Collagen scaffold modified by covalent grafting of adhesion molecules, associated methods and use thereof for cardiovascular and thoracic cell therapy and contractile tissue engineering

Abstract

Three-dimensional solid contractile collagen scaffolds having improved biological properties and electromechanical performance are provided. The scaffolds can be used for cell transplantation, including the fixation of biocompatible reagents and adhesion molecules which control cell adhesion, apoptosis, survival and/or differentiation simultaneously. Grafting adhesion molecules to the collagen matrices renders the scaffold suitable for use in vascular and cardiothoracic surgery/medicine, as well as in cell therapy for the heart and in artificial heart muscle engineering. Also, a method for grafting and optimizing the presentation of adhesion peptides or biological agents in the scaffold is provided.

Description

FIELD OF THE INVENTION[0001]The present invention relates to collagen scaffolds characterized in that they are chemically modified by covalent grafting of adhesion molecules which facilitate the cell implantation, their survival and their differentiation. The collagen scaffold (hereunder referred to as “the support” or “the scaffold”) may advantageously be used with contractile potential cells but other cell types may also be suitably used, or combined, such as angiogenic potential cells.[0002]The present invention also relates to the covalent grafting method and to the uses of such substrates for tissue engineering, cell therapy or for modifying the collagen content of devices used in the thoracic and cardiovascular medical and surgical field.[0003]The present invention relates to coated collagen substrates, especially for use in medicine, for tissue repair and regeneration.[0004]Collagen takes part in many devices used in cell therapy, for tissue engineering and in the thoracic an...

AI Technical Summary

Benefits of technology

[0062]In a specific embodiment, the coating of this agent creates spatial opportunities for depositing a biologically active agent intended to treat ischemia or any heart dysfunction, such as alpha or beta-adrenergic blocking agents or agonists, AMP kinase-activating agents, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptors, antiarrythmic agents, anticoagulants, anti-platelet aggregation agents, antidiabetic agents, antioxidants, anti-inflammatory agents, billiary acid sequestering agents, calcium channel blockers, calcium antagonists, CETP inhibitors, cholesterol and lipid regulating agents, drugs which inhibit the conversion of arachidonic acid, diuretic agents, estrogen replacement agents ionotropic agents, fatty acid analogues, fatty acid synthesis inhibitors, fibrates, histidines, nicotinic acid derivatives, nitrates, agonists or antagonists to peroxisome proliferator-activated receptors, ranolzine, statin, thalidomide, thiazolidinediones, thrombolytic agents, vasodilatators and vasopressors and other lists of SDF-1 factors, mesenchymal factors homing cells such as alpha MCP-3, OEB, TGF-alpha or -beta superfamily ligands, LIF chemokines, BMP chemokines, BMP receptors, etc., a signaling molecule such as smad or Idb3, BMP2, BMP4, . . . , also included, but not exclusively, drug, a growth factor selected from activin-A (ACTE), retinoic acid (RA), epidermal growth factor, bone morphogenetic protein, tumor growth factor TGF like “TGF-.beta”, HGF (hepatic cell growth factor), PGDF (platelet-derived growth factor), albumin, heme oxygenase, LDL (low density protein), alpha. (tumor necrosis factor), insulin-like growth factor (IGF-I and/or II), fibroblast growth factors, nerve growth factors (NGF), muscle morphogenic factor (MMF), alpha-chemokine stromal cell-derived factor (SDF)—1, VEGF (vascular endothelial cell growth factor), fibroblast growth factor (FGF) or receptors, hematopoietic growth factors, heparin, heparane sulfate, chondroitin sulfate, glycosaminoglycan, anticoagulants, thrombolytic agents, antifibrinolytic agents, antiplatelet agents, coagulation factors, tissue plasminogen activator (t-PA), thrombomodulin, high molecular weight kinogen, AT-III, C1-esterase i...

Problems solved by technology

Producing cell therapy scaffolds is difficult because such supports enable the free diffusion of nutrients and oxygen, possess the mechanical properties but also the specific biological ligands to be able to interact with the associated cells of interest so as to promote their survival and their differentiation as well.

To this day, techniques for transplanting isolated cells suffer from causing a very substantial cell mortality and often a lack of differentiation of the transplanted cells.

The lack of production of new myocardial fibers in sufficient numbers for a positive effect to be clinically transposed has been attributed to the substantial cell death occurring after the graft (approx.

The destruction of the native extracellular matrix (ECM) essentially composed of type I and type III collagen in the myocardium and its replacement with a less vascularized tissue having altered mechanical properties (less compliant), which, in addition, due to a change in its composition, does not allow an optimal interaction anymore, could explain the relatively poor results of the free cell transplantation.

However the cell survival in this type of support is still low and the differentiation remains partial, with especially a lack of terminal differentiation for cardiac myocytes5 and for endothelial cells36-39.

In the present state of our knowledge, the use of contractile tissues obtained using MATRIGEL™ is not allowed for human clinical medicine due to the origin of such compound.

Moreover, the presence of MATRIGEL™ may generate a number of side effects.

The diffusion deficiencies limit the thickness of the expected tissue and make it unsuitable for replacing a cardiac muscle.

Such accelerated matrix degradation subsequent to the strong inflammatory response is responsible for the local release of great amounts of enzymes, free radicals and various degradation products which may also compromise the survival of the cells associated with those supports.

The collagen degradation products themselves have been reported as being toxic in nature, especially for contractile cells48.

Moreover, the mechanical properties of the supports are impaired by this degradation even before the associa...

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