Method For Use Of A Double-Structured Tissue Implant For Treatment Of Tissue Defects

Abstract

A method for use of a double-structured tissue implant or a secondary scaffold stand alone implant for treatment of tissue defects. The double-structured tissue implant comprising a primary scaffold and a secondary scaffold consisting of a soluble collagen solution in combination with a non-ionic surfactant generated and positioned within the primary scaffold. A method of use of a stand alone secondary scaffold implant or unit for treatment of tissue defects.

1 . A method for use of a double-structured tissue implant (DSTI) for treatment of a tissue defect, said method comprising steps:
 a) obtaining or preparing the DSTI comprising a primary scaffold and a secondary scaffold integrated into said first scaffold wherein said primary scaffold is a porous structure prepared from collagen or a collagen-containing material, said porous structure comprising randomly or non-randomly organized pores, said primary scaffold providing a structural support for the secondary scaffold incorporated therein;   b) preparing a tissue defect for implantation of said DSTI;   c) cutting or trimming the DSTI into a size of the tissue defect;   d) rehydrating said DSTI with a physiologically acceptable solution, collagen-containing solution, buffer or saline;   e) implanting said DSTI into said defect; and   f) covering said implanted DSTI with a tissue adhesive.   
   
   
       2 . The method of  claim 1  wherein said collagen or collagen-containing material for preparation of the primary scaffold is selected from the group consisting of Type I collagen, Type II collagen, Type III collagen, Type IV collagen, Type V collagen, gelatin, collagen-containing agarose, collagen-containing hyaluronan, collagen-containing proteoglycan, collagen-containing glycosaminoglycan, collagen-containing glucosamine, collagen-containing galactosamine, collagen-containing glycoprotein, collagen-containing fibronectin, collagen-containing laminin, collagen-containing bioactive peptide, collagen-containing growth factor, collagen-containing cytokine, collagen-containing elastin, collagen-containing fibrin, collagen-containing polylactic acid, collagen-containing polyglycolic acid, collagen-containing polyamino acid, collagen-containing polycaprolactone, collagen-containing polypeptide, a copolymer thereof, a precursor thereof and a combination thereof, wherein said precursor is selected from the group consisting of alpha 1 (Type I) peptide, alpha 2 (Type I) peptide, 2 (alpha 1, Type I) peptide, 1 (alpha 2, Type I) peptide, 3 (alpha 1, Type II), and a combination thereof. 
   
   
       3 . The method of  claim 2  wherein in said DSTI, said secondary scaffold is integrated into said primary scaffold by introducing a composition comprising a soluble collagen or collagen-containing compound in combination with a non-ionic surfactant into said pores of said primary scaffold, stabilizing said composition within pores of said primary scaffold by precipitation or gelling and subjecting a resulting composite to at least lyophilization and dehydrothermal treatment. 
   
   
       4 . The method of  claim 3  wherein said soluble collagen or collagen-containing compound used for preparation of the composition for the secondary scaffold is Type I collagen, Type II collagen, methylated collagen, gelatin or methylated gelatin. 
   
   
       5 . The method of  claim 4  wherein said non-ionic surfactant used for preparation of the composition for the secondary scaffold is a PLURONIC®-type or a TRITON®-type surfactant comprising polyethylene oxide with terminal oxide groups. 
   
   
       6 . The method of  claim 5  wherein said surfactant is a derivatized polyethylene glycol or a block co-polymer of polyoxyethylene (PEO) and polyoxypropylene (PPO) having the generic organization of polymeric blocks PEG-PPO-PEG or PPO-PEG-PPO. 
   
   
       7 . The method of  claim 6  wherein said surfactant is TRITON® X100, namely polyethylene glycol p-(1,1,3,3-tetramethylbutyl)-phenyl ether, or PLURONIC® F127, namely a polymer of polyoxyethylene (PEO) and polyoxypropylene (PPO) with two 96-unit hydrophilic PEO chains surrounding one 69-unit hydrophobic PPO chain. 
   
   
       8 . The method of  claim 7  wherein said integration of the secondary scaffold into the primary scaffold results in the double-structured tissue implant comprising two structurally and functionally distinct sections, wherein one or both sections may separately be seeded with cells or incorporated with a pharmaceutical agent or modulator. 
   
   
       9 . The method of  claim 8  wherein said DSTI is implanted as a dry or rehydrated acellular DSTI or a dry or rehydrated DSTI seeded with cells. 
   
   
       10 . The method of  claim 9  wherein said implant is resistant to dissolution, resistant to change of size and shape, maintains collagen retention, maintains pH and osmolality and has a rehydration and wettability time within 30 seconds. 
   
   
       11 . The method of  claim 1  wherein in step b) preparation of a tissue defect comprises debriding said defect or debriding and subchondral microfracture. 
   
   
       12 . The method of  claim 1  additionally comprising step of coating said defect with a tissue adhesive before said implantation of said DSTI. 
   
   
       13 . The method of  claim 12  wherein said tissue adhesive is selected from the group consisting of di-aldehyde starch, 4-armed pentaerythritol tetra-thiol and polyethylene glycol diacrylate, photo-polymerizable polyethylene glycol-co-poly(α-hydroxy acid) diacrylate macromer, periodate-oxidized gelatin, serum albumin and di-functional polyethylene glycol derivatized with maleimidyl, serum albumin and di-functional polyethylene glycol derivatized succinimidyl, serum albumin and di-functional polyethylene glycol derivatized phthalimidyl, a copolymer of polyethylene glycol and polylactide, a copolymer of polyethylene glycol and polyglycolide, a copolymer of polyethylene glycol and polyhydroxybutyrate, 4-armed polyethylene glycol derivatized with succinimidyl ester and thiol and a cross-linked polyethylene glycol with methylated collagen. 
   
   
       14 . The method of  claim 13  wherein said tissue adhesive is polyethylene glycol cross-linked with methylated collagen. 
   
   
       15 . The method of  claim 1  wherein said rehydration step d) is performed before implantation of said DSTI or in situ after implantation of said DSTI in a dry form. 
   
   
       16 . A method for treatment of a cartilage, bone, tendon, skin, meniscus, ligament, skeletal, muscle, cardiac muscle or nervous tissue defect using an implantable double-structured tissue implant (DSTI), said method comprising steps:
 a) obtaining or preparing the DSTI comprising a primary scaffold and a secondary scaffold integrated into said first scaffold wherein said primary scaffold is a porous structure prepared from collagen or a collagen-containing material, said porous structure comprising randomly or non-randomly organized pores, said primary scaffold providing a structural support for the secondary scaffold incorporated therein and wherein said secondary scaffold comprises collagen or collagen-containing material in combination with a non-ionic PLURONIC®-type surfactant;   b) debriding or debriding and microfracturing said tissue defect for implantation of said DSTI;   c) cutting or trimming the DSTI into a size of the tissue defect;   d) rehydrating said DSTI with a physiologically acceptable solution, collagen-containing solution, buffer or saline;   e) implanting said DSTI into said defect; and   f) covering said implanted DSTI with a tissue adhesive.   
   
   
       17 . The method of  claim 16  wherein said physiologically acceptable solution additionally contains differentiated or undifferentiated cells, a pharmaceutical agent, drug, growth modulator, growth hormone, mediator, enzyme promoting a cell growth, enzyme promoting cell incorporation into said DSTI, enzyme promoting cell proliferation, or enzyme promoting cell division, a pharmaceutically acceptable excipient or additive. 
   
   
       18 . The method of  claim 17  wherein said differentiated cells are chondrocytes, osteoblasts, tenocytes, fibroblasts, fibrochondrocytes or ligament cells. 
   
   
       19 . The method of  claim 18  wherein said undifferentiated cells are adult or immature mesenchymal cells derived from bone marrow aspirates, iliac crest needle biopsies, immortalized cell lines, hematopoietic stem cells, neural stem cells, embryonic stem cells or stem cells obtained from other dissociable mesenchymal tissues. 
   
   
       20 . The method of  claim 19  wherein said dissociable mesenchymal tissue is a somite, muscle, or interstitial connective tissue. 
   
   
       21 . The method of  claim 19 , wherein said cells are activated with hydrostatic pressure regimen. 
   
   
       22 . The method of  claim 17  wherein said drug or modulator is selected from the group consisting of a growth factor, morphogenic factor, cytokine, membrane associated factor that promotes growth or morphogenesis, cell attachment or adhesion protein, hormone, pericellular matrix molecule, nutrient, nucleic acid, anti-neoplastic agent, vitamin, anti-inflammatory agent, enzyme and metabolic inhibitor and a combination thereof. 
   
   
       23 . The method of  claim 22  wherein said growth and morphogenic factor is a transforming growth factor, insulin-like growth factor 1, platelet-derived growth factor or bone morphogenetic protein;
 wherein said cytokine is interleukin, chemokine, macrophage chemoattractant factor, cytokine-induced neutrophil chemoattractant, integral membrane protein, integrin or growth factor receptor;   wherein said membrane associated factor that promote growth and morphogenesis is a repulsive guidance molecule;   wherein said cell attachment or adhesion protein is fibronectin or chondronectin;   wherein said hormone is growth hormone, insulin or thyroxine;   wherein said pericellular matrix molecule is perlecan, syndecan, small leucine-rich proteoglycan or fibromodulin;   wherein said nutrient is glucose or glucosamine;   wherein said nucleic acid is RNA or DNA;   wherein said anti-neoplastic agent is methotrexate or aminopterin;   wherein said vitamin is ascorbate or retinoic acid;   wherein said anti-inflammatory agent is naproxen sodium, salicylic acid, diclofenac or ibuprofen;   wherein said enzyme is phosphorylase, sulfatase or kinase; and   wherein said metabolic inhibitor is RNAi, cycloheximide and steroid.   
   
   
       24 . A method for use of a secondary scaffold for treatment of a tissue defect, said method comprising steps:
 a) preparing the secondary scaffold comprising a soluble collagen or collagen-containing compound in combination with a non-ionic surfactant neutralized to pH above 7.4%, precipitated, lyophilized and dehydrothermally treated;   b) preparing a tissue defect for implantation of said DSTI;   c) cutting or trimming the DSTI into a size of the tissue defect;   d) rehydrating said DSTI with a physiologically acceptable solution, collagen-containing solution, buffer or saline;   e) implanting said DSTI into said defect; and   f) covering said implanted DSTI with a tissue adhesive.