The development of biomaterials has a substantial role in pharmaceutical and medical strategies for the enhancement of life quality. This review work focused on versatile biomaterials based on nanocomposites comprising organic polymers and a class of layered inorganic nanoparticles, aiming for drug delivery (oral, transdermal, and ocular delivery) and tissue engineering (skin and bone therapies). Layered double hydroxides (LDHs) are 2D nanomaterials that can intercalate anionic bioactive species between the layers. The layers can hold metal cations that confer intrinsic biological activity to LDHs as well as biocompatibility. The intercalation of bioactive species between the layers allows the formation of drug delivery systems with elevated loading capacity and modified release profiles promoted by ion exchange and/or solubilization. The capacity of tissue integration, antigenicity, and stimulation of collagen formation, among other beneficial characteristics of LDH, have been observed by in vivo assays. The association between the properties of biocompatible polymers and LDH-drug nanohybrids produces multifunctional nanocomposites compatible with living matter. Such nanocomposites are stimuli-responsive, show appropriate mechanical properties, and can be prepared by creative methods that allow a fine-tuning of drug release. They are processed in the end form of films, beads, gels, monoliths etc., to reach orientated therapeutic applications. Several studies attest to the higher performance of polymer/LDH-drug nanocomposite compared to the LDH-drug hybrid or the free drug.

This work explores the synthesis, physicochemical characterization, and in vivo biocompatibility of iron-based layered double hydroxides (LDHs) with molar ratio M²⁺/(Fe³⁺ + Al³⁺) equal to 2, Fe³⁺/Al³⁺ equal to 1, and chloride anions as charge-compensating ion (abbreviated Mg₄FeAl-Cl and Zn₄FeAl-Cl) prepared by the coprecipitation method. The higher structural organization of Zn₄FeAl-Cl in comparison to Mg²⁺ analogous material was noticed by X-ray diffraction and scanning electron microscopy images. Biocompatibility of LDH was evaluated by intramuscular implantation in rats. Tablets of M₄FeAl-Cl (M = Mg, Zn) were readily identified macroscopically after 7 and 28 days of implantation, denoting slow dissolution in the internal medium; adjacent to the tablets, blood flow was preserved without tortuosity or pathological dilatations, according to the Sidestream Dark Field Imaging technique. The histological analysis showed no inflammatory response and the presence of angiogenesis and tissue remodeling with the reconstruction of the extracellular matrix and cells around the tablets, besides the induction of collagen type-I formation. Prussian blue histochemical reaction suggested higher solubility of Mg₄FeAl-Cl in the extracellular matrix compared to zinc LDH. Considering the positive biocompatibility results obtained for M₄^IIFeAl-LDH materials, experiments were conducted to intercalate the anti-inflammatory naproxen, as a model drug, into the iron-based LDHs (M₄^IIFeAl-NAP). The release profile of NAP in phosphate buffer showed 90% of the drug delivered after about 80 h. However, divalent metal leaching was verified mainly for Mg-LDH (around 50%) when compared to Zn²⁺ (around 1%). Iron-based LDHs have great potential for medical and technological applications as local drug delivery biomaterials exhibiting biocompatibility and biointegration properties.

The intercalation of protonated pilocarpine (Pilo⁺) into model LAPONITE® (Lap) is here investigated in order to address its conformational properties upon entrapment. Pilo is an alkaloid available as a drug for the treatment of glaucoma and xerostomia, and clays are potential candidates for drug delivery. Therefore, the physico-chemical characterization of the Pilo-Lap material is here studied through chemical elementary analysis, X-ray diffraction, mass spectrometry coupled to thermogravimetric analysis (TGA-MS), solid state ¹³C nuclear magnetic resonance (NMR) and Raman spectroscopy. The experimental spectroscopic data are confronted with performed calculations which confirmed the presence of pilocarpine, while the XRD data also show the immobilization of Pilo⁺ into the clay. TGA-MS analyses indicated a significant modification in the thermal decomposition profile of the organic species after intercalation. A DTG peak associated with the release of carbon dioxide and water molecules is observed at 315 °C for PiloHCl and at 378 °C for Pilo-Lap. Supported by the theoretical calculations, the experimental XRD, vibrational and NMR spectra suggest that pilocarpine may undergo geometrical changes upon the intercalation process. A characteristic fingerprint was observed as a vibrational change in the band at 768 cm⁻¹ for PiloHCl (assigned mainly to the lactone ring breathing vibrational mode) and a band at 782 cm⁻¹ for Pilo-Lap (assigned mainly to the imidazole ring bending in the plane) in the Raman spectra.

Coumaric acid (CouH), an antioxidant molecule assimilated by food consumption, was intercalated into layered double hydroxide (LDH) nanocarrier, having zinc and aluminium ions in the layers (LDH-Cou), to evaluate its pharmacological activity through in vitro and in vivo assays in mice. Therefore, the following tests were performed: coumarate delivery in saline solution, fibroblasts’ cell viability using neutral red, peritonitis induced by carrageenan, formalin test, acetic-acid-induced writhing, and tail-flick assay, for the non-intercalated CouH and the intercalated LDH-Cou system. Furthermore, different pharmacological pathways were also investigated to evaluate their possible anti-inflammatory and antinociceptive mechanisms of action, in comparison to traditionally used agents (morphine, naloxone, caffeine, and indomethacin). The LDH-Cou drug delivery system showed more pronounced anti-inflammatory effect than CouH but not more than that evoked by the classic non-steroidal anti-inflammatory drug (NSAID) indomethacin. For the analgesic effect, according to the tail-flick test, the treatment with LDH-Cou expressively increased the analgesia duration (p < 0.001) by approximately 1.7–1.8 times compared to CouH or indomethacin. Thus, the results pointed out that the LDH-Cou system induced in vivo analgesic and anti-inflammatory activities and possibly uses similar mechanisms to that observed for classic NSAIDs, such as indomethacin.

The compound p-coumaric acid (HCou) is found in many foods and presents action in the suppression of chronic diseases and protective effects on neurodegenerative disorders. This work presents the intercalation of this phytochemical species into Layered Double Hydroxides (LDHs) of magnesium–aluminum and zinc–aluminum using a coprecipitation method. Solid samples were characterized by X-ray diffraction, solid-state ¹³C Nuclear Magnetic Resonance, mass coupled thermal analysis, and vibrational spectroscopy. The amount of coumarate anions in the LDH-Cou materials is about 32–35 wt%. Better crystallinity was observed for Zn₂Al-LDH compared to Mg₂Al-LDH attributed to a better stacking of the layers. According to XRD data and the one-dimensional (1D) electron density map, the coumarate anions in Zn₂Al-LDH are accommodated in a bilayer arrangement with the aromatic ring perpendicular to the layers and the carboxylate groups interacting with the hydroxide layers. The thermogravimetric analysis coupled to mass spectrometry showed an increased thermal stability and distinct decomposition profiles of the intercalated organic species compared to the sodium coumarate salts. Interestingly, solid-state ¹³C NMR spectra combined with elemental and thermal analysis strongly suggest the presence of two intercalated structures in the case of the Mg₂Al carrier with particles containing either the monoanion (Cou⁻) or the dianion (Cou²⁻) while Zn₂Al intercalates only the monovalent coumarate anion. Biocompatibility of LDH-Cou materials was assessed by in vivo assays via tablet implantation in the rat abdominal wall. After 28 days of implantation, completing the tissue remodeling process, the healing response is positive (lack of antigenic reaction signals around both tablets), indicating a state of biointegration and biocompatibility. Also, the LDH tablets were found to promote collagen deposition without the presence of fibrotic encapsulation. These data open new opportunities for the application of LDHs intercalated with bioactive species in implantable devices.

In this work, Al cation was gradually replaced by Fe ^III in the composition of Layered Double Hydroxides (LDH) and systematically investigated for LDH application as drug carriers, ultimate aiming to improve their biointegration. The incorporation of Fe ^III into LDH layers, as well the intercalation of organic anions in the iron‐based materials, is challenging. Several studies approach the intercalation of non‐steroidal anti‐inflammatory drugs such as anionic naproxen (NAP) into Al‐LDH. Thus, NAP was applied here as a model drug for the study of compositional and structural aspects of novel Fe ^III ‐LDH carriers envisaging to shed light on the intercalation of other carboxylate drugs into these materials. LDH of general [M ₂ Fe _y Al _(1‐y) (OH) ₆ ]A ⁿ⁻ compositions (M ^II =Mg or Zn; A ⁿ⁻ =anion of charge n ) were investigated using two synthetic methods for NAP intercalation. Full X‐ray diffraction profile refinement and a crystal‐geometrical reasoning were used to strengthen the results interpretation. Unlike coprecipitation, in which probably NAP complexation with Fe ^III hinders LDH‐NAP self‐assembling, topotactic ion exchange demonstrated to be a potential approach.