Bioengineering in reproductive health

Our lab’s focus is on understanding the mechanisms that control mammalian embryo implantation and apply that knowledge to provide solutions that improve human assisted reproduction techniques (ART).

The embryonic development of humans (and mammals in general) requires the implantation of the embryo into the walls of the maternal uterus. This process is highly inefficient as on average, 25–30% of conceptions lead to successful live births and around 60% of all conceptions are lost at the time of (or soon after) implantation. However, despite the central role of implantation in human fertility, the process is still elusive to experimentation because of its inaccessibility.

To overcome the elusiveness of this process, the group combines imaging and bioengineering methods to efficiently culture and image pre-implantation embryos and allow them to implant outside the uterus in highly physiological conditions.  Our systems are accessible to imaging tools which allow us to interrogate the genetics, metabolomics, and mechanics of the embryo in a high throughput manner. Using our systems, we are capable to (i) improve embryo culture conditions and (ii) diagnose embryos with improved implantation potential.

Label-free microscopy and multi/hyperspectral imaging

Label-free Microscopy: This technique allows for analyzing cells in their native condition, i.e. without being labeled or altered in any way, by means of retrieving cells autofluorescence signals and thus providing essential metabolic information about living tissues. Combined with multispectral methods, we delve deep into the metabolic complexity of embryos and oocytes, revealing insights previously unattainable.

Hyperspectral Imaging: Our groundbreaking approach employs hyperspectral imaging to obtain the metabolic profiles of embryos and oocytes. This methodology allows us to identify key characteristics at the metabolic level, invisible to conventional techniques like brightfield imaging, offering a unique window into fundamental biological processes.

Hardware Techniques: We have extensive expertise in a variety of advanced microscopy techniques, including two-photon microscopy, laser scanning confocal microscopy, spinning disk confocal microscopy and light-sheet microscopy. The integration of these techniques with multi/hyperspectral detection methods enables us to observe biological samples of interest at cellular level with spectral characteristics.

AI and Software Analysis: We employ sophisticated data analysis tools such as spectral histogram analysis and phasor-plot analysis combined with artificial intelligence (AI) methods for classification. These techniques allow us to interpret complex multi/hyperspectral data and draw meaningful conclusions about the viability and quality of embryos and oocytes.

4D (x, y, z, and λ) Hyperspectral Autofluorescent Images of Mouse Oocytes and Blastocysts. The samples were imaged using a Zeiss LSM780 inverted microscope with a C-Apochromat 40x/1.20 W Korr Zeiss objective. The imaging conditions were maintained at 37°C and 5% CO2. A Mai-Tai DeepSee laser provided two-photon excitation at a wavelength λex = 780nm. The emitted autofluorescence spanned from 410 nm to 695 nm and was collected by a 32-channel PMT GaAsP spectral detector. The image captures multiple planes, separated by 2.5μm and 5μm steps for oocytes and embryos respectivelly. The pseudo-color representation of the hyperspectral images was achieved using additive blending to integrate the 32 channel colors for each pixel.

Bioengineering to improve embryo implantation

We have developed proprietary 3D ex vivo hydrogel-based implantation platforms which mimic the uterine microenvironment, allowing the embryo to progress towards post-implantation stages in an amenable way for optical microscopy. Working towards obtaining dynamic control of embryo culture, we have integrated our hydrogels in a microfluidic device allowing for controlled nutrient supply, oxygen concentration and long-term embryo culture. Our 3D ex vivo hydrogel-based implantation platforms allow for drug screening and determination of its impact on embryo implantation and development.

We use our 3D ex vivo implantation platform to understand embryo implantation with a focus on the biomechanics of the system. To this means we quantify the displacement of the matrix generated by the embryos using PIV or DVC algorithms. We look at the forces and resulting patterns embryos are applying in order to penetrate the hydrogel and also how external forces affect embryo implantation.

Human Embryo implanting on a 3D platform (video)

Embryo Culture Supplements Development from Human Plasma

Traditionally, embryo culture relied on Human Serum Albumin (HSA) as a key protein component. However, HSA underrepresents the rich composition of proteins present in human plasma. We work with a new-generation of supplements, which go beyond mere albumin, encompassing essential components such as growth factors and globulins, crucial for fostering optimal embryo development. In our group, we test new supplements to enhance embryo development and implantation. Our clinical grade human-derived supplements improve blastulation and implantation rates both in human and mouse embryos, showing superior lineage segregation and spatial organization compared to control counterparts.

The Bioengineering in Reproductive Health is the first Open Innovation Lab research unit at IBEC.

Due to the high translational component of our research, we have established collaboration contracts with the pharma industry, hospitals, and venture capital to bring our technology to the clinics and the market. Our Open Lab is a multidisciplinary environment where embryologists, cell biologists, optical physicists, biophysicists, and business developers synergize to create a unique environment shaped by science and entrepreneurship.

European Projects

National projects

Private sector

Finished projects

S Ojosnegros, A Seriola, AL Godeau, A Veiga (2021) Embryo implantation in the laboratory: an update on current techniques. Human Reproduction Update, Vol.00, No.0, pp. 1–30.

Martin Plöschner, Denitza Denkova, Simone De Camillis, Minakshi Das, Lindsay M. Parker, Xianlin Zheng, Yiqing Lu, Samuel Ojosnegros, and James A. Piper (2020) Simultaneous super-linear excitation-emission and emission depletion allows imaging of upconversion nanoparticles with higher sub-diffraction resolution. Optics Express 28 (16), 24308-24326.

• Embryo culture laboratory
  • IFV workstations in laminar flow hoods
  • Microscope
  • Micromanipulation-microinjection station
  • Embryo biopsy laser
  • K-systems incubator
• Cell culture laboratory
  • Biosafety cabinets
  • Incubators
  • Automated cell counter
  • Dry warming/thawing system
  • Sterile tubing welder
  • Tubing sealer
  • Centrifuges
• Advanced live imaging: photoconversion, 3D imaging, light scattering, spectroscopy
  • Crest spinning disk mounted on a Nikon Ti
  • Image analysis workstation

• Prof. Anna Veiga – Barcelona Stem Cell Bank (IDIBELL) and Dexeus Mujer, Barcelona
• Dr. Montserrat Boada/ Dr. Pere Barri – Dexeus Mujer, Barcelona
• Dr. Ayelet Lesman – Tel Aviv University (TAU), Israel
• Dr. Elena Martínez – IBEC
• Dr. Francesco Cutrale, University of Southern California (USC), USA
• Dr. Manuel Irimia – CRG, Barcelona
• Dr. Javier Ramón – IBEC

· Jorge Fuentes,
   Business Strategy, A_Ventures, Barcelona, Spain