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A New Generation of Super-Resolution Microscopy: Promising Developments for Routine Industry Use

Authors: Vincent Crave, Racha Fayad

Date of publication: 24/ 11/2020

 

Having previously worked in this domain, we are excited to share some of our findings in the field of Super-Microscopy (SRM).

The Basics: SRM at a glance

Scientists in Life Sciences are encouraged nowadays to investigate biological events in more detail than ever, especially when it comes to projects with a therapeutic aim. There is a clear need to better understand the mechanism of action of drugs and to characterize the sub-cellular localization and interaction of molecules at a nano-level.

The development of new microscopy technologies, in particular super-resolution microscopy (SRM), has further facilitated these investigations. This growth of SRM use is confirmed by the increasing number of scientific publications mentioning the use of SRM: 100 publications in 2001 against 550 in 2019.

So far, SRM has exclusively been in the hands of experts in physics and optics, but the technology has evolved in recent years and manufacturers are now bringing to market simplified versions with the promise of putting SRM in the hands of biologists.

 

Science and Tech

The basic principle of optical microscopy relies on the capacity of a microscope to differentiate two points separated by a distance “d” called diffraction limit. In order to further understand cellular & molecular events at the nano-cellular level, a need to go beyond this diffraction limit (<120nm) emerged and was successfully reached by the development of SRM technologies in the 90’s. Lately, SRM has been identified as a crucial technology to better characterize the biology of therapeutical molecules or mediators such as cell therapy, exosomes, etc. before being tested on animals and humans.

The SRM Workflow

Microscopy in general, and more specifically SRM, require time, expertise and assay optimization, that will vary according to the technology adopted. The SRM workflow consists of three major steps that will be evaluated before the purchase of a technology: sample preparation, image acquisition, reconstruction and analysis.

Depending on the type of super-resolution technology, sample preparation can be costly and challenging when choosing the right fluorophore (conventional or specific) or preparing genetically modified strains with incorporated fluorescence tags on proteins of interest. The image acquisition steps will often remain time-consuming. The size and area scanned, as well as the number of stacks, will also be factors that must be assessed when calculating the acquisition time.

Image reconstruction and analysis are key to this process. The software provided with the device as well as the expertise of the user will tremendously affect the success of this step.

Types of SRM

Three main types of SRM technologies have been developed and are primarly differentiated by their lateral resolution (10-120nm):

  1. SIM with the lowest lateral resolution (100 to 120 nm); mainly used in structural biology to observe organelles and complexes such as mitochondria, nuclear pore complexes or cytoskeleton.
  2. STED (lateral resolution of 50 to 70nm); used in live cell imaging to observe events like vesicles, microtubules, etc.
  3. PALM/STORM/F-PALM with the greatest lateral resolution of SRM ranging between 10 to 40 nm and used to precisely localize single molecules by switching on and off individual florescent molecules. For example, it provides information on single molecule diffusion in the membrane.
Article - Super Resolution Microscopy - Technology Positioniing

Figure 1: Positioning of microscopy technologies according to acquisition speed and lateral resolution

The price of the instruments remains undoubtedly one of the major challenges of this technology. A device can range in price between € 150K and € 1.5 million, depending on the technologies and softwares implemented.

Who Currently Has the Tech?

University laboratories and core facilities are the main users of SRM, the majority of whom are already equipped or looking at acquiring SRM technology. Academic labs frequently use them for basic research to decipher the molecular interaction of proteins implicated in signaling pathways of interest.

In industry, all major pharmaceutical companies are working with confocals for various applications, including drug screening, extracellular vesicles and metabolism studies.

However, in the field of biotechnology, the needs for SRM vary and depend on the application. Analyses requiring this type of system are mostly outsourced for lack of time, equipment and/or specialists.

 

Market and Business Overview 

Market Shares and Numbers

SRM is a subset of the microscopy market and represents approximately 40% of the overall microscopy market, with an estimated market size of $2.5 billion in 2019. Market demand for SRM devices is expanding, with a Compound Annual Growth Rate (CAGR) of 11.7%—the market is estimated to grow to $5.6 billion in 2026.

Indeed, the growing need for life science research to study biological events at the molecular level, coupled with technological advances in engineering, are amongst the key factors driving the growth of this market. As a result, 41% of the SRM market is focused within life science applications.

Revenues in the life sciences SRM device market are estimated at $1.02 billion in 2019 and are expected, with a CAGR of 23%, to reach $2 billion in 2022. North America and Asia are the two largest shareholders and account for the largest share of these revenues (approximately $370 million each), followed by Europe with 19% at around $197 million.

Global Players and Up-and-Coming Actors

The SRM market is consolidated with 90 % of market shares divided between a few global players. As shown in Figure 2, the international players (Nikon, Olympus, Leica, etc.) offer a panel of SRM microscopes. They currently dominate the SRM market thanks to their reknown technical expertise, professional reputation in the field and the value of their offer.

Article - Super resolution microscopy - Global Players

Figure 2: Key global players dominating the SRM market

However, since 2010, a number of small players have emerged, mostly as spin-offs from universities. They are differentiating themselves by developing a new concept of benchtop, affordable, easy-to-use SRM microscopes. These new actors are signaling a clear shift towards simplified, accessible, and compact products with the aim of democratizing the access to SRM technologies.

Some of the players include British Oxford Nanoimaging (ONI), which was incorporated in 2016 based on the work of Professor Achillefs Kapanidis Research Group at Oxford University. Having raised a total of around £23 million, ONI is a pioneer of the new generation of compact super-resolution microscopes (Nanoimager: PALM/STORM). The company is entering into partnerships with major players in the pharmaceutical field: Sanofi, Astrazeneca, Evox Therapeutics, UK Cancer Research, etc.

Another actor, launched in 2010, is French company BioAxial. BioAxial was inspired by work done by co-founder and inventor physicist, Gabriel Sirat, and has raised a total of €6.9 million. In 2014, BioAxial collaborated with Nikon to develop new SRM and were acquired by Telight in 2019. The team’s technology has been implemented not only in academic settings like Institut Pasteur but also by industrial players like Sanofi.

Start-ups & biotech companies are starting to make their mark and acquire their share of the market. The price of the technologies is an important question but the handiness and user-friendliness of the software and technologies are criteria of interest for research structures that cannot afford the recruitement of new talent specifically dedicated to run SRM.

More advances are expected in the SRM field but these new, smaller players are already helping the widespread and routine use of SRM in translational and advanced research by simplifying the workflow, increasing the throughput and providing automation.

 

In a nutshell 

The advent of new, simplified, less expensive benchtop SRM equipment is opening up new markets for a technology that has so far been limited to specialists. The innovation in the field comes through state-of-the-art technology developed in world class academic labs, spun out into start-up companies. These new players will steer the field to more applied research and routine applications. In parallel, the pharmaceutical industry is looking for more robust and simple technologies to decipher the mechanism of action of drugs at the molecular level. The fields of gene and cell therapy, as well as extracellular vesicules, are also in search of cutting edge technologies to control the quality of therapeutic products. As seen through partnerships initiated with new players, the pharmaceutical industry is actively looking for solutions and will soon be implementing the tech.

The new generation of SRM is coming and we’ll be there to share any new developments in this promising field!

Business in the midst of crisis – How will the pandemic shape the future of Life Science startups?

 

 

The Covid-19 pandemic highlighted the importance of the healthcare sector. More specifically, the pandemic showed the role of key players (startups, biotechs, & pharma) focused on infectious diseases in developing novel treatments and preventive solutions.

Most of the technology companies able to serve this purpose are deploying every possible resource to tackle the COVID-19 challenge. To this cause, a considerable financial support has been released from governments, European agencies and private funding.

But what about healthcare & life science startups not positioned on COVID 19? How can they survive in this context of unprecedented economic crisis?

Since the pandemic forced many countries to shut down, the survival of small biotechs and startups not involved in the Covid-19 fight has been threatened. These early-stage companies strongly rely on daily operational lab work. They need to be able to generate results and develop prototypes to convince capital ventures and shareholders to invest in their project.

To overcome the economic crisis following the pandemic, startups will need to rethink their strategy and revisit their priorities. Depending on their development stage, different approaches can be adopted to secure survival and plan sustainability.

Two distinct stages will be covered in this article:

  • Pre-commercial start ups focused on development
  • Commercial start-ups ready to sell or currently selling their products
Article - Business against crisis - Startup Lifecycle
Figure 1:  Positioning when market studies and business development support are required in a startup lifecycle

Companies at pre-commercial stage: How to deal with the economic crisis? A time for market investigation

Why market research is important for start-ups?

The significant reduction of lab work slowed the progression of on-going product/service development.

Following R&D, startups should focus on building-up their technology into a marketable product or service. This critical step requires an initial visualization of the end-product and a clear understanding of the end-users needs impacted by the economical situation.

In the light of the current circumstances, putting into action a clear roadmap as well as evaluating the post-Covid19 market situation can be investigated through targeted market research, allowing to:

  • Guide the strategic thinking for a successful crisis-exit action-plan
  • Speed up future market entry by probing the market segments of interest
  • Initiate new contact to establish partnerships and reference sites for future technology evaluation
  • Better steer the product development towards end-user needs and prepare for commercial stage.

How market research can help start-ups get back on track after the crisis?

One of the key to success for start-ups consist of developing a marketable product. To reach this goal, important questions must be raised before and during the development phase, in order to avoid falling into the common trap of “no market need”. This reason has been outlined as the first reason for failure by 42% of startups evaluated in a 2017 Forbes study. It is therefore essential to understand: What problem will your product/technology solve? What are the user needs and pain points? What are the existing alternatives? What are the market trends? How is competition performing and what are the gaps?

It is the right time for start-ups to redesign their strategy based on how Covid-19 has impacted the market needs and habits of futur customers.

A focused market research is thus crucial to:

  • Define the market segments to target & prioritize the applications of interest
  • Map the competitive landscape and position the technology
  • Analyze the end-users needs, expectations & purchase behavior by interviewing Key Opinion Leaders, experts & users
  • Evaluate the market dynamics & the latest trends
  • Establish a successful Go-To-Market strategy to ensure a better market access

Companies at commercial stage : How to fuel the customer pipeline after Covid-19? A time for innovative & smart commercial strategies

What are the current main challenges facing start-ups with ready-to-sell product/service?

At commercial stage, life science start-ups & biotech, especially new market entrants, have to build the commercial pipeline to generate revenue and establish reference sites.

During the pandemic, Covid-19 security measures have put business on hold. On-site conferences and exhibitions have been cancelled or postponed, preventing the identification of new prospects. Moreover, absence of face-to face meetings, seminars, or technology demonstrations in addition to budget cuts are slowing down the sales processes and impacting the purchasing decisions in 2020.

This temporary situation will have a direct impact on the business in the short and medium term. Therefore, the yearly sales targets should be re-evaluated and conventional sales methods should be re-invented.

Digital marketing, for instance, will allow the generation of new leads, but it is far from being enough to generate interest, and drive the purchase of innovative products.

How to reinvent the sales process for an efficient crisis recovery ? 

It is important to adapt the methodologies to fill the prospect pipeline with new leads.

A business development support (cf: Fig n°2) will ensure the rapid implementation of new sales approaches adapted to the Covid situation and help start-ups prepare for a boosted recovery. A smart commercial strategy should include:

  • Implementation of innovative digital tools
  • Development of targeted digital campaigns
  • Identification of qualified leads
  • Setting-up online meetings for technology presentation
  • Orchestrating webinars and online demonstrations

Through these activities, commercial support can compensate for the lack of face-to-face interaction and help build a strong pipeline of leads. The approach will drive market expansion by:

  • Initiating entry in new geographies
  • Launching a new product line or an existing product in a new market
  • Developing and maintaining the commercial pipeline to accelerate the sales process in the post-Covid 19
  • Conducting meetings and demo remotely
  • Concluding sales and increasing revenue generation

Article - Business against crisis - Business Roadmap
Figure 2: Key steps of market study and business development processes leading to tangible startup achievements

It is time for new business strategies

This unprecedented situation represents a unique opportunity to review the strategy of your company and its priorities. Faced with a highly disrupted economy, agility is one of the keys to reinvent the way start-ups conduct businesses.

For pre-commercial start-ups, it is time to better define the target markets and specify the end-users needs. These elements are crucial to prioritize and steer the post-Covid products/service development and adapt the Go-To-Market strategy.

For commercial start-ups , it is important to build up the commercial pipeline in the absence of on-site conference and meetings to ensure reaching 2020 sales target. Companies should shift traditional marketing processes towards digital-based methods and adapt to the new post-covid market practices. This will make their sales approach more effective and increase revenue generation in the years to come.

With more than 14 years of business consulting in the industry, Novoptim has acquired start-up experience and supported the implementation of transformative strategies for their clients. As a consulting firm specialized in establishing market presence in Europe, Novoptim is available to help life science start-ups & biotechs face their current challenges and speed-up their market access and client acquisition.

 

Authors: Vincent Crave, Racha Fayad, Roxane Valfort