settings Open AccessReview Light Technology for Efficient an Introduction
Cancer is currently one of the deadliest diseases causing millions of deaths every year. According to the world health organisation, cancer is the second leading cause of death globally, accounting for an estimated 9.6 million deaths, or one in six deaths, in 2018 [
1]. Despite the established standard strategies (surgery, radiotherapy, and chemotherapy) have reasonable success for certain cancers, resistant cancer cells, recurrence, and metastases remain common. Cancer is adaptive and has some intriguing survival strategies. In some cases, it is capable of pumping out some drugs out of the cells or find alternative pathways to inhibit cell death. In early cancers, surgery can remove primary tumours, but undetected, residual cancer cells develop into a life-threatening recurrence. This versatility is one of the main obstacles to improving mortality rates. To do this, it is essential to provide further technologies for assisting and treating all cancer stages and, especially, to treat metastases. These new technologies would grant more chances of survival, including ineligible patients for standard management. However, these new technologies must be able to offer additional benefits or fewer side effects compared to the currently established ones. For this reason, finding alternative options is key for future cancer treatments.
A non-conventional therapeutic modality for solid tumours, which offer advantages over standard treatments, is photodynamic therapy (PDT). In the current paradigm, the standard PDT relies on three main elements, a photosensitiser (PS), light, and molecular oxygen to elicit cell death through oxidative damage. First, a non-toxic PS is placed topically or injected systemically. After some time, the PS reaches a maximum concentration within the vasculature and subsequently in the tumour. When the PS reaches the maximum concentration at the tumour as compared to healthy tissue, appropriate light wavelengths excite the PS, which can transfer its excited-state energy, among other de-excitation processes, to either tissue substrate or surrounding oxygen. These reactions produce reactive oxygen species (ROS), specifically superoxide anion radicals and reactive singlet oxygen molecules, which kill tumour cells by both direct and indirect cell death mechanisms. Thus, the clinical effect can be produced by direct cell death (necrosis, apoptosis, among others), vascular damage (leading to tissue ischemia), immune modulation, or a combination of these. The efficacy of these mechanisms depends on many factors, such as the type of PS, cell, overall light dose or/and tumour oxygenation status, among others. PDT cytotoxicity mechanisms are different from the ones of chemotherapy, radiation therapy and immunotherapy (and their consequences too):
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PDT biological effects may be at least partially localised to the tumour, resulting in a higher concentration of the PS within the tumour in comparison to healthy cells.
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PDT uses non-ionizing radiation (in most cases) and its cytotoxic mechanisms produce limited damage to DNA and connective tissue structures (i.e., collagen), which after the treatment act as a scaffold enabling, potentially, the healing of the treated volume [
2].
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Considering the previous point, this treatment could be used as many times as required by clinicians, something that is not possible with the current established treatments (surgery, chemotherapy, and radiotherapy). PDT has no “memory effect” as radiotherapy.
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There is also a rapidly increasing body of evidence that the damage and unique mechanism of PDT treatment on tumours and their microenvironments could inhibit drug resistance pathways and re-sensitize resistant cells to standard therapies [
3].
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Emerging evidence now suggests that PDT can stimulate strong immunological responses, which depend on multiple factors that are being investigated [
4]. This is a key effect to destroy tumours that extend to distant sites after local treatment and is actively investigated [
5].
All of these different characteristics compared with those of the standard treatments, confer PDT an attractive option to be used alone or complementary (before or after) to current standard therapies. Despite the great potential of this technology, its application to deep-seated cancer and metastases remains challenging. Some issues must be solved to surpass actual technological paradigms. For example, limited light penetration depth, non-ideal photosensitisers, complex dosimetry, and complicated implementations in the clinic. Radically new light sources, advanced PS, measurement devices, and innovative application strategies are investigated to exploit the full potential of PDT.
The general aims of this review are to highlight the advantages/pitfalls, technical challenges, and opportunities of PDT from a physical and engineering perspective with a focus on technologies for light activation of PSs such as light sources, delivery devices, and systems. Important stages for PDT such as detection, imaging, and dosimetry (monitoring and dose adaptation) to enable enhanced treatments, or clinical trials and cell death mechanisms, are beyond the scope of this review. For imaging, the reader is referred to [
6,
7] and for dosimetry to [
8,
9] (and references therein). If the reader is interested in cell death mechanisms, detailed reviews can be found elsewhere [
10,
11,
12,
13,
14,
15,
16]. Finally, for a compilation of actual clinical trials, the interested reader is referred to [
17]. We hope this review will be of interest to a broad audience, from bioengineers to clinical oncologists.
The manuscript is organised as follows.
Section 2 is divided into three main subsections. First, a background subsection provides a brief description of the light absorption in tissues, PDT mechanisms and basic terminology of dose and beam parameters relevant for PDT. Then, we critically review the light sources and delivery devices for different PDT modalities. In this review, we include several PDT modalities into three main categories:
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Superficial PDT: involves skin treatments with low light penetration depth (typically <2 mm). It is also usually referred to as external PDT.
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Interstitial PDT (I-PDT): can treat tumours beyond 1 cm assisted by the use of needles, catheters, and optical fibres, but using conventional light sources—with its light penetration limits—similarly as superficial PDT.
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Deep PDT: includes a wide variety of technologies aiming at deeper penetration beyond what is achieved by conventional light sources. This section includes NIR radiation of upconversion materials, advanced PSs excited with novel nonlinear optical techniques, ionising radiation, self-illuminated compounds, and em
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