INJECTABLE FORMULATIONS FOR ORGAN AUGMENTATION
The present invention concerns therapeutic formulations containing active agents, such bioactive cell populations, and methods of making and using the same.
1 . An injectable formulation comprising bioactive cells and a temperature-sensitive cell-stabilizing biomaterial that maintains
(i) a substantially solid state at about 8° C. or below, and
(ii) a substantially liquid state at about ambient temperature or above.
2 . The formulation of claim 1 , wherein the bioactive cells comprise renal cells.
3 . The formulation of claim 1 , wherein the bioactive cells are substantially uniformly dispersed throughout the volume of the cell-stabilizing biomaterial.
4 . The formulation of claim 1 , wherein the biomaterial comprises a solid-to-liquid transitional state between about 8° C. and about ambient temperature or above.
5 . The formulation of claim 1 , wherein the substantially solid state is a gel state.
6 . The formulation of claim 1 , wherein the cell-stabilizing biomaterial comprises a hydrogel.
7 . The formulation of claim 6 , wherein the hydrogel comprises gelatin.
8 . The formulation of claim 7 , wherein the gelatin is present in the formulation at about 0.5% to about 1% (w/v).
9 . The formulation of claim 7 , wherein the gelatin is present in the formulation at about 0.75% (w/v).
10 . The formulation of claim 1 , further comprising a cell viability agent.
11 . The formulation of claim 10 , wherein the cell viability agent comprises an agent selected from the group consisting of an antioxidant, an oxygen carrier, an immunomodulatory factor, a cell recruitment factor, a cell attachment factor, an anti-inflammatory agent, an immunosuppressant, an angiogenic factor, and a wound healing factor.
12 . (canceled)
13 . The formulation of claim 11 , wherein the antioxidant is 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid.
14 . The formulation of claim 13 , wherein the 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid is present at about 50 μM to about 150 μM.
15 - 16 . (canceled)
17 . The formulation of claim 11 , wherein the oxygen carrier is a perfluorocarbon.
18 - 19 . (canceled)
20 . An injectable formulation comprising bioactive renal cells, about 0.75% (w/v) gelatin, and about 100 μM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, wherein the formulation has
(i) a substantially solid state at about 8° C. or below, and
(ii) a substantially liquid state at ambient temperature or above.
21 - 29 . (canceled)
30 . The formulation of claim 1 , further comprising biocompatible beads comprising a biomaterial.
31 . The formulation of claim 30 , wherein the beads are crosslinked.
32 . The formulation of claim 31 , wherein the crosslinked beads have a reduced susceptibility to enzymatic degradation as compared to non-crosslinked biocompatible beads.
33 . The formulation of claim 31 , wherein the crosslinked beads are carbodiimide-crosslinked beads.
34 . The formulation of claim 33 , wherein the carbodiimide is selected from the group consisting of 1-Ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC), DCC—N,N′-dicyclohexylcarbodiimide (DCC), and N,N′-Diisopropylcarbodiimide (DIPC).
35 . (canceled)
36 . The formulation of claim 32 , wherein the crosslinked beads comprise a reduced number of free primary amines as compared to non-crosslinked beads.
37 . (canceled)
38 . The formulation of claim 30 , wherein the beads are seeded with the bioactive cells.
39 . The formulation of claim 38 , wherein the bioactive cells are renal cells.
40 . The formulation of claim 30 , further comprising additional biocompatible beads that comprise a temperature-sensitive biomaterial that maintains
(i) a substantially solid state at ambient temperature or below, and
(ii) a substantially liquid state at about 37° C. or above.
41 . The formulation of claim 40 , wherein the biomaterial of the beads comprises a solid-to-liquid transitional state between ambient temperature and about 37° C.
42 . The formulation of claim 40 , wherein the substantially solid state is a gel state.
43 . The formulation of claim 40 , wherein the biomaterial of the beads comprises a hydrogel.
44 . The formulation of claim 43 , wherein the hydrogel comprises gelatin.
45 . The formulation of claim 44 , wherein the beads comprise gelatin at about 5% (w/v) to about 10% (w/v).
46 . The formulation of claim 40 , wherein the additional biocompatible beads are spacer beads.
47 . The formulation of claim 46 , wherein the spacer beads are not seeded with bioactive cells.
48 . The formulation of claim 1 , further comprising products secreted by a renal cell population.
49 . The formulation of claim 48 , wherein the secreted products are selected from the group consisting of paracrine factors, endocrine factors, juxtacrine factors, vesicles, microvessicles, exosomes and RNA.
50 - 54 . (canceled)
55 . The formulation of claim 49 , wherein the vesicles comprise a secreted product selected from the group consisting of paracrine factors, endocrine factors, juxtacrine factors, and RNA.