Fig. 1. Photoacoustic spectroscopy for biomedical detection applications. (a) Principle of photoacoustic spectroscopy; (b) schematic of photoacoustic spectroscopy for biochemical molecules and cells detection in atmosphere and liquid, insets show laser source (left) and acoustic detector (right) commonly used in photoacoustic spectroscopy

Fig. 2. Wavelength band covered by the common laser sources in photoacoustic spectroscopy and the absorption coefficient and line intensity of typical gas/biological molecules in biomedical detection

Fig. 3. Enhancement of the gas photoacoustic signal based on multi-pass cell. (a) Top: schematic of the Herriott multi-pass cell and the optical path of multiple reflections inside the cell;below: simulated spatial distribution of the light spots on the planar and concave mirrors of the cell^[38]; (b) schematic of the circular gas cell with the simulated and experimentally observed multi-rays in the cell^[41]; (c) top: open multi-pass cell and multi-rays in the cell observed in the experiment; below: measured light spots on the two mirrors of the cell^[42]; (d) schematic and photograph of compact multi-pass cell integrated with the optical fiber^[43]; (e) multi-pass cell based on high-finesse optical cavity and the scheme for locking the pump light wavelength^[44]; (f) multi-pass cell inside the laser cavity of which the length is locked to the pump wavelength by the PDH technique^[46]

Fig. 4. Photoacoustic spectroscopy based on acoustic sensors of different types and the related signal enhancement schemes. (a) Schematic of QEPAS with an enlarged view of the internal components^[61]; (b) schematic of the fiber-optic photoacoustic probe and the enlarged cantilever diaphragm^[65]; (c) schematic of the all-optical photoacoustic probe with enlarged view of the micromirror alignment against the tube and the readout fiber^[66]; (d) schematic of the thin-film F-P cavity-based photoacoustic probe for C₂H₂ sensing^[68]; (e) schematic of the radial-resonator-cavity QEPAS ^[71]; (f) left: schematic of a miniature photoacoustic probe based on a sphere-cylinder coupled acoustic resonator; right: the simulated pressure field inside the resonator and the frequency response^[72]; (g) schematic of miniature micro-cone-curved resonant cavity^[73]; (h) left: schematic of the differential photoacoustic spectroscopy with single microphone; right: 3-D schematic of the whole sensor structure with the enlarged view of the fiber-optic microphone design and photograph^[74]

Fig. 5. Photoacoustic spectroscopy for blood glucose and oxygen measurement. (a) Schematic of photoacoustic measurement system for the finger skin glucose based on tunable EC-QCL middle-infrared pulsed laser^［81］; (b) variation in the photoacoustic spectra for a diabetic volunteer with different glucose concentrations^[81]; (c) schematic of the hand-held photoacoustic system for measurement of the local tissue oxygenation^［89］; (d) in vivo assessment of mouse tissue blood oxygenation at different locations P₁, P₂ and P₃^[89]

Fig. 6. Biological molecules sensing based on photoacoustic spectroscopy. (a) Heparin sensing: (I) the principle of the fiber optic photoacoustic probe, with the signal enhanced by the reaction of the cationic dyes with the Nile Blue A; (II) experimental schematic and results for the photoacoustic measurement in phosphate buffer saline (PBS), diluted plasma and whole blood^[95]; (b) uric acid sensing: (I) schematic of the photoacoustic spectroscopy system for uric acid sensing; (II) photoacoustic signal as a function of the uric acid concentration, inset shows chromogenic reaction of the agar gel piece at various uric acid concentrations; (III) photoacoustic signal as a function of the uric acid concentration collected by smartphone^[96]

Fig. 7. Biomolecular detection based on local plasmon resonance effect of metal nanoparticles and electroluminescence (ECL)-photoacoustic synergism. (a) Schematic of the lateral flow immunoassay paper strip and photoacoustic detection for the chop mode and the scan mode^[97]; (b) schematic of the photoacoustic device for ALP detection^[98]; (c) schematic of the bipolar ECL-photoacoustic dual-modality biosensor: (I) sensing mechanism of the sensor with a soft Py-CPs@carbon fiber cloth (CFC) sensing cathode and NiFe₂O₄ nanotubes (NTs)@laser-induced graphene (LIG) catalytic anode; (II) ECL and photoacoustic output of the proposed biosensor for cancer patients and healthy controls, insets show significant difference for let-7a levels expression^[102]

Fig. 8. Schemes for the photoacoustic signal sensitization and noise reduction. (a) Photoacoustic signal enhancement with one-dimensional photonic crystal substrate: (I) schematic of the photonic crystal structure cross section and experimental setup, the linearly-polarized 632.8 nm laser light after being modulated by a mechanical chopper is delivered onto the photonic crystal substate for sample detection; (II) simulated spatial distribution of the near-field intensity for a flat acrylic substrate with a single AuNP and a photonic crystal substrate without and with a single AuNP^[104]; (b) photoacoustic signal enhancement with Helmholtz acoustic metasurface (HAM)^[105]; (c) single-wavelength water muted photoacoustic system: (I) system schematic with the inset showing the quartz photoacoustic cell; (II) simulated three-dimensional spatial distribution of acoustic pressure in the quartz photoacoustic cell; (III) simulated and measured photoacoustic spectrum curves, inset shows enlarged photoacoustic photoacoustic spectra and background noise off resonance; (IV) measured photoacoustic spectra at different water temperatures^[106]

Fig. 9. Respiratory gas detection based on photoacoustic spectroscopy. (a) Schematic of CO₂ isotopic ratio measurement based on fiber-coupled off-beam QEPAS: (I) schematic of the QEPAS system; (II) absorption coefficients of 400×10^-613CO₂, 3.56% ¹²CO₂, and 5% H₂O between 2295 cm^-1 and 2299 cm^-1 (pressure: 400 Torr, temperature: 296 K)^[113]; (b) schematic of the photoacoustic heterodyne sensor, inset shows differential photoacoustic cell^[115]; (c) schematic of NH₃ gas molecule measurement with the Nephrolux^TM photoacoustic spectroscopy system^[117]; (d) schematic of the QEPAS system for detecting the exhaled NH₃: (I) system schematic; (II) online NH₃ concentration measurement result of exhaled gas from three healthy subjects^[123]

Fig. 10. Skin released gas detection based on photoacoustic spectroscopy. (a) Noninvasive measurement of skin-released CO₂ with QEPAS^[127]: (I) calculated absorption spectra of 500×10^－6 CO₂ and 4% H₂O vapor according to the HITRAN database; (II) schematic of the QEPAS system for skin-released gas sensing; (III) static skin-released gas measurement for five different initial CO₂ concentrations in the SSH, inset shows photograph of the SSH on the skin surface; (b) two-chamber-based photoacoustic transcutaneous CO₂ sensor^[128]: (I) principle of the miniaturized photoacoustic transcutaneous CO₂ sensor; (II) photograph of the sensor before and after encapsulation; (III) temporal variation of the output signal from the system microphone and the equivalent CO₂ concentration, inset shows photograph of the test for the human skin

Fig. 11. Recent progress on photoacoustic spectroscopy. (a) High-precision multi-pass fiber-optic photoacoustic gas analyzer based on 2f/1f wavelength modulation spectroscopy^[143]; (b) quartz-enhanced multiheterodyne resonant photoacoustic spectroscopy^[144]; (c) left: schematic of the miniaturized all-fiber photoacoustic spectroscopy with its structure and principle; right: the photography of the probe and the scanning electrical microscopy images of the fiber endfacet^[145]