Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices
One aspect of the present invention generally relates to methods of sealing a wound or tissue plane or filling a void splace. In a preferred embodiment, the wound is an ophthalmic, pleural or dural wound. In certain instances, the compositions used to seal the wound or tissue plane comprises a polyalkyleneimine. In a preferred embodiment, the polyalkyleneimine is polyethyleneimine. Treatment of the polyethyleneimine with a cross-linking reagent causes the polyethyleneimine polymers to polymerize forming a seal. In certain instances, the cross-linking reagent is a polyethylene glycol having reactive terminal groups. In certain instances, the reactive terminal groups are activated esters, such as N-hydroxy succinimide ester. In certain instances, the reactive terminal groups are isocyanates. In certain instances, the polyethyleneimine has a lysine, cysteine, isocysteine or other nucleophilic group attached to the periphery of the polymer. In certain instances, the polyethyleneimine is mixed with a second polymer, such as a polyethylene glycol containing nucleophilic groups. In certain instances, the compositions used to seal the wound or tissue plane are formed by reacting a polyalkyleneimine bearing electrophilic groups with a cross-linking reagent containing nucleophilic groups. In certain instances, the electrophilic groups on the polyalkyleneimine are activated esters, such as N-hydroxy succinimide ester. In certain instances, the compositions used to seal the wound or tissue plane are formed by reacting a polyalkyleneimine bearing photopolymerizable groups with ultraviolet or visible light. Compositions used to seal the wound which contain PEI or a derivative of PEI are found to adhere tightly to the tissue. Other aspects of the present invention relate to methods of filling a void of a patient or adhering tissue. In certain instances, the methods use a polyalkyleneimine. In a preferred embodiment, the polyalkyleneimine is polyethyleneimine. Another aspect of the present invention relates to a polymeric composition formed by exposing a polyalkyleneimine to an activated polyalkylene glycol. In certain instances, the composition is attached to mammalian tissue.
1. A method of sealing a wound of a patient, comprising the steps of:
exposing an effective amount of polyethyleneimine (PEI) or polypropyleneimine (PPI) to a compound of formula III to form an adhesive composition; and
applying said adhesive composition to a wound of a patient, thereby sealing the wound of the patient, wherein:
the compound of formula III is represented by:
B R 1-III ) 2-4 ;
R 1-III represents independently for each occurrence amino succinimidyl glutarate, succinimidyl glutarate, succinimidyl α-methyl butanoic acid, succinimidyl propionic acid, succinimidyl 3-methyl glutarate, succinimidyl 3,3-dimethyl glutarate, or —C(O)(CH 2 ) 8 C(O)R 3-III ;
R 3-III represents independently for each occurrence
B represents poly(ethylene glycol) (PEG) with a weight average molecular weight of about 3,400 Daltons, about 4,600 Daltons, about 6,000 Daltons, about 8,000 Daltons, about 10,000 Daltons, or about 20,000 Daltons; and
the PEI has a weight average molecular weight of about 800 Daltons, about 1,300 Daltons, about 2,000 Daltons, or about 25,000 Daltons;
the PPI is G1 DAB-PPI or G2 DAB-PPI;
G1 DAB-PPI is
and
G2 DAB-PPI is
2. A method of augmenting soft tissue or filling a void of a patient, comprising the steps of:
exposing an effective amount of polyethyleneimine (PEI) or polypropyleneimine (PPI) to a compound of formula III to form an adhesive composition; and
applying said adhesive composition to soft tissue or a void of a patient, thereby augmenting the soft tissue or filling the void of the patient, wherein:
the compound of formula III is represented by:
B R 1-III ) 2-4 ;
wherein
R 1-III represents independently for each occurrence —C(O)(CH 2 ) 8 C(O)R 3-III ;
R 3-III represents independently for each occurrence
B represents poly(ethylene glycol) (PEG) with a weight average molecular weight of about 3,400 Daltons, about 4,600 Daltons, about 6,000 Daltons, about 8,000 Daltons, about 10,000 Daltons, or about 20,000 Daltons;
the PEI has a weight average molecular weight of about 800 Daltons, about 1,300 Daltons, about 2,000 Daltons, or about 25,000 Daltons; and
the PPI is G1 DAB-PPI or G2 DAB-PPI;
G1 DAB-PPI is
and
G2 DAB-PPI is
3. A method of adhering tissue of a patient, comprising the steps of:
exposing an effective amount of polyethyleneimine (PEI) or polypropyleneimine (PPI) to a compound of formula III to form an adhesive composition;
applying said adhesive composition to a first tissue of a patient to form an adhesive tissue; and
contacting said adhesive tissue with a second tissue of the patient, thereby adhering the first tissue and the second tissue of the patient, wherein:
the compound of formula III is represented by:
B R 1-III ) 2-4 ;
wherein
R 1-III represents independently for each occurrence —C(O)(CH 2 ) 8 C(O)R 3-III ;
R 3-III represents independently for each occurrence
B represents poly(ethylene glycol) (PEG) with a weight average molecular weight of about 3,400 Daltons, about 4,600 Daltons, about 6,000 Daltons, about 8,000 Daltons, about 10,000 Daltons, or about 20,000 Daltons; and
the PEI has a weight average molecular weight of about 800 Daltons, about 1,300 Daltons, about 2,000 Daltons, or about 25,000 Daltons;
the PPI is G1 DAB-PPI or G2 DAB-PPI;
G1 DAB-PPI is
and
G2 DAB-PPI is
4. The method according to any one of claims 1 - 3 , wherein said wound, void, or tissue of the patient is in the eye, liver, lung, heart, pancreas, dura mater of the nervous system, an artery, a cardiac artery, a cardiac vein, cartilage, a vertebral disk, or breast.
5. The method according to any one of claims 1 - 3 , further comprising the step of applying a polymer or hydrogel to the wound, void, or tissue of the patient; wherein said polymer or hydrogel is poly(lactic acid), poly(glycolic acid), a copolymer of poly(lactic acid) and poly(glycolic acid), collagen, hyaluronic acid, albumin, cellulose, elastin, fibrin, fibronectin, gelatine, heparin, heparin sulfate, polylysine, poly(vinyl acetate), polyvinylpyrrolidone, poly(acrylic acid), poly(ethylene glycol), poly(propylene glycol)-poly(ethylene glycol) copolymer, trimethylene carbonate, a polypeptide comprising the tripeptide Arg-Gly-Asp, or a polyalkyleneimine hydrogel.
6. The method according to any one of claims 1 - 3 , further comprising the step of applying a mesh to the wound, void, or tissue of the patient.
7. The method according to any one of claims 1 - 3 , further comprising applying a medicament, colorant, flavoring, scent, fibrous additive, thickener or plasticizer.
8. The method of according to any one of claims 1 - 3 , wherein the PEI and the compound of formula III are combined in an aqueous solution; and wherein subsequent to mixing and crosslinking the aqueous solution has an osmolality of 100-700 mOsm/kg.
9. The method of according to any one of claims 1 - 3 , wherein the adhesive composition forms a hydrogel; and the hydrogel formed has pores in the range of about 1 micron to about 100 microns in diameter.
10. The method according to any one of claims 1 - 3 , further comprising the step of sterilizing the PEI or compound of formula III to provide a Sterility Assurance Level (SAL) of at least about 10 −3 .
11. The method according to any one of claims 1 - 3 , wherein an effective amount of polyethyleneimine (PEI) is exposed to a compound of formula III to form the adhesive composition.
12. The method according to any one of claims 1 - 3 , wherein an effective amount of polypropyleneimine (PPI) is exposed to a compound of formula III to form the adhesive composition.