UAL), power-assisted liposuction (PAL), twin- cannula (assisted) liposuction (TCAL or TCL), or external ultrasound-assisted liposuction (XUAL or EUAL), or water-assisted liposuction (WAL).
  • SAL suction- assisted liposuction
  • UAL ultrasound-assisted liposuction
  • PAL power-assisted liposuction
  • TCAL or TCL twin-cannula
  • XUAL or EUAL external ultrasound-assisted liposuction
  • WAL water-assisted liposuction
  • liposuction procedures listed above can be used with any of the following procedures that vary the amount of fluid injected during the procedure, such as, e.g., dry liposuction, wet liposuction, super-wet liposuction, tumescent liposuction, or laser- assisted liposuction.
  • An autologous soft tissue transfer procedure typically uses adipose tissue collected from a liposuction procedure.
  • the harvested tissue may be used directly to make the disclosed compositions, it is more typically processed to purify and/or enrich for healthy adipocytes and regenerative cells.
  • the harvested adipose tissue may be separated from any debris and/or contaminants such as, e.g. , blood, serum, proteases, lipases, lipids and other oils, and/or other bodily fluids; tumescent fluid and/or other materials used in the liposuction procedure; and/or other impurities suctioned during the procedure.
  • Methods useful in separating debris and/or contaminants from adipose tissue useful to make the disclosed compositions including, without limitation, centrifugation, sedimentation, filtration, and/or absorption.
  • the harvested adipose tissue may be processed by washing in a physiological buffer like saline to remove any debris and/or contaminants.
  • a lipectomy procedure harvests adipose tissue by surgical excision from a donor site in a manner that minimizes damage to the blood supply of the tissue using standard surgical operative procedures. This harvested tissue is then implanted into the region needing the soft tissue replacement.
  • a tissue flap or tissue graft procedure typically uses adipose tissue collected from a lipectomy procedure.
  • a tissue flap is a section of living tissue that maintained its blood supply as the tissue is moved from one area of the body to another.
  • a local flap uses a piece of skin and underlying tissue that lie adjacent to the wound, including adipose tissue. The flap remains attached at one end so that it continues to be nourished by its original blood supply, and is repositioned over the wounded area.
  • a regional flap uses a section of tissue that is attached by a specific blood vessel. When the flap is lifted, it needs only a very narrow attachment to the original site to receive its nourishing blood supply from the tethered artery and vein.
  • a musculocutaneous flap also called a muscle and skin flap, is used when the area to be covered needs more bulk and a more robust blood supply. Musculocutaneous flaps are often used in breast reconstruction to rebuild a breast after mastectomy.
  • the transverse rectus abdominus myocutaneous flap (TRAM flap) is a tissue flap procedure that uses muscle, fat and skin from an abdomen to create a new breast mound after a mastectomy. This type of flap remains "tethered" to its original blood supply. In a bone/soft tissue flap, bone, along with the overlying skin, is transferred to the wounded area, carrying its own blood supply.
  • a wound that is wide and difficult or impossible to close directly may be treated with a skin graft.
  • a skin graft is a patch of healthy skin that is taken from one area of the body, called the "donor site," and used to cover another area where skin is missing or damaged.
  • a split-thickness skin graft commonly used to treat burn wounds, uses only the layers of skin closest to the surface.
  • a full-thickness skin graft might be used to treat a burn wound that is deep and large, or to cover jointed areas where maximum skin elasticity and movement are needed. As its name implies, a full-thickness (all layers) section of skin from the donor site are lifted.
  • a composite graft is used when the wound to be covered needs more underlying support, as with skin cancer on the nose.
  • a composite graft requires lifting all the layers of skin, adipose tissue, and sometimes the underlying cartilage from the donor site.
  • the amount of adipose tissue collected will typically vary from individual to individual and can depend on a number of factors including, but not limited to, amount of adipose tissue required for the soft tissue replacement method, aesthetic expectations, age, body habitus, coagulation profile, hemodynamic stability, co-morbidities, and physician preference.
  • a liposuction procedure may harvest from about 1 mL to about 1500 mL of adipose tissue.
  • a lipectomy procedure typically harvests about 1 g to about 5,000 g.
  • Adipose tissue comprises multiple regenerative cells.
  • regenerative cell refers to any cells that cause or contribute to complete or partial regeneration, restoration, or substitution of structure or function of an organ, tissue, or physiologic unit or system to thereby provide a therapeutic, structural or cosmetic benefit.
  • regenerative cells include stem cells, progenitor cells, and precursor cells.
  • stem cell refers to a multipotent regenerative cell with the potential to differentiate into a variety of other cell types that perform one or more specific functions and has the ability to self-renew. Some of the stem cells disclosed herein may be pluripotent.
  • stem cells include, without limitation, adipose-derived stem cells (ASCs; adipose- derived stromal cells), endothelial-derived stem cells (ESCs), hemopoietic stem cells (HSCs), and mesenchyma stem cells (MSCs).
  • ASCs adipose-derived stem cells
  • ESCs endothelial-derived stem cells
  • HSCs hemopoietic stem cells
  • MSCs mesenchyma stem cells
  • progenitor cell refers to an oligopotent regenerative cell with the potential to differentiate into more than one cell type, or a unipotent regenerative cell with the potential to differentiate into only a single cell type, that performs one or more specific functions and has limited or no ability to self-renew.
  • progenitor cells include, without limitation, endothelial progenitor cells, keratinocytes, monoblasts, myoblasts, and pericytes.
  • precursor cell refers to a unipotent regenerative cell with the potential to differentiate into one cell type that performs one or more specific functions and may retain extensive proliferative capacity that enables the cells to proliferate under appropriate conditions.
  • precursor cells include, without limitation, adipoblast (lipoblast or preadipocytes), de-differentiated adipocytes, angioblasts, endothelial precursor cells, fibroblasts, lymphoblasts, and macrophages.
  • Harvested adipose tissue can be supplemented with regenerative cells such as, e.g., stem cells, progenitor cells, and precursor cells.
  • Regenerative cells may promote new blood vessel formation, diminish necrosis, and/or promote a supportive microenvironment in the transplanted tissue, thereby improving survivability of the transplanted tissue.
  • Regenerative cells can be obtained form a variety of sources. For example, adipose tissue is rich in regenerative cells that have the ability to restore and reconstruct various soft tissue defects in response to local differentiation clues from the recipient site.
  • a portion of the collected adipose tissue may be further processed in order to purify regenerative cells that can then be added back to the remainder of the harvested adipose tissue in order to enrich this material for these cells.
  • Exemplary methods describing such cell enrichment procedures can be found in, e.g. , U.S. Patent Publication 2005/0025755, Yoshimura, et al., Characterization of Freshly Isolated and Cultured Cells Derived form the Fatty and Fluid Portions of liposuction Aspirates, J. Cell. Physiol.
  • harvested adipose tissue can be supplemented with regenerative cells obtained from cell cultures, such as, e.g. , primary cell cultures and established cell cultures.
  • regenerative cells obtained from cell cultures, such as, e.g. , primary cell cultures and established cell cultures.
  • a portion of harvested adipose tissue from an individual can be cultured in a manner to produce primary cell cultures enriched for regenerative cells.
  • established cell lines derived from regenerative cells from adipose tissue, or another tissue source can be cultured, harvested, and added to adipose tissue collected from an individual. Exemplary methods describing such cell culture compositions and procedures can be found in, e.g. , U.S. Patent Publication 2009/0246182; U.S. Patent Publication 2009/0317367; U.S.
  • Patent Publication 2008/0299213 Rehman, et al., Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells, Circulation, 109: r52-r58 (2004); Kilroy, et al., Cytokine Profile of Human Adipose-Derived Stem Cells: Expression of Angiogenic, Hematopoietic, and Pro-Inflammatory Factors, J. Cell. Physiol., 212: 702-709 (2007); each of which is hereby incorporated by reference in its entirety. [032] Harvested adipose tissue may be immediately used to make the compositions disclosed herein.
  • harvested adipose tissue may be stored for use at some future date.
  • Harvested tissue is typically stored using a slow freezing method of the tissue to -20 ° C, with or without cryopreservatives.
  • Stored adipose tissue can typically be stored for at least 6 months.
  • compositions comprising a compound having the structure of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof,
  • each dashed line represents the presence or absence of a bond
  • R , R 2 and R 3 are each independently selected from H or d_ 6 alkyl
  • R 6 is C0 2 H, C0 2 R 7 , CON(R 7 ) 2 , CONHCH 2 CH 2 OH, CON(CH 2 CH 2 OH) 2 , CH 2 OR 7 , P(0)(OR 7 ) 2 , or
  • R 7 is H or Ci_ 6 hydrocarbyl
  • Z and Z 2 are each independently selected from CH or N
  • W and W 2 are each independently selected from CH, CH 2 , optionally substituted aryl, or optionally substituted heteroaryl
  • m is 0, 1 , 2, 3, 4, 5, or 6
  • o is 0, 1 , 2, 3, 4
  • p is 0 or 1
  • V is Ci -6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • the method of preparing the compounds represented by formula I can be found in, e.g., Donde, et el., 10,10-Dialkyl Prostanoic Acid Derivatives as Agents for Lowering Intraocular Pressure, U.S. Patent 6,875,787; Donde, et el., 10, 10-Dialkyl Prostanoic Acid Derivatives as Agents for Lowering Intraocular Pressure, U.S. Patent Publication 2004/0235958; Donde, et al., Treatment of Inflammatory Bowel Disease, U.S. Patent Publication 2005/0164992, each of which is hereby incorporated by reference in its entirety.
  • any reference to a compound herein by structure, name, or any other means includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • pharmaceutically acceptable salts such as sodium, potassium, and ammonium salts
  • prodrugs such as ester prodrugs
  • tautomers or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • any structure or name for a compound used herein may refer to any stereoisomer or any mixture of stereoisomers.
  • a compound or chemical structural feature such as aryl when referred to as being “optionally substituted,” it includes a feature that has no substituents (i.e. "unsubstituted"), or a feature that is "substituted,” meaning that the feature has one or more substituents.
  • substituted has the ordinary meaning known to one of ordinary skill in the art, and includes a moiety that replaces one or more hydrogen atoms attached to a parent compound or structural feature.
  • the substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g.
  • the substituent comprises: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms independently selected from: N, O, S, Si, F, CI, Br, or I; provided that the substituent comprises at least one atom selected from: C, N, O, S, Si, F, CI, Br, or I.
  • a substituent may consist of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 non- hydrogen atoms and any necessary hydrogen atoms.
  • Some non-hydrogen atoms may include C, N, O, S, Si, F, CI, Br, I, P, etc.
  • substituents include, but are not limited to, alkyi, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, carboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesul
  • substituents may also be a combination of any of the above substituents, wherein a hydrogen atom of one substituent is replaced by another substituent.
  • substituents may be a combination of alkyi and aryl (e.g. CH 2 -phenyl, C 2 H 4 -heteraryl, etc.), alkyi and alkoxy (e.g. CH 2 OCH 2 ), alkyi and halo (e.g. C 2 H 4 CI, C 3 H 6 F, etc.), acyl and hydroxyl (e.g. -COCH 2 OH), etc.
  • alkyi and aryl e.g. CH 2 -phenyl, C 2 H 4 -heteraryl, etc.
  • alkyi and alkoxy e.g. CH 2 OCH 2
  • alkyi and halo e.g. C 2 H 4 CI, C 3 H 6 F, etc.
  • acyl and hydroxyl e.g. -COCH 2 OH
  • a substituent may be R A , F, CI, CN, OR A , CF 3 , N0 2 , NR A R B , COR A , C0 2 R A A COR B , CONR A R B , etc.
  • Each R A may independently be H, or Ci_i 2 alkyl, including: linear or branched alkyl having a formula C a H a+1 , or cycloalkyl having a formula C a H a .-i , wherein a is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12, such as linear or branched alkyl of a formula: CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , CsH-n , C 6 H 13 , C 7 H 15 , C 8 H 17 , C 9 H 19 , C 10 H 21 , etc., or cycloalkyl of a formula: C 3 H 5 , C 4 H 7 , C 5 H 9 , C 6 H-
  • Each R B may independently be H, or C - 2 alkyl, including: linear or branched alkyl having a formula C a H a+ , or cycloalkyl having a formula C a H a , wherein a is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12, such as linear or branched alkyl of a formula: CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H- 1 - 1 , C 6 H 13 , C 8 H 17 , C 7 H 15 , C 9 H 19 , C 10 H 21 , etc., or cycloalkyl of a formula: C 3 H 5 , C 4 H 7 , C 5 H 9 , C 6 H-
  • molecular weight is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.
  • hydrocarbyl has the broadest meaning generally understood in the art, and may include a moiety composed of carbon and hydrogen. Some examples may include alkyl, alkenyl, alkynyl, aryl, etc., and combinations thereof, and may be linear, branched, cyclic, or a combination thereof. Hydrocarbyl may be bonded to any other number of moieties (e.g.
  • hydrocarbyl groups include but are not limited to C-i alkyl, C 2 alkyl, C 2 alkenyl, C 2 alkynyl, C 3 alkyl, C 3 alkenyl, C 3 alkynyl, C 4 alkyl, C 4 alkenyl, C 4 alkynyl, C 5 alkyl, C 5 alkenyl, C 5 alkynyl, C 6 alkyl, C 6 alkenyl, C 6 alkynyl, phenyl, etc.
  • alkyi has the broadest meaning generally understood in the art, and may include a moiety composed of carbon and hydrogen containing no double or triple bonds.
  • Alkyi may be linear alkyi, branched alkyi, cycloalkyi, or a combination thereof, and in some embodiments, may contain from one to thirty-five carbon atoms.
  • alkyi may include C - 0 linear alkyi, such as methyl (-CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3 ), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), n-pentyl (- CH 2 CH 2 CH 2 CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), etc.; C 3- i 0 branched alkyi, such as C 3 H 7 (e.g.
  • C 4 H 9 e.g. branched butyl isomers
  • C5H-1 -1 e.g. branched pentyl isomers
  • C 6 H 13 e.g. branched hexyl isomers
  • C 7 H 15 e.g. heptyl isomers
  • C 3 _i 0 cycloalkyi such as C 3 H 5 (e.g. cyclopropyl), C 4 H 7 (e.g. cyclobutyl isomers such as cyclobutyl, methylcyclopropyl, etc.), C 5 H 9 (e.g.
  • cyclopentyl isomers such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.) C 6 H-
  • heterocyclyl has the broadest meaning generally understood in the art, and may include a heterocyclic ring, or a ring containing one or more heteroatom as ring atoms.
  • aryl has the broadest meaning generally understood in the art, and may include an aromatic ring or aromatic ring system such as phenyl, naphthyl, etc. Any aryl identified herein may be C 6 -io aryl-
  • heteroaryl also has the meaning understood by a person of ordinary skill in the art, and may refer to an "aryl” which has one or more heteroatoms in the ring or ring system.
  • heteroaryl may include, but are not limited to, pyridinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzoimidazolyl, etc. Any heteroaryl identified herein may be C 3 . 9 heteroaryl.
  • haloalkyl refers to alkyi having one or more halo substituents.
  • the compound has the structure of formula II,
  • each dashed line represents the presence or absence of a bond
  • R , R 2 and R 3 are each independently selected from H or Ci_ 6 alkyi
  • R 4 is H or Ci_ 6 hydrocarbyl
  • Z and Z 2 are each independently selected from CH or N
  • W and W 2 are each independently selected from CH, CH 2 , optionally substituted aryl, or optionally substituted heteroaryl
  • m is 0, 1 , 2, 3, or 4
  • o is 0, 1 , 2, 3, or 4
  • p is 0 or 1
  • V is CH 3 , aryl, optionally substituted aryl, or optionally substituted heteroaryl.
  • U is N, O, or S; R 5 is F, CI, Br, I, Ci -6 hydrocarbyl; and n is 0, 1 , 2, 3, 4, 5, 6, or 7; and.
  • U is S; R 5 is F, CI, Br, or I; and n is 1 , 2, or 3.
  • W 2 is thienyl.
  • each dashed line represents the presence or absence of a bond
  • R , R 2 and R 3 are each independently selected from H or Ci_ 6 alkyl
  • R 4 is H or C1-C6 hydrocarbyl
  • W and W 2 are each independently selected from CH, CH 2 , optionally substituted aryl, or optionally substituted heteroaryl
  • m is 0, 1 , 2, 3, or 4
  • o is 0, 1 , 2, 3, or 4
  • p is 0 or 1
  • V is CH 3 , optionally substituted aryl or optionally substituted heteroaryl.
  • the compound has the structure of formula IV:
  • each dashed line represents the presence or absence of a bond
  • R , R 2 and R 3 are each independently selected from H or Ci_ 6 linear alkyl
  • R 4 is H, Ci_ 6 hydrocarbyl
  • m is 0, 1 , 2, 3, or 4
  • o is 0, 1 , 2, 3, or 4
  • p is 0 or 1
  • V is CH 3 , optionally substituted aryl or optionally substituted heteroaryl.
  • the compound has the structure of formula V:
  • the compound has a structure of one of the following compounds listed in Table 1.
  • the compound has a structure of compound 1,2,3, 4, or 5.
  • the compound has a structure of compound 6.
  • compositions comprising a compound having the structure of formula VI
  • each dashed line represents the presence or absence of a bond
  • Z 2 and Z 3 are independently CH or N
  • Z Z 4 , Z 5 , and Z 6 are each independently CR 9 , CHR 9 , NH, O, or S
  • A is -(CH 2 )m-Ar-(CH 2 )o- wherein Ar is optionally substituted aryl or optionally substituted heteroaryl, the sum of m and o is from 1 , 2, 3, or 4, and wherein one CH 2 may be substituted with S or O
  • R 8 is H, hydrocarbyl, or hydrocarbyl-OH
  • R 9 is independently H, Ci -6 alkyl, OH, F, CI, Br, I, or O
  • J is Ci -6 alkyl, Ci -6 -O-alkyl,
  • the compound has the structure of formula VII,
  • each dashed line represents the presence or absence of a bond
  • Z 2 is CH or N
  • Z 5 is CH 2 , NH, O, or S
  • Z 7 is CH 2 , O, or S
  • R 8 is H, Ci_ 6 hydrocarbyl, or Ci_ 6 hydrocarbyl-OH
  • R 9 and R are independently Ci_ 6 alkyl, OH, F, CI, Br, I, or O
  • R 2 is H, OH, O, F, CI, Br, I , Ci_ 4 -O-alkyl, Ci_ 4 haloalkyl, or aryl.
  • the compound has the structure of formula VIII,
  • each dashed line represents the presence or absence of a bond
  • Z 2 is CH or N
  • Z 5 is CH 2 , NH, O, or S
  • Z 7 and Z 8 are independently CH 2 , O, or S
  • R 8 is H, Ci -6 hydrocarbyl, or Ci_ 6 alkyl-OH
  • R 9 and R are independently Ci -6 alkyl, OH, F, CI, Br, I, or O
  • R 2 is H, OH, O, F, CI, Br, I, Ci_ 4 -O-alkyl, C ⁇ haloalkyl, or aryl.
  • the compound has a structure of compound 6, 7, 8, 9, 10, 1 1 ,
  • compositions comprising a compound having the structure of formula IX
  • X 1 and X 5 are independently CH or N; X 7 is NH, O, or S; X 8 and X 9 are independently CH or N; RR 33 iiss ooppttiioonnaallllyy ssuubbssttiittuutteedd aarryyll oorr ooppttiioonnaallllyy ssuutbstituted heteroaryl; and R 4 is Ci_ 6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • the compound has the structure of formula X,
  • X 10 , X 12 , X 13 , X 14 , and X 15 are each independently CR 9 or N;
  • R 6 is independently H, OH, O, F, CI, Br, I, C-i-6 alkyl, Ci_ 6 -O-alkyl, CN, or Ci -6 alkyl-CN;
  • R 9 is independently H, OH, O, F, CI, Br, I, d_ - l o alkyl, Ci_i 0 -O-alkyl, or C 4 .i 0 -O-alkyl-heterocyclyl.
  • the compound has the structure of formula XI,
  • R 6 , R 7 , and R 8 are each independently H, OH, O, F, CI, Br, I, d. 6 alkyl, d_ 6 - 9 is H, OH, O, or F, CI, Br, I, C 1-10 alkyl, C 1-10 -O-alkyl, or
  • R 20 is H , F, CI, Br, or I.
  • the compound has a structure of compound 14, 15, 16, 17, 18, 19, 20, 21 , 22, or 23, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.
  • compositions comprising a compound having the structure of compound 24, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable amine salt thereof.
  • a pharmaceutically acceptable salt is a sodium salt and a potassium salt.
  • a pharmaceutically acceptable amine salt is an aminoglycoside salt and a triethanolamine salt.
  • compositions disclosed herein may optionally comprise any number and combination of compounds disclosed herein.
  • a composition can comprise, e.g. , two or more compounds, three or more compounds, four or more compounds or five or more compounds.
  • aspects of the present specification provide, in part, a hydrogel material comprising a glycosaminoglycan polymer.
  • the hydrogel material disclosed herein can further comprise two or more different glycosaminoglycan polymers.
  • glycosaminoglycan is synonymous with “GAG” and "mucopolysaccharide” and refers to long unbranched polysaccharides consisting of a repeating disaccharide units.
  • the repeating unit consists of a hexose (six-carbon sugar) or a hexuronic acid, linked to a hexosamine (six-carbon sugar containing nitrogen) and pharmaceutically acceptable salts thereof.
  • glycosaminoglycans include chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronan.
  • Non-limiting examples of an acceptable salt of a glycosaminoglycans includes sodium salts, potassium salts, magnesium salts, calcium salts, and combinations thereof.
  • Glycosaminoglycan and their resulting polymers useful in the hydrogel materials and methods disclosed herein are described in, e.g., Piron and Tholin, Polysaccharide Crosslinking, Hydrogel Preparation, Resulting Polysaccharides(s) and Hydrogel(s), uses Thereof, U.S.
  • Patent Publication 2003/0148995 Lebreton, Cross-Linking of Low and High Molecular Weight Polysaccharides Preparation of Injectable Monophase Hydrogels; Lebreton, Viscoelastic Solutions Containing Sodium Hyaluronate and Hydroxypropyl Methyl Cellulose, Preparation and Uses, U.S. Patent Publication 2008/0089918; Lebreton, Hyaluronic Acid-Based Gels Including Lidocaine, U.S. Patent Publication 2010/0028438; and Polysaccharides and Hydrogels thus Obtained, U.S.
  • GAGs useful in the hydrogel materials and methods disclosed herein are commercially available, such as, e.g. , hyaluronan-based dermal fillers JUVEDERM ® , JUVEDERM ® 30, JUVEDERM ® Ultra, JUVEDERM ® Ultra Plus, JUVEDERM ® Ultra XC, and JUVEDERM ® Ultra Plus XC (Allergan Inc, Irvine, California). Table 2 lists representative GAGs.
  • GalNAc ⁇ -D-N-acetylgalactosamine
  • GalNAc(4S) ⁇ -0- ⁇ -3 ⁇ 3 ⁇ 3 ⁇ 53 ⁇ -4-0-5 ⁇ 3 ⁇
  • GalNAc(6S) ⁇ - ⁇ - ⁇ - ⁇ - ⁇ - ⁇ - ⁇
  • GalNAc(4S,6S) ⁇ -0- ⁇ -3 ⁇ 3 ⁇ 3 ⁇ 53 ⁇ -4-0, 6-O-sulfate
  • GlcNAc a-D-N-acetylglucosamine
  • GlcNS a-D-N-sulfoglucosamine
  • GlcNS(6S) g-D-N-sulfoglucosamine-6-O-sulfate
  • chondroitin sulfate polymer refers to an unbranched, sulfated polymer of variable length comprising disaccharides of two alternating monosaccharides of D-glucuronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc) and pharmaceutically acceptable salts thereof.
  • a chondroitin sulfate polymer may also include D-glucuronic acid residues that are epimerized into L- iduronic acid (IdoA), in which case the resulting disaccharide is referred to as dermatan sulfate.
  • a chondroitin sulfate polymer can have a chain of over 100 individual sugars, each of which can be sulfated in variable positions and quantities. Chondroitin sulfate polymers are an important structural component of cartilage and provide much of its resistance to compression. Any chondroitin sulfate polymer is useful in the hydrogel materials disclosed herein with the proviso that the chondroitin sulfate polymer improves a condition of the skin.
  • Non-limiting examples of pharmaceutically acceptable salts of chondroitin sulfate include sodium chondroitin sulfate, potassium chondroitin sulfate, magnesium chondroitin sulfate, calcium chondroitin sulfate, and combinations thereof.
  • keratan sulfate polymer refers to a polymer of variable length comprising disaccharide units, which themselves include ⁇ -D-galactose and N-acetyl-D-galactosamine (GalNAc) and pharmaceutically acceptable salts thereof. Disaccharides within the repeating region of keratan sulfate may be fucosylated and N-Acetylneuraminic acid caps the end of the chains.
  • Any keratan sulfate polymer is useful in the hydrogel materials disclosed herein with the proviso that the keratan sulfate polymer improves a condition of the skin.
  • pharmaceutically acceptable salts of keratan sulfate include sodium keratan sulfate, potassium keratan sulfate, magnesium keratan sulfate, calcium keratan sulfate, and combinations thereof.
  • hyaluronic acid polymer is synonymous with "HA polymer”
  • hyaluronic acid polymer and “hyaluronate polymer” refers to an anionic, non-sulfated glycosaminoglycan polymer comprising disaccharide units, which themselves include D-glucuronic acid and D-N-acetylglucosamine monomers, linked together via alternating ⁇ -1 ,4 and ⁇ -1 ,3 glycosidic bonds and pharmaceutically acceptable salts thereof.
  • Hyaluronan polymers can be purified from animal and non-animal sources.
  • Polymers of hyaluronan can range in size from about 5,000 Da to about 20,000,000 Da. Any hyaluronan polymer is useful in the hydrogel materials disclosed herein with the proviso that the hyaluronan improves a condition of the skin.
  • Non-limiting examples of pharmaceutically acceptable salts of hyaluronan include sodium hyaluronan, potassium hyaluronan, magnesium hyaluronan, calcium hyaluronan, and combinations thereof.
  • crosslinked refers to the intermolecular bonds joining the individual polymer molecules, or monomer chains, into a more stable structure like a gel.
  • a crosslinked glycosaminoglycan polymer has at least one intermolecular bond joining at least one individual polymer molecule to another one.
  • the crosslinking of glycosaminoglycan polymers typically result in the formation of a hydrogel. Such hydrogels have high viscosity and require considerable force to extrude through a fine needle.
  • Glycosaminoglycan polymers disclosed herein may be crosslinked using dialdehydes and disufides crosslinking agents including, without limitation, multifunctional PEG- based crosslinking agents, divinyl sulfones, diglycidyl ethers, and bis-epoxides.
  • Non-limiting examples of hyaluronan crosslinking agents include multifunctional PEG-based crosslinking agents like pentaerythritol tetraglycidyl ether (PETGE), divinyl sulfone (DVS), 1 ,4-butanediol diglycidyl ether (BDDE), 1 ,2-bis(2,3- epoxypropoxy)ethylene (EGDGE), 1 ,2,7,8-diepoxyoctane (DEO), biscarbodiimide (BCDI), adipic dihydrazide (ADH), bis(sulfosuccinimidyl)suberate (BS), hexamethylenediamine (HMDA), 1-(2,3- epoxypropyl)-2,3-epoxycyclohexane, or combinations thereof.
  • PEG-based crosslinking agents like pentaerythritol tetraglycidyl ether (PETGE), divinyl sulfone (
  • cross-linking agents are disclosed in Stroumpoulis and Tezel, Tunably Crosslinked Polysaccharide Compositions, U.S. Patent Application 12/910,466, filed October 22, 2010, which is incorporated by reference in its entirety.
  • Non- limiting examples of methods of crosslinking glycosaminoglycan polymers are described in, e.g. , Glycosaminoglycan polymers useful in the hydrogel materials and methods disclosed herein are described in, e.g. , Piron and Tholin, Polysaccharide Crosslinking, Hydrogel Preparation, Resulting Polysaccharides(s) and Hydrogel(s), uses Thereof, U.S.
  • Patent Publication 2003/0148995 Lebreton, Cross-Linking of Low and High Molecular Weight Polysaccharides Preparation of Injectable Monophase Hydrogels and Polysaccharides and Hydrogels thus Obtained, U.S. Patent Publication 2006/0194758;; Lebreton, Viscoelastic Solutions Containing Sodium Hyaluronate and Hydroxypropyl Methyl Cellulose, Preparation and Uses, U.S. Patent Publication 2008/0089918; Lebreton, Hyaluronic Acid-Based Gels Including Lidocaine, U.S. Patent Publication 2010/0028438; and Di Napoli, Composition and Method for Intradermal Soft Tissue Augmentation, International Patent Publication WO 2004/073759, each of which is hereby incorporated by reference in its entirety.
  • a hydrogel material comprises a crosslinked glycosaminoglycan polymer where the crosslinked glycosaminoglycan polymer is present in an amount sufficient to improve a skin condition as disclosed herein.
  • a hydrogel material comprises a crosslinked chondroitin sulfate polymer, a crosslinked dermatan sulfate polymer, a crosslinked keratan sulfate polymer, a crosslinked heparan polymer, a crosslinked heparan sulfate polymer, or a crosslinked hyaluronan polymer.
  • a hydrogel material comprises a crosslinked glycosaminoglycan where the crosslinked glycosaminoglycan represents, e.g. , about 1 % by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, or about 9%, or about 10% by weight, of the total glycosaminoglycan present in the hydrogel material.
  • a hydrogel material comprises a crosslinked glycosaminoglycan where the crosslinked glycosaminoglycan represents, e.g., at most 1 % by weight, at most 2% by weight, at most 3% by weight, at most 4% by weight, at most 5% by weight, at most 6% by weight, at most 7% by weight, at most 8% by weight, at most 9% by weight, or at most 10% by weight, of the total glycosaminoglycan present in the hydrogel material.
  • the crosslinked glycosaminoglycan represents, e.g., at most 1 % by weight, at most 2% by weight, at most 3% by weight, at most 4% by weight, at most 5% by weight, at most 6% by weight, at most 7% by weight, at most 8% by weight, at most 9% by weight, or at most 10% by weight, of the total glycosaminoglycan present in the hydrogel material.
  • a hydrogel material comprises a crosslinked glycosaminoglycan where the crosslinked glycosaminoglycan represents, e.g., about 0% to about 10% by weight, about 1 % to about 10% by weight, about 3% to about 10% by weight, or about 5% to about 10% by weight, of the total glycosaminoglycan present in the hydrogel material.
  • a hydrogel material comprises a crosslinked glycosaminoglycan where the crosslinked glycosaminoglycan is present at a concentration of, e.g., about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 1 1 mg/mL, about 12 mg/mL, about 13 mg/mL, about 13.5 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, or about 20 mg/mL.
  • a hydrogel material comprises a crosslinked glycosaminoglycan where the crosslinked glycosaminoglycan is present at a concentration of, e.g. , at least 1 mg/mL, at least 2 mg/mL, at least 3 mg/mL, at least 4 mg/mL, at least 5 mg/mL, at least 10 mg/mL, at least 15 mg/mL, at least 20 mg/mL, or at least 25 mg/mL.
  • a hydrogel material comprises a crosslinked glycosaminoglycan where the crosslinked glycosaminoglycan is present at a concentration of, e.g., at most 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, at most 5 mg/mL, at most 10 mg/mL, at most 15 mg/mL, at most 20 mg/mL, or at most 25 mg/mL.
  • a hydrogel material comprises a crosslinked glycosaminoglycan where the crosslinked glycosaminoglycan is present at a concentration of, e.g.
  • aspects of the present specification provide, in part, a hydrogel material comprising hyaluronan polymers of low molecular weight, hyaluronan polymers of high molecular weight, or hyaluronan polymers of both low and high molecular weight.
  • high molecular weight when referring to "hyaluronan” refers to hyaluronan polymers having a mean molecular weight of 1 ,000,000 Da or greater.
  • Non-limiting examples of a high molecular weight hyaluronan polymers include hyaluronan polymers about 1 ,500,000 Da, about 2,000,000 Da, about 2,500,000 Da, about 3,000,000 Da, about 3,500,000 Da, about 4,000,000 Da, about 4,500,000 Da, and about 5,000,000 Da.
  • the term "low molecular weight" when referring to "hyaluronan” refers to hyaluronan polymers having a mean molecular weight of less than 1 ,000,000 Da.
  • Non-limiting examples of a low molecular weight hyaluronan polymers include hyaluronan polymers of about 200,000 Da, about 300,000 Da, about 400,000 Da, about 500,000 Da, about 600,000 Da, about 700,000 Da, of about 800,000 Da, and about 900,000 Da.
  • a hydrogel material comprises crosslinked hyaluronan polymers of low molecular weight.
  • a hydrogel material comprises crosslinked hyaluronan polymers having a mean molecular weight of, e.g. , about 100,000 Da, about 200,000 Da, about 300,000 Da, about 400,000 Da, about 500,000 Da, about 600,000 Da, about 700,000 Da, about 800,000 Da, or about 900,000 Da.
  • a hydrogel material comprises crosslinked hyaluronan polymers having a mean molecular weight of, e.g., at most 100,000 Da, at most 200,000 Da, at most 300,000 Da, at most 400,000 Da, at most 500,000 Da, at most 600,000 Da, at most 700,000 Da, at most 800,000 Da, at most 900,000 Da, or at most 950,000.
  • a hydrogel material comprises crosslinked hyaluronan polymers having a mean molecular weight of, e.g.
  • a hydrogel material comprises crosslinked hyaluronan polymers of high molecular weight.
  • a hydrogel material comprises a crosslinked hyaluronan polymers having a mean molecular weight of, e.g. , about 1 ,000,000 Da, about 1 ,500,000 Da, about 2,000,000 Da, about 2,500,000 Da, about 3,000,000 Da, about 3,500,000 Da, about 4,000,000 Da, about 4,500,000 Da, or about 5,000,000 Da.
  • a hydrogel material comprises a crosslinked hyaluronan polymers having a mean molecular weight of, e.g.
  • a hydrogel material comprises a crosslinked hyaluronan polymers having a mean molecular weight of, e.g. , about 1 ,000,000 Da to about 5,000,000 Da, about 1 ,500,000 Da to about 5,000,000 Da, about 2,000,000 Da to about 5,000,000 Da, about 2,500,000 Da to about 5,000,000 Da, about 2,000,000 Da to about 3,000,000 Da, about 2,500,000 Da to about 3,500,000 Da, or about 2,000,000 Da to about 4,000,000 Da.
  • a hydrogel material comprises a crosslinked hyaluronan polymers where the crosslinked hyaluronan polymers comprise a combination of both high molecular weight hyaluronan polymers and low molecular weight hyaluronan polymers, in various ratios.
  • a hydrogel material comprises a crosslinked hyaluronan polymers where the crosslinked hyaluronan polymers comprises a combination of both high molecular weight hyaluronan polymers and low molecular weight hyaluronan polymers in a ratio of about 20: 1 , about 15:1 , about 10: 1 , about 5:1 , about 1 : 1 , about 1 :5 about 1 :10, about 1 : 15, or about 1 :20.
  • aspects of the present specification provide, in part, a hydrogel material comprising a crosslinked glycosaminoglycan polymer having a degree of crosslinking.
  • degree of crosslinking refers to the percentage of glycosaminoglycan polymer monomeric units, such as, e.g., the disaccharide monomer units of hyaluronan that are bound to a cross-linking agent.
  • the degree of crosslinking is expressed as the percent weight ratio of the crosslinking agent to glycosaminoglycan monomeric unit within the crosslinked portion of the hydrogel material. It is measured by the weight ratio of glycosaminoglycan monomers to crosslinker.
  • a hydrogel material that that has a crosslinked glycosaminoglycan polymer with a 4% degree of crosslinking means that on average there are four crosslinking molecules for every 100 glycosaminoglycan monomeric units. Every other parameter being equal, the greater the degree of crosslinking, the harder the hydrogel becomes.
  • a degree of crosslinking useful to make the hydrogel materials disclosed herein include about 1 % to about 15%.
  • a hydrogel material comprises a crosslinked glycosaminoglycan where the degree of crosslinking is about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 1 1 %, about 12%, about 13%, about 14%, or about 15%.
  • a hydrogel material comprises a crosslinked glycosaminoglycan where the degree of crosslinking is at most 1 %, at most 2%, at most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most 8%, at most 9%, at most 10%, at most 1 1 %, at most 12%, at most 13%, at most 14%, or at most 15%.
  • a hydrogel material comprises a crosslinked glycosaminoglycan where the degree of crosslinking is about 1 % to about 15%, about 2% to about 1 1 %, about 3% to about 10%, about 1 % to about 5%, about 10% to about 15%, about 1 1 % to about 15%, about 6% to about 10%, or about 6% to about 8%.
  • aspects of the present specification provide, in part, a hydrogel material comprising an uncrosslinked glycosaminoglycan polymer.
  • uncrosslinked refers to a lack of intermolecular bonds joining the individual glycosaminoglycan polymer molecules, or monomer chains. As such, an uncrosslinked glycosaminoglycan polymer is not linked to any other glycosaminoglycan polymer by an intermolecular bond.
  • a hydrogel material comprises an uncrosslinked chondroitin sulfate polymer, an uncrosslinked dermatan sulfate polymer, an uncrosslinked keratan sulfate polymer, an uncrosslinked heparan polymer, an uncrosslinked heparan sulfate polymer, or an uncrosslinked hyaluronan polymer.
  • Uncrosslinked glycosaminoglycan polymers are water soluble and generally remain fluid in nature. As such, uncross-linked glycosaminoglycan polymers are often mixed with a glycosaminoglycan polymer-based hydrogel material as a lubricant to facilitate the extrusion process of the hydrogel material through a fine needle.
  • a hydrogel material comprises an uncrosslinked glycosaminoglycan polymer where the uncrosslinked glycosaminoglycan polymer is present in an amount sufficient to improve a skin condition as disclosed herein.
  • a hydrogel material comprises an uncrosslinked glycosaminoglycan where the uncrosslinked glycosaminoglycan is present at a concentration of, e.g.
  • mg/mL about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 1 1 mg/mL, about 12 mg/mL, about 13 mg/mL, about 13.5 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20 mg/mL, about 40 mg/mL, or about 60 mg/mL.
  • a hydrogel material comprises an uncrosslinked glycosaminoglycan where the uncrosslinked glycosaminoglycan is present at a concentration of, e.g., at least 1 mg/mL, at least 2 mg/mL, at least 3 mg/mL, at least 4 mg/mL, at least 5 mg/mL, at least 10 mg/mL, at least 15 mg/mL, at least 20 mg/mL, at least 25 mg/mL at least 35 mg/mL, or at least 40 mg/mL.
  • a hydrogel material comprises an uncrosslinked glycosaminoglycan where the uncrosslinked glycosaminoglycan is present at a concentration of, e.g., at most 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, at most 5 mg/mL, at most 10 mg/mL, at most 15 mg/mL, at most 20 mg/mL, or at most 25 mg/mL.
  • a hydrogel material comprises an uncrosslinked glycosaminoglycan where the uncrosslinked glycosaminoglycan is present at a concentration of, e.g., about 1 mg/mL to about 60 mg/mL, about 10 mg/mL to about 40 mg/mL, about 7.5 mg/mL to about 19.5 mg/mL, about 8.5 mg/mL to about 18.5 mg/mL, about 9.5 mg/mL to about 17.5 mg/mL, about 10.5 mg/mL to about 16.5 mg/mL, about 1 1.5 mg/mL to about 15.5 mg/mL, or about 12.5 mg/mL to about 14.5 mg/mL.
  • a hydrogel material comprises uncrosslinked hyaluronan polymers of low molecular weight.
  • a hydrogel material comprises a uncrosslinked hyaluronan having a mean molecular weight of, e.g., about 100,000 Da, about 200,000 Da, about 300,000 Da, about 400,000 Da, about 500,000 Da, about 600,000 Da, about 700,000 Da, about 800,000 Da, or about 900,000 Da.
  • a hydrogel material comprises uncrosslinked hyaluronan polymers having a mean molecular weight of, e.g., at most 100,000 Da, at most 200,000 Da, at most 300,000 Da, at most 400,000 Da, at most 500,000 Da, at most 600,000 Da, at most 700,000 Da, at most 800,000 Da, at most 900,000 Da, or at most 950,000.
  • a hydrogel material comprises uncrosslinked hyaluronan polymers having a mean molecular weight of, e.g., about 100,000 Da to about 500,000 Da, about 200,000 Da to about 500,000 Da, about 300,000 Da to about 500,000 Da, about 400,000 Da to about 500,000 Da, about 500,000 Da to about 950,000 Da, about 600,000 Da to about 950,000 Da, about 700,000 Da to about 950,000 Da, about 800,000 Da to about 950,000 Da, about 300,000 Da to about 600,000 Da, about 300,000 Da to about 700,000 Da, about 300,000 Da to about 800,000 Da, or about 400,000 Da to about 700,000 Da.
  • a hydrogel material comprises uncrosslinked hyaluronan polymers of high molecular weight.
  • a hydrogel material comprises an uncrosslinked hyaluronan having a mean molecular weight of, e.g., about 1 ,000,000 Da, about 1 ,500,000 Da, about 2,000,000 Da, about 2,500,000 Da, about 3,000,000 Da, about 3,500,000 Da, about 4,000,000 Da, about 4,500,000 Da, or about 5,000,000 Da.
  • a hydrogel material comprises an uncrosslinked hyaluronan polymers having a mean molecular weight of, e.g., at least 1 ,000,000 Da, at least 1 ,500,000 Da, at least 2,000,000 Da, at least 2,500,000 Da, at least 3,000,000 Da, at least 3,500,000 Da, at least 4,000,000 Da, at least 4,500,000 Da, or at least 5,000,000 Da.
  • a hydrogel material comprises an uncrosslinked hyaluronan polymers having a mean molecular weight of, e.g., about 1 ,000,000 Da to about 5,000,000 Da, about 1 ,500,000 Da to about 5,000,000 Da, about 2,000,000 Da to about 5,000,000 Da, about 2,500,000 Da to about 5,000,000 Da, about 2,000,000 Da to about 3,000,000 Da, about 2,500,000 Da to about 3,500,000 Da, or about 2,000,000 Da to about 4,000,000 Da.
  • a hydrogel material comprises an uncrosslinked hyaluronan polymers having a mean molecular weight of, e.g., greater than 2,000,000 Da and less than about 3,000,000 Da, greater than 2,000,000 Da and less than about 3,500,000 Da, greater than 2,000,000 Da and less than about 4,000,000 Da, greater than 2,000,000 Da and less than about 4,500,000 Da, greater than 2,000,000 Da and less than about 5,000,000 Da.
  • a hydrogel material comprises uncrosslinked hyaluronan polymers where the uncrosslinked hyaluronan comprises a combination of both high molecular weight hyaluronan polymers and low molecular weight hyaluronan polymers, in various ratios.
  • a hydrogel material comprises an uncrosslinked hyaluronan polymers where the uncrosslinked hyaluronan polymers comprises a combination of both high molecular weight hyaluronan polymers and low molecular weight hyaluronan polymers in a ratio of about 20: 1 , about 15: 1 , about 10: 1 , about 5: 1 , about 1 :1 , about 1 :5 about 1 : 10, about 1 : 15, or about 1 :20.
  • aspects of the present specification provide, in part, a hydrogel material comprising a substantially uncrosslinked glycosaminoglycan polymer.
  • substantially uncrosslinked refers to the presence of uncrosslinked glycosaminoglycan polymers in a hydrogel material disclosed herein at a level of at least 90% by weight of the hydrogel material, with the remaining at most 10% by weight of the hydrogel material being comprised of other components including crosslinked glycosaminoglycan polymers.
  • a hydrogel material comprises a substantially uncrosslinked chondroitin sulfate polymer, a substantially uncrosslinked dermatan sulfate polymer, a substantially uncrosslinked keratan sulfate polymer, a substantially uncrosslinked heparan polymer, a substantially uncrosslinked heparan sulfate polymer, or a substantially uncrosslinked hyaluronan polymer.
  • a hydrogel material comprises an uncrosslinked glycosaminoglycan where the uncrosslinked glycosaminoglycan represents, e.g.
  • a hydrogel material comprises an uncrosslinked glycosaminoglycan where the uncrosslinked glycosaminoglycan represents, e.g., about 90% to about 100% by weight, about 93% to about 100% by weight, about 95% to about 100% by weight, or about 97% to about 100% by weight, of the total glycosaminoglycan present in the hydrogel material.
  • aspects of the present specification provide, in part, a hydrogel material that is essentially free of a crosslinked glycosaminoglycan polymer.
  • the term “essentially free” refers to a hydrogel material where only trace amounts of cross-linked matrix polymers can be detected.
  • a hydrogel material comprises a chondroitin sulfate that is essentially free of a crosslinked chondroitin sulfate polymer, a dermatan sulfate essentially free of a crosslinked dermatan sulfate polymer, a keratan sulfate essentially free of a crosslinked keratan sulfate polymer, a heparan essentially free of a crosslinked heparan polymer, a heparan sulfate essentially free of a crosslinked heparan sulfate polymer, or a hyaluronan sulfate essentially free of a crosslinked hyaluronan polymer.
  • aspects of the present specification provide, in part, a hydrogel material that is entirely free of a crosslinked glycosaminoglycan polymer.
  • the term “entirely free” refers to a hydrogel material that within the detection range of the instrument or process being used, crosslinked glycosaminoglycan polymers cannot be detected or its presence cannot be confirmed.
  • a hydrogel material comprises a chondroitin sulfate that is entirely free of a crosslinked chondroitin sulfate polymer, a dermatan sulfate entirely free of a crosslinked dermatan sulfate polymer, a keratan sulfate entirely free of a crosslinked keratan sulfate polymer, a heparan entirely free of a crosslinked heparan polymer, a heparan sulfate entirely free of a crosslinked heparan sulfate polymer, or a hyaluronan sulfate entirely free of a crosslinked hyaluronan polymer.
  • a hydrogel material comprising a ratio of crosslinked glycosaminoglycan polymer and uncrosslinked glycosaminoglycan polymer.
  • This ratio of crosslinked and uncrosslinked glycosaminoglycan polymer is also known as the gel:fluid ratio. Any gel:fluid ratio is useful in making the hydrogel materials disclosed herein with the proviso that such ratio produces a hydrogel material disclosed herein that improves a skin condition as disclosed herein.
  • Non- limiting examples of gel:fluid ratios include 100:0, 98:2, 90:10, 75:25, 70:30, 60:40, 50:50, 40:60, 30:70, 25:75, 10:90; 2:98, and 0: 100.
  • a hydrogel material comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer where the gel:fluid ratio is, e.g., about 0:100, about 1 :99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91 , or about 10:90.
  • a hydrogel material comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer where the gel:fluid ratio is, e.g.
  • a hydrogel material comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer where the gel:fluid ratio is, e.g. , about 0:100 to about 3:97, about 0: 100 to about 5:95, or about 0: 100 to about 10:90.
  • a hydrogel material comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer where the gel:fluid ratio is, e.g. , about 15:85, about 20:80, about 25:75, about 30:70, about 35:65, about 40:60, about 45:55, about 50:50, about 55:45, about 60:40, about 65:35, about 70:30, about 75:25, about 80:20, about 85: 15, about 90: 10, about 95:5, about 98:2, or about 100:0.
  • a hydrogel material comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer where the gel:fluid ratio is, e.g. , at most 15:85, at most 20:80, at most 25:75, at most 30:70, at most 35:65, at most 40:60, at most 45:55, at most 50:50, at most 55:45, at most 60:40, at most 65:35, at most 70:30, at most 75:25, at most 80:20, at most 85: 15, at most 90: 10, at most 95:5, at most 98:2, or at most 100:0.
  • the gel:fluid ratio is, e.g. , at most 15:85, at most 20:80, at most 25:75, at most 30:70, at most 35:65, at most 40:60, at most 45:55, at most 50:50, at most 55:45, at most 60:40, at most 65:35, at most 70:30,
  • a hydrogel material comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer where the gel:fluid ratio is, e.g. , about 10:90 to about 70:30, about 15:85 to about 70:30, about 10:90 to about 55:45, about 80:20 to about 95:5, about 90: 10 to about 100:0, about 75:25 to about 100:0, or about 60:40 to about 100:0.
  • a hydrogel material disclosed herein may be formed into a porous material like a sponge. The porous material can serve both as a bulking agent to fill the tissue space as well as a substrate to support tissue growth.
  • a hydrogel material disclosed herein may be processed into a porous material using standard methods known in the art, including, e.g. , freeze-drying, gas foaming, and/or negative templating using porogens.
  • the pore size of a porous material can be controlled, e.g., by adjusting the concentration of GAG and the particle size of the porogen.
  • the excess porogen is then extracted, for example, by immersing in water or other suitable solvent.
  • the resultant porous material can then be dried and used.
  • Such methods are described in, e.g., Kaplin, et al., Concentrated Aqueous Silk Fibroin Solution and Use Thereof, U.S.
  • Patent Application 12/883, 139 and, Guang-Liang et al., Drug Delivery Platforms Comprising Silk Fibroin Hydrogels and Uses Thereof, U.S. Patent Application 12/873,563, each of which is hereby incorporated by reference in its entirety.
  • a hydrogel material disclosed herein may be formed into solid particles.
  • the hydrogel particles can serve both as a bulking agent to fill the tissue space as well as a substrate to support tissue growth.
  • a hydrogel material is processed into particles simply by manually or mechanically pulverizing the material and optionally mixed with a carrier phase such as, e.g., water or a saline solution to form an injectable or topical substance like a solution, oil, lotion, gel, ointment, cream, slurry, salve, or paste.
  • a carrier phase such as, e.g., water or a saline solution to form an injectable or topical substance like a solution, oil, lotion, gel, ointment, cream, slurry, salve, or paste.
  • the disclosed hydrogel materials may be monophasic or multiphasic compositions.
  • a hydrogel may be milled to a particle size from about 10 ⁇ to about 1000 ⁇ in diameter.
  • a particle size may be about 15 ⁇ to about 30 ⁇ , about 25 ⁇ to about 50 ⁇ , about 45 ⁇ to about 75 ⁇ , about 70 ⁇ to about 100 ⁇ , about 50 ⁇ to about 200 ⁇ , about 150 ⁇ to about 300 ⁇ , about 250 ⁇ to about 400 ⁇ , about 350 ⁇ to about 500 ⁇ , about 450 ⁇ to about 600 ⁇ , about 550 ⁇ to about 700 ⁇ , about 650 ⁇ to about 800 ⁇ , about 750 ⁇ to about 900 ⁇ , or about 850 ⁇ to about 1000 ⁇ .
  • Saline is then added as a carrier phase by first determining the bulk volume of a hydrogel material, then vigorously pulverizing the hydrogel into particles while incorporating an appropriate volume of saline to achieve a desired carrier to hydrogel particle ratio.
  • hydrogel milling may be accomplished by means of a forced sieving of bulk hydrogel through a series of stainless steel cloth sieves of decreasing pore sizes.
  • compositions as disclosed herein are viscoelastic in that the composition has an elastic component (solid-like such as, e.g. , crosslinked glycosaminoglycan polymers) and a viscous component (liquid-like such as, e.g. , uncrosslinked glycosaminoglycan polymers or a carrier phase) when a force is applied (stress, deformation).
  • the rheological attribute that described this property is the complex modulus (G * ), which defines a composition's total resistance to deformation.
  • the complex modulus can be defined as the sum of the elastic modulus (G') and the viscous modulus (G").
  • Elastic modulus refers to the ability of a hydrogel material to resists deformation, or, conversely, an object's tendency to be non-permanently deformed when a force is applied to it.
  • Elastic modulus characterizes the firmness of a composition and is also known as the storage modulus because it describes the storage of energy from the motion of the composition.
  • ⁇ stress/strain
  • stress is the force causing the deformation divided by the area to which the force is applied
  • strain is the ratio of the change caused by the stress to the original state of the object.
  • Viscous modulus is also known as the loss modulus because it describes the energy that is lost as viscous dissipation.
  • a tan ⁇ is obtained from the dynamic modulus at a frequency of 0.628 rad/s.
  • a lower tan ⁇ corresponds to a stiffer, harder, or more elastic composition.
  • a hydrogel material disclosed herein exhibits a complex modulus.
  • a hydrogel material exhibits a complex modulus of, e.g. , about 25 Pa, about 50 Pa, about 75 Pa, about 100 Pa, about 125 Pa, about 150 Pa, about 175 Pa, about 200 Pa, about 250 Pa, about 300 Pa, about 350 Pa, about 400 Pa, about 450 Pa, about 500 Pa, about 550 Pa, about 600 Pa, about 650 Pa, about 700 Pa, about 750 Pa, or about 800 Pa.
  • a hydrogel material exhibits a complex modulus of, e.g., at most 25 Pa, at most 50 Pa, at most 75 Pa, at most 100 Pa, at most 125 Pa, at most 150 Pa, at most 175 Pa, at most 200 Pa, at most 250 Pa, at most 300 Pa, at most 350 Pa, at most 400 Pa, at most 450 Pa, at most 500 Pa, at most 550 Pa, at most 600 Pa, at most 650 Pa, at most 700 Pa, at most 750 Pa, or at most 800 Pa.
  • a hydrogel material exhibits a complex modulus of, e.g.
  • a hydrogel material disclosed herein exhibits an elastic modulus.
  • a hydrogel material exhibits an elastic modulus of, e.g., about 25 Pa, about 50 Pa, about 75 Pa, about 100 Pa, about 125 Pa, about 150 Pa, about 175 Pa, about 200 Pa, about 250 Pa, about 300 Pa, about 350 Pa, about 400 Pa, about 450 Pa, about 500 Pa, about 550 Pa, about 600 Pa, about 650 Pa, about 700 Pa, about 750 Pa, about 800 Pa, about 850 Pa, about 900 Pa, about 950 Pa, about 1 ,000 Pa, about 1 ,200 Pa, about 1 ,300 Pa, about 1 ,400 Pa, about 1 ,500 Pa, about 1 ,600 Pa, about 1700 Pa, about 1800 Pa, about 1900 Pa, about 2,000 Pa, about 2, 100 Pa, about 2,200 Pa, about 2,300 Pa, about 2,400 Pa, or about 2,500 Pa.
  • an elastic modulus of, e.g., about 25 Pa, about 50 Pa, about 75 Pa, about 100 Pa, about 125 Pa, about 150 Pa, about 175 Pa, about 200 Pa,
  • a hydrogel material exhibits an elastic modulus of, e.g., at least 25 Pa, at least 50 Pa, at least 75 Pa, at least 100 Pa, at least 125 Pa, at least 150 Pa, at least 175 Pa, at least 200 Pa, at least 250 Pa, at least 300 Pa, at least 350 Pa, at least 400 Pa, at least 450 Pa, at least 500 Pa, at least 550 Pa, at least 600 Pa, at least 650 Pa, at least 700 Pa, at least 750 Pa, at least 800 Pa, at least 850 Pa, at least 900 Pa, at least 950 Pa, at least 1 ,000 Pa, at least 1 ,200 Pa, at least 1 ,300 Pa, at least 1 ,400 Pa, at least 1 ,500 Pa, at least 1 ,600 Pa, at least 1700 Pa, at least 1800 Pa, at least 1900 Pa, at least 2,000 Pa, at least 2, 100 Pa, at least 2,200 Pa, at least 2,300 Pa, at least 2,400 Pa, or at least 2,500 Pa.
  • a hydrogel material exhibits an elastic modulus of, e.g., at most 25 Pa, at most 50 Pa, at most 75 Pa, at most 100 Pa, at most 125 Pa, at most 150 Pa, at most 175 Pa, at most 200 Pa, at most 250 Pa, at most 300 Pa, at most 350 Pa, at most 400 Pa, at most 450 Pa, at most 500 Pa, at most 550 Pa, at most 600 Pa, at most 650 Pa, at most 700 Pa, at most 750 Pa, at most 800 Pa, at most 850 Pa, at most 900 Pa, at most 950 Pa, at most 1 ,000 Pa, at most 1 ,200 Pa, at most 1 ,300 Pa, at most 1 ,400 Pa, at most 1 ,500 Pa, or at most 1 ,600 Pa.
  • a hydrogel material exhibits an elastic modulus of, e.g., about 25 Pa to about 150 Pa, about 25 Pa to about 300 Pa, about 25 Pa to about 500 Pa, about 25 Pa to about 800 Pa, about 125 Pa to about 300 Pa, about 125 Pa to about 500 Pa, about 125 Pa to about 800 Pa, about 500 Pa to about 1 ,600 Pa, about 600 Pa to about 1 ,600 Pa, about 700 Pa to about 1 ,600 Pa, about 800 Pa to about 1 ,600 Pa, about 900 Pa to about 1 ,600 Pa, about 1 ,000 Pa to about 1 ,600 Pa, about 1 ,100 Pa to about 1 ,600 Pa, about 1 ,200 Pa to about 1 ,600 Pa, about 500 Pa to about 2,500 Pa, about 1 ,000 Pa to about 2,500 Pa, about 1 ,500 Pa to about 2,500 Pa, about 2,000 Pa to about 2,500 Pa, about 1 ,300 Pa to about 1 ,600 Pa, about 1 ,400 Pa to about 1 ,700 Pa,
  • a hydrogel material disclosed herein exhibits a tensile modulus.
  • a hydrogel material exhibits a tensile modulus of, e.g., about 1 MPa, about 10 MPa, about 20 MPa, about 30 MPa, about 40 MPa, about 50 MPa, about 60 MPa, about 70 MPa, about 80 MPa, about 90 MPa, about 100 MPa, about 200 MPa, about 300 MPa, about 400 MPa, about 500 MPa, about 750 MPa, about 1 GPa, about 5 GPa, about 10 GPa, about 15 GPa, about 20 GPa, about 25 GPa, or about 30 GPa.
  • a hydrogel material exhibits a tensile modulus of, e.g., at least 1 MPa, at least 10 MPa, at least 20 MPa, at least 30 MPa, at least 40 MPa, at least 50 MPa, at least 60 MPa, at least 70 MPa, at least 80 MPa, at least 90 MPa, at least 100 MPa, at least 200 MPa, at least 300 MPa, at least 400 MPa, at least 500 MPa, at least 750 MPa, at least 1 GPa, at least 5 GPa, at least 10 GPa, at least 15 GPa, at least 20 GPa, at least 25 GPa,or at least 30 GPa
  • a hydrogel material exhibits a tensile modulus of, e.g., about 1 MPa to about 30 MPa, about 10 MPa to about 50 MPa, about 25 MPa to about 75 MPa, about 50 MPa to about 100 MPa, about 100 MPa to about 300 MP
  • a hydrogel material disclosed herein exhibits shear modulus.
  • a hydrogel material exhibits a shear modulus of, e.g., about 1 MPa, about 10 MPa, about 20 MPa, about 30 MPa, about 40 MPa, about 50 MPa, about 60 MPa, about 70 MPa, about 80 MPa, about 90 MPa, about 100 MPa, about 200 MPa, about 300 MPa, about 400 MPa, about 500 MPa, about 750 MPa, about 1 GPa, about 5 GPa, about 10 GPa, about 15 GPa, about 20 GPa, about 25 GPa, or about 30 GPa.
  • a hydrogel material exhibits a shear modulus of, e.g., at least 1 MPa, at least 10 MPa, at least 20 MPa, at least 30 MPa, at least 40 MPa, at least 50 MPa, at least 60 MPa, at least 70 MPa, at least 80 MPa, at least 90 MPa, at least 100 MPa, at least 200 MPa, at least 300 MPa, at least 400 MPa, at least 500 MPa, at least 750 MPa, at least 1 GPa, at least 5 GPa, at least 10 GPa, at least 15 GPa, at least 20 GPa, at least 25 GPa,or at least 30 GPa
  • a hydrogel material exhibits a shear modulus of, e.g., about 1 MPa to about 30 MPa, about 10 MPa to about 50 MPa, about 25 MPa to about 75 MPa, about 50 MPa to about 100 MPa, about 100 MPa to about 300 MPa, about 200
  • a hydrogel material disclosed herein exhibits a bulk modulus.
  • a hydrogel material exhibits a bulk modulus of, e.g., about 5 GPa, about 6 GPa, about 7 GPa, about 8 GPa, about 9 GPa, about 10 GPa, about 15 GPa, about 20 GPa, about 25 GPa, about 30 GPa, about 35 GPa, about 40 GPa, about 45 GPa, about 50 GPa, about 60 GPa, about 70 GPa, about 80 GPa, about 90 GPa, about 100 GPa.
  • a hydrogel material exhibits a bulk modulus of, e.g., at least 5 GPa, at least 6 GPa, at least 7 GPa, at least 8 GPa, at least 9 GPa, at least 10 GPa, at least 15 GPa, at least 20 GPa, at least 25 GPa, at least 30 GPa, at least 35 GPa, at least 40 GPa, at least 45 GPa, at least 50 GPa, at least 60 GPa, at least 70 GPa, at least 80 GPa, at least 90 GPa, at least 100 GPa.
  • a hydrogel material exhibits a bulk modulus of, e.g., about 5 GPa to about 50 GPa, about 5 GPa to about 100 GPa, about 10 GPa to about 50 GPa, about 10 GPa to about 100 GPa, or about 50 GPa to about 100 GPa.
  • a hydrogel material disclosed herein exhibits a viscous modulus.
  • a hydrogel material exhibits a viscous modulus of, e.g., about 10 Pa, about 20 Pa, about 30 Pa, about 40 Pa, about 50 Pa, about 60 Pa, about 70 Pa, about 80 Pa, about 90 Pa, about 100 Pa, about 150 Pa, about 200 Pa, about 250 Pa, about 300 Pa, about 350 Pa, about 400 Pa, about 450 Pa, about 500 Pa, about 550 Pa, about 600 Pa, about 650 Pa, or about 700 Pa.
  • a hydrogel material exhibits a viscous modulus of, e.g., at most 10 Pa, at most 20 Pa, at most 30 Pa, at most 40 Pa, at most 50 Pa, at most 60 Pa, at most 70 Pa, at most 80 Pa, at most 90 Pa, at most 100 Pa, at most 150 Pa, at most 200 Pa, at most 250 Pa, at most 300 Pa, at most 350 Pa, at most 400 Pa, at most 450 Pa, at most 500 Pa, at most 550 Pa, at most 600 Pa, at most 650 Pa, or at most 700 Pa.
  • a hydrogel material exhibits a viscous modulus of, e.g., about 10 Pa to about 30 Pa, about 10 Pa to about 50 Pa, about 10 Pa to about 100 Pa, about 10 Pa to about 150 Pa, about 70 Pa to about 100 Pa, about 50 Pa to about 350 Pa, about 150 Pa to about 450 Pa, about 250 Pa to about 550 Pa, about 350 Pa to about 700 Pa, about 50 Pa to about 150 Pa, about 100 Pa to about 200 Pa, about 150 Pa to about 250 Pa, about 200 Pa to about 300 Pa, about 250 Pa to about 350 Pa, about 300 Pa to about 400 Pa, about 350 Pa to about 450 Pa, about 400 Pa to about 500 Pa, about 450 Pa to about 550 Pa, about 500 Pa to about 600 Pa, about 550 Pa to about 650 Pa, or about 600 Pa to about 700 Pa.
  • a viscous modulus of, e.g., about 10 Pa to about 30 Pa, about 10 Pa to about 50 Pa, about 10 Pa to about 100 Pa, about 10 Pa to about 150 Pa, about 70 Pa to about 100 Pa
  • a hydrogel material disclosed herein exhibits a tan ⁇ .
  • a hydrogel material exhibits a tan ⁇ of, e.g., about 0.1 , about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1 , about 1.2, about 1.3, about
  • a hydrogel material exhibits a tan ⁇ of, e.g., at most 0.1 , at most 0.2, at most 0.3, at most 0.4, at most 0.5, at most 0.6, at most 0.7, at most 0.8, at most 0.9, at most 1 .0, at most 1.1 , at most 1.2, at most 1.3, at most 1 .4, at most 1.5, at most 1.6, at most 1.7, at most 1 .8, at most 1.9, at most 2.0, at most 2.1 , at most 2.2, at most 2.3, at most 2.4, or at most
  • a hydrogel material exhibits a tan ⁇ of, e.g., about 0.1 to about 0.3, about 0.3 to about 0.5, about 0.5 to about 0.8, about 1.1 to about 1.4, about 1.4 to about 1.7, about 0.3 to about 0.6, about 0.1 to about 0.5, about 0.5 to about 0.9, about 0.1 to about 0.6, about 0.1 to about 1.0, about 0.5 to about 1.5, about 1.0 to about 2.0, or about 1.5 to about 2.5.
  • a hydrogel material disclosed herein having hardness refers to various properties of an object in the solid phase that gives it high resistance to various kinds of shape change when force is applied. Hardness is measured using a durometer and is a unitless value that ranges from zero to 100. The ability or inability of a hydrogel to be easily compressed will affect its suitability for application in different tissue replacement roles, i.e., mechanical compliance as bone, fat, connective tissue. Hardness will also affect the ability of a hydrogel to be effectively comminuted, the reason being that a hard material may be more easily and consistently comminuted. Hardness will also affect extrudability, as a soft material may be more readily able to be slightly compressed during injection to pack with other particles or change shape to pass through a syringe barrel or needle.
  • a hydrogel material disclosed herein exhibits low hardness.
  • a hydrogel material exhibits a hardness of, e.g., about 5, about 10, about 15, about 20, about 25, about 30, or about 35.
  • a hydrogel material exhibits a hardness of, e.g., at most 5, at most 10, at most 15, at most 20, at most 25, at most 30, or at most 35.
  • a hydrogel material exhibits a hardness of, e.g., about 5 to about 35, about 10 to about 35, about 15 to about 35, about 20 to about 35, or about 25 to about 35, about 5 to about 40, about 10 to about 40, about 15 to about 40, about 20 to about 40, about 25 to about 40, or about 30 to about 40.
  • a hydrogel material disclosed herein exhibits medium hardness.
  • a hydrogel material exhibits a hardness of, e.g., about 40, about 45, about 50, about 55, or about 60.
  • a hydrogel material exhibits a hardness of, e.g., at least 40, at least 45, at least 50, at least 55, or at least 60.
  • a hydrogel material exhibits a hardness of, e.g., at most 40, at most 45, at most 50, at most 55, or at most 60.
  • a hydrogel material exhibits a hardness of, e.g., about 35 to about 60, about 35 to about 55, about 35 to about 50, about 35 to about 45, about 40 to about 60, about 45 to about 60, about 50 to about 60, about 55 to about 60, about 40 to about 65, about 45 to about 65, about 50 to about 65, about 55 to about 65.
  • a hydrogel material disclosed herein exhibits high hardness.
  • a hydrogel material exhibits a hardness of, e.g., about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100.
  • a hydrogel material exhibits a hardness of, e.g., at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100.
  • a hydrogel material exhibits a hardness of, e.g., about 65 to about 100, about 70 to about 100, about 75 to about 100,about 80 to about 100, about 85 to about 100, about 90 to about 100, about 65 to about 75, about 65 to about 80, about 65 to about 85, about 65 to about 90, about 65 to about 95, about 60 to about 75, about 60 to about 80, about 60 to about 85, about 60 to about 90, or about 60 to about 95.
  • a hydrogel material disclosed herein exhibits high resistant to deformation.
  • a hydrogel material exhibits resistant to deformation of, e.g., about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91 %, about 90%, about 89%, about 88%, about 87%, about 86%, or about 85%.
  • a hydrogel material exhibits resistant to deformation of, e.g., at least 99%, at least 98%, at least 97%, at least 96%, at least 95%, at least 94%, at least 93%, at least 92%, at least 91 %, at least 90%, at least 89%, at least 88%, at least 87%, at least 86%, or at least 85%.
  • a hydrogel material exhibits resistant to deformation of, e.g., at most 99%, at most 98%, at most 97%, at most 96%, at most 95%, at most 94%, at most 93%, at most 92%, at most 91 %, at most 90%, at most 89%, at most 88%, at most 87%, at most 86%, or at most 85%.
  • a hydrogel material exhibits resistant to deformation of, e.g., about 85% to about 100%, about 87% to about 100%, about 90% to about 100%, about 93% to about 100%, about 95% to about 100%, or about 97% to about 100%.
  • a hydrogel material disclosed herein exhibits high tensile strength. Tensile strength has three different definitional points of stress maxima. Yield strength refers to the stress at which material strain changes from elastic deformation to plastic deformation, causing it to deform permanently. Ultimate strength refers to the maximum stress a material can withstand when subjected to tension, compression or shearing. It is the maximum stress on the stress-strain curve. Breaking strength refers to the stress coordinate on the stress-strain curve at the point of rupture, or when the material pulls apart.
  • a hydrogel material disclosed herein exhibits high yield strength relative to other polymer classes.
  • a silk fibroin material exhibits a yield strength of, e.g., about 0.1 MPa, about 0.5 MPa, about 1 MPa, about 5 MPa, about 10 MPa, about 20 MPa, about 30 MPa, about 40 MPa, about 50 MPa, about 60 MPa, about 70 MPa, about 80 MPa, about 90 MPa, about 100 MPa, about 200 MPa, about 300 MPa, about 400 MPa, about 500 MPa.
  • a hydrogel material exhibits a yield strength of, e.g., at least 0.1 MPa, at least 0.5 MPa, at least 1 MPa, at least 5 MPa, at least 10 MPa, at least 20 MPa, at least 30 MPa, at least 40 MPa, at least 50 MPa, at least 60 MPa, at least 70 MPa, at least 80 MPa, at least 90 MPa, at least 100 MPa, at least 200 MPa, at least 300 MPa, at least 400 MPa, at least 500 MPa.
  • a hydrogel material exhibits a yield strength of, e.g., at most 1 MPa, at most 5 MPa, at most 10 MPa, at most 20 MPa, at most 30 MPa, at most 40 MPa, at most 50 MPa, at most 60 MPa, at most 70 MPa, at most 80 MPa, at most 90 MPa, at most 100 MPa, at most 200 MPa, at most 300 MPa, at most 400 MPa, at most 500 MPa, at most 600 MPa, at most 700 MPa, at most 800 MPa, at most 900 MPa, at most 1000 MPa, at most 1500 MPa, or at most 2000 MPa.
  • a hydrogel material exhibits a yield strength of, e.g., about 1 MPa to about 50 MPa, about 1 MPa to about 60 MPa, about 1 MPa to about 70 MPa, about 1 MPa to about 80 MPa, about 1 MPa to about 90 MPa, about 1 MPa to about 100 MPa, about 10 MPa to about 50 MPa, about 10 MPa to about 60 MPa, about 10 MPa to about 70 MPa, about 10 MPa to about 80 MPa, about 10 MPa to about 90 MPa, about 10 MPa to about 100 MPa, about 10 MPa to about 200 MPa, about 10 MPa to about 300 MPa, or about 100 MPa to about 300 MPa.
  • a hydrogel material disclosed herein exhibits high ultimate strength.
  • a hydrogel material exhibits an ultimate strength of, e.g., about 0.1 MPa, about 0.5 MPa, about 1 MPa, about 5 MPa, about 10 MPa, about 20 MPa, about 30 MPa, about 40 MPa, about 50 MPa, about 60 MPa, about 70 MPa, about 80 MPa, about 90 MPa, about 100 MPa, about 200 MPa, about 300 MPa, about 400 MPa, about 500 MPa.
  • a hydrogel material exhibits an ultimate strength of, e.g., at least 0.1 MPa, at least 0.5 MPa, at least 1 MPa, at least 5 MPa, at least 10 MPa, at least 20 MPa, at least 30 MPa, at least 40 MPa, at least 50 MPa, at least 60 MPa, at least 70 MPa, at least 80 MPa, at least 90 MPa, at least 100 MPa, at least 200 MPa, at least 300 MPa, at least 400 MPa, at least 500 MPa.
  • a hydrogel material exhibits an ultimate strength of, e.g., at most 1 MPa, at most 5 MPa, at most 10 MPa, at most 20 MPa, at most 30 MPa, at most 40 MPa, at most 50 MPa, at most 60 MPa, at most 70 MPa, at most 80 MPa, at most 90 MPa, at most 100 MPa, at most 200 MPa, at most 300 MPa, at most 400 MPa, at most 500 MPa, at most 600 MPa, at most 700 MPa, at most 800 MPa, at most 900 MPa, at most 1000 MPa, at most 1500 MPa, or at most 2000 MPa.
  • a hydrogel material exhibits an ultimate strength of, e.g., about 1 MPa to about 50 MPa, about 1 MPa to about 60 MPa, about 1 MPa to about 70 MPa, about 1 MPa to about 80 MPa, about 1 MPa to about 90 MPa, about 1 MPa to about 100 MPa, about 10 MPa to about 50 MPa, about 10 MPa to about 60 MPa, about 10 MPa to about 70 MPa, about 10 MPa to about 80 MPa, about 10 MPa to about 90 MPa, about 10 MPa to about 100 MPa, about 10 MPa to about 200 MPa, about 10 MPa to about 300 MPa, or about 100 MPa to about 300 MPa.
  • a hydrogel material disclosed herein exhibits high breaking strength.
  • a hydrogel material exhibits a breaking strength of, e.g. , about 0.1 MPa, about 0.5 MPa, about 1 MPa, about 5 MPa, about 10 MPa, about 20 MPa, about 30 MPa, about 40 MPa, about 50 MPa, about 60 MPa, about 70 MPa, about 80 MPa, about 90 MPa, about 100 MPa, about 200 MPa, about 300 MPa, about 400 MPa, about 500 MPa.
  • a hydrogel material exhibits a breaking strength of, e.g.
  • At least 0.1 MPa at least 0.5 MPa, at least 1 MPa, at least 5 MPa, at least 10 MPa, at least 20 MPa, at least 30 MPa, at least 40 MPa, at least 50 MPa, at least 60 MPa, at least 70 MPa, at least 80 MPa, at least 90 MPa, at least 100 MPa, at least 200 MPa, at least 300 MPa, at least 400 MPa, at least 500 MPa.
  • a hydrogel material exhibits a breaking strength of, e.g., at most 1 MPa, at most 5 MPa, at most 10 MPa, at most 20 MPa, at most 30 MPa, at most 40 MPa, at most 50 MPa, at most 60 MPa, at most 70 MPa, at most 80 MPa, at most 90 MPa, at most 100 MPa, at most 200 MPa, at most 300 MPa, at most 400 MPa, at most 500 MPa, at most 600 MPa, at most 700 MPa, at most 800 MPa, at most 900 MPa, at most 1000 MPa, at most 1500 MPa, or at most 2000 MPa.
  • a hydrogel material exhibits a breaking strength of, e.g., about 1 MPa to about 50 MPa, about 1 MPa to about 60 MPa, about 1 MPa to about 70 MPa, about 1 MPa to about 80 MPa, about 1 MPa to about 90 MPa, about 1 MPa to about 100 MPa, about 10 MPa to about 50 MPa, about 10 MPa to about 60 MPa, about 10 MPa to about 70 MPa, about 10 MPa to about 80 MPa, about 10 MPa to about 90 MPa, about 10 MPa to about 100 MPa, about 10 MPa to about 200 MPa, about 10 MPa to about 300 MPa, or about 100 MPa to about 300 MPa.
  • aspects of the present specification provide, in part, a hydrogel material disclosed herein having a transparency and/or translucency.
  • Transparency also called pellucidity or diaphaneity
  • translucency also called translucence or translucidity
  • the opposite property is opacity.
  • Transparent materials are clear, while translucent ones cannot be seen through clearly.
  • the silk fibroin hydrogels disclosed herein may, or may not, exhibit optical properties such as transparency and translucency. In certain cases, e.g., superficial line filling, it would be an advantage to have an opaque hydrogel.
  • hydrogel In other cases such as development of a lens or a "humor" for filling the eye, it would be an advantage to have a translucent hydrogel. These properties could be modified by affecting the structural distribution of the hydrogel material. Factors used to control a hydrogel's optical properties include, without limitation, polymer concentration, gel crystallinity, and hydrogel homogeneity.
  • a hydrogel material disclosed herein is optically transparent.
  • a hydrogel material transmits, e.g., about 75% of the light, about 80% of the light, about 85% of the light, about 90% of the light, about 95% of the light, or about 100% of the light.
  • a hydrogel material transmits, e.g., at least 75% of the light, at least 80% of the light, at least 85% of the light, at least 90% of the light, or at least 95% of the light.
  • a hydrogel material transmits, e.g., about 75% to about 100% of the light, about 80% to about 100% of the light, about 85% to about 100% of the light, about 90% to about 100% of the light, or about 95% to about 100% of the light.
  • a hydrogel material disclosed herein is optically opaque.
  • a hydrogel material transmits, e.g., about 5% of the light, about 10% of the light, about 15% of the light, about 20% of the light, about 25% of the light, about 30% of the light, about 35% of the light, about 40% of the light, about 45% of the light, about 50% of the light, about 55% of the light, about 60% of the light, about 65% of the light, or about 70% of the light.
  • a hydrogel material transmits, e.g., at most 5% of the light, at most 10% of the light, at most 15% of the light, at most 20% of the light, at most 25% of the light, at most 30% of the light, at most 35% of the light, at most 40% of the light, at most 45% of the light, at most 50% of the light, at most 55% of the light, at most 60% of the light, at most 65% of the light, at most 70% of the light, or at most 75% of the light.
  • a hydrogel material transmits, e.g., about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 45%, about 5% to about 50%, about 5% to about 55%, about 5% to about 60%, about 5% to about 65%, about 5% to about 70%, about 5% to about 75%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 15% to about 55%, about 15% to about 60%, about 15% to about 65%, about 15% to about 70%, about 15% to about 75%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% to about 55%, about 25% to about 60%, about 25% to about 65%, about 25% to about 70%, or about 25% to about 75%, of
  • a hydrogel material disclosed herein is optically translucent.
  • a hydrogel material diffusely transmits, e.g., about 75% of the light, about 80% of the light, about 85% of the light, about 90% of the light, about 95% of the light, or about 100% of the light.
  • a hydrogel material diffusely transmits, e.g., at least 75% of the light, at least 80% of the light, at least 85% of the light, at least 90% of the light, or at least 95% of the light.
  • a hydrogel material diffusely transmits, e.g., about 75% to about 100% of the light, about 80% to about 100% of the light, about 85% to about 100% of the light, about 90% to about 100% of the light, or about 95% to about 100% of the light.
  • Viscosity is resistance of a fluid to shear or flow caused by either shear stress or tensile stress. Viscosity describes a fluid's internal resistance to flow caused by intermolecular friction exerted when layers of fluids attempt to slide by one another and may be thought of as a measure of fluid friction. The less viscous the fluid, the greater its ease of movement (fluidity).
  • Viscosity can be defined in two ways; dynamic viscosity ( ⁇ , although ⁇ is sometimes used) or kinematic viscosity (v).
  • Dynamic viscosity also known as absolute or complex viscosity, is the tangential force per unit area required to move one horizontal plane with respect to the other at unit velocity when maintained a unit distance apart by the fluid.
  • the SI physical unit of dynamic viscosity is the Pascal- second (Pa s), which is identical to N-m-2-s.
  • Dynamic viscosity symbolize by is also used, is measured with various types of rheometers, devices used to measure the way in which a liquid, suspension or slurry flows in response to applied forces.
  • the viscosity of a material is highly temperature dependent and for either dynamic or kinematic viscosity to be meaningful, the reference temperature must be quoted.
  • a dynamic viscosity is measured at 1 Pa with a cone/plane geometry 2 40cm and a temperature of 20 °C.
  • Examples of the dynamic viscosity of various fluids at 20 °C is as follows: water is about 1.0 x 10 ⁇ 3 Pa s, blood is about 3-4 x 10 ⁇ 3 Pa s, vegetable oil is about 60-85 x 10 ⁇ 3 Pa s, motor oil SE 30 is about 0.2 Pa s, glycerin is about 1.4 Pa s, maple syrup is about 2-3 Pa s, honey is about 10 Pa s, chocolate syrup is about 10-25 Pa s, peanut butter is about 150-250 Pa s, lard is about 1 ,000 Pa s, vegetable shortening is about 1 ,200 Pa s, and tar is about 30,000 Pa s.
  • a hydrogel material disclosed herein exhibits a dynamic viscosity of, e.g. , about 10 Pa s, about 20 Pa s, about 30 Pa s, about 40 Pa s, about 50 Pa s, about 60 Pa s, about 70 Pa s, about 80 Pa s, about 90 Pa s, about 100 Pa s, about 125 Pa s, about 150 Pa s, about 175 Pa s, about 200 Pa s, about 225 Pa s, about 250 Pa s, about 275 Pa s, about 300 Pa s, about 400 Pa s, about 500 Pa s, about 600 Pa s, about 700 Pa s, about 750 Pa s, about 800 Pa s, about 900 Pa s, about 1 ,000 Pa s, about 1 ,100 Pa s, or about 1 ,200 Pa s.
  • a hydrogel material disclosed herein exhibits a dynamic viscosity of, e.g., at most 10 Pa s, at most 20 Pa s, at most 30 Pa s, at most 40 Pa s, at most 50 Pa s, at most 60 Pa s, at most 70 Pa s, at most 80 Pa s, at most 90 Pa s, at most 100 Pa s, at most 125 Pa s, at most 150 Pa s, at most 175 Pa s, at most 200 Pa s, at most 225 Pa s, at most 250 Pa s, at most 275 Pa s, at most 300 Pa s, at most 400 Pa s, at most 500 Pa s, at most 600 Pa s, at most 700 Pa s, at most 750 Pa s, at most 800 Pa s, at most 900 Pa s, or at most 1000 Pa s.
  • a hydrogel material disclosed herein exhibits a dynamic viscosity of, e.g., about 10 Pa s to about 100 Pa s, about 10 Pa s to about 150 Pa s, about 10 Pa s to about 250 Pa s, about 50 Pa s to about 100 Pa s, about 50 Pa s to about 150 Pa s, about 50 Pa s to about 250 Pa s, about 100 Pa s to about 500 Pa s, about 100 Pa s to about 750 Pa s, about 100 Pa s to about 1 ,000 Pa s, about 100 Pa s to about 1 ,200 Pa s, about 300 Pa s to about 500 Pa s, about 300 Pa s to about 750 Pa s, about 300 Pa s to about 1 ,000 Pa s, or about 300 Pa s to about 1 ,200 Pa s.
  • Cohesivity also referred to as cohesion cohesive attraction, cohesive force, or compression force is a physical property of a material, caused by the intermolecular attraction between like-molecules within the material that acts to unite the molecules. Cohesivity is expressed in terms of grams-force (gmf). Cohesiveness is affected by, among other factors, the molecular weight ratio of the initial free glycosaminoglycan polymer, the degree of crosslinking of glycosaminoglycan polymers, the amount of residual free glycosaminoglycan polymers following crosslinking, and the pH of the hydrogel material.
  • a composition should be sufficiently cohesive as to remain localized to a site of administration. Additionally, in certain applications, a sufficient cohesiveness is important for a composition to retain its shape, and thus functionality, in the event of mechanical load cycling.
  • a hydrogel material disclosed herein exhibits cohesivity, on par with water.
  • a hydrogel material disclosed herein exhibits sufficient cohesivity to remain localized to a site of administration.
  • a hydrogel material disclosed herein exhibits sufficient cohesivity to retain its shape.
  • a hydrogel material disclosed herein exhibits sufficient cohesivity to retain its shape and functionality.
  • a hydrogel material disclosed herein has a cohesivity of, e.g., about 10 gmf, about 20 gmf, about 30 gmf, about 40 gmf, about 50 gmf, about 60 gmf, about 70 gmf, about 80 gmf, about 90 gmf, about 100 gmf, about 150 gmf, or about 200 gmf.
  • a hydrogel material disclosed herein has a cohesivity of, e.g., at least 10 gmf, at least 20 gmf, at least 30 gmf, at least 40 gmf, at least 50 gmf, at least 60 gmf, at least 70 gmf, at least 80 gmf, at least 90 gmf, at least 100 gmf, at least 150 gmf, or at least 200 gmf.
  • a hydrogel material disclosed herein has a cohesivity of, e.g., at most 10 gmf, at most 20 gmf, at most 30 gmf, at most 40 gmf, at most 50 gmf, at most 60 gmf, at most 70 gmf, at most 80 gmf, at most 90 gmf, at most 100 gmf, at most 150 gmf, or at most 200 gmf.
  • a hydrogel material disclosed herein has a cohesivity of, e.g., about 50 gmf to about 150 gmf, about 60 gmf to about 140 gmf, about 70 gmf to about 130 gmf, about 80 gmf to about 120 gmf, or about 90 gmf to about 1 10 gmf .
  • a hydrogel material disclosed herein has a cohesivity of, e.g., about 10 gmf to about 50 gmf, about 25 gmf to about 75 gmf, about 50 gmf to about 150 gmf, about 100 gmf to about 200 gmf, about 100 gmf to about 300 gmf, about 100 gmf to about 400 gmf, about 100 gmf to about 500 gmf, about 200 gmf to about 300 gmf, about 200 gmf to about 400 gmf, about 200 gmf to about 500 gmf, about 200 gmf to about 600 gmf, about 200 gmf to about 700 gmf, about 300 gmf to about 400 gmf, about 300 gmf to about 500 gmf, about 300 gmf to about 600 gmf, about 300 gmf to about 400 gmf, about 300 gmf to
  • aspects of the present specification provide, in part, a hydrogel material disclosed herein that exhibits a physiologically-acceptable osmolarity.
  • osmolarity refers to the concentration of osmotically active solutes in solution.
  • a physiologically- acceptable osmolarity refers to an osmolarity in accord with, or characteristic of, the normal functioning of a living organism. As such, administration of a hydrogel material as disclosed herein exhibits an osmolarity that has substantially no long term or permanent detrimental effect when administered to a mammal.
  • Osmolarity is expressed in terms of osmoles of osmotically active solute per liter of solvent (Osmol/L or Osm/L). Osmolarity is distinct from molarity because it measures moles of osmotically active solute particles rather than moles of solute. The distinction arises because some compounds can dissociate in solution, whereas others cannot.
  • osmolarity of a hydrogel material disclosed herein can be measured using a conventional method that measures solutions.
  • a hydrogel material disclosed herein exhibits a physiologically-acceptable osmolarity.
  • a hydrogel material exhibits an osmolarity of, e.g., about 100 mOsm/L, about 150 mOsm/L, about 200 mOsm/L, about 250 mOsm/L, about 300 mOsm/L, about 350 mOsm/L, about 400 mOsm/L, about 450 mOsm/L, or about 500 mOsm/L.
  • a hydrogel material exhibits an osmolarity of, e.g.
  • a hydrogel material exhibits an osmolarity of, e.g.
  • a hydrogel material exhibits an osmolarity of, e.g.
  • aspects of the present specification provide, in part, a hydrogel material disclosed herein that exhibits a physiologically-acceptable osmolality.
  • osmolality refers to the concentration of osmotically active solutes per kilo of solvent in the body.
  • a physiologically-acceptable osmolality refers to an osmolality in accord with, or characteristic of, the normal functioning of a living organism. As such, administration of a hydrogel material disclosed herein exhibits an osmolality that has substantially no long term or permanent detrimental effect when administered to a mammal.
  • Osmolality is expressed in terms of osmoles of osmotically active solute per kilogram of solvent (osmol/kg or Osm/kg) and is equal to the sum of the molalities of all the solutes present in that solution.
  • the osmolality of a solution can be measured using an osmometer.
  • the most commonly used instrument in modern laboratories is a freezing point depression osmometer. This instruments measure the change in freezing point that occurs in a solution with increasing osmolality (freezing point depression osmometer) or the change in vapor pressure that occurs in a solution with increasing osmolality (vapor pressure depression osmometer).
  • a hydrogel material disclosed herein exhibits a physiologically-acceptable osmolality.
  • a hydrogel material exhibits an osmolality of, e.g. , about 100 mOsm/kg, about 150 mOsm/kg, about 200 mOsm/kg, about 250 mOsm/kg, about 300 mOsm/kg, about 350 mOsm/kg, about 400 mOsm/kg, about 450 mOsm/kg, or about 500 mOsm/kg.
  • a hydrogel material exhibits an osmolality of, e.g.
  • a hydrogel material exhibits an osmolality of, e.g.
  • a hydrogel material exhibits an osmolality of, e.g.
  • a hydrogel material disclosed herein is typically resistant to biodegradation upon administration to an individual.
  • resistant to biodegradation is synonymous with “resistant to bioerosion”, “resistant to bioresorption”, “non-biodegradable”, “non-bioerodable” and “non-bioresorbable” and refers to a hydrogel material disclosed herein that is not prone to degrading, eroding, resorbing, decomposing, or breaking down to any substantial or significant degree while implanted in an individual. This resistence to biodegradation enables the hydrogel to retain and maintain the tissue space in order to promote new tissue growth into the space.
  • Non-limiting examples of substantial non-degradation or resistance to biodegradation include less than 10% degradation of a hydrogel material over a time period measured, less than 5% degradation of a hydrogel material over a time period measured, less than 3% degradation of a hydrogel material over a time period measured, less than 1 % degradation of a hydrogel material over a time period measured.
  • a hydrogel material disclosed herein is substantially non-biodegradable or resistant to biodegradation upon administration to an individual.
  • hydrogel material should be degradable or time.
  • the rate of degradation imparted on the gel will be determined by the speed of replacement with fat and maintenance of volume.
  • hydrogel material will be resistant to degradation early on with degradation occurring over several months.
  • a hydrogel material is substantially non-biodegradable or resistance to biodegradation for, e.g., about 10 days, about 20 days, about 30 days, about 40 days, about 50 days, about 60 days, about 70 days, about 80 days, or about 90 days, before biodegradation occurs.
  • a hydrogel material is substantially non-biodegradable or resistant to biodegradation for, e.g., at least 10 days, at least 20 days, at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 70 days, at least 80 days, or at least 90 days, before biodegradation occurs.
  • a hydrogel material is substantially non-biodegradable or resistant to biodegradation for, e.g., at most 10 days, at most 20 days, at most 30 days, at most 40 days, at most 50 days, at most 60 days, at most 70 days, at most 80 days, or at most 90 days, before biodegradation occurs.
  • a hydrogel material is substantially nonbiodegradable or resistant to biodegradation for, e.g., about 10 days to about 30 days, about 20 days to about 50 days, about 40 days to about 60 days, about 50 days to about 80 days, or about 60 days to about 90 days, before biodegradation occurs.
  • biodegradation of a hydrogel material disclosed herein occurs with substantially first order release kinetics over a period of, e.g., about 7 days after, about 15 days, about 30 days, about 45 days, about 60 days, about 75 days, or about 90 days after degradation begins.
  • biodegradation of a hydrogel material disclosed herein occurs with substantially first order release kinetics over a period of e.g., at least 7 days, at least 15 days, at least 30 days, at least 45 days, at least 60 days, at least 75 days, or at least 90 days after degradation begins.
  • biodegradation of a hydrogel material disclosed herein occurs with substantially first order release kinetics over a period of, e.g., about 10 days to about 30 days, about 20 days to about 50 days, about 40 days to about 60 days, about 50 days to about 80 days, or about 60 days to about 90 days, after degradation begins.
  • compositions disclosed herein may optionally comprise one or more additional materials useful as a filler for tissue space.
  • Exemplary filler materials suitable with the compositions and methods disclosed herein include, without limitation, fillers comprising a polypeptide such as, e.g., a silk protein, (like silk fibroin), a resilin, a resilin-like polypeptide, an elastin, an elastin-like polypeptide, a silk protein- elastin-like polypeptide, an abductin, a byssus, a gliadin, a glutenin, abductin, keratin, gelatin, or collagen; fillers comprising a polysaccharide such as, e.g., cellulose, agarose, chitosan, or chitin; and fillers comprising a polyester such as, e.g., D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, caprolactone.
  • These additional tissue space fillers may be administered as a separate component, or may be complexed with a hydrogel material disclosed herein.
  • compositions disclosed herein may optionally comprise one or more immunosuppressive agents that reduce, and preferably prevent, rejection of the transplanted tissue.
  • immunosuppressive agent is synonymous with “immunosuppressive drug” and refers to a compound that inhibits or interferes with normal immune function.
  • immunosuppressive agents suitable with the compositions and methods disclosed herein include, without limitation, agents that inhibit T- cell/B-cell costimulation pathways like agents that interfere with the coupling of T-cells and B-cells via the CTLA4 and B7 pathways, including cyclosporine A, myophenylate mofetil, rapamicin, and anti-thymocyte globulin.
  • An immunosuppressive drug is administered in a formulation that is compatible with the route of administration and is administered to an individual at a dosage sufficient to achieve the desired therapeutic effect.
  • compositions disclosed herein may further and optionally comprise another agent or combination of agents that provide a beneficial effect when the composition is administered to an individual.
  • beneficial agents include, without limitation, an anti-itch agent, an anti-cellulite agent, an anti-scarring agent, an anti-inflammatory agent, an anesthetic agent, an anti-irritant agent, a vasoconstrictor, a vasodilator, an anti-hemorrhagic agent like a hemostatic agent or anti-fibrinolytic agent, a desquamating agent, a tensioning agent, an anti-acne agent, a pigmentation agent, an anti- pigmentation agent, or a moisturizing agent.
  • agents are known in the art and described in, e.g.
  • a composition disclosed herein comprises an immunosuppressive agent, an anti-itch agent, an anti-cellulite agent, an anti-scarring agent, an anti-inflammatory agent, an anesthetic agent, an anti-irritant agent, a vasoconstrictor, a vasodilator, an anti-hemorrhagic agent like a hemostatic agent or anti-fibrinolytic agent, a desquamating agent, a tensioning agent, an anti-acne agent, a pigmentation agent, an anti-pigmentation agent, and/or a moisturizing agent in an amount of, e.g., about 0.1 %, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8% about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0%, or about 10% by weight of the total composition.
  • a composition disclosed herein comprises an immunosuppressive agent, an anti-itch agent, an anti-cellulite agent, an anti-scarring agent, an anti-inflammatory agent, an anesthetic agent, an anti-irritant agent, a vasoconstrictor, a vasodilator, an anti-hemorrhagic agent like a hemostatic agent or anti-fibrinolytic agent, a desquamating agent, a tensioning agent, an anti-acne agent, a pigmentation agent, an anti- pigmentation agent, and/or a moisturizing agent in an amount of, e.g.
  • a composition disclosed herein comprises an immunosuppressive agent, an anti-itch agent, an anti-cellulite agent, an anti-scarring agent, an anti-inflammatory agent, an anesthetic agent, an anti-irritant agent, a vasoconstrictor, a vasodilator, an anti-hemorrhagic agent like a hemostatic agent or anti-fibrinolytic agent, a desquamating agent, a tensioning agent, an anti-acne agent, a pigmentation agent, an anti- pigmentation agent, and/or a moisturizing agent in an amount of, e.g., at most 0.1 %, at most 0.2%, at most 0.3%, at most 0.4%, at most 0.5%, at most 0.6%, at most 0.7%, at most 0.8% at most 0.9%, at most 1.0%, at most 2.0%, at most 3.0%, at most 4.0%, at most 5.0%, at most 6.0%, at most 7.0%, at most 8.0%, at most 9.0%, or at
  • a composition disclosed herein comprises an anti-inflammatory agent in an amount of, e.g., about 0.1 % to about 0.5%, about 0.1 % to about 1.0%, about 0.1 % to about 2.0%, about 0.1 % to about 3.0%, about 0.1 % to about 4.0%, about 0.1 % to about 5.0%, about 0.2% to about 0.9%, about 0.2% to about 1.0%, about 0.2% to about 2.0%, about 0.5% to about 1.0%, or about 0.5% to about 2.0% by weight of the total composition.
  • a composition disclosed herein comprises an immunosuppressive agent, an anti-itch agent, an anti-cellulite agent, an anti-scarring agent, an antiinflammatory agent, an anesthetic agent, an anti-irritant agent, a vasoconstrictor, a vasodilator, an anti- hemorrhagic agent like a hemostatic agent or anti-fibrinolytic agent, a desquamating agent, a tensioning agent, an anti-acne agent, a pigmentation agent, an anti-pigmentation agent, and/or a moisturizing agent at a concentration of, e.g., about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/m
  • a composition disclosed herein comprises an immunosuppressive agent, an anti-itch agent, an anti-cellulite agent, an anti-scarring agent, an anti-inflammatory agent, an anesthetic agent, an anti-irritant agent, a vasoconstrictor, a vasodilator, an anti-hemorrhagic agent like a hemostatic agent or anti-fibrinolytic agent, a desquamating agent, a tensioning agent, an anti-acne agent, a pigmentation agent, an anti-pigmentation agent, and/or a moisturizing agent at a concentration of, e.g., at least 0.01 mg/mL, at least 0.02 mg/mL, at least 0.03 mg/mL, at least 0.04 mg/mL, at least 0.05 mg/mL, at least 0.06 mg/mL, at least 0.07 mg/mL, at least 0.08 mg/mL, at least 0.09 mg/mL, at least 0.1 mg/m
  • a composition disclosed herein comprises an immunosuppressive agent, an anti-itch agent, an anti-cellulite agent, an anti-scarring agent, an antiinflammatory agent, an anesthetic agent, an anti-irritant agent, a vasoconstrictor, a vasodilator, an anti- hemorrhagic agent like a hemostatic agent or anti-fibrinolytic agent, a desquamating agent, a tensioning agent, an anti-acne agent, a pigmentation agent, an anti-pigmentation agent, and/or a moisturizing agent at a concentration of, e.g., at most 0.01 mg/mL, at most 0.02 mg/mL, at most 0.03 mg/mL, at most 0.04 mg/mL, at most 0.05 mg/mL, at most 0.06 mg/mL, at most 0.07 mg/mL, at most 0.08 mg/mL, at most 0.09 mg/mL, at most 0.1 mg/mL
  • a composition disclosed herein comprises an anti-inflammatory agent at a concentration of, e.g. , about 0.01 mg/mL to about 0.7 mg/mL, about 0.06 mg/mL to about 0.7 mg/mL, about 0.01 mg/mL to about 1.0 mg/mL, about 0.05 mg/mL to about 1.0 mg/mL, about 0.06 mg/mL to about 1.0 mg/mL, about 0.1 mg/mL to about 1.0 mg/mL, about 0.1 mg/mL to about 2.0 mg/mL, about 0.1 mg/mL to about 3.0 mg/mL, about 0.1 mg/mL to about 4.0 mg/mL, about 0.1 mg/mL to about 5.0 mg/mL, about 0.2 mg/mL to about 0.9 mg/mL, about 0.2 mg/mL to about 1 .0 mg/mL, about 0.2 mg/mL to about 2.0 mg/mL, about 0.5 mg/mL to about 1.0 mg/mL, or about
  • a composition disclosed herein does not comprise an immunosuppressive agent, an anti-itch agent, an anti-cellulite agent, an anti-scarring agent, an antiinflammatory agent, an anesthetic agent, an anti-irritant agent, a vasoconstrictor, a vasodilator, an anti- hemorrhagic agent like a hemostatic agent or anti-fibrinolytic agent, a desquamating agent, a tensioning agent, an anti-acne agent, a pigmentation agent, an anti-pigmentation agent, and/or a moisturizing agent.
  • a compound disclosed herein, or a composition comprising such a compound is generally administered to an individual as a pharmaceutical composition.
  • Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present specification, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, with conventional acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use.
  • the therapeutically efficient amount typically is between about 0.0001 % (w/v) and about 5% (w/v), preferably about 0.001 % (w/v) to about 1.0% (w/v) in liquid formulations.
  • pharmaceutical composition refers to a therapeutically effective concentration of an active compound, such as, e.g.
  • the pharmaceutical composition does not produce an adverse, allergic, or other untoward or unwanted reaction when administered to an individual.
  • a pharmaceutical composition disclosed herein is useful for medical and veterinary applications.
  • a pharmaceutical composition may be administered to an individual alone, or in combination with other supplementary active compounds, agents, drugs or hormones.
  • the pharmaceutical compositions may be manufactured using any of a variety of processes, including, without limitation, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, and lyophilizing.
  • the pharmaceutical composition can take any of a variety of forms including, without limitation, a sterile solution, suspension, emulsion, lyophilizate, tablet, pill, pellet, capsule, powder, syrup, elixir, or any other dosage form suitable for administration.
  • the compounds disclosed herein may also be incorporated into a drug delivery platform in order to achieve a controlled compound release profile over time.
  • a drug delivery platform comprises a compound disclosed herein dispersed within a polymer matrix, typically a biodegradable, bioerodible, and/or bioresorbable polymer matrix.
  • polymer refers to synthetic homo- or copolymers, naturally occurring homo- or copolymers, as well as synthetic modifications or derivatives thereof having a linear, branched or star structure. Copolymers can be arranged in any form, such as, e.g. , random, block, segmented, tapered blocks, graft, or triblock. Polymers are generally condensation polymers. Polymers can be further modified to enhance their mechanical or degradation properties by introducing cross-linking agents or changing the hydrophobicity of the side residues. If crosslinked, polymers are usually less than 5% crosslinked, usually less than 1 % crosslinked.
  • Suitable polymers for use in a drug delivery platform include, without limitation, alginates, aliphatic polyesters, polyalkylene oxalates, polyamides, polyamidoesters, polyanhydrides, polycarbonates, polyesters, polyethylene glycol, polyhydroxyaliphatic carboxylic acids, polyorthoesters, polyoxaesters, polypeptides, polyphosphazenes, polysaccharides, and polyurethanes.
  • the polymer usually comprises at least about 10% (w/w), at least about 20% (w/w), at least about 30% (w/w), at least about 40% (w/w), at least about 50% (w/w), at least about 60% (w/w), at least about 70% (w/w), at least about 80% (w/w), or at least about 90% (w/w) of the drug delivery platform.
  • biodegradable, bioerodible, and/or bioresorbable polymers and methods useful to make a drug delivery platform are described in, e.g. , Drost, et. al., Controlled Release Formulation, U.S. Patent 4,756,91 1 ; Smith, et. al., Sustained Release Drug Delivery Devices, U.S.
  • Patent 5,378,475 Wong and Kochinke, Formulation for Controlled Release of Drugs by Combining Hyrophilic and Hydrophobic Agents, U.S. Patent 7,048,946; Hughes, et. Al., Compositions and Methods for Localized Therapy of the Eye, U.S. Patent Publication 2005/0181017; Hughes, Hypotensive Lipid-Containing Biodegradable Intraocular Implants and Related Methods, U.S. Patent Publication 2005/0244464; Altman, et al., Silk Fibroin Hydrogels and Uses Thereof, U.S. Patent Application 12/764,039, filed on April 20, 2010; each of which is incorporated by reference in its entirety.
  • a polymer composing the matrix is a polypeptide such as, e.g. , silk fibroin, keratin, or collagen.
  • a polymer composing the matrix is a polysaccharide such as, e.g., cellulose, agarose, elastin, chitosan, chitin, or a glycosaminoglycan like chondroitin sulfate, dermatan sulfate, keratan sulfate, or hyaluronic acid (as discussed supra).
  • a polymer composing the matrix is a polyester such as, e.g., D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, and combinations thereof.
  • a suitable polymer for forming a suitable disclosed drug delivery platform depends on several factors.
  • the more relevant factors in the selection of the appropriate polymer(s) include, without limitation, compatibility of polymer with a drug, desired release kinetics of a drug, desired biodegradation kinetics of platform at implantation site, desired bioerodible kinetics of platform at implantation site, desired bioresorbable kinetics of platform at implantation site, in vivo mechanical performance of platform, processing temperatures, biocompatibility of platform, and patient tolerance.
  • Other relevant factors that, to some extent, dictate the in vitro and in vivo behavior of the polymer include the chemical composition, spatial distribution of the constituents, the molecular weight of the polymer and the degree of crystallinity.
  • a drug delivery platform includes both a sustained release drug delivery platform and an extended release drug delivery platform.
  • sustained release refers to the release of a compound disclosed herein over a period of about seven days or more.
  • extended release refers to the release of a compound disclosed herein over a period of time of less than about seven days.
  • a sustained release drug delivery platform releases a compound disclosed herein with substantially first order release kinetics over a period of, e.g. , about 7 days after administration, about 15 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration.
  • a sustained release drug delivery platform releases a compound disclosed herein with substantially first order release kinetics over a period of, e.g. , at least 7 days after administration, at least 15 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.
  • a drug delivery platform releases a compound disclosed herein with substantially first order release kinetics over a period of, e.g. , about 1 day after administration, about 2 days after administration, about 3 days after administration, about 4 days after administration, about 5 days after administration, or about 6 days after administration.
  • a drug delivery platform releases a compound disclosed herein with substantially first order release kinetics over a period of, e.g. , at most 1 day after administration, at most 2 days after administration, at most 3 days after administration, at most 4 days after administration, at most 5 days after administration, or at most 6 days after administration.
  • a pharmaceutical composition disclosed herein can optionally include a pharmaceutically acceptable carrier that facilitates processing of an active compound into pharmaceutically acceptable compositions.
  • a pharmaceutically acceptable carrier is synonymous with “pharmacological carrier” and refers to any carrier that has substantially no long term or permanent detrimental effect when administered and encompasses terms such as "pharmacologically acceptable vehicle, stabilizer, diluent, additive, auxiliary, or excipient.”
  • Such a carrier generally is mixed with an active compound or permitted to dilute or enclose the active compound and can be a solid, semi-solid, or liquid agent. It is understood that the active compounds can be soluble or can be delivered as a suspension in the desired carrier or diluent.
  • aqueous media such as, e.g. , water, saline, glycine, hyaluronic acid and the like
  • solid carriers such as, e.g., starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like
  • solvents dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient.
  • Selection of a pharmacologically acceptable carrier can depend on the mode of administration.
  • any pharmacologically acceptable carrier is incompatible with the active compound, its use in pharmaceutically acceptable compositions is contemplated.
  • Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7 th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20 th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G.
  • a pharmaceutical composition disclosed herein may optionally include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like.
  • buffers include, without limitation, acetate buffers, borate buffers, citrate buffers, phosphate buffers, neutral buffered saline, and phosphate buffered saline.
  • antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.
  • Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition, such as, e.g. , sodium chlorite and chelants, such as, e.g.
  • Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor.
  • the pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical composition useful in the invention.
  • aspects of the present specification provide, in part, a method of treating a soft tissue condition of an individual by administering a composition disclosed herein.
  • the term “treating,” refers to reducing or eliminating in an individual a cosmetic or clinical symptom of a soft tissue condition characterized by a soft tissue imperfection, defect, disease, and/or disorder; or delaying or preventing in an individual the onset of a cosmetic or clinical symptom of a condition characterized by a soft tissue imperfection, defect, disease, and/or disorder.
  • the term “treating” can mean reducing a symptom of a condition characterized by a soft tissue defect, disease, and/or disorder by, e.g.
  • a soft tissue defect, disease, and/or disorder can be determined by observing one or more cosmetic, clinical symptoms, and/or physiological indicators associated with the condition. An improvement in a soft tissue defect, disease, and/or disorder also can be indicated by a reduced need for a concurrent therapy. Those of skill in the art will know the appropriate symptoms or indicators associated with specific soft tissue defect, disease, and/or disorder and will know how to determine if an individual is a candidate for treatment with a compound or composition disclosed herein.
  • a composition or compound is administered to an individual.
  • An individual is typically a human being.
  • any individual who is a candidate for a conventional soft tissue replacement procedure is a candidate for a soft tissue replacement procedure disclosed herein.
  • the presently disclosed compositions and methods may apply to individuals seeking a small/moderate enlargement, shape change or contour alteration of a body part or region, which may not be technically possible or aesthetically acceptable with existing soft tissue implant technology.
  • Pre-operative evaluation typically includes routine history and physical examination in addition to thorough informed consent disclosing all relevant risks and benefits of the procedure.
  • a soft tissue condition includes, without limitation, a soft tissue imperfection, defect, disease, and/or disorder.
  • a soft tissue condition includes breast imperfection, defect, disease and/or disorder, such as, e.g. , a breast augmentation, a breast reconstruction mastopexy, micromastia, thoracic hypoplasia, Tru's syndrome, defects due to implant complications like capsular contraction and/or rupture; a facial imperfection, defect, disease or disorder, such as, e.g.
  • a facial augmentation, a facial reconstruction Parry-Romberg syndrome, lupus erythematosus profundus, dermal divots, sunken cheeks, thin lips, nasal imperfections or defects, retro-orbital imperfections or defects, a facial fold, line and/or wrinkle like a glabellar line, a nasolabial line, a perioral line, and/or a marionette line, and/or other contour deformities or imperfections of the face; a neck imperfection, defect, disease or disorder; a skin imperfection, defect, disease and/or disorder; other soft tissue imperfections, defects, diseases and/or disorders, such as, e.g., an augmentation or a reconstruction of the upper arm, lower arm, hand, shoulder, back, torso including abdomen, buttocks, upper leg, lower leg including calves, foot including plantar fat pad, eye, genitals, or other body part, region or area, or a disease or disorder affecting these body parts, regions or areas
  • the amount of adipose tissue and/or hydrogel material used with any of the methods as disclosed herein will typically be determined based on the alteration and/or improvement desired, the reduction and/or elimination of a soft tissue condition symptom desired, the clinical and/or cosmetic effect desired by the individual and/or physician, and the body part or region being treated.
  • the effectiveness of adipose tissue and/or hydrogel material administration may be manifested by one or more of the following clinical and/or cosmetic measures: altered and/or improved soft tissue shape, altered and/or improved soft tissue size, altered and/or improved soft tissue contour, altered and/or improved tissue function, improved transplant tissue survival, improved patient satisfaction and/or quality of life, and decreased use of implantable foreign material.
  • effectiveness of adipose tissue and/or hydrogel material administration may be manifested by one or more of the following clinical and/or cosmetic measures: increased breast size, altered breast shape, altered breast contour, sustained engraftment, decreased rate of liponecrotic cyst formation, improved patient satisfaction and/or quality of life, and decreased use of breast implant.
  • effectiveness of adipose tissue and/or hydrogel material administration in treating a facial soft tissue may be manifested by one or more of the following clinical and/or cosmetic measures: increased size, shape, and/or contour of facial feature like increased size, shape, and/or contour of lip, cheek or eye region; altered size, shape, and/or contour of facial feature like altered size, shape, and/or contour of lip, cheek or eye region shape; reduction or elimination of a wrinkle, fold or line in the skin; resistance to a wrinkle, fold or line in the skin; rehydration of the skin; increased elasticity to the skin; reduction or elimination of skin roughness; increased and/or improved skin tautness; reduction or elimination of stretch lines or marks; increased and/or improved skin tone, shine, brightness and/or radiance; increased and/or improved skin color, reduction or elimination of skin paleness; sustained engraftment of composition; decreased side effects; improved patient satisfaction and/or quality of life.
  • effectiveness of adipose tissue and/or hydrogel material administration for sphincter support may be manifested by one or more of the following clinical measures: decreased frequency of incontinence, sustained engraftment, improved patient satisfaction and/or quality of life, and decreased use of implantable foreign filler.
  • an effective amount is synonymous with “effective amount”, “therapeutically effective dose”, and/or " effective dose” and refers to the amount of compound that will elicit the biological, cosmetic or clinical response being sought by the practitioner in an individual in need thereof.
  • an effective amount is an amount sufficient to promote formation of a blood supply sufficient to support the transplanted tissue.
  • an effective amount is an amount sufficient to promote formation of new blood vessels and associated vasculature (angiogenesis) and/or an amount sufficient to promote repair or remodeling of existing blood vessels and associated vasculature.
  • an effective amount can be extrapolated from in vitro and in vivo assays as described in the present specification.
  • an effective amount can be extrapolated from in vitro and in vivo assays as described in the present specification.
  • One skilled in the art will recognize that the condition of the individual can be monitored throughout the course of therapy and that the effective amount of a compound or composition disclosed herein that is administered can be adjusted accordingly.
  • the amount of a compound added is, e.g., 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg.
  • the amount of a compound added is, e.g., 0.01 mg/mL, 0.05 mg/mL, 0.1 mg/mL, 0.5 mg/mL, 1 mg/mL, 5 mg/mL, 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 150 mg/mL, 200 mg/mL, 250 mg/mL, 500 mg/mL, 750 mg/mL, or 1000 mg/mL.
  • the amount of a compound added is, e.g., 0.01 mg/10 mL of tissue, 0.05 mg/10 mL of tissue, 0.1 mg/10 mL of tissue, 0.5 mg/10 mL of tissue, 1 mg/10 mL of tissue, 5 mg/10 mL of tissue, 10 mg/10 mL of tissue, 20 mg/10 mL of tissue, 30 mg/10 mL of tissue, 40 mg/10 mL of tissue, 50 mg/10 mL of tissue, 60 mg/10 mL of tissue, 70 mg/10 mL of tissue, 80 mg/10 mL of tissue, 90 mg/10 mL of tissue, 100 mg/10 mL of tissue, 150 mg/10 mL of tissue, 200 mg/10 mL of tissue, 250 mg/10 mL of tissue, 500 mg/10 mL of tissue, 750 mg/10 mL of tissue, or 1000 mg/10 mL of tissue.
  • the amount of a compound added is, e.g., about 0.01 mg to about 0.1 mg, about 0.1 mg to about 1 mg, about 1 mg to about 10 mg, about 10 mg to about 100 mg, or about 100 mg to about 1000 mg. In other aspects of this embodiment, the amount of a compound added is, e.g., about 0.01 mg/mL to about 0.1 mg/mL, about 0.1 mg/mL to about 1 mg/mL, about 1 mg/mL to about 10 mg/mL, about 10 mg/mL to about 100 mg/mL, or about 100 mg/mL to about 1000 mg/mL.
  • the amount of a compound added is, e.g., about 0.01 mg/10 mL of tissue to about 0.1 mg/10 mL of tissue, about 0.1 mg/10 mL of tissue to about 1 mg/10 mL of tissue, about 1 mg/10 mL of tissue to about 10 mg/10 mL of tissue, about 10 mg/10 mL of tissue to about 100 mg/10 mL of tissue, or about 100 mg/10 mL of tissue to about 1000 mg/10 mL of tissue.
  • the amount of a compound added is, e.g., about 0.0001 % (w/v) to about 5% (w/v), about 0.001 % (w/v) to about 5% (w/v), about 0.01 % (w/v) to about 5% (w/v), about 0.1 % (w/v) to about 5% (w/v), or about 1 % (w/v) to about 5% (w/v).
  • the amount of a compound added is, e.g., about 0.001 % (w/v) to about 1.0% (w/v), about 0.01 % (w/v) to about 1.0% (w/v), or about 0.1 % (w/v) to about 1.0% (w/v).
  • a composition disclosed herein can be mixed with the harvested adipose tissue and, as such, be administered simultaneously with the adipose tissue. Additionally, or alternatively, a composition disclosed herein can be administered after administration of the adipose tissue. In aspects of this embodiment, a composition disclosed herein is administered to the individual additionally, or alternatively, e.g., about 1 day after adipose tissue implantation, about 2 days after adipose tissue implantation, about 3 days after adipose tissue implantation, or about 4 days after adipose tissue implantation. In other aspects, a composition disclosed herein is administered to the individual additionally, or alternatively, e.g.
  • the daily dose can be, e.g., twice a day, three times a day, or four times a day.
  • compositions or adipose tissue may be administered by any means known to persons of ordinary skill in the art including, without limitation, syringe with needle, catheter, or by direct surgical implantation.
  • the disclosed composition or adipose tissue can be administered once, or over a plurality of times. Ultimately, the timing used will follow quality care standards.
  • the route of administration may include axillary, periareolar, and/or inframammary routes.
  • the route of administration can be frontal, temporal, zygomatic, periocular, amdibula, perioral or chin routes.
  • the route of administration may include transurethral or periurethral routes.
  • the transplant may be delivered via an antegrade route.
  • the routes discussed herein do not exclude the use of multiple routes to achieve the desired clinical effect, or umbilical incision.
  • cell-enhanced tissue may be delivered through a transaxillary endoscopic subpectoral approach.
  • a composition or compound administered to an individual to treat a soft tissue condition promotes formation of a blood supply sufficient to support the transplanted tissue.
  • Blood supply formation includes, without limitation, formation of new blood vessels and associated vasculature (angiogenesis) and repair or remodel of existing blood vessels and associated vasculature.
  • aspects of the present specification disclose, in part, a method of treating a soft tissue condition of an individual, the method comprising the steps of a) administering the adipose tissue to a site of the soft tissue condition; and b) administering a composition comprising a compound as disclosed herein to the site of the soft tissue condition.
  • the adipose tissue and compound(s) administered include the adipose tissue disclosed herein.
  • the adipose tissue is administered separately from a composition comprising the compound.
  • adipose tissue is administered first, followed by administration of a composition comprising the compound.
  • a composition comprising a compound is administered first, followed by administration of adipose tissue.
  • the composition comprising a compound further comprises an HA.
  • a second composition comprising HA is administered at the same time, before, or after the administration of the first composition that comprises one or more of the compounds disclosed herein.
  • aqueous layer was extracted with 100 mL ether and the combined ether solution washed with brine and then dried (MgS0 4 ), filtered and evaporated to leave a yellow oil (6.333 g) that was used directly in the next step.
  • HMPA propargyl iodide
  • THF 1.0 mL
  • the solution was stirred in a -40 °C bath overnight and then 20 mL saturated ammonium chloride solution and 10 mL water were added.
  • the mixture was extracted with dichloromethane (20 mL) and ethyl acetate (2 x 20 mL).
  • the combined organic extracts were dried (MgS0 4 ), filtered and evaporated. Purification by flash chromatography on silica gel (5-10% ethyl acetate/hexanes) gave 198 mg (0.27 mmol, 31 %) of (33).
  • alkyne (34) 40 mg, 0.077 mmol
  • a solution of alkyne (34) 40 mg, 0.077 mmol
  • 0.5 mL 95% ethanol 95% ethanol
  • the flask was purged with H 2 and allowed to stir under 1 atm H 2 for 22 hours.
  • the mixture was then filtered through celite and purified by flash chromatography on silica gel (55% ethyl acetate/hexanes) to give 17 mg (0.032 mmol, 43%) of the alkene (38).
  • Biopsy samples of skin wound tissues were analyzed with Western blots day-7 and day-14 post- surgery. Tissue samples about 1 mm thick were taken from both sides of the wound. Protein was extracted, and FGF-2/VEGF expression was monitored, with Western blot analysis.
  • adipose tissue is harvested from the woman.
  • the procedure is performed at the individual's bedside.
  • the physician examines the individual's habitus for a suitable site or sites to harvest adipose tissue and selects the lateral and medial thigh regions.
  • the harvested area is injected subcutaneously with a standard tumescent fluid solution containing a saline solution, 0.5% lidocaine, and about 0.001 % epinephrine.
  • a standard tumescent fluid solution containing a saline solution, 0.5% lidocaine, and about 0.001 % epinephrine.
  • a small puncture wound is made in order to transverse the dermis.
  • the blade is turned 360 degrees to complete the wound.
  • a two-holed blunt harvesting cannula (3 mm inner diameter) connected to a vacuum pump at low negative pressure (0.5 atm) is then inserted into the subcutaneous adipose tissue plane.
  • the cannula is then moved throughout the plane to disrupt the connective tissue architecture.
  • the volume of aspirate obtained is about 300 mL.
  • the harvest adipose tissue is processed by centrifugation at 3,000 g for 3 minutes to separate healthy adipocytes and regenerative cells from blood, infiltration fluid and cell debris.
  • a compound of formula I such as, e.g. , Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5, is mixed with an effective amount of HA and the processed adipose tissue.
  • the amount of compound added is an amount sufficient to promote formation of a blood supply sufficient to support the transplanted tissue.
  • This composition is then transferred to 3 mL syringes.
  • One-holed blunt infiltration cannulas (3 mm inner diameter) are used to place the adipose tissue subcutaneously over the lateral sternum and medial breast bilaterally, 70 mL on the right and 50 mL on the left.
  • the adipose tissue is administered in a tear like fashion to increase the surface area to volume ratio.
  • the adipose tissue is first administered into the individual, and a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • the adipose tissue is first administered into the individual, and a compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a compound of formula I such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • the individual is monitored for approximately 7 days.
  • the physician evaluates the engrafted tissue and determines that the engraftment was successful. Both the woman and her physician are satisfied with the results of the procedure. Approximately one month after the procedure, the woman indicates that her quality of life has improved.
  • compositions and methods disclosed herein for a breast augmentation illustrates the use of compositions and methods disclosed herein for a breast augmentation.
  • adipose tissue is harvested from the woman.
  • the procedure is performed at the individual's bedside.
  • the physician examines the individual's habitus for a suitable site or sites to harvest adipose tissue and selects the lateral and medial thigh regions.
  • a 10-blade scalpel a small puncture wound is made in order to transverse the dermis.
  • the blade is turned 360 degrees to complete the wound.
  • a two-holed blunt harvesting cannula (3 mm inner diameter) connected to a syringe is then inserted into the subcutaneous adipose tissue plane.
  • the cannula is then moved throughout the plane to disrupt the connective tissue architecture.
  • the volume of aspirate obtained is about 600 mL.
  • the harvest adipose tissue is processed by centrifugation at 2,700 g for 5 minutes to separate healthy adipocytes and regenerative cells from blood, infiltration fluid and cell debris.
  • the centrifuged adipose tissue is then washed once is a Ringer's saline solution with lactone.
  • a compound of formula I such as, e.g. , Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5, is mixed with an effective amount of HA and the processed adipose tissue.
  • the amount of compound added is an amount sufficient to promote formation of a blood supply sufficient to support the transplanted tissue.
  • This composition is then transferred to 10 mL syringes.
  • One-holed blunt infiltration cannulas (3 mm inner diameter) are used to place the adipose tissue subcutaneously using axillary, periareolar, and inframammary routes bilaterally, 190 mL on the right and 245 mL on the left.
  • the adipose tissue is administered in a tear like fashion to increase the surface area to volume ratio.
  • the adipose tissue is first administered into the individual, and then a compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a compound of formula I such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where
  • a compound of formula I such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 is first administered into the individual, and then adiposes tissue and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., adipose tissue first and then HA or HA first and then adipose tissue) into the same, or in the vicinity of, the region where the compound was administered.
  • adiposes tissue and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., adipose tissue first and then HA or HA first and then adipose tissue) into the same, or in the vicinity of, the region where the compound was administered.
  • composition comprising HA is first administered into the individual, and then adiposes tissue and a compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 are subsequently administered (either at the same time, or sequentially i.e., adipose tissue first and then compound or compound first and then adipose tissue) into the same, or in the vicinity of, the region where the HA was administered.
  • a compound of formula I such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 are subsequently administered (either at the same time, or sequentially i.e., adipose tissue first and then compound or compound first and then adipose tissue) into the same, or in the vicinity of, the region where the HA was administered.
  • the individual is monitored for approximately 7 days.
  • the physician evaluates the engrafted tissue and determines that the engraftment was successful. Both the woman and her physician are satisfied with the results of the procedure. Approximately one month after the procedure, the woman indicates that her quality of life has improved.
  • compositions and methods disclosed herein for a breast disorder illustrates the use of compositions and methods disclosed herein for a breast disorder.
  • adipose tissue is harvested from the woman.
  • the procedure is performed at the individual's bedside.
  • the physician examines the individual's habitus for a suitable site or sites to harvest adipose tissue and selects the abdomen, buttock, lateral and medial thigh, and trochanter regions.
  • a 12-blade scalpel a small puncture wound is made in order to transverse the dermis.
  • the blade is turned 360 degrees to complete the wound.
  • a two-holed blunt harvesting cannula (3 mm inner diameter) connected to a syringe is then inserted into the subcutaneous adipose tissue plane. The cannula is then moved throughout the plane to disrupt the connective tissue architecture.
  • the volume of aspirate obtained is about 1 ,400 mL.
  • the harvested adipose tissue is divided into two, approximately equal portions. One portion is processed by gravity sedimentation to separate healthy adipocytes and regenerative cells from blood, infiltration fluid and cell debris. The other portion is used to isolate regenerative cells. This portion is digested with 0.075% collagenase in buffered saline for 30 minutes on a shaker at 37 ° C. Regenerative cells are then separated from mature adipocytes and connective tissue by centrifuging at 800 g for 10 minutes. The pellet containing the regenerative cells is then washed three times with buffered saline. The washed regenerative cells are then added back to the sediment purified adipose tissue.
  • a compound of formula I such as, e.g. , Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5, is mixed with an effective amount of HA and the processed adipose tissue.
  • the amount of compound added is an amount sufficient to promote formation of a blood supply sufficient to support the transplanted tissue.
  • This composition is then transferred to 10 mL syringes.
  • One-holed blunt infiltration cannulas (3 mm inner diameter) are used to place the adipose tissue subcutaneously in multiple planes axillary, periareolar, and inframammary routes bilaterally, 380 mL on the right and 370 mL on the left.
  • the adipose tissue is administered in a tear like fashion to increase the surface area to volume ratio.
  • the adipose tissue is first administered into the individual, and a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • the adipose tissue is first administered into the individual, and a compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a compound of formula I such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • the individual is monitored for approximately 7 days.
  • the physician evaluates the engrafted tissue and determines that the engraftment was successful. Both the woman and her physician are satisfied with the results of the procedure. Approximately one month after the procedure, the woman indicates that her quality of life has improved.
  • compositions and methods disclosed herein for a facial disorder.
  • a 28-year-old woman presented with a lean face. She felt her face looked old, sad and bitter because of the less fullness of her cheek contour.
  • Pre-operative evaluation of the person includes routine history and physical examination in addition to thorough informed consent disclosing all relevant risks and benefits of the procedure. The physician evaluating the individual determines that she is a candidate for a soft tissue replacement method using the compositions and methods disclosed herein.
  • adipose tissue is harvested from the woman.
  • the procedure is performed at the individual's bedside.
  • the physician examines the individual's habitus for a suitable site or sites to harvest adipose tissue and selects the abdominal region.
  • the harvested area is injected subcutaneously with a standard tumescent fluid solution containing a saline solution, 0.08% lidocaine, and about 0.001 % epinephrine.
  • a standard tumescent fluid solution containing a saline solution, 0.08% lidocaine, and about 0.001 % epinephrine.
  • a small puncture wound is made in order to transverse the dermis.
  • the blade is turned 360 degrees to complete the wound.
  • a two-holed blunt harvesting cannula (2.5 mm inner diameter) connected to a 60 mL syringe is then inserted into the subcutaneous adipose tissue plane.
  • the cannula is then moved throughout the plane to disrupt the connective tissue architecture.
  • the volume of aspirate obtained is about 50 mL.
  • the harvest adipose tissue is processed by washing the harvested tissue with saline to remove lidocaine, oil and residual blood. The washed tissue is then centrifugation at 100 g for 2 minutes to separate healthy adipocytes and regenerative cells from any remaining blood, infiltration fluid and cell debris.
  • a compound of formula I such as, e.g. , Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5, is mixed with an effective amount of HA and the processed adipose tissue.
  • the amount of compound added is an amount sufficient to promote formation of a blood supply sufficient to support the transplanted tissue.
  • This composition is then transferred to 20 mL syringes.
  • One-holed blunt infiltration cannulas (3 mm inner diameter) are used to place about 15 mL of adipose tissue subcutaneously and under superficial musculoaponeurotix system into the left and right cheeks.
  • the adipose tissue is first administered into the individual, and a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • the adipose tissue is first administered into the individual, and a compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a compound of formula I such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • compositions and methods disclosed herein for a facial disorder illustrates the use of compositions and methods disclosed herein for a facial disorder.
  • a compound of formula I such as, e.g. , Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5, is mixed with an effective amount of HA and the processed adipose tissue.
  • the amount of compound added is an amount sufficient to promote formation of a blood supply sufficient to support the transplanted tissue.
  • This composition is then transferred to 20 mL syringes.
  • One-holed blunt infiltration cannulas (3 mm inner diameter) are used to place about 2.5 mL of adipose tissue subcutaneously and under superficial musculoaponeurotix system into the upper eyelid regions.
  • the adipose tissue is first administered into the individual, and a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • the adipose tissue is first administered into the individual, and a compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a compound of formula I such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • the individual is monitored for approximately 7 days.
  • the physician evaluates the engrafted tissue and determines that the engraftment was successful. Both the woman and her physician are satisfied with the results of the procedure because she looked younger. Approximately one month after the procedure, the woman indicates that her quality of life has improved.
  • compositions and methods disclosed herein for a breast disorder.
  • adipose tissue is harvested from the woman as described in Example 6, except that 200 mL of adipose tissue is collected.
  • the harvested adipose tissue is divided into two, approximately equal portions. One portion is processed by saline washing and centrifugation as described in Example 6. The other portion is used to isolate regenerative cells. This portion is digested with 0.075% collagenase in buffered saline for 30 minutes on a shaker at 37 ° C. Regenerative cells are then separated from mature adipocytes and connective tissue by centrifuging at 800 g for 10 minutes. The pellet containing the regenerative cells is then washed three times with buffered saline. The washed regenerative cells are then added back to the purified adipose tissue.
  • a compound of formula I such as, e.g. , Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5, is mixed with an effective amount of HA and the processed adipose tissue.
  • the amount of compound added is an amount sufficient to promote formation of a blood supply sufficient to support the transplanted tissue.
  • This composition is then transferred to 10 mL syringes.
  • One-holed blunt infiltration cannulas (3 mm inner diameter) are used to place about 16 mL of adipose tissue subcutaneously and under superficial musculoaponeurotix system into the left and right temporal and cheeks regions.
  • the adipose tissue is first administered into the individual, and a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • the adipose tissue is first administered into the individual, and a compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a compound of formula I such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • compositions and methods disclosed herein for treating stress urinary incontinence illustrates the use of compositions and methods disclosed herein for treating stress urinary incontinence.
  • adipose tissue is harvested from the man.
  • the procedure is performed at the individual's bedside.
  • the physician examines the individual's habitus for a suitable site or sites to harvest adipose tissue and selects the abdomen, and lateral and medial thigh regions.
  • a 12-blade scalpel a small puncture wound is made in order to transverse the dermis.
  • the blade is turned 360 degrees to complete the wound.
  • a two-holed blunt harvesting cannula (3 mm inner diameter) connected to a syringe is then inserted into the subcutaneous adipose tissue plane.
  • the cannula is then moved throughout the plane to disrupt the connective tissue architecture.
  • the volume of aspirate obtained is about 900 mL.
  • a compound of formula I such as, e.g. , Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5, is mixed with an effective amount of HA and the processed adipose tissue.
  • the amount of compound added is an amount sufficient to promote formation of a blood supply sufficient to support the transplanted tissue.
  • This composition is then transferred to 20 mL syringes.
  • One-holed blunt infiltration cannulas (14-gauge) are used to place about 800 mL of adipose tissue transdermal ⁇ into the bladder neck and proximal urethra regions.
  • the adipose tissue is first administered into the individual, and a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a composition comprising compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and HA is subsequently administered into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • the adipose tissue is first administered into the individual, and a compound of formula I, such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • a compound of formula I such as, e.g., Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and a composition comprising HA are subsequently administered (either at the same time, or sequentially i.e., compound of formula I first and then HA or HA first and then compound of formula I) into the same, or in the vicinity of, the region where the adipose tissue was implanted.
  • the individual is monitored after the procedure. Approximately three days after the transplant, the man indicates that he experiences a decreased frequency of incontinence. Approximately one month after the procedure, the individual indicates that his quality of life has improved. The physician evaluates the engrafted tissue and determines that the long-term engraftment was successful.
  • compositions and methods disclosed herein for a breast defect correction.
  • a 56-year-old woman presents with a surgically removed breast due to cancer.
  • Pre-operative evaluation of the person includes routine history and physical examination in addition to thorough informed consent disclosing all relevant risks and benefits of the procedure.
  • the physician evaluating the individual determines that she is a candidate for a soft tissue replacement method using the compositions and methods disclosed herein.
  • a breast mound is formed using a TRAM-flap procedure.
  • a portion of abdomen tissue including skin, adipose tissue, minor muscles and connective tissues, is taken from the patient's abdomen and transplanted onto the breast site. This tissue is then used to create a breast mound.
  • a composition comprising a compound of formula I, such as, e.g. , Compound 1 , Compound 2, Compound 3, Compound 4, and/or Compound 5 and an effective amount of HA is then administered into the breast mound region.
  • the amount of compound administered is an amount sufficient to promote formation of a blood supply sufficient to support the transplanted tissue.
  • the individual is monitored for approximately 7 days.
  • the physician evaluates the engrafted tissue and determines that the engraftment was successful. Both the woman and her physician are satisfied with the results of the procedure. Approximately one month after the procedure, the woman indicates that her quality of life has improved. Subsequent surgery is performed to create a nipple and areola.

Abstract

L'invention concerne des compositions et des procédés pour traiter une anomalie d'un tissu mou d'un individu.
EP12708198.2A 2011-02-17 2012-02-16 Compositions et procédés améliorés de remplacement de tissu mou Withdrawn EP2675491A2 (fr)

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US201161444078P 2011-02-17 2011-02-17
US13/193,744 US8697056B2 (en) 2010-08-19 2011-07-29 Compositions and soft tissue replacement methods
PCT/US2012/025412 WO2012112757A2 (fr) 2011-02-17 2012-02-16 Compositions et procédés améliorés de remplacement de tissu mou

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US8697057B2 (en) 2010-08-19 2014-04-15 Allergan, Inc. Compositions and soft tissue replacement methods
EP2814526B1 (fr) * 2012-02-16 2016-11-02 Allergan, Inc. Compositions et procédés perfectionnés de remplacement de tissu mou
WO2013123272A1 (fr) * 2012-02-16 2013-08-22 Allergan, Inc. Compositions et procédés perfectionnés de remplacement de tissu mou
CN114748682A (zh) * 2022-04-26 2022-07-15 深圳湾实验室 用于制备烧创伤敷料的组合物及其制剂和制备方法

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BR112013021035A2 (pt) 2016-10-11

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