Hyaluronic Acid Microspheres Research Articles

Nanoclay-Modified Hyaluronic Acid Microspheres for Bone Induction by Sustained rhBMP-2 Delivery.

Microspheres (MSs) are ideal candidates as biological scaffolds loading with growth factors or cells for bone tissue engineering to repair irregular alveolar bone defects by minimally invasive injection. However, the high initial burst release of growth factor and low cell attachment limit the application of microspheres. The modification of microspheres often needs expensive experiments facility or complex chemical reactions, which is difficult to achieve and may bring other problems. In this study, a sol-grade nanoclay, laponite XLS is used to modify the surface of MSs to enhance its affinity to either positively or negatively charged proteins and cells without changing the interior structure of the MSs. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used as a representation of growth factor to check the osteoinduction ability of laponite XLS-modified MSs. By modification, the protein sustained release, cell loading, and osteoinduction ability of MSs are improved. Modified by 1% laponite XLS, the MSs can not only promote osteogenic differentiation of MC3T3-E1 cells by themselves, but also enhance the effect of the rhBMP-2 below the effective dose. Collectively, the study provides an easy and viable method to modify the biological behavior of microspheres for bone tissue regeneration.

Injectable Amphipathic Artesunate Prodrug‐Hydrogel Microsphere as Gene/Drug Nano‐Microplex for Rheumatoid Arthritis Therapy

AbstractArtemisinin and its derivatives (artemisinins) are first‐line chemotherapeutic agents of lethal malaria, which also showed tremendous value in many other diseases including chronic inflammation. Unfortunately, almost all artemisinins are rapid‐acting medicines with an extremely short half‐life in vivo, which significantly limits their clinical application for these new adaptation diseases. In this study, a locally injectable long‐acting gene/artemisinin co‐delivery nano‐microplex consisting of a biodegradable hyaluronic acid (HA) microsphere and releasable gene/artemisinin co‐delivery nano‐lipoplex is developed first, to obtain an improved efficacy for rheumatoid arthritis (RA). Briefly, a cationic multicomponent drug‐embedded liposome with pharmacological activity is first reported based on two novel artemisinin derivatives (dAPC and dACC), which possess mimic phospholipids and cationic lipids, respectively. A cationic artemisinin‐embedded lipoplex is first reported as a medicative gene carrier here. An in situ injectable TNF‐α siRNA/artemisinin co‐delivery nano‐microplex (MTAsi@MG) is further prepared by immobilization of TNF‐α siRNA/lipoplex on porous microfluidic HA microspheres. Using this nano‐microplex for intra‐articular injection, the sustaining activity of gene therapy and artemisinin efficacy for RA long‐term treatment is first realized. Undoubtedly, this intra‐articular injectable TNF‐α siRNA/artemisinin co‐delivery nano‐microplex based on dAPC/dACC lipoplex and microfluidic microspheres would be one of the most potent gene/drug co‐delivery systems for RA therapy.

Silencing Gene‐Engineered Injectable Hydrogel Microsphere for Regulation of Extracellular Matrix Metabolism Balance (Small Methods 4/2022)

Rechargeable Batteries In article number 2101201, Wenguo Cui, Xiaodong Liu, and co-workers construct an injectable circRNA silencing-hydrogel microsphere, capable of targeting nutrient-restricted microenvironments to regulate the extracellular matrix metabolism balance by grafting circSTC2 silencing genes-loaded DOTAP/Chol/DOPE cationic liposomes on methacrylated hyaluronic acid microspheres via amide bonds, which can precisely control the release of gene vectors and effectively silence pathological genes in nucleus pulposus cells.

Pulmonary drug delivery with aerogels: engineering of alginate and alginate–hyaluronic acid microspheres

In this study, the aerogel technology was used to prepare pulmonary drug carriers consisting of alginate and alginate–hyaluronic acid by an emulsion gelation technique and supercritical CO2 drying. During the preparation process, the emulsification rate and inner phase viscosity were varied to control the diameter of aerogel microspheres. Results showed that the aerogel microspheres were highly porous (porosity > 98%) with low densities in the range between 0.0087 and 0.0634 g/cm3 as well as high surface areas between 354 and 759 m2/g. The obtained microspheres showed aerodynamic diameter below 5 µm making them suitable for pulmonary drug delivery. An in vitro drug release study with the model drug sodium naproxen was conducted and a non-Fickian drug release mechanism was observed, with no significant difference between the release profiles of alginate and alginate–hyaluronic acid microspheres. During the emulsion gelation step, the feasibility of using the capillary number to estimate the largest stable droplet size in the emulsions was also studied and it was found that using this number, the droplet size in the emulsions may well be predicted.

Preparation and evaluation of adipic dihydrazide cross-linked hyaluronic acid microspheres for cephalexin

Hyaluronic acid also called as Hyaluronan, Sodium Hyaluronate (SA), sodium salt form of Hyaluronic acid is a biodegradable, biocompatible, and viscoelastic linear polysaccharide of a wide molecular weight range (1000 to 10,000,000 Da). In this project, described a method for preparing HA microspheres at different pH conditions by adapting a non-toxic and aqueous based crosslinking chemistry for sustained drug delivery of drugs. The derivatization chemistry of HA utilizing adipic dihydrazide has been used to construct hydrogels, applied for microsphere preparation. ADH was coupled efficiently to carbodimide-activated glucoronic acid residues of hyluronans. These ADH modified hyaluronan can be loaded with drug molecules and then cross linked into hydrogel. The drug was present in the bulk of hydrogel droplets which are present in liquid paraffin are precipitated by IPA. Formulating HA microspheres with this method have several advantages. Preliminary studies were conducted to confirm the better ratio of HA and ADH to show maximum entrapment efficiency and drug release. Then microspheres were prepared at different pH conditions and formulations were subjected to evaluation of various parameters like percentage yield, particle size, drug entrapment efficiency, porosity and bulk density, surface morphology, in vitro drug release among which F2B was optimized as best formulation which showed 74.6% entrapment efficiency and above 90% of drug release in 12 hours indicating Hyaluronic acid microspheres can be used as good carriers for sustained drug delivery of drugs.

A Versatile Microencapsulation Platform for Hyaluronic Acid and Polyethylene Glycol.

Cell microencapsulation is a rapidly expanding field with broad potential for stem cell therapies and tissue engineering research. Traditional alginate microspheres suffer from poor biocompatibility, and microencapsulation of more advanced hydrogels is challenging due to their slower gelation rates. We have developed a novel, noncytotoxic, nonemulsion-based method to produce hydrogel microspheres compatible with a wide variety of materials, called core-shell spherification (CSS). Fabrication of microspheres by CSS derived from two slow-hardening hydrogels, hyaluronic acid (HA) and polyethylene glycol diacrylate (PEGDA), was characterized. HA microspheres were manufactured with two different crosslinking methods: thiolation and methacrylation. Microspheres of methacrylated HA (MeHA) had the greatest swelling ratio, the largest average diameter, and the lowest diffusion barrier. In contrast, PEGDA microspheres had the smallest diameters, the lowest swelling ratio, and the highest diffusion barrier, while microspheres of thiolated HA had characteristics that were in between the other two groups. To test the ability of the hydrogels to protect cells, while promoting function, diabetic NOD mice received intraperitoneal injections of PEGDA or MeHA microencapsulated canine islets. PEGDA microspheres reversed diabetes for the length of the study (up to 16 weeks). In contrast, islets encapsulated in MeHA microspheres at the same dose restored normoglycemia, but only transiently (3–4 weeks). Nonencapsulated canine islet transplanted at the same dose did not restore normoglycemia for any length of time. In conclusion, CSS provides a nontoxic microencapsulation procedure compatible with various hydrogel types.Impact statementCore-shell spherification, described here for the first time, is a versatile method of coating cells to protect them following transplantation. Before the invention of this technique, only instantaneously hardening hydrogels, like alginate, could be used to encapsulate cells. With this new technology, biocompatible hydrogels can now be used for encapsulation without harsh emulsion chemicals. The technique involves a temporary shell of alginate around the slow-hardening gel that provides time for crosslinking to occur. Subsequently, the alginate shell is easily removed, leaving the cells in a protective microsphere with a higher surface area for diffusion than large encapsulating devices.

Dopamine-functionalized hyaluronic acid microspheres for effective capture of CD44-overexpressing circulating tumor cells

As one of the biomarkers of liquid biopsy, circulating tumor cells (CTCs) provides important clinical information for cancer diagnosis. However, accurate separation and identification of CTCs remains a great deal of challenge. In present work, we developed novel dopamine-functionalized hyaluronic acid microspheres (HA-DA microspheres) to capture CD44-overexpressing CTCs. The dopamine was grafted onto the hyaluronic acid chain, which was polymerized and cross-linked by oxidation of the catechol groups. Afterwards, a facile microfluidic chip was designed and developed to fabricate the HA-DA microspheres with a diameter of about 45 μm. Our results showed that the CD44+ cells (i.e., HeLa, HepG2, A549, MCF-7 and DU-145 cells) could be selectively captured. Then a double-layer microfluidic filter (DLMF) was fabricated for dynamic isolation and detection of CTCs in blood samples. Many slit openings with 15 μm in height were designed to allow white blood cells to clear away, while the microspheres with CTCs were intercepted in the DLMF, which achieved effective separation of CTCs from blood cells. The approach exhibited high capture efficiency even at the cell density as low as 10 cells/mL. We believe the DLMF integrated with HA-DA microspheres could be a promising approach for isolation and detection of CD44-overexpressing CTCs, which is useful for prognosis and early metastasis of cancer patients.

Regenerative and Resorbable PLA/HA Hybrid Construct for Tendon/Ligament Tissue Engineering.

Tendon and ligament shows extremely limited endogenous regenerative capacity. Current treatments are based on the replacement and or augmentation of the injured tissue but the repaired tissue rarely achieve functionality equal to that of the preinjured tissue. To address this challenge, tissue engineering has emerged as a promising strategy. This study develops a regenerative and resorbable hybrid construct for tendon and ligament engineering. The construct is made up by a hollow poly-lactic acid braid with embedded microspheres carrying cells and an anti-adherent coating, with all the parts being made of biodegradable materials. This assembly intends to regenerate the tissue starting from the interior of the construct towards outside while it degrades. Fibroblasts cultured on poly lactic acid and hyaluronic acid microspheres for 6h were injected into the hollow braid and the construct was cultured for 14days. The cells thus transported into the lumen of the construct were able to migrate and adhere to the braid fibers naturally, leading to a homogeneous proliferation inside the braid. Moreover, no cells were found on the outer surface of the coating. Altogether, this study demonstrated that PLA/HA hybrid construct could be a promising material for tendon and ligament repair.

261-OR: Core-Shell Spherification: A New Microencapsulation Platform for Hyaluronic Acid and PEGDA

Cell microencapsulation associated with islet transplantation is a rapidly expanding field. Traditional alginate microspheres still suffer from poor biocompatibility, and microencapsulation of more advanced hydrogels is challenging due to their slower gelation rates. We have developed a novel, non-cytotoxic, non-emulsion based method to produce hydrogel microspheres compatible with a wide variety of materials, called Core-Shell Spherification (CSS). Here, we demonstrate fabrication of microspheres via CSS derived from two slow-hardening hydrogels: hyaluronic acid (HA) and polyethylene glycol diacrylate (PEGDA). HA microspheres were manufactured with two different crosslinking methods: thiolation and methacrylation. Microspheres of methacrylated HA (MeHA) had the greatest swelling ratio, the largest average diameter and the lowest diffusion barrier. In contrast PEGDA microspheres had the smallest diameters, the lowest swelling ratio and the highest diffusion barrier, while microspheres of thiolated HA (ThHA) had characteristics that were in between the other two groups. To test the ability of the hydrogels to protect cells while promoting function, diabetic NOD mice received xenotransplants via intraperitoneal injections of PEGDA or MeHA microencapsulated canine islets. PEGDA microspheres reversed diabetes for the length of the study (up to 16 weeks). In contrast, islets encapsulated in MeHA microspheres at the same dose restored normoglycemia, but only transiently (3-4 weeks). Non-encapsulated canine islet transplanted at the same dose did not restore normoglycemia for any length of time. In conclusion, CSS appears to offer several advantages to current cell encapsulation technologies, including a non-toxic microencapsulation procedure compatible with various hydrogel types. Disclosure F. Karanu: Employee; Self; LIkarda LLC. S. Harrington: Employee; Self; Likarda, LLC. L. Ott: Employee; Self; Likarda, LLC.

Alginate and hybrid alginate-hyaluronic acid aerogel microspheres as potential carrier for pulmonary drug delivery

The aim of the present study was the preparation of aerogel microspheres based on alginate and hyaluronic acid for the potential application in pulmonary drug delivery. Both polymers are commonly used in the pharmaceutical and medical fields because of their nontoxicity, biodegradability and biocompatibility characteristics. The bio-based microspheres were produced using an emulsion gelation process with a subsequent drying step by supercritical CO2. The microspheres were characterized by FTIR and SEM. Furthermore, their BET surface area, particle size distribution, and their aerodynamic properties were determined. The microspheres showed a low density in the range of 0.035 – 0.063 g/cm3 and a high porosity of 97.6–98.7 %, as well as good in vitro aerodynamic properties with dA values of about 5 μm. The obtained properties of the alginate- hyaluronic acid microspheres suggest that they are potentially suitable as drug carrier for pulmonary delivery.

Formulation and Characterization of Native and Crosslinked Hyaluronic Acid Microspheres for Dermal Delivery of Sodium Ascorbyl Phosphate: A Comparative Study.

The present work evaluates for the first time the use of urea-crosslinked hyaluronic acid (HA-CL), a novel derivative of native hyaluronic acid (HA), to produce microspheres (MS) by emulsification-solvent evaporation, for dermal delivery of sodium ascorbyl phosphate (SAP). As the term of comparison, HA MS were prepared. A pre-formulation study—investigation of the effects of polymers solutions properties (pH, viscosity) and working conditions—led to the production of optimized HA-CL MS and HA-CL—SAP MS with: almost unimodal size distributions; mean diameter of 13.0 ± 0.7 and 9.9 ± 0.8 µm, respectively; spherical shape and rough surface; high yield, similar to HA MS and HA–SAP MS (≈ 85%). SAP was more efficiently encapsulated into HA-CL MS (78.8 ± 2.6%) compared to HA MS (69.7 ± 4.6%). Physical state, thermal properties, relative moisture stability of HA-CL MS and HA-CL–SAP MS were comparable to those of HA MS and HA–SAP MS. However, HA-CL–SAP MS exhibited an extended drug release compared to HA–SAP MS, despite the same kinetic mechanism—contemporaneous drug diffusion and polymer swelling/dissolution. Therefore, HA-CL formulation showed a greater potential as microcarrier (for encapsulation efficiency and release kinetic), that could be improved, in future, using suitable excipients.

Utilizing hyaluronic acid as a versatile platform for fluorescence resonance energy transfer-based glucose sensing.

Here, we utilized the ultrasonic emulsification technique to generate hyaluronic acid microspheres incorporating a fluorescence-based glucose biosensor. We synthesized a novel lanthanide ion luminophore based on Eu3+. Eu sulfosuccinimidyl dextran (Eu-dextran) and Alexa Fluor 647 sulfosuccinimidyl-ConA (Alexa Fluor 647-ConA) were encapsulated in hyaluronic acid hydrogel to generate microspheres. Glucose sensing was carried out using a fluorescence resonance energy transfer (FRET)-based assay principle. A proportional fluorescence intensity increase was found within a 0.5-10-mM glucose concentration range. The glucose-sensing strategy showed an excellent tolerance for potential interferents. Meanwhile, the fluorescent signal of hyaluronic acid microspheres was very stable after testing for 72h in glucose solution. Overall, hyaluronic acid microspheres encapsulating sensing biomolecules offer a stable and biocompatible biosensor for a variety of applications including cell culture systems, tissue engineering, detection of blood glucose, etc. Graphical abstract We report an ingenious biosensor encapsulated in hyaluronic acid microspheres for monitoring of glucose. Glucose sensing is carried out using a fluorescence resonance energy transfer-based assay principle with a novel lanthanide ions luminophore. The glucose detection system has excellent biocompatibility and stability for monitoring of glucose.

EGF-Loaded Hyaluronic Acid Based Microparticles as Effective Carriers in a Wound Model

Epidermal growth factor (EGF) is widely recognized to be involved in the regenerative process, but only a few studies document its effect on acute wounds when EGF release is sustained over a period of time by encapsulation in an emulsion-based hydrogel. Among hydrogels, hyaluronic acid (HA) is a promising carrier because it is biodegradable and known to bind to the components of the Extracellular Matrix (ECM) which undergoes remodeling during regeneration. Coupled with EGF in microparticulates, it may serve to directly deliver the cytokine to the impaired ECM to stimulate cells for ECM remodeling. In this study, a very simple and effective way is demonstrated to produce EGF-conjugated HA microspheres for the purpose of targeted and sustained EGF delivery to damaged ECM in acute wounds. This approach is advantageous due to its simplicity which may serve to accelerate research in wound regeneration and relevant drug discovery.

Assessment of bone healing ability of calcium phosphate cements loaded with platelet lysate in rat calvarial defects.

Injectable calcium phosphate cements have been used as a valid alternative to autologous bone grafts for bone augmentation with the additional advantage of enabling minimally invasive implantation procedures and for perfectly fitting the tissue defect. Nevertheless, they have low biodegradability and lack adequate biochemical signaling to promote bone healing and remodeling. In previous invitro studies, we observed that the incorporation of platelet lysate directly into the cement paste or loaded in hyaluronic acid microspheres allowed to modulate the cement degradation and the invitro expression of osteogenic markers in seeded human adipose derived stem cells. The present study aimed at investigating the possible effect of this system in new bone formation when implanted in calvarial bilateral defects in rats. Different formulations were assessed, namely plain calcium phosphate cements, calcium phosphate cements loaded with human platelet lysate, hybrid injectable formulations composed of the calcium phosphate cement incorporating hyaluronin acid non-loaded microparticles (20% hyaluronin acid) or with particles loaded with platelet lysate. The degradability and new bone regrowth were evaluated in terms of mineral volume in the defect, measured by micro-computed tomography and histomorphometric analysis upon 4, 8 and 12 weeks of implantation. We observed that the incorporation of hyaluronin acid microspheres induced an overly rapid cement degradation, impairing the osteoconductive properties of the cement composites. Moreover, the incorporation of platelet lysate induced higher bone healing than the materials without platelet lysate, up to four weeks after surgery. Nevertheless, this effect was not found to be significant when compared to the one observed in the sham-treated group.

Effect of molecular weight of hyaluronic acid (HA) on viscoelasticity and particle texturing feel of HA dermal biphasic fillers.

BackgroundHyaluronic acid (HA) dermal biphasic fillers are synthesized for their efficacy in correcting aesthetic defects such as wrinkles, scars and facial contouring defects. The fillers consist of crosslinked HA microspheres suspended in a noncrosslinked HA. To extend the duration of HAs within the dermis and obtain the particle texturing feel, HAs are crosslinked to obtain the suitable mechanical properties.ResultsHyaluronic acid (HA) dermal biphasic fillers are prepared by mixing the crosslinked HA microspheres and the noncrosslinked HAs. The elastic modulus of the fillers increased with raising the volume fraction of the microspheres. The mechanical properties and the particle texturing feel of the fillers made from crosslinked HA (1058 kDa) microspheres suspended in noncrosslinked HA (1368 kDa) are successfully achieved, which are adequate for the fillers.ConclusionsDermal biphasic HA fillers made from 1058 kDa exhibit suitable elastic moduli (211 to 420 Pa) and particle texturing feel (scale 7 ~ 9).

Effects of hyaluronic acid and chitosan microspheres on mRNA expression of matrix metalloproteinases-1,-3,-13 and tissue inhibitor of metalloproteinases-1 in the inflammatory chondrocytes

Objective To investigate the effect of hyaluronic acid (HA)/chitosan (CS) microspheres on the expression of matrix metalloproteinases (MMPs)-1,-3 and-13 and tissue inhibitor of MMPs (TIMP-1) mRNA in chondrocytes exposed to interleukin (IL)-1 β in vitro,and study the mechanism,then explore the optimal ratio of HA to CS for protecting chondrocytes.Methods HA microspheres,CS nanopaticles and different ratio of HA/CS microspheres were added to culture medium for 24 h,respectively,after 10 μg/L IL-1 β was added to the culture medium of rat chondrocytes and co-cultured for 24 h.The expression levels of MMP-1,-3 and-13,and TIMP-1 mRNA were detected by using reverse transcriptasepolymerase chain reaction (RT-PCR).The concentration of nitric oxide (NO) in the supernatants was measured by Griess reaction.Results HA/CS microspheres could significantly down-regulate the expression of MMP-1,-3,and-13 mRNA (0.467 ±0.072,0.621 ±0.125 and 0.53 ±0.12,respectively) of chondrocytes,while had little effects on the expression of TIMP-1 mRNA (0.69 ± 0.13).Conclusion HA/CS could effectively interrupt the inflammatory cascade reaction caused by IL-1 β through inhibiting NO production. Key words: Hyaluronic acid; Chitosan; Interleukin-1β; Matrix metalloproteinases; Chondrocytes

Optimization of spray-dried hyaluronic acid microspheres to formulate drug-loaded bone substitute materials

We present here our first results concerning the evaluation of hyaluronic acid (HA) as a candidate to formulate an organic–mineral cement with sustained release properties. Incorporating drug-loaded microspheres in mineral bone cements is an alternative strategy to improve their ability as drug delivery materials. To synthesize microspheres according to a reproducible process and control at the same time their morphology and their encapsulation efficiency is one of the main challenges of the conception of such drug-loaded bone substitute. In this context, we investigated the potentialities of two HA, differing by their molecular weight, to form microspheres by a spray-drying technique. Erythrosin B (EB) was encapsulated as a model drug and spray-drying process conditions were optimized. To perform this, the rheological behavior and viscosity of HA solutions have been related to their spray-drying ability, and then to the resulting microparticles morphological properties and size distribution. Reproducible microspheres, answering to the requirements in terms of size and encapsulation efficiency, have been obtained from both HA. However the HA exhibiting the lowest molecular weight, HA600, led to smaller microparticles, with a higher polydispersity index. Their swelling ability, related to their stability upon rehydration, also appeared reduced. In this context, HA850, with the highest molecular weight, was selected and the possibility to modulate drug release by HA850 microspheres incorporation into a mineral cement was explored. EB release kinetics from HA microspheres, HA microspheres loaded cement and reference cement were followed at 37°C, in Tris buffer at pH7.4, using European Pharmacopoeia flow-through cells. Results showed that HA microspheres incorporation into a mineral cement permitted to modify the cement drug release profile and led to a sustained release.

Preparation and evaluation of spray-dried hyaluronic acid microspheres for intranasal delivery of fexofenadine hydrochloride

Hyaluronic acid (HA)-based microspheres containing PEG 6000 and/or sodium taurocholate (NaTC) were prepared by the spray-drying method for nasal delivery of fexofenadine hydrochloride (HCl). Their physicochemical properties including particle size and drug contents were determined, while their morphology examined by a scanning electron microscope (SEM). The effects of the solubilizer (PEG 6000) and the permeation enhancer (NaTC) on the in vitro release characteristics of fexofenadine ·HCl were observed. Moreover, the in vitro permeation of fexofenadine ·HCl was determined using the human nasal cell (HNE) monolayers cultured on Transwell ® inserts. After nasal administration, fexofenadine ·HCl in rabbit plasma was determined by the LC–MS/MS system. Fexofenadine ·HCl-loaded microspheres were of spherical shape with 20–30 μm mean diameter. The loading efficiency was about 95%. In vitro release of fexofenadine ·HCl from the microspheres was significantly increased with the addition of PEG 6000. Although NaTC did not alter the in vitro release of drug from the microspheres, its addition further increased the in vitro permeation of fexofenadine ·HCl across the HNE cell monolayers. Moreover, the bioavailability of fexofenadine ·HCl after nasal administration of the microsphere formulation to rabbits was increased up to about 48% while that of the control solution was only about 3%. These results indicated that the HA microsphere formulation could further be developed into a clinically useful nasal delivery system of fexofenadine ·HCl.

Foreign Body Granuloma Due to Matridex Injection for Cosmetic Purposes

A new resorbable filler, Matridex, became commercially available during the last years with scarce evidence regarding side effects. A 43-year-old woman complained of multiple, painful, reddish, nonulcerated, hard nodules on both cheeks and periocular regions. Four weeks before, she had been injected by a general practitioner with Matridex for aesthetic purposes to correct wrinkles in the same areas of the nodular eruption. Histopathology showed a diffuse suppurative granulomatous reaction with the presence of multinucleate giant cells and many neutrophils involving the entire dermis. No areas of caseation were observed. The inflammatory granulomatous reaction surrounded 2 different types of nonpolarizing, bluish, exogenous material: one arranged in filamentous structures and the second composed by large spherical particles. All nodules were incised and drained; the patient received systemic antibiotic treatment for 2 consecutive weeks. The nodules progressively regressed and almost complete resolution was seen after 6 months. Matridex is a new resorbable filler constituted by a mixture of nonanimal-stabilized hyaluronic acid (HA), cross-linked HA, and dextranomer microspheres. Foreign body reactions have been described in association with other HA fillers, but a granulomatous reaction after the injection of Matridex has not been reported yet. Interestingly, in our patient, we were able to identify both fragments of HA: the filamentous particles and the spherical particles of dextranomer microspheres within the infiltrate, these last giving a characteristic and recognizable appearance to the histopathological picture.