A LC-QTOF Method for the Determination of PEGDE Residues in Dermal Fillers.

Hyaluronic acid is one of the most important ingredients in dermal fillers, where it is often cross-linked to gain more favorable rheological properties and to improve the implant duration. Poly(ethylene glycol) diglycidyl ether (PEGDE) has been recently introduced as a crosslinker because of its very similar chemical reactivity with the most-used crosslinker BDDE, while giving special rheological properties. Monitoring the amount of the crosslinker residues in the final device is always necessary, but in the case of PEGDE, no methods are available in literature. Here, we present an HPLC-QTOF method, validated according to the guidelines of the International Council on Harmonization, which enables the efficient routine examination of the PEGDE content in HA hydrogels.

Rheological Investigation as Tool to Assess Physicochemical Stability of a Hyaluronic Acid Dermal Filler Cross-Linked with Polyethylene Glycol Diglycidyl Ether and Containing Calcium Hydroxyapatite, Glycine and L-Proline.

(1) Background: Dermal fillers are commonly used in aesthetic practice and their rheological characterization is of much interest today, as well as the stability study of the finished formula against external stimuli of a different nature (biological and physicochemical). Rheological tools have been exploited to characterize the physiochemical behaviour of a hyaluronic acid (HA) based dermal filler subjected to different thermal conditions over time. The collected results provide an index of its rheological stability. (2) Methods: After a preliminary Amplitude sweep test, the Frequency sweep test was performed in order to study the stability of a HA dermal filler cross-linked with Polyethylene Glycol Diglycidyl Ether (PEGDE) and containing Calcium Hydroxyapatite (CaHA), Glycine and L-Proline subjected to different conditions. Also, a shear rate ramp test was performed in order to investigate the filler's flow behavior. (3) Results and Conclusions: G' (elastic modulus), G'' (viscous modulus) and consequentially tan δ (tangent of the phase angle) show a similar trend at different thermal conditions, underlining that the product is not affected by the storage conditions. The viscosity of the dermal filler decreases with an increasing shear rate, so a non-Newtonian shear thinning pseudoplastic behavior was demonstrated in all tested conditions.

Comparative Physicochemical Analysis among 1,4-Butanediol Diglycidyl Ether Cross-Linked Hyaluronic Acid Dermal Fillers.

(1) Background: Injectable hyaluronic acid (HA) dermal fillers are used in several chirurgical practices and in aesthetic medicine. HA filler stability can be enhanced through different cross-linking technologies; one of the most frequently cross-linker used is 1,4-butanediol diglycidyl ether (BDDE), also present in the HA-BDDE dermal filler family of the company Matex Lab S.p.A. (Brindisi, Italy). Our overview is focused on their characterization, drawing a correlation between matrix structure, rheological and physicochemical properties related to their cross-linking technologies. (2) Methods: Four different injectable HA hydrogels were characterized through optical microscopic examination and rheological behavior investigation. (3) Results: The cross-linked HA dermal fillers showed a fibrous "spiderweb-like" matrix structure and an elastic and solid-like profile. (4) Conclusions: The comparative analysis represents a preliminary characterization of these injectable medical devices in order to identify their best field of application.

Physico-Chemical Characterization and In Vitro Biological Evaluation of a Bionic Hydrogel Based on Hyaluronic Acid and l-Lysine for Medical Applications.

Hyaluronic acid (HA) is an endogenous polysaccharide, whose hydrogels have been used in medical applications for decades. Here, we present a technology platform for stabilizing HA with a biocrosslinker, the amino acid L-lysine, to manufacture bionic hydrogels for regenerative medicine. We synthetized bionic hydrogels with tailored composition with respect to HA concentration and degree of stabilization depending on the envisaged medical use. The structure of the hydrogels was assessed by microscopy and rheology, and the resorption behavior through enzymatic degradation with hyaluronidase. The biological compatibility was evaluated in vitro with human dermal fibroblast cell lines. HA bionic hydrogels stabilized with lysine show a 3D network structure, with a rheological profile that mimics biological matrixes, as a harmless biodegradable substrate for cell proliferation and regeneration and a promising candidate for wound healing and other medical applications.

Image-Guided Surgical Simulation in Minimally Invasive Liver Procedures: Development of a Liver Tumor Porcine Model Using a Multimodality Imaging Assessment.

Background: Image-guided liver surgery and interventions are growing as part of the current trend to translate liver procedures into minimally invasive approaches. Hands-on surgical training in such techniques is required. Consequently, a meaningful and realistic liver tumor model using multi-imaging modalities, such as ultrasound (US), computed tomography (CT), magnetic resonance (MR), cone beam-CT (CBCT), is mandatory. The first aim of this study is to develop a novel tumor-mimic model and assess it with multi-imaging modalities. The second aim is to evaluate the usefulness of the model during image-guided liver procedures. Materials and Methods: The tumor-mimic model is made of a composition of hydrogel, smashed muscle, and gadolinium contrast solution. Five ex vivo livers and three pigs were included in the study. Procedures were performed in an experimental hybrid operating room. Under general anesthesia, US guidance was required to inject the biotumor formula into the pig's liver. US, CT, CBCT, and MR acquisitions were then performed after the initial injection. In vivo models were then used to perform liver procedures, including US-guided biopsy, radiofrequency ablation, and laparoscopic resection. Results: The formula developed is easily injected generating a tissue-like material. Visualization using multi-imaging modalities was appropriate, thereby allowing to perform image-guided techniques. Conclusion: A novel design of an in vivo and ex vivo tissue-like tumor liver model is presented. Due to the multimodality imaging appraisal, it may provide a realistic and meaningful model allowing to perform image-guided liver procedures.

Toward Physicochemical and Rheological Characterization of Different Injectable Hyaluronic Acid Dermal Fillers Cross-Linked with Polyethylene Glycol Diglycidyl Ether.

(1) Background: Injectable hyaluronic acid (HA) dermal fillers are used to restore volume, hydration and skin tone in aesthetic medicine. HA fillers differ from each other due to their cross-linking technologies, with the aim to increase mechanical and biological activities. One of the most recent and promising cross-linkers is polyethylene glycol diglycidyl ether (PEGDE), used by the company Matex Lab S.p.A., (Brindisi, Italy) to create the HA dermal filler PEGDE family. Over the last few years, several studies have been performed to investigate the biocompatibility and biodegradability of these formulations, but little information is available regarding their matrix structure, rheological and physicochemical properties related to their cross-linking technologies, the HA content or the degree of cross-linking. (2) Methods: Seven different injectable HA hydrogels were subjected to optical microscopic examination, cohesivity evaluation and rheological characterization in order to investigate their behavior. (3) Results: The analyzed cross-linked dermal fillers showed a fibrous "spiderweb-like" matrix structure, with each medical device presenting different and peculiar rheological features. Except for HA non cross-linked hydrogel 18 mg/mL, all showed an elastic and cohesive profile. (4) Conclusions: The comparative analysis with other literature works makes a preliminary characterization of these injectable medical devices possible.

Design of Nanocomposite Injectable Hydrogels for Minimally Invasive Surgery.

Biocompatible hydrogels are materials that hold great promise in medicine and biology since the porous structure, the ability to entrap a large amount of water, and the tunability of their mechanical and tissue adhesive properties make them suitable for several applications, including wound healing, drug and cell delivery, cancer treatment, bioelectronics, and tissue regeneration. Among the possible developed systems, injectable hydrogels, owing to their properties, are optimal candidates for in vivo minimally invasive procedures. To be injectable, a hydrogel must be liquid before and during the injection, but it must quickly jellify after injection to form a soft, self-standing, solid material. The possibility to work with a liquid precursor encoding the functions that will be available after gelation allows the development of biocompatible materials that can be employed in surgery and, in particular, in noninvasive procedures. The underlying idea is to reach the target tissue by using just a needle, or by exploiting the natural body orifices, reducing surgery procedure time, induced pain, and risk of infections. Hydrogels with different properties can be obtained by changing the type of cross-linking, the cross-linking density or the molecular weight of the polymer, or by introducing pending functional groups. The introduction of a nanofiller in the hydrogel network allows for expanding the suite of the structural and functional properties and for better mimicking native tissues. In this Account, we discuss how to provide a hydrogel network with designed properties by playing with both the polymeric chains and the fillers. We present selected examples from the literature that show how to introduce stiffness, stretchability, adhesiveness, self-healing, anisotropy, antimicrobial activity, biodegradability, and conductivity in injectable hydrogels. We further describe how the chemical composition, the mechanical properties, and the microarchitecture of the hydrogel influence cell adhesion, proliferation, and differentiation. Examples of injectable hydrogels for innovative minimally invasive procedures are then discussed in detail; in particular, we showcase the use of hydrogels for tumor resection and as vascular chemoembolization agents. We further discuss how one can improve the rheological properties of injectable hydrogels to exploit them in osteochondral tissue engineering. The effect of the introduction of a conductive filler is then presented in relation to the development of electroactive scaffolds for cardiac-tissue engineering and neural and nerve repair. We believe that the rational design of biocompatible, injectable hybrid hydrogels with tunable properties will likely play a crucial role in reducing the invasiveness and improving the outcome of several clinical and surgical setups.

Injectable Hybrid Hydrogels, with Cell-Responsive Degradation, for Tumor Resection.

Biocompatible soft materials have recently found applications in interventional endoscopy to facilitate resection of mucosal tumors. When neoplastic lesions are in organs that can be easily damaged by perforation, such as stomach, intestine, and esophagus, the formation of a submucosal fluid cushion (SFC) is needed to lift the tumor from the underlying muscle during the resection of neoplasias. Such procedure is called endoscopic submucosal dissection (ESD). We describe an injectable, biodegradable, hybrid hydrogel able to form a SFC and to facilitate ESD. The hydrogel, based on polyamidoamines, contains breakable silica nanocapsules covalently bound to its network and able to release biomolecules. To promote degradation, the hydrogel is composed of cleavable disulfide moieties that are reduced by the cells through secretion of glutathione. The same stimulus triggers the breaking of the silica nanocapsules; therefore, the entire hybrid material can be completely degraded and its decomposition depends entirely on the presence of cells. Interestingly, the hydrogel precursor solution showed rapid gelation when injected in vivo and afforded a long-lasting high mucosal elevation, keeping the cushion volume constant during the dissection. This novel material can provide a solution to ESD limitations and promote healing of tissues after surgery.