Metasurfaces have attracted considerable attention because of their unique optical capabilities to control the fundamental properties of light, such as amplitude, phase, and polarization. The flat nature of metasurfaces can help reduce the complexities and bulk of conventional optical systems. After a decade of rapid progress, metasurfaces are close to maturity and have found their role in various optical applications. This review emphasizes the significant advancements and emerging applications of metasurfaces in biomedical optics, particularly focusing on beam shaping for laser treatments, light-sheet fluorescence microscopy, HiLo microscopy, and optical trapping. Looking forward, we discuss foreseeable challenges for integrating metasurfaces into biomedical, preclinical, and clinical systems.

AAF

abruptly autofocusing

AI

artificial intelligence

AR

augmented reality

Al2O3

aluminum oxide

C. elegans

Caenorhabditis elegans

DIC

differential interference contrast

DMD

digital micromirror device

DOE

diffractive optical element

EBL

electron beam lithography

FDTD

finite-difference time-domain

FEM

finite element method

FOV

field of view

FWHM

full width at half-maximum

GaN

gallium nitride

GFP

green fluorescent protein

LiDAR

light detection and ranging

LSFM

light-sheet fluorescence microscopy

MRI

magnetic resonance imaging

NA

numerical aperture

NIL

nanoimprint lithography

OCT

optical coherence tomography

PDT

photodynamic therapy

RCWA

rigorous coupled wave analysis

SEIRA

surface-enhanced infrared absorption

SERS

surface-enhanced Raman scattering

SLM

spatial light modulator

SPIM

selective plane illumination microscopy

STED

stimulated emission depletion

TiO2

titanium dioxide

VR

virtual reality

3D

three-dimensional

In the face of this rapid evolution and diversification in modern biomedical fields, conventional methods are increasingly struggling to keep pace, particularly in terms of delivering the miniaturized optical equipment required for precise disease diagnosis and targeted treatment.1,2 The gap between the ever-increasing demand and the limitations of current technologies seemed impossible to bridge. Recently, the emergence of metasurfaces offers an innovative solution.3–7 These optical elements, composed of an array of designed subwavelength structures, are characterized by reduced dimensionality of metamaterials. With a thickness usually less than a few wavelengths, metasurfaces manipulate the fundamental properties of light, including amplitude, phase, and polarization, yielding a desired spatial profile of the optical field. This capability marks the birth of a new era in optics, enabling the production of flat, lightweight, and compact optical components with highly customizable functionalities. The versatility of metasurfaces has been highlighted in their ability to outperform their bulkier counterparts and demonstrate new optical phenomena across a wide range of the electromagnetic spectrum from x rays to terahertz frequencies.8–12 Many optical components based on metasurfaces have been realized, including metalens, waveplates, polarizers, and holograms.13–24 They have also been extended to a variety of practical applications, revolutionizing areas such as bioimaging,25–33 biosensing,34–38 spectrometry,39 polarimetry,40 augmented reality (AR),41 virtual reality (VR),42 cloaking,43 light detection and ranging (LiDAR),44 and communication.45 

Metasurfaces have demonstrated their effectiveness in a multitude of biomedical applications.46,47 The application of metasurfaces to overcome optical aberration limitations in endoscopic optical coherence tomographic catheters is demonstrated, and an improved transverse resolution for long depths of focus is obtained.48 The proposed nano-optic endoscopic probe opens up new avenues not only for the applications of the metasurface but also for the new and compact design of optical coherence tomography (OCT) instruments. In another work, the freedom of the metasurface is exploited to design a bijective illumination collection OCT probe. This design ensures lateral resolution from the depth of focus through the creation of a one-to-one mapping between the incident and detected light.49 These applications clearly demonstrate the practical applications of meta-optics for clinical usage. Metasurfaces have also been implemented in magnetic resonance imaging (MRI) systems.50,51 It is shown that the design limitations of MRI systems can be overcome and that dynamic metasurfaces can improve the imaging performance with a better signal-to-noise ratio. Sub-diffraction-limited imaging has greatly benefited from the recent advances in metasurface fabrication. The concept of super-resolution imaging has been well addressed by the metamaterial community. The invention of perfect lenses, superlenses, super oscillations, and many more have shown efficient and compact optical components that can be directly implanted to obtain super-resolution imaging via metasurfaces.52 In another novel usage of the metasurface for biomedical imaging purposes, a differential interference contrast (DIC) microscope has been developed that uses the metasurface with radial shear interferometry to perform edge detection, particle motion tracking, and label-free cell imaging.53 A guided-mode resonator metasurface has also been proposed to obtain phase contrast imaging and highlighted its benefits. In the field of bioimaging, metasurfaces have proven to be highly effective in enhancing the resolution and sensitivity of optical imaging technologies, thereby significantly advancing our understanding of complex biological systems. They have also demonstrated substantial potential in biosensing, in which they are used to increase the sensitivity for detecting environments, biomolecules, and cells.54 

A quick literature review on the medical use of lasers as therapeutic devices reveals that the application of lasers in medicine has a long history of more than 40 years.55 Clinical application of visible and near-infrared laser light has become a regular technique for treating pain, wound healing, inflammation, and repairing deeper tissues and nerves. These research trends suggest that as soon as any new laser device is invented, it is used in medical engineering for various purposes. In addition, special designs of continuous and pulsed-wave lasers have always been an active area of research for various reasons. With the recent advancement of nanophotonic metasurfaces, it is evident that the size, shape, and efficiency of laser-based biomedical instruments can be drastically improved.

The research field of application of lasers for biology and medical studies involves a variety of aspects of laser–tissue interaction and hence faces multiple major challenges. At the fundamental level, the limitation imposed by the scattering, absorption, and specimen-induced aberration inside the deep tissue restricts the passage of light through it. The laser–tissue interaction is complicated and deals with the photo-physical, photo-chemical, and photo-biological phenomena. Each of them has different conditional requirements for their control. Clinical application of laser technology in medicine is a nontrivial task. It requires expertise and high-end knowledge of both lasers as well as medicine for the effective use of this technique for curing diseases or performing surgeries. There are other challenges from the biological and the instrumentation side, and many studies need to be performed to make this technique much easier and more direct for broader usage.

Recent developments in nanophotonics have shown that the creation of light patterns of desired shapes and sizes can effectively be done using metasurfaces.56 Structured light has already proven its importance and solved many of the fundamental issues related to resolution and contrast in the field of microscopy. Most advanced optical microscopes use structured light patterns for high-resolution and multidimensional imaging. For example, light-sheet fluorescence microscopy (LSFM), stimulated emission depletion (STED) microscopes, and their derivatives regularly use special beam structures as their main functional element.57 On the one hand, biomedical applications of lasers have become a separate branch in the field of optics and lasers. On the other hand, the research field of structured light has grown rapidly, with a constant influx of novel structured light patterns. However, there are still knowledge gaps in our understanding of the phenomenon of laser–tissue interaction and its ultimate use in curing diseases.

One of the issues with fluorescence microscopy is the out-of-focus light, which blurs the image. Optical sectioning microscopy allows the imaging of thick biological samples by combining a series of two-dimensional images obtained at different depths. The out-of-focus background is removed using a variety of methods. One of the important optical sectioning microscopy techniques is LSFM. High-resolution light-sheet systems are essential for advanced biological studies and have proven to be an effective tool in these situations.58 One of the issues in miniaturizing advanced light-sheet systems is the bulky components, together with the need for special optical components for shaping light. Many techniques have been developed in the past to reduce the illumination arm of a light-sheet. Metasurfaces have shown great potential for overcoming some of the limitations of light-sheet systems.59 

Another important optical sectioning method is the use of structured light illumination to obtain optically sectioned images. In all these methods, multiple images are acquired and axial scanning of the sample is required. Maintaining constant magnification and uniform illumination for the extended depth requires variable-focus lenses. However, variable focus using conventional optics is difficult in this regard. The metasurface is beneficial in system design due to its compact size and ability to craft the desired light properties in a controlled manner.

Microscopic or sub-microscopic objects can be held or manipulated using the optical tweezer technique with a highly focused laser beam.60 In this process, the shape of the optical field plays a crucial role. Optical tweezers have been widely used to study biological and physical phenomena, including the motion of molecules, cells, and the dynamics of DNA.61 They have also been studied for the development of new medical treatments, such as the targeted delivery of drugs to cells. For medical usage, all these advanced studies require miniature optical instruments and new optical field patterns and devices. Due to ultra-compact sizes and the ability to tailor optical field patterns at the nanoscale, metasurface optics can play a crucial role in realizing compact optical tweezer devices. The high numerical aperture (NA) metalenses can replace the bulky microscope objectives, which are essential for obtaining high optical gradient forces.62 

There are many comprehensive reviews on the topic of metasurfaces.63–67 The primary focus of this review is on the recent finding and development in our work focusing on the biomedical applications of the metasurface, and therefore, it does not cover other aspects. First, the fundamental principles of metasurfaces are introduced. Then, we discuss the potential of metasurfaces for miniaturizing biomedical instruments and enhancing their performance. Specifically, we focus on beam shaping for laser treatment, optical sectioning microscopy, and optical tweezer. Finally, we evaluate the existing technological hurdles of metasurfaces from the perspective of preclinical and clinical systems. The artistic summary of this paper is shown in Fig. 1.

FIG. 1.

Overview of the contents of this paper. This illustration presents the range of applications using meta-optics, including beam shaping for laser treatments, light-sheet fluorescence microscopy, variable optical sectioning based on HiLo microscopy, and an optical tweezer.

FIG. 1.

Overview of the contents of this paper. This illustration presents the range of applications using meta-optics, including beam shaping for laser treatments, light-sheet fluorescence microscopy, variable optical sectioning based on HiLo microscopy, and an optical tweezer.

Close modal

The fundamental principle of metasurfaces is based on the manipulation of the phase, amplitude, and polarization of light waves through the scattering of electromagnetic radiation from subwavelength-sized structures, often termed meta-atoms. The design involves tailoring the geometry and arrangement of the meta-atoms to achieve the desired optical response. Typically, the design process starts with specifying the optical properties required for the metasurface, such as the polarization and working wavelength of the incident light. The choice of materials usually depends on the desired working wavelength and the fabrication feasibility. Various materials, including metals, dielectrics, semiconductors, and their combinations, can be used for metasurfaces. Then, numerical methods, such as finite-difference time-domain (FDTD), finite element method (FEM), and rigorous coupled wave analysis (RCWA), are used to simulate the interaction between the incident light and meta-atom to obtain the phase and intensity (transmission or reflection) of scattering light. The light modulation mechanisms can be categorized into multi-resonances, gap-plasmons, geometric phase methods, high-index-contrast structures, and so on.3 An example of a metalens design with no polarization selectivity realized by a commercial simulation software (CST Studio Suite) is shown in Fig. 2. The design is based on a working wavelength of 532 nm. To achieve polarization-insensitive performance, we choose cylindrical gallium nitride (GaN) structures placed on an aluminum oxide (Al2O3) substrate. GaN has a high refractive index and low loss in visible wavelengths, making it suitable for achieving full-phase coverage of light. Furthermore, it is compatible with mainstream semiconductor fabrication processes, which allows for practical implementation of the design. The periodic boundary conditions for the x and y directions are set, making the individual unit cells behave as if they are part of an infinite array. Meanwhile, the z direction is set as “open,” providing freedom for light to propagate in and out of the computational region. The diameter of 850 nm-height GaN nanocylinders varies from 100 to 185 nm, and each different radius can be considered as a point light source with a distinct phase, thereby realizing 360° phase modulation [Figs. 2(a) and 2(b)]. The phase distribution required for focusing is determined by the equation ϕx,y=2πλ(x2+y2f2f), where λ is the wavelength of light, f is the focal length, and (x, y) are the coordinates of each meta-atom. This equation presents the phase profile necessary to convert a plane wave into a converging wavefront. Finally, by arranging the meta-atoms with different diameters according to the required phase profile shown in Fig. 2(c), we can realize the metasurface with a focusing function. Of course, the design parameters of different functional optical elements can vary depending on the specific requirements, which is the versatility of metasurfaces. One of the most common approaches for fabricating metasurfaces is electron beam lithography (EBL), which can achieve a high resolution and accuracy. Other techniques, such as laser direct writing, photomask process, nanoimprint lithography (NIL), and so on, have also been used to fabricate metasurfaces with high precision and scalability. These fabrication methods are common in semiconductor manufacturing processes.68–75 However, there is a significant difference when it comes to the creation of metasurfaces compared to typical semiconductor chips: metasurfaces only require single-layer structures, as opposed to the dozens of circuit layers that are often needed for conventional chip production. This simplification drastically reduces the complexity of the manufacturing process, which, in turn, leads to a significant reduction in the cost of metasurface production. In addition, the design flexibility and the ability of metasurfaces offer the potential for mass production and integration into consumer products.

FIG. 2.

(a) GaN nanopillar as unit cells. (b) Phase shifts of unit cells. (c) Phase requirement of focusing.

FIG. 2.

(a) GaN nanopillar as unit cells. (b) Phase shifts of unit cells. (c) Phase requirement of focusing.

Close modal

Metasurfaces have a broad range of applications, from enhancing diagnostic imaging to enabling precise surgical techniques. We start by exploring their use in beam shaping for laser treatments.

One of the most desirable situations in any medical laser treatment is the selective exposure of the intended area without affecting the surrounding and the preceding tissues. A precise structure of the optical beam can serve this purpose for the development of new laser therapeutic devices. In recent years, laser has become an important tool in phototherapeutic techniques for clinical uses. In all these devices, mostly the fundamental Gaussian beam directly coming out of the lasers has been used. Past research trends suggest that as soon as any new laser device is invented, they will be used in medical engineering for various purposes. Special designs of continuous and pulsed-wave lasers have always been an active area of research. The Gaussian beam is the conventional mode for most laser devices. However, with the progress in the knowledge of optical beam shaping techniques, many new fundamental optical modes have been theoretically and experimentally observed and used for various applications. For example, Bessel beams, Laguerre–Gaussian beams, and Mathew beams, etc., have been considered the fundamental modes of laser cavity with different geometries.76 With advances in spatial light modulating devices, experimental generation and control of amplitude, phase, and polarization properties of these beams is straightforward. There is a whole new class of beams known as nondiffracting beams, whose properties are quite different in comparison with the usual Gaussian beam. In the past decade, these beams have been interesting areas of beam shaping and finding important applications in a variety of fields, ranging from microscopy to optical communications.77 Among these beams, Airy beams are relatively new and have been extensively studied for their peculiar properties of nondiffraction, self-healing, and parabolic path. Propagation properties of these beams in linear and nonlinear media have been investigated in many research studies. However, the application of these beams inside the laser–tissue interaction has not been explored yet. There exists a significant knowledge gap, which could potentially pave the way for the development of innovative techniques in medical laser therapy.

The main areas of low-level laser light therapy include wound healing, tissue repairing, relief of pain, relief of inflammation, and neurogenic pain. For the treatment of all these conditions, the photoreceptor is exposed to the light with the proper characteristics to cause the photo-induced chemical changes inside the exposed areas. The absorption of the optical field in the biological tissues is possible due to the naturally available optical window of the wavelength range (600–1150 nm). This window is mostly used for diagnostic purposes. Medical applications of laser therapy are diverse. Many methodologies exist, and different kinds of light sources have been used. In the previous studies, the effect of laser wavelength, polarization, coherent vs noncoherent light sources, amount of DOEs, and continuous or pulsed light have been investigated. In all these studies, a Gaussian light beam has been used. There are no reports on the study of the shape of the beam, which offer its own set of advantages. Each beam shape has different propagation and focusing properties. The shape of the focal spot is entirely controlled by the form of its wavefront and intensity distribution.

In laser–tissue interaction, when the energy of the light crosses the threshold, it can produce three kinds of changes: (a) photo-thermal, (b) photo-mechanical, and (c) photo-chemical. The extent of photo-thermal and photo-mechanical effects is contingent upon the intensity of radiation, with a negligible impact observed when the energy deposition rate is low. Utilizing this advantage selectively, energy can be deposited in the tissues. Optical dose is one of the most critical parameters of laser therapy. While overdose results in a negative impact, underdose does not give any positive results. Most lasers uses the Gaussian beam, which can cause laser–tissue interactions in tightly focused regions, but its high energy power may produce thermal damage in unwanted fragile and sensitive regions when treating deeper parts of bulk tissue. The high numerical aperture light focusing has limitations in penetrating deep into the tissue due to its short working distances. A common constraint of many current laser surgery instruments is their lack of flexibility in altering output spatial profiles. Additionally, surgical regions are often highly diffuse, making it difficult to accurately deliver energy at deeper locations. Optical beams such as ring Airy beams and abrupt autofocusing phenomena will be helpful in such a scenario. The other envision advantage of using abrupt autofocusing (AAF) beams in laser therapy is their hollow beam shape, which will help in avoiding unwanted exposure to a larger area. For precise delivery of power at greater penetration depths, such a beam will be highly useful without affecting the surface of tissues and other intermediate planes.

Airy beams are relatively new and were introduced theoretically and experimentally a decade ago. These beams are fascinating because of their notable features of transverse acceleration due to which beams follow a parabolic propagation path. The diameter of the central lobe of these beams remains constant during propagation due to which they are called nondiffracting beams. Airy beams can be obtained by the cubic phase modulation of the incident Gaussian beam. When a part of the beam is obstructed, it can self-heal. Airy beams have many variants, among which cylindrically symmetric Airy beams, also known as the ring-Airy beam, have a unique property of abrupt autofocusing. The unique autofocusing properties of these beams have been shown to effectively deliver high-energy pulses deep within thick transparent samples without inducing any material damage prior to the focal point. This property helps in increasing the working distance from the source of the beam. This interesting feature of the beam is particularly useful for laser ablation applications.78,79 The ring-Airy beams are characterized by the main lobe and the number of side lobes. The propagation characteristic of these beams is shown as well with the intensity at the peak. The intensity at the focal point is at least one order of magnitude higher than the intensity during propagation. For the experimental realization of these beams, either a spatial light modulator or a volume holographic beam shaping element can be used.80 These devices are commonly used; however, they are bulky and difficult to integrate into surgical instruments. In recent studies, some of these limitations have been overcome using metasurfaces-based elements.46 

Many laser beam shaping methods have been proposed, such as the use of amplitude mask projection, fiber bundles, digital micromirror devices (DMDs), spatial light modulators (SLMs), and diffractive optical elements (DOEs). However, they have disadvantages in terms of power consumption, pixelated resolution, and bulky size. The generation of AAF by using a dielectric metasurface is demonstrated.81,82 The complex optical field associated with the AAF beam can be expressed in the following equation:
E0=Ai[(r0r)/w]exp[a(r0r)/w],
(1)
where Ai represents the Airy function, r0 represents the radius defining the primary ring, r is the radius, w represents the scaling factor, and a represents the exponential decay factor. The intensity distribution for propagation dynamics of the AAF beam at the wavelength of 532 nm created by using a GaN metasurface is shown in Fig. 3(a).
FIG. 3.

(a) Intensity distribution of the AAF beam. (b) Experimental self-healing test of the AAF beam. (c) Intensity profiles of AAF focusing spots w/wo obstacle. (d) Cross-sectional images of the skin after AAF beam treatment. (e) Sub-surface images at different depths.81 

FIG. 3.

(a) Intensity distribution of the AAF beam. (b) Experimental self-healing test of the AAF beam. (c) Intensity profiles of AAF focusing spots w/wo obstacle. (d) Cross-sectional images of the skin after AAF beam treatment. (e) Sub-surface images at different depths.81 

Close modal

To investigate the metasurface-generated AAF beam’s capacity for self-healing, opaque beam barriers with different sizes are employed to partially occlude the beam preceding its focal plane. On the imposition of an opaque block occluding a quarter and half of the initial ring-Airy pattern, it is discerned that the central focusing profile exhibited persistence, remaining unaltered, as shown in Figs. 3(b) and 3(c). Despite the partial incompleteness of the surrounding side-lobe rings, the central focal spot maintains its tightly focusing and axial symmetry, which provides a compelling testimony to the self-healing capacity intrinsic to the AAF beam. The potential application of the AAF beam in biomedical laser treatments is examined using swine skin tissue. Through the application of OCT imaging to the skin samples exposed to the AAF beam, a well-defined, localized photocoagulation region is visibly identified [Fig. 3(d)]. Most importantly, the surface of skin tissue does not get damaged. The clear delineation of this region illustrates the precision and control offered by the AAF beam in a highly scattering environment, particularly in ensuring that the laser effect is concentrated on the targeted area while minimizing collateral damage to the surrounding tissue. This work not only provides an efficient beam shaping method but also makes the system more compact. Moreover, the versatility of these optical components can be extended beyond skin treatments. They can also be employed in retinal surgeries and can be integrated with endoscopic tools for minimally invasive surgery.

Optical sectioning microscopy allows the acquisition of three-dimensional (3D) images of biological or material samples by selectively detecting a thin plane within the specimen. This approach enables researchers to visualize the internal structures of the sample with improved clarity and resolution. There are several optical sectioning microscopy techniques available, each with its own advantages and limitations, such as confocal microscopy, two-photon microscopy, LSFM, HiLo microscopy, OCT, and so on.83–86 

1. Light-sheet fluorescence microscopy

Light-sheet fluorescence microscopy, also called selective plane illumination microscopy (SPIM), is a powerful imaging technique particularly used in the biological sciences.87 It works by side-on illuminating the specimen with a thin sheet of light, while a separate objective collects the emitted fluorescence. Since only the observed plane is illuminated, LSFM greatly reduces photobleaching and phototoxicity compared to other methods, such as confocal microscopy, that illuminate the entire specimen. This makes LSFM ideal for long-term imaging of live specimens. Because it illuminates a plane of the specimen at once, LSFM allows for fast, high-throughput imaging, which is beneficial for observing dynamic processes, such as embryonic development or neural activity. LSFM can image deeper into scattering tissues compared to many other fluorescence microscopy techniques, allowing for the visualization of larger biological structures in 3D. For practical considerations of the illumination part of LSFM, the utilization of a focused light beam plays a crucial role in generating the excitation light-sheet. The sectioning ability and the axial resolution (Raxial) of the resulting image are related to the beam waist (w0) of a Gaussian beam. This relationship can be expressed by the following equation:88 
Raxial=2w0=2nλπNA.
(2)
Here, f represents the focal length of the lens, n signifies the refractive index, and NA corresponds to the numerical aperture. Similarly, the Rayleigh range (zr) can be associated with the field of view (FOV) of the image. Specifically, the FOV can be determined using the following equation:
FOV=2Zr=2πw02λ.
(3)
Remarkably, the FOV defined by the aforementioned equation also corresponds to the full width at half-maximum (FWHM) of the axial intensity distribution of the Gaussian beam. In contrast to traditional imaging techniques, such as wide-field and confocal microscopy, LSFM offers the advantage of achieving a more isotropic volumetric resolution. This is due to the fact that the axial resolution is primarily determined by the waist of the excitation beam rather than its Rayleigh range. The axial resolution of an image can be characterized by the thickness of the beam at its focal position, referred to as Dbeam. Similar to the definitions employed for Gaussian beams, Dbeam can be determined by considering the diameter of the Airy disk, which represents the central lobe of the Airy pattern. Mathematically, it can be expressed as
Dbeam=1.22*λNA.
(4)
Here, λ represents the wavelength of the light used in the imaging system, while NA denotes the numerical aperture associated with the focusing optics. This relationship highlights the significance of thickness of the beam in determining the axial resolution of the images formed with apertured beams. By carefully considering the properties of the Airy disk and optimizing the parameters, such as wavelength and numerical aperture, researchers can enhance the ability to resolve fine details along the axial direction in imaging applications.

In conventional LSFM, the system configuration involves bulky optical components and a sample holder, which must all fit into a limited space. This creates practical limitations, especially when attempting to miniaturize the system or handle and trace biological specimens. Recently, the implementation of cylindrical metalens and light-sheet metalens in LSFM for live biological samples has been presented. By incorporating thin metalens into the system, the size of the illumination arm in an LSFM can be drastically reduced.89,90 This also allows for a substantial reduction in the complexity of the system, as shown in Fig. 4(a), overcoming the practical challenges associated with component integration. The light-sheet metalens is made from a set of GaN nanopillars that can span a full 2π phase range, as shown in Fig. 4(b). Figure 4(c) shows the optical microscope (OM) image of the light-sheet metalens. To validate the imaging capability of our LSFM equipped with the proposed metalens for volumetric samples, the fluorescent beads embedded within an agar medium are imaged. Such fluorescent beads are used as a benchmark to evaluate both the system performance and the optical sectioning capability. A comparative analysis of fluorescence images captured with and without the inclusion of the light-sheet metalens is shown in Figs. 4(d) and 4(e), respectively. When the light-sheet produced by the metalens is employed, it results in the excitation and observation of a singular bead (diameter: 15 μm). Contrarily, upon removal of the metalens, out-of-focus background noise generated from de-focused beads becomes apparent. This means that there is no optical sectioning capability without light-sheet illumination. In addition, the efficacy of our system in executing high-resolution fluorescence imaging of live organisms at the cellular scale is demonstrated by scrutinizing the developmental trajectory via analysis of the germline in live Caenorhabditis elegans (C. elegans). The germline of C. elegans constitutes an assortment of germ cell nuclei in varied stages of development. In the quest to probe the aptitude of our LSFM system for live C. elegans imaging under differing fluorescence conditions, germ cell nuclei are marked using mCherry or green fluorescent protein (GFP)-tagged histone. The selected excitation wavelength for mCherry and GFP is 532 and 491 nm, respectively. The anatomical complexity of live worms often hampers the clear observation of the germline due to obstructions caused by other internal organs, predominantly the gut. Moreover, the propensity of gut cells to produce autofluorescence signals often disrupts the fluorescence detection from germline nuclei when the gut is situated between the gonad and the objective lenses. However, the LSFM images exhibit clearly distinguishable individual germline nuclei, as well as nuclei within developing embryos, even in cases where the worm’s orientation typically obstructs clarity, as shown in Figs. 4(f) and 4(g) depicting high-contrast embryonic images captured via the metalens LSFM. The LSFM, when augmented with the metalens, efficiently facilitates optimal illumination for optical sectioning. Impressively, even with low magnification objectives (20×), the system is capable of distinctly identifying the nucleus of ∼8 μm in diameter within individual oocytes. This demonstrates the ability of the system to achieve single-cell resolution for C. elegans. Individual nuclei within late-stage embryos of C. elegans can be clearly distinguished by using the LSFM system. Their work demonstrates the transformative potential of metasurface-based microscopy, such as its claimed ability to simplify complexity. Notably, they managed to decrease the optical path from a scale of tens of centimeters to a mere several hundred nanometers, with no detriment to the imaging performance.

FIG. 4.

(a) Photograph of the light-sheet metalens microscopy system. (b) SEM image of nanopillars. (c) OM image of light-sheet metalens. The system (d) with and (e) without light-sheet metalens and the corresponding fluorescence images. (f) Light-sheet fluorescence image of the mCherry-tagged C. elegans. (g) Light-sheet fluorescence image of green fluorescent protein-tagged C. elegans.89 

FIG. 4.

(a) Photograph of the light-sheet metalens microscopy system. (b) SEM image of nanopillars. (c) OM image of light-sheet metalens. The system (d) with and (e) without light-sheet metalens and the corresponding fluorescence images. (f) Light-sheet fluorescence image of the mCherry-tagged C. elegans. (g) Light-sheet fluorescence image of green fluorescent protein-tagged C. elegans.89 

Close modal

2. HiLo microscopy

In the field of widefield microscopy, a diverse range of structured illumination patterns has been utilized to obtain optically sectioned images of volumetric organ tissues, including, but not limited to, speckle and periodic grid patterns.85,91 Despite its widespread application, structured illumination microscopy remains inherently prone to the generation of artifacts due to inaccuracies in grid translation or perturbations in the sample positioning. In addition, it needs to acquire a considerable number of images, usually more than a few dozen, to produce a final optical sectioning image with satisfactory quality, resulting in a long processing time. HiLo microscopy stands out for its capability to generate optically sectioned images at a high operational speed and without any motion-related artifacts. By selecting the appropriate cutoff frequencies, it is feasible to extract both high and low spatial frequency components at in-focus planes. This extraction process employs paired uniform and structured illumination images, respectively, thus enabling the reconstruction of optically sectioned images. Furthermore, it offers the flexibility to alter the optical sectioning thickness. The first image (iu), is uniformly illuminated, while the second image operates under non-uniform illumination, exemplified by a structurally illuminated image (is). The uniformly illuminated image is comprehensively described as92,
iux,y=iinx,y+iout(x,y).
(5)
It constitutes both in-focus and out-of-focus components, denoted as iin(x, y) and iout(x, y), respectively, with x and y symbolizing spatial coordinates. From this uniformly illuminated image, it is feasible to extract high spatial frequency content in-focus (iHi),
iHix,y=F1(Iu(fx,fy)×HPcf(fx,fy)).
(6)
This equation involves an inverse Fourier transform of the uniformly illuminated image, which is subsequently subjected to a Gaussian high-pass filter with a cutoff frequency (HPcf). Simultaneously, the structured illuminated image (is) can be presented as follows:
isx,y=iinx,ysx,y+iout(x,y).
(7)
This equation considers the modulation coefficient under structured illumination, denoted as s(x, y). In terms of contrast, the structured illuminated image displays a clear difference, offering a high image contrast at the in-focus plane and a poor contrast at the defocus region. Building upon this contrast difference, the low spatial frequency components of the in-focus plane, represented as iLo, can be obtained as
iLox,y=F1(FCx,y×iux,y×LPcffx,fy).
(8)
This equation involves an inverse Fourier transform of the uniformly illuminated image multiplied by the local spatial contrast of the structured illuminated image, which is subsequently filtered through a Gaussian low-pass filter with the same cutoff frequency (cf). The local spatial contrast, C, is the ratio of the standard deviation to the mean value of the structured illuminated image within a specified sampling window,
Cx,y=SD(is)M(is),
(9)
where ⟨SD(is)⟩ and ⟨M(is)⟩ are the standard deviation and mean value of is, respectively. Finally, the optically sectioned HiLo image, iHiLo(x, y), is determined by summing the high and low spatial frequency components, balanced by a scaling factor, η, as outlined in the following equation:
iHiLox,y=iHix,y+ηiLo(x,y).
(10)
HiLo microscopy has, indeed, shown its capability to obtain excellent sliced images. However, obtaining 3D information of cells still requires axial scanning. To address this issue, various tunable focal lenses come into play. Liquid crystal lenses and elastomeric membrane lenses are among the most recently utilized tunable focal lenses. Liquid crystal lenses, however, have limitations such as non-immediate response, spherical aberration, and distortion, resulting from non-ideal spherical profiles. On the other hand, elastomeric membrane lenses suffer from the same limitations mentioned earlier and are also unsuitable for use in the vertical direction due to the effects of gravity. Dynamic devices, such as SLMs and DMDs, have also been used, but they tend to be bulky and their pixelated structures lead to undesirable diffraction orders and lower resolutions. These drawbacks hinder their widespread adoption in microscopy applications. Recently, a new concept called the moiré metalens has been proposed as a potential solution.93–95 It consists of two complementary metasurfaces that are arranged in a specific configuration. By adjusting the relative rotation angle between these two metasurfaces, the focal length of the metalens can be effectively altered. To achieve the focusing functionality, two identical metasurfaces are meticulously designed and positioned facing each other, with one being inverted relative to the other. The phase distribution of the metasurface is shown in Fig. 5(a) and can be expressed using the following equation:96 
Φr,θ0=round(r2/λF0)θ0
(11)
where r represents the radial coordinate on the metasurface, λ represents the operational wavelength, F0 represents the reference focal length, and θ0 represents the reference rotation angle. The round (·) function is applied to ensure that the operand is rounded to the next higher integer, thus mitigating the sectoring effect. The phase profile provided by the two cascaded metasurfaces can be expressed as
Φint=Φr,θ0+Φr,θ0θ=ar2θ,
(12)
where a represents a constant and θ represents the relative rotation angle. To fulfill the phase profile for the focusing lens, a can be obtained as 1/(λF0), where λ is the wavelength of operation and F0 is the reference focal length. In this specific scenario, a value of a = 100 mm−2 is employed. Therefore, the relation between the tunable focal length (fθ) and θ can be expressed as follows:
fθ=π/aθλ.
(13)
Figure 5(b) shows the measured beam profiles of the moiré metalens, depicting variations along the propagation axis under disparate rotation angles, where θ ranges from 180° to 350°. The dependency of the focal lengths on the rotation angles is shown in Fig. 5(c), which is qualitatively congruent with the predictions made by the underlying theory. The adaptability of the focal range of the moiré metalens allows for an alteration between 10 and 125 mm under the wavelength of 532 nm. The average focusing efficiency is about 35%. The telecentric configuration is used for procuring uniform magnification, as shown in Fig. 5(d). The moiré metalens is placed at the Fourier plane of the front objective lens, which allows for an adjustment of the focal length of the system. Generation of structured illumination is carried out using a DMD. Figures 5(e) and 5(f) show the fluorescent portrayals of 45 μm microspheres under uniform illumination and structured illumination, respectively. The optical sectioning capability of the system can reach 7.5 μm, corresponding to illuminated spatial frequencies of ∼34 lp/mm. Fig. 5(g) shows the corresponding optical sectioning image of the significant attenuation of out-of-focus background noise. Figures 5(h)5(j) shows optically sectioned images of villi at three different focal depths, which are respective to rotation angles of 5°, 180°, and 340° via the HiLo imaging process. They also show the considerable suppression of out-of-focus background noise while simultaneously maintaining a clear observation of the in-focus fine structures.
FIG. 5.

(a) Concept of focal length tuning by using moiré metalens. (b) The beam profiles of moiré metalens with different rotation angles. (c) The relation between focal length and rotation angles. (d) Telecentric configuration with structure illumination. (e) The image of fluorescence microscope under uniform illumination. (f) The image of the fluorescence microscope under structure illumination. (g) The optical sectioning image after HiLo algorithm processing. (h)–(j) The optical sectioning images of villi at different focal lengths.93 

FIG. 5.

(a) Concept of focal length tuning by using moiré metalens. (b) The beam profiles of moiré metalens with different rotation angles. (c) The relation between focal length and rotation angles. (d) Telecentric configuration with structure illumination. (e) The image of fluorescence microscope under uniform illumination. (f) The image of the fluorescence microscope under structure illumination. (g) The optical sectioning image after HiLo algorithm processing. (h)–(j) The optical sectioning images of villi at different focal lengths.93 

Close modal

Optical tweezers with the metasurface are an emerging field of research that has the potential to develop efficient systems. It has been demonstrated in multiple recent studies that metasurfaces are ideal candidates for the wide variety of optical tweezer systems. The main advantages of metasurface in optical systems are miniaturization, easy integration, multiple functionality, and the complex optical field landscape, which can lead to the dynamic manipulation of particles, active particle sorting, and near-field optical effects.

Airy beams have been generated using metasurfaces.97–99 However, the limited number of designed parameters for the composed unit cells due to a constant period and fabrication constraints pose a challenge in achieving sufficient phase modulation to cover the entire 2π regions.100 Previous studies have attempted to address this issue by compromising on operation bandwidth, size, or transmission efficiency.101–103 Another approach involves employing geometric phase methods,21 commonly referred to as Panchratnam–Berry phase methods, to offer additional phase compensation by arranging different rotation angles of unit cell. While this method can alleviate the difficulty of phase modulation, it is restricted to specific polarization states of the incident light. A vertically accelerated 2D Airy beam is generated in the visible region by using a cubic-phase dielectric metasurface, regardless of the incidence polarization state of light. To analyze the propagation characteristics of the Airy beam, numerical calculations and FDTD simulations are performed. The experimental finding confirmed that the Airy beam follows a reciprocal curve in a free space, thereby providing support for the design and simulation predictions. By integrating the metasurface into an optical manipulation system, microparticles are guided and captured along the beam’s trajectory. The attracted particles are not only displaced laterally but also ensnared in the axial direction due to the intense gradient force generated by the Airy beam. To evaluate the optical manipulation performance, the trapping stiffness of the system is assessed. The dynamic motion of the attracted microparticles is observed in real time in three dimensions.

The phase distribution of the Airy metasurface is determined using the geometrical optics approach.104,105 For simplicity, a one-dimensional trajectory curve is utilized, which is reduced from a two-dimensional trajectory plane of an accelerating beam (z = 0). Here, (x0, z0) is any place along the trajectory curve, and z = f(x) is the reciprocal propagation trajectory curve of the accelerating beam. The location where the tangent and the metasurface cross can be determined using the equation given by x = x0z0/f′(x0), and the tangential equation of the position is given by z = f′(x)(xx0) + z0, in accordance with the concept of geometric optics.47 The equation (x) = (xx0) · sin θ · k0 represents the phase difference between the intersection point of (x0, z0) and the minimal optical path from the metasurface, and k0 = 2π/λ is the amplitude of the wave vector, determines the phase difference between the intersection point of (x0, z0) and the minimal optical path from the metasurface.

sin θ can be expressed as dx/z0 in the paraxial approximation, with the result that the phase gradient of the metasurface follows the equation
dϕ(x)/dx=k0/f(x0).
(14)
Supposing independence between the reciprocal propagation trajectory formulas for x and y, the expression for the trajectory curve for 2D acceleration is given by
z=a/x,z=a/y.
(15)
Equation (16) gives the following description of the metasurfaces phase distribution:
ϕ(x,y)=k0(x3+y3)/12a.
(16)
The mathematical expression representing the cubic-phase profile derived from the principles of geometrical optics is equivalent to the phase distribution observed in the vertically accelerated 2D Airy beam according to the paraxial Helmholtz equation. In our study, we used a trajectory constant value of a = 0.033 mm2 and an operational wavelength of λ = 532 nm.

The beam trajectory of a vertically accelerated 2D Airy beam along the u–z plane, as well as the cross section of intensity distribution at various propagation planes, are shown in Fig. 6(a) through numerical calculations. The u direction represents the diagonal path along which the primary lobe of a vertically accelerated 2D Airy beam deflects relative to the xy plane. Figure 6(b) shows the optical tweezer setup incorporating cubic phase metasurface to generate airy optical trap. Figure 6(c) shows experimentally measured intensity corresponding to laterally shifted main lobe position along the axial direction. The experimental details are presented in Ref. 106. A bright-field view of a sporadic distribution of polymer microspheres suspended in water is shown in Fig. 6(d). The microspheres are drawn into the main lobe of the beam in a transverse plane after the input power surpasses the threshold power for optical guiding, and they are navigated through the longitudinal direction of the propagation path of beam, enabling their penetration into the deep regions. After illuminating the sample, the distribution of microspheres changes in various places because of the asymmetrical intensity distribution of the vertically accelerated Airy beam, and the number of beads in the exposed areas decreases over time.

FIG. 6.

(a) Numerically calculated intensity distribution of the Airy beam in the direction of propagation. The colored dotted line box shows the corresponding transverse intensity profiles. (b) Experimental configuration of optical manipulation by the vertically accelerated 2D Airy beam, generated by a cubic phase metasurface. (c) The size and direction of the intensity gradient along the transverse (xy) planes at various propagation depths. The experimental intensity values of the main lobe shift at z = 0.5, 1.0, and 2.0 mm, respectively. (d) After illuminating the focused beam, the corresponding distribution of the distribution of 3 μm microspheres suspended in the water appears at different depths.106 

FIG. 6.

(a) Numerically calculated intensity distribution of the Airy beam in the direction of propagation. The colored dotted line box shows the corresponding transverse intensity profiles. (b) Experimental configuration of optical manipulation by the vertically accelerated 2D Airy beam, generated by a cubic phase metasurface. (c) The size and direction of the intensity gradient along the transverse (xy) planes at various propagation depths. The experimental intensity values of the main lobe shift at z = 0.5, 1.0, and 2.0 mm, respectively. (d) After illuminating the focused beam, the corresponding distribution of the distribution of 3 μm microspheres suspended in the water appears at different depths.106 

Close modal

The ultrathin, compact, and flat nature of the metasurfaces allows for the realization of numerous optical trapping potentials for the simultaneous guiding and sorting of particles. Additionally, fiber optic probes and microfluidic devices can be directly integrated with our metasurface based on the beam shaper. Additionally, trapping potentials along the axial direction can be modified using an adjustable metasurface based on a beam shaper. Other unconventional light beams can be produced using our method from a metasurface with varying operation wavelengths, without the use of any additional optical components, and are not just restricted to Airy beams.

We have reviewed the recent advancements in metasurface technology, particularly its promising implications for optical biomedical applications, including beam shaping for laser treatments, LSFM, HiLo microscopy, and optical trapping. With respect to conventional refractive elements, there are several advantages to metasurface optical elements. In the case of laser–tissue interaction experiments or instrumentation, microscopic-sized devices are generally used for biomedical applications, such as endoscopes and laser surgery knives, and metasurface-based light shaping devices will provide advantages that are extremely difficult to obtain using conventional optical elements at microscopic scale sizes for tip-top devices.107 For example, when designing the multiview light-sheet microscope system, complexity can be drastically reduced due to the ultracompact sizes and weights of metasurface-based optical elements. The multiview light-sheet requires illuminations from several directions, and each illumination arm requires multiple components. In this situation, a single element for illumination that has the ability to hook up with the sample holder will provide an unparalleled superiority.108 Similarly, for the optical tweezer setup that incorporates microfluidic devices, the microscopic size illumination obtained from the metalens can greatly reduce the overall system design and efficiency.109,110 In addition, the multifunctional illumination light pattern can further provide advantages that are very difficult to realize with single elements using conventional refractive optics or light modulating devices. Very recently, we have demonstrated that high-quality optical imaging can be performed even with the simple combination of the two-lens system.111 The results are reasonably good, and the optical performance of the system is equally well with a similar conventional optical-based microscope system. All these applications make us believe that metasurface-based optical elements have great potential for future biomedical optical instruments. With respect to the recent developments, we believe that it is the beginning of newer dimensions to reduce the dimensionality of optical elements for biomedical applications, and with the newer developments of metasurface optics, multifunctionality, high efficiency, and low-cost alternatives for clinical instruments are possible.

Here, we engage in a brief discussion on the current limitations in the field of metasurface technology, exploring potential solutions and offering perspectives on the future direction of this promising area.

Recently, a lot of efforts have been made to highlight the differences and similarities as well as the pros and cons between meta-optics and DOEs.112,113 This topic is open, and a lot of debate is going on. However, there is a general consensus on certain aspects. The advantages of the ability to modulate light with different kinds of phase modulation mechanisms, polarization control, and manipulations are among the most distinct features of metasurfaces over conventional DOEs. In addition, metasurfaces can uniquely manage chromatic dispersion by using unit cell design, but it is a notable challenge in broadband applications for DOEs. The compatibility with CMOS technology is also a significant advantage of metasurfaces, which is paving the way for seamless integration into active optical devices and electronics. As with any other application field of metasurfaces, biomedical applications inherit all the advantages and limitations of metasurfaces, such as the size of the optical element, cost, system design, and fabrication. We should note that each method has its advantages and limitations, and metasurfaces have their own, which have been thoroughly reviewed recently.114,115 With further development, we believe that most of these limitations can be overcome. All these developments may show the potential of metasurfaces over conventional DOEs and refractive optical elements. However, exploring their collaborative potential might be more meaningful. Many high-end imaging applications demonstrated so far utilize hybrid optical elements, with refractive optical elements playing a significant role. In such scenarios, meta-optics complements the conventional system, offering unparalleled advantages. Currently, hybrid system designs, whether conventional DOE or metalens, can provide solutions for numerous requirements in biomedical instruments, for instance, in the design of fiber-based laser delivery and imaging systems for endoscopic surgeries, where instrument size is a crucial criterion.

Although there is a current inclination to develop larger-scale metasurfaces, the trajectory for biomedical applications appears to be shifting toward the utilization of components with reduced diameters. This shift is driven by the potential use of these components inside the human body. For instance, the requirement of very fine diameters in ureteroscopes limits the size and space for optical components, affecting image quality and flexibility in adjusting the focus and depth of field. Achieving near-diffraction limit with a high performance of small-size metasurfaces is still a fundamental challenge. Therefore, the emphasis is not just on replacing existing components but on ensuring high efficiency, innovative functionality, enhanced performance, and compact size. Furthermore, attributes such as customizability, low energy consumption, scalability, flatness, and compatibility with CMOS mass production processes become increasingly important. It is important to note that the requirements of biomedical applications are different as compared to the other optical applications. For any practical clinical applications, instruments have to go through additional rigorous tests and should be compatible with the standard practices. Therefore, one of the most important considerations in integrating metasurfaces into in vivo applications, such as medical imaging inside the body, is assuring biocompatibility. The materials selected for metasurfaces must not cause adverse effects when interacting with living tissues, cells, or organs, and hence the need for non-toxic, non-inflammatory materials. Commonly utilized dielectric materials in metasurfaces, such as titanium dioxide (TiO2), silicon, and GaN, are noteworthy for their non-toxicity, hypoallergenic properties, and high chemical and mechanical stability, in addition to their suitability for mass production via semiconductor processes. However, the issue of long-term stability and durability in a challenging biomedical environment remains to be addressed. This includes preserving structural completeness and optical properties under diverse conditions, including exposure to body fluids, temperature variations, and mechanical stresses.

The integration of augmented reality (AR) with metasurface technology will be set to create a paradigm shift in medical diagnostics, treatment, and education. Recently, significant efforts have been dedicated to applying metasurfaces in AR.116 Owing to their powerful capabilities, metasurfaces are facilitating the development of innovative AR display solutions. These solutions offer an improved imaging quality, an enhanced functionality, a reduced weight, and a smaller size. In surgical settings, AR can provide surgeons with real-time, enhanced visuals during procedures to give a comprehensive view of the surgical area. This might include highlighting specific tissues or blood vessels, thus greatly enhancing the precision and safety of surgical operations.

Many uses of metasurfaces in biomedical optics, particularly optical imaging, and microscopy, consider them as efficient alternatives to conventional optics. The primary objective of these applications is to offer multifunctionality, a feat that is challenging with other techniques. This trend is expected to persist in the near future until fundamental limits are reached. For the illumination consideration, the performance for coherent and partially coherent imaging limits has recently been explored.117 Characterizing optical performance by integrating metasurfaces with various optical sources and detectors for high-resolution imaging is an area that requires significant attention for the development of clinical devices. In addition, metasurfaces for biomedical imaging applications is a multi-disciplinary field that will help address multiple problems. For example, a compact microscope design has great potential for practical usage for clinical purposes and can also address the industrial product inspection problem. The outcome of the metasurface design can be utilized for other optical field systems. Advanced optical systems can also help with chemical engineering problems, such as surface monitoring and real-time compositional changes in biochemicals. Beam shaping through metasurfaces can reduce the size of the current laser surgery and endoscopic instruments, which can greatly benefit a wide variety of clinical applications, including photodynamic therapy (PDT), ophthalmology, dermatology, and cosmetics. Metasurfaces also need to be seamlessly integrated with existing biomedical technologies and devices. So far, we can see that interdisciplinary research is of considerable importance for overcoming these barriers.

A significant challenge for metasurfaces is their pronounced chromatic aberration.113,115 A common limitation in metalenses is that different wavelengths of light are focused at different points, leading to color fringing and blurred images. While this issue is minimal in applications requiring only a single wavelength, it becomes problematic in applications requiring multiple wavelengths. Researchers have made strides in developing achromatic designs covering the entire visible spectrum, but these require precise nanostructure engineering to control light phase compensation at multiple wavelengths simultaneously. However, these designs still have two primary drawbacks: lower efficiency due to the choice of unit cells for phase compensation and small pupil size due to phase compensation limits. Continued research in materials and structure, alongside leveraging artificial intelligence (AI) to address metasurface dispersion, appears to be promising. AI not only aids in the complex design and optimization of metasurfaces but also directly corrects chromatic aberration in images.114,118–120

Moreover, the potential utility of metasurfaces extends to the realm of cancer diagnosis and treatment in prospective scenarios. To illustrate, conventionally, medical practitioners perform biopsies to procure samples, subsequently examining cellular arrangement and dimensions under a microscope. Determining the presence of cancer is contingent upon the expertise of a pathologist. However, the integration of metasurfaces with AI computational capabilities holds promise for more precise cancer diagnosis and disease progression assessment, circumventing reliance on subjective judgment based solely on individual experience. Even within controlled laboratory settings, researchers employ murine xenograft models to monitor tumor growth rates. The criteria for instigating tumor growth rate monitoring involve the attainment of a minimum dimension of 5 mm or greater in width and length.121–123 By harnessing metasurface technology, the early detection of smaller tumor sizes within live mice becomes feasible, facilitating the timely initiation of drug administration for efficacy evaluation. Furthermore, the application of metasurfaces finds pertinence in the context of photodynamic PDT.124,125 Notably, tumors are transduced with photosensitive proteins (e.g., KillerRed) via viral vectors, thereby enabling the generation of reactive oxygen species (ROS) upon illumination. These ROS induce DNA damage and then kill cancer cells with precise spatiotemporal control. Given the inherent characteristics expounded upon earlier, metasurfaces offer a viable avenue for integration into this domain, amplifying their potential contributions.

A metasurface type that was not previously mentioned, the resonant metasurface, shows potential for highly sensitive detection of target analyses due to the localized field enhancement caused by plasmonic resonance in metallic nanostructures or near-field scattering in dielectric structures.126–128 This type of metasurface could provide a pathway for highly sensitive detection of molecules at nanoscales or even smaller scales, with applications in refractive index sensing, surface-enhanced Raman scattering (SERS), and surface-enhanced infrared absorption (SEIRA). In addition, in the field of bioelectronics and healthcare, metasurfaces hold promise for novel medical devices and implants, enabling miniaturization and improved performance. However, substantial work lies ahead in meeting these high expectations. Undoubtedly, the field of metasurfaces continues to evolve and remains a vibrant area of research, promising innovative solutions for optical biomedical applications and beyond.

In contrast to biosensing, the constraints of metasurfaces in biomedical imaging instrumentation are inherently more profound. Conventional optics in this context are meticulously optimized for performance over the decades. To adapt meta-optics for clinical applications, a recalibration of their performance becomes imperative. Clinical requirements impose more stringent criteria, particularly concerning size, optical performance, and materials used. Thus, the challenges in applying metasurfaces in biomedical imaging extend beyond those encountered in biosensing, demanding a nuanced consideration of their fundamental limitations and the need for tailored adjustments to meet the specific demands of clinical scenarios.

We would like to thank Kuo-Yen Huang for the insightful discussions and invaluable feedback that greatly enriched this article. This work was supported by the National Science and Technology Council, Taiwan (Grant Nos. NSTC 112-2221-E-002-055-MY3, NSTC 112-2221-E-002-212-MY3, and MOST-108-2221-E-002-168-MY4), National Taiwan University (Grant Nos. NTU-CC-113L891102, NTU-113L8507, NTU-CC-112L892902, NTU-107L7728, NTU-107L7807, and NTU-YIH-08HZT49001), National Health Research Institutes (Grant No. NHRI-EX113-11327EI), the University Grants Committee/Research Grants Council of the Hong Kong Special Administrative Region, China (Project Nos. AoE/P-502/20, CRF C1015‐21E, C5031-22-G, CRF 8730064, GRF 15303521, 11310522, 11305223, and 11300123), City University of Hong Kong (Project Nos. 9380131, 9610628, and 7005867), and JST CREST (Grant No. JPMJCR1904).

The authors have no conflicts to disclose.

C.H.C. and S.V. contributed to the conception and structure of the manuscript and the original draft preparation. Y.L. and D.P.T. contributed to the substantial review and final manuscript preparation. P.-C.Y. and D.P.T. supervised the review. All authors read and approved the final manuscript.

Cheng Hung Chu: Writing – original draft (equal); Writing – review & editing (equal). Sunil Vyas: Writing – original draft (supporting); Writing – review & editing (supporting). Yuan Luo: Supervision (lead); Writing – original draft (equal); Writing – review & editing (equal). Pan-Chyr Yang: Supervision (lead); Writing – original draft (equal); Writing – review & editing (equal). Din Ping Tsai: Supervision (lead); Writing – original draft (equal); Writing – review & editing (equal).

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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