Eskitoros-Togay (2020) et al. incorporated different ratios of HANPs and curcumin into the same PCL/poly (ethylene oxide) (PCL/PEO) mixed matrix to form membranes by electrospinning. The encapsulation efficiency of curcumin in the electrospun membranes was 86–94%. The fiber membrane containing 0.3% HANPs showed a gradual increasing trend in the first hour of release and only reached 43% of curcumin released from the release time to the eighth hour, indicating that the controlled release of curcumin can be achieved in a simulated environment to prolong the action of the drug after implantation ^[1][96]. By varying the weight ratio of sodium alginate and gelatin (A/G = 40/60, 50/50, and 60/40) and adding different concentrations of HANPs (1, 2, 5, 10, and 20% w/w) to the film solution, Türe (2019) et al. explored whether the addition of HANPs alters the physical, mechanical, thermal, and antimicrobial properties of the films. In addition, tetracycline hydrochloride (TH) was chosen as a model to study drug release in water. Their results showed that the swelling rate and weight loss decreased as the amount of alginate. Membrane structures with high alginate content were denser compared to the increased amount of HA that resulted in rougher surfaces. Films with lower tensile and elastic modulus values with greater than 1% HANPs for A/G = 50/50 and 60/40 ^[2][97]. The amount of TH released decreased with increasing amount of HA, as the addition of HA acted as a barrier and reduced the drug release. In this study, swelling behavior and TH release have similar patterns. Prakash (2019) et al. fabricated HANPs-incorporated polyvinyl alcohol-sodium alginate (PVA-SA) membranes for controlled release of the antibiotic amoxicillin to treat subosseous periodontal defects ^[3][98]. In this study, the polymer tends to degrade, leading to drug release, and SA dissolves faster in aqueous systems compared with PVA at room temperature; therefore, when SA degrades in the polymer matrix, the drug molecules tend to detach from the membrane and acts on the infected area. The result showed that the amount of amoxicillin released 43% of the drug on day 3, 72% on day 6, and 87% on day 10, suggesting that the drug release from these composite membranes were sustained. Ramírez-Agudelo (2018) et al. released doxycycline (Dox) and HANPs from biodegradable polymer composite nanofibers of PCL/gelatin for local drug delivery ^[4][99]. Dox and HANPs were encapsulated at various PCL/Gel ratios (70:30, 60:40, 50:50 wt%). They prepared Dox/HANPs-loaded PCL-Gel composite fibers by electrospinning. The release kinetics of Dox can be shown in two phases: in the first phase, all scaffolds exhibited about 60% burst effect release in the first hour; in the second release stage, the remaining loaded drug can be released within 55 h. Baldino (2018) et al. studied the silver-loaded HANPs being incorporated into PVA membranes obtained by supercritical CO₂ (SC-CO₂) assisted phase inversion ^[5][100]. Their results show that HA-Ag NPs loaded in PVA membranes were more active than the HANPs alone. The bactericidal results show that the Ag⁺ concentration in the HA-Ag NPs can be reduced from 22 ppm to 11 ppm, which has a bacteriostatic effect on E. coli, and the Ag⁺ in the composite membranes can prolong and control its release behavior, which can be used in biomedicine, coating and filter applications.

Kim (2004) et al. prepared HA porous scaffolds by polymeric reticulate method with HA-PCL composite after embedding with the antibiotic drug TCH ^[6][101]. The HA/PCL ratio had a strong effect on release. In a short period (<2 h), about 20–30% of the drug was released. However, the release rate persisted for a long time and was highly dependent on the extent of coating HA/PCL dissolution. Zhang (2021) et al. prepared 3D scaffolds by using PCL/PEO/HA with different HA concentrations by direct ink writing (DIW) ^[7][102]. Vancomycin (VAN) was incorporated into composite scaffolds, and the drug release properties of the composites were investigated. The release kinetics of PCL/PEO/HA samples containing low and high VAN loadings (3% and 9% w/w) were determined in vitro. The VAN-loaded PCL/PEO/HA scaffolds exhibited a first-order immediate release, i.e., a large burst of release within a half hour. In addition to drug concentration and drug–polymer interactions, scaffolds with higher porosity and surface/volume ratio have faster VAN release profile, which can be used for hemostasis and anti-inflammation related to bone tissue applications. Martínez-Vázquez (2015) et al. fabricated Si-doped HA/gelatin porous scaffolds at moderate temperatures by using a rapid prototyping system and analyzed the release profiles of vancomycin from different scaffolds ^[8][103]. Less than 30% of vancomycin was released from the scaffold within 1 h, and the antibiotic release continued for 8 h. Hu (2014) et al. used the anti-inflammatory drug IBU to study the drug release behavior of HA/poly(l-lactic acid) (PLLA) nanocomposite scaffolds ^[9][104]. The IBU loaded in the nanocomposite exhibited a sustained release curve, and the release kinetics followed the Higuchi model with a diffusion process. Zhang (2012) et al. prepared a novel vancomycin (VCM)-loaded M-HA/CS composite scaffold by freeze-drying and used it for in vivo drug release and antibacterial studies ^[10][105]. The results indicated that drug-VCM loaded M-HA/CS composites can release VCM for a long time after implantation in vivo and exhibit effective antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Liang (2021) et al. prepared a composite hydrogel scaffold of HA and sodium alginate (SA) by using 3D printing ^[11][106]. Additives naringin (NG) and calcitonin gene-related peptide (CGRP) were used as osteogenic factors for the fabrication of drug-loaded scaffolds. The HA/SA scaffold can continuously and stably release NG and CGRP until the 21st day, and the drug was mainly released from the large pores of the scaffold to achieve the purpose of bone regeneration.

Bi (2019) et al. investigated the drug loading behavior on HANPs, HANPs/ SA, and HANPs/SA/CS composite ^[12][107] and the drug release behavior of doxorubicin hydrochloride (Dox·HCl)-loaded HANPs/SA/CS microspheres for drug delivery system in phosphate-buffered saline (PBS) solutions with different pH values (pH 7.4, 6.5, and 5.0). The drug loading and encapsulation efficiency of HANPs were 5.9% ± 0.6% and 11.8% ± 1.2%, respectively, which were lower than those of the composite microspheres. This finding might be attributed to the weak electrostatic interaction between HANPs and drug molecules. The 3D network structure of the microspheres helps to load more drugs because the drug molecules are not only absorbed into the 3D network structure of the microspheres but also on the surface of the microspheres. However, the drug loading of HANPs/SA microspheres is higher than that of HANPs/SA/CS microspheres because their surface is coated with a thin film; the film may become an obstacle for drug molecules to be absorbed into the internal structure of the microspheres. The Dox-loaded microspheres showed faster drug release properties with decreasing environment pH. HA and CS were degradable in acidic media, and their different release behavior types were attributed to the different levels of degradability under various medium conditions. Dox-loaded microspheres adopt slow-release behavior, which can be attributed not only to electrostatic interactions between hydroxyl and amine groups but also to the uniform dispersion of HA nanoparticles inside the microspheres and on the surface. Xue (2018) et al. prepared polyvinyl alcohol (PVA)/HA composite microspheres with different HA contents by in situ synthesis and the synergistic effect of emulsification–crosslinking ^[13][108]. In this study, vancomycin hydrochloride (VH) was selected as a model drug to embed in microspheres by immersion. The PVA microspheres have larger swelling degree after proper crosslinking with glutaraldehyde through hydrogen bonding or ionic interactions and have good drug VH encapsulation efficiency and VH loading capacity. He (2021) et al. designed and fabricated microspheres and scaffolds assembled using HA and vancomycin hydrochloride (VH)-loaded polytrimethylene carbonate (PTMC) and PLLA core/shell microspheres ^[14][109]. Combining drugs, active growth substances, and CS in the same microsphere carrier provides sustained long-term release. The drug loading (original encapsulated drug = 2.6 mg) and drug loading efficiency (200 mg) of VH in the microspheres were 1.52 ± 0.06 mg and 58.3% ± 3.9%, respectively. Zhang (2010) et al. prepared pH-sensitive SA/HA nanocomposite beads in sol–gel as drug delivery vehicles, with iclofenac sodium (DS) as a model drug. Factors affecting the swelling behavior, drug loading, and controlled release behavior of SA/HA nanocomposite microspheres were studied in detail. Compared with pure SA hydrogel beads, the SA/HA-DS nanocomposite beads prepared under optimal conditions can prolong the release of DS up to 8 h. Calasans-Maia (2019) et al. prepared alginate-encapsulated nanobicarbonate hydroxyapatite (CHA) microspheres for topical delivery of minocycline (MINO) to inhibit the growth of Enterococcus faecalis ^[15][110]. The amount of MINO adsorbed on the CHA powder depends on the initial concentration of MINO in the solution, the quality of CHA, and the pH of the solution. Adsorption experiments were performed using 1.5 mg/mL MINO in PBS buffer solution (pH = 7.4) containing 50 mg/mL CHA powder. After 24 h, the amount of antibiotic loaded on the CHA powder was 25.1 ± 2.2 µg MINO/mg CHA. The MINO loss of CHA during microsphere processing was about 40%. The MINO release profile of CHA microspheres loaded with 15.1 ± 1.4 µg MINO/mg CHA in PBS buffer was evaluated. A rapid release of approximately 60% of the initially loaded MINO (9.1 µg MINO/mg CHA) was observed within the first 24 h, and the remaining 6.0 µg MINO/mg CHA sustained release was observed over 10 days. Padmanabhan (2018) et al. prepared core–shell nanocomposites with gum–acacia (GA) as shell and HANPs as core for drug delivery and tissue engineering and studied the drug release behavior of naringenin ^[16][111]. The uneven distribution of naringenin in the HANP matrix may result in a rapid release pattern. By contrast, in the case of GA-HA, the colloidal nature of GA helps to bind to naringenin efficiently, allowing for better distribution of the drug throughout the core–shell nanocomposites. Electrospinning, 3D printing, and freeze drying are commonly used to composite HANPs into thin films, regenerated membranes, scaffolds, microspheres, and coatings; drugs can also be loaded according to the composite structure to meet different clinical applications.

Prasanna (2018) et al. synthesized HANPs as nanocarriers for sustained release of the antibiotic amoxicillin for treatment of bone infections. Nanoparticles were then coated on PVA and SA in a layer-by-layer spray coating. Layer-by-layer coating of HANPs/PVA/SA resulted in sustained release of amoxicillin, which was observed for 30 days ^[17][112]. Bose (2018) et al. investigated the influence of PCL coating on alendronate drug release kinetics in vitro ^[18][113]. The results showed that PCL coating would minimize the burst release of alendronate from plasma-sprayed Mg-doped HA coated commercially with pure titanium (cp-Ti). In the absence of PCL coating, about 75% of alendronate was released within the first 12 h. The samples with 2 and 4 wt% PCL coatings exhibited slower burst release, with values of 34% and 26%, respectively. After 24 h, the samples without PCL coating released >75% alendronate. The samples with PCL coating released about 50% alendronate. Kong (2016) et al. used the anticancer drug DOX as a model drug to load into the resulting HANPs-polyethyleneimine (PEI)-hyaluronic acid (HyA) nanoparticles ^[19][114]. DOX@HANPs-PEI-HyA nanoparticles were subjected to buffer solutions with different pH values at 37 °C to examine the DOX release behavior in vitro. The cumulative DOX release percentage of DOX@HANPs-PEI-HyA at pH 7.4 was only 23% over 48 h, while more than 88% DOX release was observed at pH 5.0. Under acidic conditions, the amino group of DOX was protonated, which weakened the adsorption between HANPs and DOX. Meanwhile, PEI was swollen in the acidic environment due to the protonation of amine groups. Therefore, these reasons strongly promote DOX diffusion out of DOX@HANPs-PEI-HyA under acidic conditions. Therefore, this pH-responsive drug release property of DOX@HANPs-PEI-HyA nanoparticles makes it promising for cancer therapy due to the weak acidity of tumor tissues and tumor cells. Numerous studies have highlighted the role of HANPs in promoting the regeneration of tissues with polymers, and Table 1 2 briefly summarizes the different polymer-HA composite morphologies mentioned above.