1. A flexible structure comprising integrated sensing means, said integrated sensing means being at least partly encapsulated in a flexible and electrically insulating body, said integrated sensing means further being adapted to sense deformations of the flexible structure.
2. A flexible structure according to claim 1, wherein the flexible and electrically insulating body is a polymer-based body.
3. A flexible structure according to claim 2, wherein the flexible polymer-based body is formed in a photosensitive polymer.
4. A flexible structure according to claim 3, wherein the photosensitive polymer is a SU-8 based polymer.
5. A flexible structure according to claim 4, wherein the SU-8 based polymer is an XP SU-8 polymer.
6. A flexible structure according to claim 3, wherein the photosensitive polymer is a polyimide polymer.
7. A flexible structure according to claim 3, wherein the photosensitive polymer is a BCB cyclotene polymer.
8. A flexible structure according to claims 2, wherein the flexible polymer-based body comprises by a first and a second polymer layer.
9. A flexible structure according to claim 8, wherein the integrated sensing means is at least partly embedded into the first and the second polymer layer.
10. A flexible structure according to claim 1, wherein the integrated sensing means comprises at least one resistor, the resistance of the at least one resistor being dependent on deformations of the flexible structure.
11. A flexible structure according to claim 10, wherein the at least one resistor is defined by a conducting layer.
12. A flexible structure according to claim 11, wherein the conducting layer is a metal layer.
13. A flexible structure according to claim 12, wherein the conducting layer is a gold layer.
14. A flexible structure according to claim 10, wherein the at least one resistor is defined by a semiconductor layer.
15. A flexible structure according to claim 14, wherein the semiconductor layer comprises silicon.
16. A chip comprising a flexible structure according to claim 1, the chip further comprising a substantially rigid portion comprising an integrated electrical conductor being at least partly encapsulated in an electrically insulating body, said integrated electrical conductor being connected to the integrated sensing means and being electrically accessible via a contact terminal on an exterior surface part of the substantially rigid portion.
17. A chip according to claim 16, wherein the substantially rigid portion comprises a first and a second polymer layer, and wherein the integrated electrical conductor is at least partly embedded into the first and the second polymer layer of the substantially rigid portion.
18. A chip according to claim 17, wherein the polymer layers of the substantially rigid portion are formed in photosensitive polymer layers.
19. A chip according to claim 17, wherein the integrated electrical conductor comprises a gold layer.
20. A chip according to claim 17, wherein the integrated electrical conductor comprises silicon.
21. A chip according to claim 17, further comprising at least three resistors, the at least three resistors forming part of the substantially rigid portion of the chip.
22. A chip according to claim 21, comprising three resistors.
23. A chip according to claim 22, wherein the three resistors are at least partly embedded into the first and the second polymer layer of the substantially rigid portion.
24. A chip comprising two flexible structures according to claim 10, the chip further comprising a substantially rigid portion comprising integrated electrical conductors each being at least partly encapsulated in an electrically insulating body, a number of said integrated electrical conductors being connected to the integrated sensing means and being electrically accessible via contact terminals on an exterior surface part of the substantially rigid portion.
25. A chip according to claim 24, further comprising two resistors, the two resistors forming part of the substantially rigid portion of the chip.
26. A chip according to claim 25, wherein the substantially rigid portion comprises a first and a second polymer layer, and wherein the integrated electrical conductors and the two resistors are at least partly embedded into the first and the second polymer layer of the substantially rigid portion of the chip.
27. A chip according to claim 25, wherein the four resistors are connected so as to form a Wheatstone Bridge.
28. A chip according to claim 16, further comprising a polymer-based substrate supporting the substantially rigid portion of the chip.
29. A chip according to claim 28, wherein the substrate is formed in a photosensitive polymer.
30. A chip according to claim 29, wherein the photosensitive polymer is a SU-8 based polymer.
31. A chip according to claim 30, wherein the SU-8 based polymer is a XP SU-8 polymer.
32. A chip according to claim 29, wherein the photosensitive polymer is a polyimide polymer.
33. A chip according to claim 29, wherein the photosensitive polymer is a BCB cyclotene polymer.
34. A chip according to claim 16, further comprising a silicon-based substrate supporting the substantially rigid portion of the chip.
35. A sensor for measuring the presence of a substance in a fluidic, said sensor comprising a chip according to claim 16.
36. An actuator comprising a flexible structure, said flexible structure comprising integrated actuator means being electrically accessible and being at least partly encapsulated in a flexible and electrically insulating body, said integrated actuator means being adapted to deform upon accessing the integrated actuator means electrically thereby inducing deformations of the flexible structure in accordance with deformations of the integrated actuator means.
37. An actuator according to claim 36, wherein the integrated actuator means comprises a metal layer, and wherein the flexible and electrically insulating body is a polymer-based body.
38. An actuator according to claim 37, wherein the polymer-based body is formed in a photosensitive polymer layer.
39. A chip according to claim 38, wherein the photosensitive polymer is a SU-8 based polymer.
40. A chip according to claim 39, wherein the SU-8 based polymer is a XP SU-8 polymer.
41. A chip according to claim 38, wherein the photosensitive polymer is a polyimide polymer.
42. A chip according to claim 38, wherein the photosensitive polymer is a BCB cyclotene polymer.
43. A chip comprising an actuator according to claim 36, further comprising a polymer-based substrate supporting a substantially rigid portion of the chip.
44. A chip according to claim 43, wherein the substrate is formed in a photosensitive polymer.
45. An actuator comprising an actuator according to claim 36, further comprising a silicon-based substrate supporting a substantially rigid portion of the chip.
46. A method of manufacturing a chip, the method comprising the steps of
providing a first electrically insulating layer,
patterning the first electrically insulating layer so as to form a first part of a flexible cantilever,
providing, onto a first area of the layer forming the first part of the flexible cantilever, a first conducting layer, and patterning the first conducting layer so as to form at least one conductor on the first area of the patterned first electrically insulating layer,
providing, onto a second and different area of the layer forming the first part of the flexible cantilever, a second conducting layer, and patterning the second conducting layer so as to form at least one resistor on the second area of the patterned first electrically insulating layer, and
providing, onto the first and second areas of the layer forming the first part of the flexible cantilever, a second electrically insulating layer so as to at least partly encapsulate the at least one conductor and the at least one resistor, and patterning the second electrically insulating layer so as to form a second part of a cantilever.
47. A method according to claim 46, wherein at least one conductor on the first area is connected to at least one resistor on the second area.
48. A method according to claim 46, wherein the electrically insulating layers are polymer layers.
49. A method according to claim 48, wherein the polymer layers are formed in photosensitive polymer layers.
50. A chip according to claim 49, wherein the photosensitive polymer is a SU-8 based polymer.
51. A chip according to claim 50, wherein the SU-8 based polymer is a XP SU-8 polymer.
52. A chip according to claim 49, wherein the photosensitive polymer is a polyimide polymer.
53. A chip according to claim 49, wherein the photosensitive polymer is a BCB cyclotene polymer.
54. A method according to claim 46, wherein the conducting layers are gold layers.
55. A method according to claim 46, further comprising the steps of providing a third layer onto the second electrically insulating layer, and patterning the third layer so as to form a substrate that only supports the first area of the second electrically insulating layer.
56. A method according to claim 55, wherein the third layer is formed in a photosensitive polymer layer.
57. A chip according to claim 56, wherein the photosensitive polymer is a SU-8 based polymer.
58. A chip according to claim 57, wherein the SU-8 based polymer is a XP SU-8 polymer.
59. A chip according to claim 56, wherein the photosensitive polymer is a polyimide polymer.
60. A chip according to claim 56, wherein the photosensitive polymer is a BCB cyclotene polymer.
61. A method according to claim 55, wherein the third layer is a silicon-based layer.
62. A method according to claim 55, further comprising the steps of
providing a sacrificial layer on a silicon wafer, upon which the first electrically insulating layer is provided, and
removing the silicon wafer after providing and patterning of the third layer.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
What is claimed is:
1. A cell culture comprising host cells having their genome manipulated to:
a) express a chemical or biological molecule useful in a therapeutic composition; and
b) not express a PrP protein due to the alteration of any endogenous PrP sequences.
2. The cell culture of claim 1 wherein the endogenous PrP gene is ablated.
3. The cell culture of claim 2, wherein the genome of the host cell is further altered to express an exogenous PrP gene, which gene expression enhances viability of the cell.
4. The cell culture of claim 3, wherein the exogenous PrP gene is from a species genetically diverse from the host cell, and wherein the genetically diverse exogenous PrP gene renders the host cell resistant to prion infection by the PrPSc form of the host cell species.
5. The cell culture of claim 4, wherein:
a) the host cells are primate cells; and
b) the genetically diverse exogenous gene is from a species selected from the group consisting of: mouse, hamster, and rat.
6. The cell culture of claim 4, wherein:
a) the host cells are from a species selected from the group consisting of horse, cow, sheep, dog and cat; and
b) the genetically diverse exogenous PrP gene is selected from the group consisting of: mouse, hamster, or rat.
7. The cell culture of claim 4, wherein the exogenous PrP gene genetically diverse from the host cell is operably linked to an inducible promoter.
8. The cell culture of claim 1, wherein the host cells are hybridoma cells.
9. A method for producing a therapeutic composition free from infectious prion contamination comprising:
a) ablating an endogenous PrP gene in a mammalian somatic host cells;
b) producing a therapeutic composition in said host cells; and
c) isolating said therapeutic composition from said host cells;
wherein the isolated therapeutic composition is characterized by an inability to transmit a prion-mediated pathology to a subject of the same species as the host cells.
10. The method of claim 9, wherein the therapeutic composition is for human use.
11. The method of claim 9, wherein the therapeutic is for bovine, equine, canine, feline or ovine use.
12. The method of claim 9, wherein the therapeutic composition is selected from the group consisting of: a peptide, a protein, an antisense molecule, a ribozyme, a viral vector, an expression vector, and a plasmid.
13. A method for producing a therapeutic composition free from infectious prion contamination comprising:
a) ablating an endogenous PrP gene in a host cell;
b) introducing exogenous PrP sequences from a species genetically diverse from said host cell into said host cell;
c) expressing said exogenous PrP sequences;
d) manipulating the genome of the cell to produce a therapeutic composition from said host cell; and
e) isolating said therapeutic composition from said host cell;
wherein the expression of the exogenous PrP sequences allows necessary expression of PrP and wherein the isolated therapeutic composition cannot transmit a prion-mediated pathology to a subject of the same species as the host cell.
14. The method of claim 13, wherein the exogenous PrP gene is operatively fused to an inducible promoter.
15. The method of claim 13, wherein the therapeutic composition is for human use.
16. The method of claim 13, wherein the therapeutic composition is for bovine, equine, porcine, canine, feline or ovine use.
17. The method of claim 13, wherein the therapeutic composition is selected from the group consisting of: a peptide, a protein, an antisense molecule, a ribozyme, a viral vector, an expression vector, and a plasmid.
18. A method for producing a therapeutic composition free from infectious prion contamination comprising:
a) ablating the endogenous PrP gene in a somatic host cell;
b) introducing exogenous PrP sequences from a genetically similar species, said exogenous sequences operably linked to an inducible promoter;
c) suppressing expression of the exogenous PrP sequences;
d) producing a therapeutic composition in said host cell; and
e) isolating the therapeutic composition from said host cell;
wherein the isolated therapeutic composition produced during suppression of PrP expression cannot transmit a prion-mediated pathology to a subject of the same species as the host cell.
19. The method of claim 18, wherein the therapeutic composition is for human treatment.
20. The method of claim 18, wherein the therapeutic composition is for bovine, equine, porcine, canine, feline or ovine treatment.
21. The method of claim 18, wherein the therapeutic composition is selected from the group consisting of: a peptide, a protein, an antisense molecule, a ribozyme, a viral vector, an expression vector, and a plasmid.
22. An isolated therapeutic composition is characterized by an inability to transmit a prion-mediated pathology to a subject of the same species as the host cells.
23. The composition of claim 22, wherein the composition is produced using the method of claim 9.
24. The composition of claim 22, wherein the composition is produced using the method of claim 13.
25. The composition of claim 22, wherein the composition is produced using the method of claim 18.
26. The isolated composition of claim 22, wherein the therapeutic composition is for human use.
27. The isolated composition of claim 22, wherein the therapeutic composition is for bovine, equine, canine, feline or ovine use.
28. The isolated composition of claim 22, wherein the therapeutic composition is comprised of a peptide, a protein, an antisense molecule, a ribozyme, a viral vector, an expression vector, and a plasmid.
29. A method of producing antibodies free from infectious prion contamination comprising:
a) inoculating a mammal with an antigen to produce antibodies specific to said antigen;
b) fusing isolated B lymphocytes expressing said antibodies to a mammalian cell line to establish a hybridoma line which expresses said antibodies;
c) producing said antibodies; and
d) isolating said antibodies;
wherein the hybridoma line has an altered endogenous PrP gene and said isolated antibodies cannot transmit a prion-mediated pathology to a subject of the same species as the host cell.
30. The method of claim 29, wherein the endogenous PrP gene is altered prior to the establishment of the hybridoma line.
31. The method of claim 29, wherein the endogenous PrP gene is altered in the B lymphocytes and the mammalian cell line prior to the establishment of the hybridoma line.
32. The method of claim 29, wherein the hybridoma is further altered to express exogenous PrP sequences.
33. The method of claim 29, wherein the expression of the exogenous PrP sequences is operably linked to an inducible promoter that can suppress expression of PrP during antibody production.
34. A method for producing humanized antibodies free from infectious prion contamination comprising:
a) introducing an expression vector comprised of sequences encoding an antibody into a primate cell line with an altered endogenous PrP gene;
b) producing said antibodies by induction of said expression vector; and
c) isolating said antibodies;
wherein the isolated antibodies are free from infectious primate prions and cannot transmit prion-mediated disease to primate subjects receiving said isolated antibodies.
35. The method of claim 34, wherein the primate cell line has an ablated endogenous PrP gene.
36. The method of claim 34, wherein the primate cell line is further altered to express an exogenous PrP gene.
37. The method of claim 34, wherein the expression of the exogenous PrP sequence is operably linked to an inducible promoter that can suppress expression of PrP during antibody production.
38. An isolated antibody characterized by an inability to transmit a prion-mediated pathology to a subject of the same species as the host cells.
39. The antibody of claim 38, wherein the antibody is produced using the method of claim 29.
40. The antibody of claim 38, wherein the antibody is produced using the method of claim 34.
41. The isolated antibody of claim 38, wherein the antibody is for human therapeutic use.
42. The isolated antibody of claim 38, wherein the antibody is for bovine, equine, porcine, canine, feline or ovine therapeutic use.