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Morphology & Ultrastructure Characterization Service

Introduction Morphology and Ultrastructure Characterization Workflow What We Can Offer FAQs

Introduction

Modern therapeutics depend on DDS like LNPs to deliver sensitive payloads, with nanocarrier performance governed by physical structure. Accurate morphology/ultrastructure characterization is a key CQA, and our service offers quantitative data to link physicochemical properties with biological function for better formulation design.

Creative Biolabs' Custom Morphology and Ultrastructure Characterization Service uses gold-standard high-resolution TEM and advanced image analysis to de-risk pipelines, ensure reproducible performance, and provide structural data connecting formulation to function, supporting lead candidates toward clinical validation.

Morphology and Ultrastructure Characterization Services

The structural integrity and organization of nanocarriers are core detectable indicators that directly influence their efficacy and safety profile. Our services provide high-resolution data on these indicators using industry-leading methodologies:

Core Detectable Indicators

Overall Particle Morphology Includes sphericity (whether particles are standard spheres), presence of non-spherical particles (e.g., ellipsoids/irregular shapes), and particle surface smoothness (presence of depressions or protrusions).
Internal Ultrastructure Such as the number of lipid bilayer layers (unilamellar/multilamellar vesicles), distribution state of core payload (whether uniformly encapsulated), and presence of hollow/solid structures or phase separation.
Dispersibility and Agglomeration Determine if particles are monodispersed, the presence of minor aggregation (size of small aggregates) or severe agglomeration, and morphological characteristics of agglomerates.
Structural Integrity Evaluate whether LNPs exhibit structural damage (e.g., membrane rupture, content leakage) or form oversized particles due to fusion during preparation or storage.
Surface Modification Visualization For LNPs with surface modifications (e.g., PEGylation, ligand conjugation), observe the uniformity of the modification layer (e.g., whether PEG chains form a continuous surface layer).

Corresponding Detection Methods

  • Cryogenic Transmission Electron Microscopy (Cryo-TEM)
    • Advantages: Samples are rapidly frozen (-196°C) and fixed in vitreous ice, requiring no staining/dehydration. It enables observation of LNP 3D morphology and internal structure under near-physiological conditions, with a resolution of 0.1–1 nm. It clearly reveals bilayer details and payload distribution, making it the "gold standard" for current LNP ultrastructure analysis.
    • Applicable Indicators: Internal ultrastructure, structural integrity, surface modification visualization.
  • Transmission Electron Microscopy (TEM, Conventional Negative Staining)
    • Advantages: Uses negative stains (e.g., phosphotungstic acid) to outline particle contours. It is relatively easy to operate and cost-effective, enabling rapid observation of overall particle morphology, dispersibility, and agglomeration, with a resolution of ~1–2 nm.
    • Limitations: Samples require dehydration and staining, which may cause LNP shrinkage or morphological distortion, making it unsuitable for precise internal structure analysis.
    • Applicable Indicators: Overall particle morphology, dispersibility, and agglomeration.
  • Scanning Electron Microscopy (SEM)
    • Advantages: Generates 3D stereoscopic images by scanning the particle surface with an electron beam, enabling intuitive observation of LNP surface topography (e.g., smoothness, protrusions) and spatial structure of agglomerates, with a resolution of ~1–10 nm.
    • Limitations: Samples require gold sputtering; internal structures cannot be observed. It is more suitable for analyzing micrometer-scale particles, with weaker detail presentation for nanoscale LNPs compared to TEM.
    • Applicable Indicators: Particle surface morphology, characteristics of large-sized agglomerates.
  • Atomic Force Microscopy (AFM)
    • Advantages: Obtains topographic information by "touching" the particle surface with a probe in liquid or air environments. It can simultaneously analyze 3D parameters of LNPs (e.g., height, width) with a resolution of 0.1 nm. No complex sample processing is required, and it can observe morphological changes under dynamic conditions (e.g., structure alterations induced by temperature/pH).
    • Applicable Indicators: Overall particle morphology, surface smoothness, structural integrity (e.g., height differences caused by membrane damage).
  • Focused Ion Beam Scanning Electron Microscopy (FIB-SEM)
    • Advantages: Combines the "nano-cutting" function of FIB with the imaging capability of SEM. It enables layer-by-layer cutting and 3D reconstruction of LNPs, clearly revealing internal multi-layered structures, core-shell distribution, and payload encapsulation state, with a resolution of 1–5 nm.
    • Application Scenarios: Used when in-depth analysis of complex LNP ultrastructure (e.g., multilamellar vesicles, composite drug delivery systems) is required.
    • Applicable Indicators: Internal ultrastructure, core-shell distribution.

Workflow

Our comprehensive approach is designed for clarity, reproducibility, and alignment with regulatory expectations, ensuring a smooth transition from R&D to cGMP manufacturing.

Required Starting Materials

  • Nanocarrier Sample: Purified LNP, liposome, or polymeric micelle formulation (with concentration and estimated size).
  • Detailed Formulation Protocol: Specific lipid/polymer ratios, buffers, and mixing conditions used in preparation.
  • Target API Specifications: Molecular weight and concentration of the encapsulated drug or nucleic acid.
Required Starting Materials
Initial Consultation & Scope Definition

Key Steps Involved

  1. Initial Consultation & Scope Definition: Expert discussion to define project goals (e.g., optimize LNP-mRNA condensation, characterize batch variation) and select the appropriate high-resolution microscopy technique (TEM vs. Cryo-TEM).
  2. Specialized Sample Preparation: Samples undergo processing such as negative staining (for standard TEM visualization of external features) or cryo-vitrification (for Cryo-TEM, which preserves the native, hydrated internal structure without artifacts).
  3. High-Resolution Imaging Acquisition: Acquisition of thousands of high-magnification micrographs using state-of-the-art Transmission Electron Microscopy (TEM) or Cryo-TEM.
  4. Quantitative Morphology & Ultrastructure Analysis: Advanced image processing software is used to measure and categorize structural attributes, including mean particle diameter, polydispersity index (PDI), shape factor, and internal feature analysis (e.g., evidence of drug condensation, core integrity).
  5. Final Data Interpretation & Reporting: Experienced structural biologists interpret the quantitative data and visual evidence, correlating findings with the client's requested functional metrics (e.g., predicted release rate).

Final Deliverables

  • High-Resolution Micrograph Archive: Original TEM and/or Cryo-TEM image files suitable for publication and regulatory submission.
  • Quantitative Particle Diameter Distribution Report: Statistical analysis of particle size, including mean diameter and PDI for the population.
  • Encapsulation Status and Integrity Analysis: Visual and quantitative report on core-shell integrity, lamellarity, and payload condensation state.
Specialized Sample Preparation
Initial Consultation & Scope Definition

Estimated Timeframe

The typical timeframe for this service ranges from 4 to 8 weeks, depending on the complexity of the nanocarrier system (standard LNP vs. complex hybrid vector) and the required resolution (standard TEM is faster than deep-analysis Cryo-TEM).

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What We Can Offer

As an excellent seller, Creative Biolabs' Morphology and Ultrastructure Characterization Service provides a robust and flexible solution specifically tailored to meet the demanding quality and regulatory standards of advanced biopharmaceuticals. We ensure your nanomedicine's physical form is flawlessly characterized, minimizing risk and accelerating your time to market.

Customized High-Fidelity Protocols
Develop bespoke sample preparation and imaging protocols (including Negative Staining, Freeze-Fracture, and Cryo-TEM) optimized for novel or sensitive nanocarrier compositions, such as Lip polyplexes (LPPs) and polymer-DNA complexes.

Gold-Standard Cryo-TEM
Access to state-of-the-art Cryo-TEM technology to visualize your nanocarriers in their native, hydrated state, guaranteeing the most accurate assessment of internal ultrastructure, lipid lamellarity, and nucleic acid condensation.

Integrated Quality Assurance (QA)
Implementation of protocols aligned with Quality-by-Design (QbD) and Process Analytical Technology (PAT) principles, ensuring that all structural data is reproducible and clinically meaningful.

One-Stop Structural-Functional Analysis
A seamless service covering everything from initial sample consultation and preparation to expert interpretation that directly correlates morphology and ultrastructure findings with expected encapsulation efficiency and release kinetics.

Quantitative and Regulatory-Ready Documentation
Provision of detailed reports, statistical analyses (including PDI, size distribution, and shape factor), and publication-quality image archives suitable for direct inclusion in IND and BLA submissions.

Broad Sample Versatility
Capability to characterize a wide range of complex drug delivery systems, including LNPs, liposomes, micelles, polymer-based vectors, and viral-like particles (VLPs).

Case Study

Some studies have conducted TEM and cryo-EM imaging on samples recovered from different storage temperatures to investigate the influence of storage temperature on the particle structure of LNP. Both TEM and cryo-electron microscope images show that the diameter of LNP is relatively monodisperse in freshly prepared samples and samples stored at 4 °C or -20 °C for one week. Samples that were thawed after being stored at ultra-low temperatures showed that LNP significantly aggregated and fused into large structures.

The effects of different storage temperatures on the particle structure of LNP were detected by using transmission electron microscopy (TEM) and cryo-electron microscopy (cryo-EM) imaging. (OA Literature)Fig.1 Cryo-electron microscopy (Cryo-EM; top row) and transmission electron microscopy (TEM; bottom row) images of LNP stored for 7 days.1

Customer Reviews

  • [Enhanced Stability Research Efficiency] "Using Creative Biolabs' Custom Morphology and Ultrastructure Characterization Service in our stability trials significantly facilitated the identification of structural degradation pathways in our liposomal peptide vaccine. The definitive evidence provided by Cryo-TEM was unattainable with DLS alone."

    — John Smith, [June 2025]

  • [Balanced Speed and Resolution] "Using Creative Biolabs' Custom Morphology and Ultrastructure Characterization Service in our research greatly improved the structural confirmation of our complex 3-component hybrid vector. Their rapid Negative Staining TEM was crucial for selecting the top three candidates before proceeding to more intensive functional screening."

    — Ali Con, [April 2025]

  • [Accurate Encapsulation Verification] "Using Creative Biolabs' Custom Morphology and Ultrastructure Characterization Service in our research effectively enabled the visual verification of successful mRNA encapsulation in our ionizable lipid delivery system. This visual confirmation offered a major advantage over purely spectroscopic methods."

    — Mary Jess, [August 2025]

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FAQs

What structural differences can your service detect that standard DLS (Dynamic Light Scattering) cannot?

While DLS provides a quick measure of average hydrodynamic size and PDI, it reveals nothing about morphology or internal structure. Our service uses Cryo-TEM to definitively visualize features DLS misses, such as non-spherical shapes, aggregation states, the number of lipid bilayers (lamellarity), and the physical state of the encapsulated payload.

Which method is best for visualizing my LNP-mRNA encapsulation? TEM or Cryo-TEM?

We highly recommend Cryo-TEM for LNP-mRNA systems. Standard TEM requires dehydration and staining, which can distort the fragile lipid bilayer and obscure the condensed nucleic acid core. Cryo-TEM images the hydrated particle in its native state, providing the most accurate visualization of the core-shell integrity and the nucleic acid condensation status within the lipid matrix.

Can you analyze hybrid or multi-component carriers, such as Lip polyplexes (LPPs)?

Yes. Our specialized sample preparation and imaging protocols are designed to handle complex, multi-component systems like LPPs, polymeric hybrid vectors, and stealth formulations. We can differentiate between the lipid and polymer components and assess the intricate interactions between them and the therapeutic payload.

Creative Biolabs provides world-class, custom structural validation services for the most advanced therapeutic nanocarriers. By linking morphology and ultrastructure to your therapeutic goals, we empower your drug development decisions with scientific precision.

Contact Our Team for More Information and to Discuss Your Project

Reference

  1. Kim, Byungji, et al. "Optimization of storage conditions for lipid nanoparticle-formulated self-replicating RNA vaccines." Journal of Controlled Release 353 (2023): 241-253. https://doi.org/10.1016/j.jconrel.2022.11.022. Distributed under Open Access license CC BY 4.0, without modification.
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