The Use of Lasers in Medicine

The US Food and Drug Administration (FDA) website states that: ‘Medical lasers are medical devices that use precisely focused light sources to treat or remove tissues.’ ¹ In recent years, lasers have been used for the diagnosis and treatment of an increasing number of medical conditions. Ongoing research into laser therapeutics by medical institutions and commercial companies continues to produce novel, effective and patient-friendly alternatives to more traditional care pathways. In addition, pathology testing is set to be revolutionized by photonics based, miniature chips within the next 10 to 15 years.

According to a 2022 report published by Research and Markets, the global medical lasers market reached a value of US$ 3.70 Billion in 2021 and is expected to increase to US$ 7.01 Billion by 2027.² The uplift in value of this sector highlights the new treatments and medical conditions being successfully and cost-effectively treated by laser technologies.

In the UK, the NHS currently employs 25,000 people in pathology laboratories all of which use photonics-based instruments to test patient samples. This costs the NHS US$ 2 billion annually, or the equivalent of 4% of its budget.³

Medical Conditions Diagnosed and Treated with Lasers

Lasers can be used for a range of medical procedures as the beam itself is so small and accurate it allows surgeons to safely and effectively treat tissue without injuring the surrounding area.

Cosmetic dermatologists use lasers for the effective removal or treatment of tattoos, scars, stretch marks, sunspots, wrinkles, birthmarks, spider veins and unwanted hair. Other specialists in the field of cosmetics have also more recently adopted the use of lasers e.g., for dental tooth whitening.

Outside of the cosmetic market, lasers are used for an increasingly broad range of medical treatments. Ophthalmologists have been using lasers for eye surgery since the late 1980’s, using the technology to treat a range of conditions including refractive errors, posterior capsular opacity, glaucoma, diabetic eye disease and retinal tears. Other branches of surgery are also successfully using lasers to aid in the treatment of certain illnesses, tumours, kidney stones and prostate glands are all routinely removed using lasers in surgery.

There are a number of benefits to using laser treatments as supposed to more traditional surgical techniques. Laser treatments carry the same risks as open surgery including pain, bleeding and scarring but the recovery time for the patient, and hence the post recovery cost for the hospital, has been shown to be much reduced. In addition, the laser light beam does not pose health risks to the patient or medical team in the way that other treatments e.g., radiation therapy might do.

The Future of Lasers in Medicine

With an increasing, aging population in many countries globally, the traditional central testing pathology laboratories are both unaffordable and unsustainable. It is envisaged that by 2035, with advances in integrated photonics, point of care tests will be taken at the GP surgery or bedside using miniature chips. It is already estimated that point of care testing will reach US$ 31 billion by 2025, reducing pathology laboratory testing requirements by up to a quarter.⁴

The use of lasers in medicine offers a host of other potential applications for the future e.g., the use of spectroscopy to monitor blood glucose, highly localized irradiation for light-activated cancer treatments via key-hole surgery are amongst a vast array of other diagnostic and treatments currently already being used or in active trials.^{5, 6}

Ensuring that these pioneers in healthcare have the correct wavelengths and other laser light properties to meet the continuing development of medical applications is an important focus area for laser and medical equipment manufacturers.

Wavelength Engineering Using Non-Linear, Optical Crystals

Non-linear optical (NLO) crystals provide an enormously flexible solution for generating new wavelengths from existing, off-the-shelf laser sources. Although there are a wide variety of commercially available laser sources covering the extended optical spectrum it is still not always possible to find a direct or cost effective light source for all applications. It is in these cases
where a practical, direct source is not available that wavelength conversion using highly efficient, non-linear optical crystals provides a powerful solution.

When considering non-linear optical, crystal materials, lithium niobate (LiNbO3) is a particularly attractive option since it has a very high non-linear coefficient . With its high efficiency, ability to be periodically poled and broad optical transmission, MgO-doped, periodically poled lithium niobate (MgO:PPLN) becomes a highly flexible solution for the generation wavelengths from 400nm to 5μm.

Examples of Wavelengths Required for Medical Application

Lasers are used in ophthalmology more than in any other medical specialty. The transparent nature of the human eye makes it possible to target intraocular structures without the need for endoscopy or separate surgery. Wavelengths of interest include 689nm used in photodynamic therapy (PDT), PDT is a treatment that involves light-sensitive medicine and a light source to destroy abnormal cells. PDT is used to treat age-related macular degeneration (AMD)⁷. Laser light at 810 nm is used in transpupillary thermotherapy (TTT) which is the most common type of laser treatment for eye melanoma. TTT uses the infrared light to heat and kill the tumor.⁸

Flow cytometry is a widely used method in biomedical research and increasingly in clinical diagnostics.⁹ It is a powerful and rapid technique to analyze physical and chemical properties of single cells or particles as they are suspended in liquid and pass in a narrow line across laser beams. Fluorescence together with scattered laser light is then filtered, detected, and analyzed. In addition to analysis, many flow cytometers can also sort and purify cell populations of interest for downstream analysis based on the identified properties of cells or particles. Lasers are exclusively used for flow cytometry due to their power, uniform, and focused illumination properties. Multiple monochromatic laser wavelengths provide multiparametric detection possibilities with the use of many different fluorescent labels. The most commonly used antibody labels in biosciences fluoresce at the following wavelengths 405, 445, 488, 532, 561, 633, 640, 660, and 810nm.¹⁰

In both of these examples the wavelengths of interest cover the visible and NIR regions of the optical spectrum. Non-linear wavelength conversion provides a powerful method for the generation of visible wavelengths from IR laser sources and can therefore be used to ‘fill’ the wavelength gaps that exist between direct laser sources.

Visible Wavelength Generation

Wavelengths covering the visible region of the optical spectrum can be generated via Second Harmonic Generation (SHG), or Sum Frequency Generation (SFG). With appropriate choice of the pump lasers either fixed or tunable wavelength output can be produced.

Second harmonic generation (SHG), or frequency doubling, is the most commonly used second order non-linear process. In SHG, two input pump photons with the same wavelength λ_P are combined through a nonlinear process to generate a third photon at λ_SHG, where, λ_SHG = λ_P/2 (or in terms of frequency f_SHG = 2f_P).

MgO:PPLN SHG crystals can be fabricated to work with a wide range of commercially available pump laser wavelengths from 976nm to 2100nm, allowing generation of frequency doubled light between 488nm and 1050nm.

Example:High efficiency SHG of 1064nm light using PPLN can generate 532nm light at Watt levels of power suitable for skin treatment including removal of port wine stains, birthmarks, melanomas, tattoo & hair removal.

Sum frequency generation (SFG) combines two input photons at λ_P and λ_S to generate an output photon at λ_SFG, where λ_SFG = (1/ λ_P + 1/ λ_S) -1 (or in terms of frequency f_SHG = f_P + f_S). By combining readily available fixed (e.g. 1550nm) and tunable (e.g. 780/810nm) pump laser sources MgO:PPLN SFG crystals can provide tunable output light between 500-700nm.

Example: High efficiency SFG using PPLN can combine tunable 1560nm and fixed 1064nm sources to generate light around 633nm for use in flow cytometry.

Ease of Use

MgO:PPLN can be readily manufactured into a variety of forms from bulk crystal to waveguide providing both a wide application range as well as enhanced conversion efficiency. Wavelength conversion chips, either using bulk crystal or waveguide forms, can then easily be packaged with fiber-coupled input and output – for enhanced ease of use. The combination of a fiber-coupled package together with a high precision temperature controller provides a plug and play wavelength conversion solution ready for benchtop use or OEM integration.

Summary

In conclusion, the use of PPLN provides a practical solution for the generation of a wide range of wavelengths that are of importance in medical applications. It offers an alternative solution to existing, costly laser sources and a solution for wavelengths that are not readily accessible via direct laser sources. This highly efficient material can be packaged into components ready for integration into OEM lasers and medical equipment.

As a leading supplier of PPLN-based wavelength conversion products Covesion is able to offer advice on customer specific solutions, as well as technical support in their set-up, use and optimization. With an extensive portfolio of COTS products, as well as custom design capabilities, Covesion is well placed to support the widest range of wavelength conversion applications.

References

1. https://www.fda.gov/radiation-emitting-products/surgical-and-therapeutic-products/medical-lasers
2. https://www.researchandmarkets.com/reports/5615173/medical-lasers-market-global-industry-trends?gclid=EAIaIQobChMI9Nztl9nW_gIVieDtCh2HAQ13EAAYAiAAEgIYnPD
3. https://photonicsuk.org/wp-content/uploads/2021/10/Photonics_2035_Vision_Web_1.0.pdf
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349820/
5. https://www.azooptics.com/Article.aspx?ArticleID=2146
6. M. Houe et al, J. Phys. D Appl. Phys., 28:1747–1763, 1995
7. Photodynamic Therapy for Age-Related Macular Degeneration | Johns Hopkins Medicine
8. B. Faisting et al, Medical Laser Application, Volume 25, Issue 4, November 2010, Pages 214-222
9. How a Flow Cytometer Works | Thermo Fisher Scientific – UK
10. Trends in flow cytometry lasers call for more new wavelengths | Laser Focus World

Introduction

Spectroscopy is the study of the absorption and emission of light and other radiation by matter, as related to the dependence of these processes on the wavelengths of radiation. It plays a vital role in various scientific and industrial fields by providing valuable insights into the composition, structure, and dynamics of materials. Spectroscopy techniques are employed in a wide range of applications, including chemistry, physics, biology, environmental science, materials science, pharmaceuticals, and many others. The global spectroscopy market size reached $16 billion (USD) in the year 2022 and is expected to hit around $31 billion (USD) by 2032 with increased utilization of spectroscopy methods for testing purposes.  There are rising demands from the laboratories for newly developed technology and the market is growing at a CAGR of 7.3% ^[1].

Efficiency and versatility are critical factors in spectroscopy, as researchers strive to obtain accurate and detailed information in a timely manner. To meet these demands, there is a constant need for innovative and advanced spectroscopy techniques that offer enhanced sensitivity, broad tunability, and improved signal generation. Periodically poled lithium niobate (PPLN) has emerged as a valuable platform for various spectroscopy techniques, enabling efficient and versatile manipulation of light-matter interactions. By exploiting its unique properties and periodic poling structure, PPLN offers enhanced wavelength conversion capabilities, broad tunability, and increased detection sensitivity. This white paper explores the potential of PPLN in spectroscopy applications, including nonlinear optical spectroscopy, sum frequency generation spectroscopy, and raman spectroscopy.

Properties of PPLN for Spectroscopy

PPLN offers a large nonlinear coefficient, enabling efficient wavelength conversion and generation of nonlinear optical signals. Its wide transparency range covers a broad spectral range, allowing researchers to access different regions of the electromagnetic spectrum. Moreover, PPLN exhibits a high damage threshold, making it capable of handling intense laser beams. These properties, combined with the flexibility of PPLN in achieving quasi-phase matching conditions through periodic poling, make it an attractive material for spectroscopy applications.

Large Nonlinear Coefficient: PPLN possesses a large nonlinear coefficient. The highest nonlinear coefficient is d33=25pm/V, which corresponds to interactions that are parallel to the z-axis, i.e. type 0 phase matching. For periodically poled MgO:LN, the effective nonlinear coefficient d_eff is typically 14pm/V, which is much higher than traditional nonlinear crystals such as lithium triborate (LBO, 0.85pm/V), beta barium borate (BBO, 2.5pm/V) or potassium titanyl phosphate (KTP, 3.4pm/V). This property allows efficient frequency conversion processes, such as second-harmonic generation (SHG), sum frequency generation (SFG), difference frequency generation (DFG), and optical parametric oscillation (OPO), optical parametric amplification (OPA), which are essential for various spectroscopic applications.

Wide Transparency Range: PPLN exhibits a broad transparency range that extends from the ultraviolet (UV) to the mid-infrared (mid-IR) spectrum. The transparency window covers wavelengths from approximately 380nm to 5μm. This wide transparency range enables PPLN to be utilized for spectroscopic studies across a broad range of wavelengths.

High Damage Threshold: PPLN has a high damage threshold, allowing it to withstand high-intensity laser radiation. This property is crucial for spectroscopy applications that involve intense laser beams, as it ensures the crystal’s stability and longevity under demanding operating conditions. For femtosecond laser source, PPLN could handle up to 8GW/cm² power intensity. 

Flexibility in Wavelength Conversion: PPLN can be engineered to exhibit a quasi-phase-matching (QPM) structure by periodically poling the crystal. This process creates a series of alternating regions with opposite polarization orientations. By selecting the appropriate poling period, the QPM wavelength can be adjusted to match specific application requirements. This flexibility in wavelength conversion enables efficient and precise tuning of generated or converted frequencies for spectroscopic investigations.

Broad Tunability: The QPM structure of PPLN allows for broad tunability of the generated or converted wavelengths. By adjusting the temperature of the crystal, the phase-matching condition can be tailored, leading to tunable output across a wide range of wavelengths. This tunability is advantageous for spectroscopy techniques that require the ability to scan or access different wavelengths.

PPLN Used in Spectroscopy

Two-Photon Absorption Spectroscopy is a nonlinear optical technique that involves the simultaneous absorption of two photons by a molecule or material. The process occurs when the combined energy of two lower-energy photons matches the energy required for an electronic transition that would typically require a single higher-energy photon. In this technique, a pulsed laser source with a relatively long pulse duration and a near-infrared (NIR) wavelength is used to excite the sample. The longer pulse duration helps to ensure that two photons are absorbed simultaneously, leading to fluorescence emission or other measurable signals. PPLN is employed in two-photon absorption spectroscopy as a frequency doubler to convert the NIR laser wavelength to a shorter wavelength, typically in the visible range^[2]. PPLN’s large nonlinear coefficient and flexibility in wavelength conversion enable efficient SHG of the NIR laser light. By exploiting the QPM property of PPLN, the conversion efficiency can be significantly enhanced, resulting in a stronger and more detectable signal for two-photon absorption spectroscopy^[3].

Sum Frequency Generation (SFG) spectroscopy is a powerful and non-linear optical technique used to study the surface and interface properties of materials^[4]. It provides valuable information about molecular vibrations and interactions at interfaces, which are essential for understanding the behavior of surfaces, thin films, and interfaces in various applications, such as catalysis, bio interfaces, and materials science. SFG spectroscopy involves two incident photons interacting to generate a new frequency (sum frequency) equal to the sum of the frequencies of the two incident photons. SFG is highly surface-specific and can selectively probe the molecular vibrations at the interface or surface without interference from the bulk material. This makes it particularly suitable for studying molecular structures and dynamics at buried interfaces. SFG spectroscopy provides vibrational information about the molecules present at the interface, enabling researchers to study molecular orientations, hydrogen bonding, and other interactions. SFG Spectroscopy is a non-destructive technique that can probe surfaces and interfaces without altering the sample. And it’s highly sensitive to molecular structures and orientations, allowing researchers to study monolayers or very thin films. The surface-selective nature of SFG makes it an ideal tool to study buried interfaces, such as those found in bio-membranes or electrode-electrolyte interfaces. SFG can be combined with time-resolved measurements, allowing researchers to study dynamic processes at interfaces on a femtosecond timescale^[5].

PPLN is good material to generate coherent SFG signals with high sensitivity and tunability. PPLN crystals can be engineered with different periodicities, enabling tunability of the generated SFG signal over a wide range of frequencies. The quasi-phase-matching condition in PPLN greatly enhances the efficiency of the SFG process, resulting in stronger and more easily detectable signals. PPLN crystals can be designed to cover a broad range of infrared and visible wavelengths, making them compatible with a variety of laser sources. And PPLN provides coherent SFG signals, allowing for phase-sensitive measurements and various coherence-based spectroscopic techniques. Due to the high conversion efficiency, PPLN-based SFG setups can achieve excellent sensitivity, enabling the study of monolayers or weakly interacting interfaces.

PPLN also has shown great potential in enhancing Raman spectroscopy, a widely used technique for molecular identification and analysis. Raman spectroscopy provides valuable information about molecular vibrations and chemical composition, but it often suffers from weak signals, limiting its sensitivity and applicability in certain scenarios. PPLN can overcome these limitations and enhance Raman signals through processes such as Stimulated Raman Scattering (SRS) and Coherent anti-Stokes Raman Scattering^[6]. SRS is a non-linear optical process that can significantly amplify weak Raman signals by using a powerful pump laser to stimulate Raman transitions. The process involves the interaction of the pump laser with the sample, leading to an amplification of the Raman signal at a different frequency. PPLN can be employed as a nonlinear medium for SRS due to its unique property of quasi-phase matching, which allows efficient energy conversion from the pump to the Raman-shifted signal. Researchers used PPLN crystals to build all-solid-state laser system for SRS microscopy. They demonstrated SRS microscopy at a 30-µs pixel dwell time with high chemical contrast, signal-to-noise ratio in excess of 45 and no need for balanced detection^[7].

Coherent Anti-Stokes Raman Scattering (CARS) Spectroscopy is a powerful nonlinear optical technique used for label-free chemical imaging and vibrational spectroscopy. It allows the detection and characterization of molecular vibrations by exploiting the Raman scattering phenomenon. CARS spectroscopy involves the interaction of three laser beams: a pump beam, a Stokes beam, and a probe beam. The pump and Stokes beams are combined to generate a coherent anti-Stokes signal at a lower frequency, which is then detected using the probe beam. The frequency difference between the pump and Stokes beams corresponds to a vibrational mode of interest. A PPLN-based OPA system could amplify the emitted imaging signal from SHG and CARS microscopy imaging, and the amplified optical signal is strong enough to be detected by a biased photodiode under ordinary room light conditions^[8].

PPLN for Wavelength Conversion

Second harmonic generation (SHG), or frequency doubling, is the most commonly used second order non-linear process. In SHG, two input pump photons with the same wavelength λ_P are combined through a nonlinear process to generate a third photon at λ_SHG, where λ_SHG = λ_P/2 (or in terms of frequency f_SHG = 2f_P).

MgO:PPLN SHG crystals can be fabricated with QPM grating periods suitable for a wide range of commercially available pump laser wavelengths from 976 nm to 2100 nm, allowing generation of frequency doubled light between 488nm and 1050nm.

Sum frequency generation (SFG) combines two input photons at λ_P and λ_S to generate an output photon at λ_SFG , where λ_SFG = (1/ λ_P + 1/ λ_S)^-1 (or in terms of frequency f_SHG = f_P + f_S).

By combining readily available fixed (e.g. 1550nm) and tunable (e.g. 780/810nm) pump laser sources MgO:PPLN SFG crystals can provide tunable output light between 500-700nm.

Difference frequency generation (DFG) occurs when two input photons at λ_P and λ_S are incident on the crystal, the presence of the lower frequency signal photon λ_S, stimulates the pump photon λ_P, to emit a signal photon λ_S and idler photon at λ_i , where λ_i = (1/ λ_P – 1/ λ_S)^-1 (or in terms of frequency f_i = f_P – f_S). In this process, two signal photons and one idler photon exit the crystal resulting in an amplified signal field. This is known as optical parametric amplification(OPA). Furthermore, by placing the nonlinear crystal within an optical resonator, also known as an optical parametric oscillator(OPO), the efficiency can be significantly enhanced.

References

1. https://www.precedenceresearch.com/spectroscopy-market.
2. D. Xu, et. al , “Widely-tunable synchronisation-free picosecond laser source for multimodal CARS, SHG and two-photon microscopy,” Biomedical Optics Express , vol. 12, no. 2 , p. 1010, 2021.
3. H. He, et, al. , “Deep-tissue two-photon micrescopy with a frequency-doubled all-fiber mode-locked laser at 937nm,” Advanced Photonics Nexus, vol. 1(2), p. 026001, 2022.
4. A. Morita, Theory of Sum Frequency Generation Spectroscopy, Springer.
5. A. Ghosh, et. al, , “Femtosecond time-resolved and two-dimensional vibrational sum frequency spectroscopic instrumentation to study structural dynamics at interfaces,” Review of Scientific Instruments , vol. 79, p. 093907, 2008.
6. D. Polli, et. ac, “Broadband Coherent Raman Scattering Microscopy,” Laser & Photonics reviews , vol. 12, no. 9, 2018.
7. T. Steinle, et. al. , “Synchronization-free all-solid-state laser system for stimulated Raman scattering microscopy,” Light: Science & Applications, vol. 5, 2016.
8. Y. Sun, et al. , “Nonlinear optical imaging by detection with optical parametric amplification (invited paper),” Journal of Innovative Optical Health Sciences, vol. 16, no. 1, p. 2245001, 2023.