Multi-well fourier ptychographic and fluorescence imaging

1. An imaging device comprising:

a plurality of light sources operable to sequentially illuminate a transparent well with plane wave illumination at different angles;

a first excitation light source operable to provide excitation light of a first range of wavelengths to the transparent well, the first excitation light source oriented to direct the excitation light to approximately a center of the transparent well;

an optical system; and

an image sensor configured to receive light propagated through the optical system from the transparent well, the image sensor operable to take a sequence of intensity measurements of light passing through a sample being imaged in the transparent well, the sequence of intensity measurements taken while the sample is sequentially illuminated at different angles by the plurality of light sources, the image sensor further operable to generate image data for a first fluorescence image of the sample using light emitted by the sample in response to being illuminated by excitation light from the first excitation light source.

2. The imaging device of claim 1 , wherein the first excitation light source is configured to direct the excitation light at an angle to a plane at a bottom surface of the transparent well.

3. The imaging device of claim 2 , wherein the plurality of light sources is operable to illuminate the transparent well with plane wave illumination in a direction approximately perpendicular to a bottom surface of the transparent well.

4. The imaging device of claim 1 , wherein the plurality of light sources comprises a light-emitting diode matrix.

5. The imaging device of claim 1 , further comprising a processor configured to use a Fourier ptychography reconstruction process to determine an improved resolution bright-field image of the sample using the sequence of intensity measurements, wherein the improved resolution bright-field image has higher resolution than images based on the sequence of intensity measurements.

6. The imaging device of claim 5 , wherein the processor performs time-lapsed imaging by determining one or both of the improved resolution bright-field image and the first fluorescence image on a periodic basis.

7. The imaging device of claim 1 , wherein the first excitation light source and the plurality of light sources are activated at different exposure times of the image sensor.

8. The imaging device of claim 1 , wherein the optical system comprises a collection optical element and a focusing optical element, the collection optical element configured to collect light propagated from the transparent well and the focusing optical element configured to focus light from the collection optical element propagated to the image sensor.

9. The imaging device of claim 8 , wherein the optical system has a filter in an optical path between the collection optical element and the focusing optical element, the filter configured to block light in the first range of wavelengths, and wherein illumination from the plurality of light sources is within a passband of the filter.

10. The imaging device of claim 1 ,

further comprising a second excitation light source configured to provide excitation light of a second range of wavelengths to the transparent well;

wherein the image sensor is further configured to acquire a second fluorescence image of the sample based at least on light emitted by the sample in response to excitation light from the second excitation light source; and

further comprising a processor configured to combine the first fluorescence image and the second fluorescence image to generate a multi-color fluorescence image of the sample.

11. The imaging device of claim 10 , wherein the optical system has a dual band emission filter between the collection optical element and the focusing optical element, the dual band emission filter configured to block light of the first range of wavelengths and block light of the second range of wavelengths.

12. The imaging device of claim 1 , wherein the transparent well is in a multi-well plate having at least six wells.

13. The imaging device of claim 1 , wherein the transparent well is in a 6-well plate or a 12-well plate.

14. An imaging system comprising:

a body configured to receive a multi-well plate with a plurality of transparent wells;

a plurality of light sources operable to sequentially illuminate the transparent wells in parallel, each transparent well illuminated with plane wave illumination at different angles;

a plurality of imaging devices arranged in one to one correspondence with the transparent wells of the multi-well plate, each imaging device comprising:

a first excitation light source operable to provide excitation light of a first range of wavelengths to a transparent well, the first excitation light source oriented to direct the excitation light to approximately a center of the transparent well;

an optical system; and

an image sensor configured to receive light propagated through the optical system from the transparent well, the image sensor operable to take a sequence of intensity measurements of light passing through a sample being imaged in the transparent well, the sequence of intensity measurements taken while the sample is sequentially illuminated at different angles by the plurality of light sources, the image sensor further operable to generate image data for a first fluorescence image of the sample light emitted by the sample in response to being illuminated by excitation light from the first excitation light source; and

a processor configured to use a Fourier ptychography reconstruction process to determine an improved resolution bright-field image of each of the samples in the transparent wells in parallel using the ssequence of intensity measurements, wherein the improved resolution bright-field image has higher resolution than images using the sequence of intensity measurements.

15. The imaging system of claim 14 , wherein the first excitation light source of each imaging device is configured to direct the excitation light at an angle to a plane at a bottom surface of the transparent well.

16. The imaging system of claim 15 , wherein the plurality of light sources of each imaging device is operable to illuminate the transparent well with plane wave illumination in a direction approximately perpendicular to the bottom surface of the transparent well.

17. The imaging system of claim 14 , wherein the multi-well plate includes has at least six wells.

18. The imaging system of claim 14 , wherein the multi-well plate is a 6-well plate or a 12-well plate.

19. An imaging method, comprising:

illuminating a multi-well plate with excitation light of a first range of wavelengths;

for each well in the multi-well plate, generating a fluorescence image of a sample located in the well during operation;

sequentially illuminating each well in the multi-well plate with plane wave illumination at a plurality of illumination angles using a plurality of light sources;

for each well in the multi-well plate, generating, using an image sensor, a sequence of intensity measurements based at least in part on light passing through the sample being imaged in the corresponding well based on the sequential illumination at the plurality of illumination angles; and

for each well in the multi-well plate, reconstructing with a Fourier ptychography reconstruction process an improved resolution bright-field image of the sample being imaged based on the sequence of intensity measurements, the improved resolution bright-field image having higher resolution than images using the intensity measurements.

20. The imaging method of claim 19 , wherein the fluorescence images are generated in parallel for all the wells in the multi-well plate.