On October 12, 2026, Jui-Yu Lin and Chuan-Yuan Lin published a narrative review of diluted and hyperdiluted CaHA/CMC in Aesthetic Plastic Surgery, covering literature from 2016–2025. It synthesizes published evidence and proposes descriptive categories; it is neither a new material study nor a new randomized controlled trial. [1]
For CaHA microsphere development and procurement, the review raises a practical question: when the same particles are used in different carriers or formulation states, which properties can raw-material tests describe, and which need to be measured in the composite? Separating these questions helps prevent changes in formulation behavior from being presented as improvements in microsphere quality.
Particles and carrier together determine formulation behavior
CaHA/CMC combines calcium hydroxylapatite particles with a carboxymethylcellulose-based carrier. A 2024 rheology study examined a specific finished CaHA/CMC product and its CMC carrier separately and found that they responded differently to dilution. Measurements of the composite therefore cannot simply be assigned to one component, and tests on CMC alone cannot replace tests on the finished formulation. [2]
Material evaluation can distinguish the particles themselves, their distribution within the carrier, and the response of the whole formulation to applied forces. Size and morphology describe particles; storage modulus and complex viscosity describe the system's viscoelastic behavior under specified conditions. Relating these measurements to tissue changes over time requires relevant biological or clinical evidence.
This distinction matters when reporting development results. A higher G′ indicates a stronger elastic response under the test conditions used. Support duration, tissue remodeling, and safety each require evidence that addresses the relevant outcome. An initial physical parameter cannot answer all of these questions.
Dilution does not demonstrate better microsphere quality
The 2024 study by McCarthy and colleagues reported that increasing aqueous dilution reduced the measured storage modulus G′ and complex viscosity η* of CaHA/CMC, increased the loss factor tan δ, and changed cohesivity. These findings describe the physical state of a specific product under the study conditions. [2]
Adding diluent changes the solids fraction, carrier concentration, and conditions governing interactions between particles. Comparisons of dispersion and flow should also document mixing, measurement timing, and sample preparation. A statement that a diluted formulation spreads more readily does not establish whether the behavior is reproducible between samples or over time.
Phase composition, impurities, and particle integrity require separate tests. In the absence of chemical changes or particle damage, adding diluent does not increase CaHA purity or establish better crystallinity. Whether a different particle distribution produces a different tissue response needs separate investigation; easier dispersion alone does not demonstrate better clinical outcomes.
The 2025 exchange concerns methods and clinical interpretation
A second 2024 study measured CaHA/CMC at different dilutions and compared its viscoelastic parameters with published HA and PLLA data. It explored the range of physical properties achievable through dilution. Similar parameters across materials do not, by themselves, establish similar long-term performance. [3]
In a 2025 letter, Hicks and Öhrlund questioned the rheological interpretation of biphasic materials, comparisons across studies, and clinical conclusions drawn from initial measurements. In a reply published on the same day, the original researchers argued that CaHA/CMC composites can be characterized rheologically and explained that HA data were used as a physical reference, without claiming biochemical equivalence. The letter and reply should be read together rather than treating either position as a settled conclusion. [4,5]
Material sources, author affiliations, and disclosures also deserve attention. The letter's authors disclosed employment at Galderma; the original study and reply disclosed Merz employment or professional relationships for some authors. These disclosures provide context, while the methods and conclusions still need to be assessed against the study design and data. [3–5]
For formulation development, each test should have a defined purpose. Rheology compares deformation and flow behavior; extrusion tests measure resistance in a specified apparatus. Tissue response, duration, and clinical risks require corresponding evidence. Temperature, measurement geometry, frequency, strain range, shear history, and the syringe assembly should be documented before comparing results.
What a nominal 25–45 μm specification leaves to define
In procurement, “25–45 μm” is a specification that needs a clear definition. It might refer to an agreed size range, a sieve fraction, or a distribution requirement. Supplier and developer should establish which meaning applies. Guidance on 25–45 μm CaHA microsphere specifications should likewise be read alongside measurement methods and lot-acceptance conditions.
For example, two batches with a reported D50 of 35 μm have the same median size on the stated statistical basis, but may differ in distribution width and tails. D10, D90, out-of-range particles, and the treatment of agglomerates also need to be checked, including whether the distribution is volume- or number-based. Results obtained with different instruments, dispersants, or dispersion procedures cannot be compared solely by their numerical values.
Morphology assessment also needs an adequate sampling basis. A 2024 study used microscopy and image analysis to compare particles from specific CaHA and PLLA products, illustrating how size, shape, and fragments can be examined. Its findings do not establish the properties of another supplier's raw materials. [6] Batch evaluation should define sampling, field selection, particle counts, and the criteria used to distinguish intact particles, fragments, and agglomerates.
Particle-size analysis and SEM imaging should be interpreted together. Size-distribution data characterize the particle population, while SEM helps identify morphology, fractured particles, and agglomeration. Because the methods may differ in measurement principles, sampling, and statistical basis, their results should be interpreted jointly rather than treated as directly interchangeable numerical measurements.
Test CMC compatibility in the composite formulation
Even with unchanged CaHA microspheres, a change in CMC grade, concentration, or formulation conditions calls for renewed composite testing. Records should identify the CMC grade, viscosity-related specifications, preparation conditions, and mixing sequence before evaluating particle uniformity. Separate CaHA and CMC certificates describe tests on the raw materials individually.
Composite samples also need evaluation through processing, storage, and simulated use. Depending on the product design, this can include particle integrity before and after mixing, solids distribution at different sampling positions, and sedimentation or aggregation over a defined observation period. Rheology and extrusion tests should use consistent temperatures, sample resting times, and apparatus conditions.
These comparisons can help locate the source of a difference in the particles, carrier, or process. If raw-material results are similar but formulations behave differently, dispersion and preparation records should be checked before assigning the difference to a single particle-size value. Changes to raw-material specifications should also draw on these formulation results.
Connect raw-material tests with batch and process changes
Phase, composition, and particle characterization provide different information. XRD identifies crystalline phases, FTIR helps examine characteristic chemical groups, and size analysis and microscopy describe particle populations. For a defined formulation, each result should address a specific risk or explain a relevant difference, rather than simply adding more tests without interpretation criteria.
Methods and requirements for impurities, residues, microorganisms, and bacterial endotoxins should follow the intended use and product risk assessment. A customer's raw-material specification or certificate-of-analysis limit should not be treated as a universal standard for injectable formulations. Passing raw-material tests does not replace final-formulation validation.
Changes in feedstock, calcination, classification, or post-processing should be linked to batch records and measurement methods before deciding whether additional formulation studies are needed. Process changes and quality control for CaHA particles require attention beyond individual acceptance results: a new batch may meet existing D50 or phase requirements while differing in distribution tails, morphology, or surface characteristics. Change assessment should establish whether the material remains suitable for the validated formulation and process.
CaHA/CMC findings cannot simply be transferred to HA–CaHA
CMC and hyaluronic acid (HA) are different polymers, and the carrier also depends on its grade, formulation, and processing. Similar CaHA particle sizes do not remove the need to reassess dispersion, viscoelasticity, and storage behavior after changing the carrier. Dilution research on a CMC-based product cannot, on its own, establish the performance of another polymer system.
“HA–CaHA hybrid” also needs a precise definition: mixing finished products, formulating the components together, and other preparation routes are different research objects. Similar ingredient names or particle sizes do not establish component interchangeability or equivalent safety and effectiveness of finished products.
What the new review asks of upstream material evaluation
The review presents its categories as descriptive tools and emphasizes that heterogeneous evidence does not establish validated treatment algorithms. [1] Material developers can use it to organize research questions, while keeping application discussions separate from raw-material acceptance criteria or clinical guarantees.
CaHA microsphere development needs to connect three sets of records: particle specifications and test results, formulation testing with the carrier, and further validation for the intended use. A passing D50 result does not complete that chain. Clear sampling, measurement methods, batch identification, and process conditions allow downstream teams to judge which development stage the available evidence supports.
References
- Lin JY, Lin CY. Diluted and Hyperdiluted Calcium Hydroxylapatite/Carboxymethylcellulose as a Technique Platform: A Narrative Review with Practical Taxonomy, Injection Mapping, and Safety. Aesthetic Plastic Surgery. Published online October 12, 2026. DOI: 10.1007/s00266-026-06378-x.
- McCarthy AD, Soares DJ, Chandawarkar A, et al. Dilutional rheology of Radiesse: Implications for regeneration and vascular safety. Journal of Cosmetic Dermatology. 2024;23(6):1973–1984. DOI: 10.1111/jocd.16216.
- McCarthy AD, Soares DJ, Chandawarkar A, et al. Comparative Rheology of Hyaluronic Acid Fillers, Poly-l-lactic Acid, and Varying Dilutions of Calcium Hydroxylapatite. Plastic and Reconstructive Surgery – Global Open. 2024;12(8):e6068. DOI: 10.1097/GOX.0000000000006068.
- Hicks JA, Öhrlund Å. Comparative Rheology of Hyaluronic Acid Fillers, Poly-l-lactic Acid, and Varying Dilutions of Calcium Hydroxylapatite. Plastic and Reconstructive Surgery – Global Open. 2025;13(2):e6561. DOI: 10.1097/GOX.0000000000006561.
- Soares DJ, McCarthy AD, Chandawarkar A, et al. Reply: Comparative Rheology of Hyaluronic Acid Fillers, Poly-l-lactic Acid, and Varying Dilutions of Calcium Hydroxylapatite. Plastic and Reconstructive Surgery – Global Open. 2025;13(2):e6504. DOI: 10.1097/GOX.0000000000006504.
- McCarthy AD, Hartmann C, Durkin A, et al. A morphological analysis of calcium hydroxylapatite and poly-l-lactic acid biostimulator particles. Skin Research and Technology. 2024;30(6):e13764. DOI: 10.1111/srt.13764.