Gelatin–Sodium Alginate Composite Hydrogel for Sustained Release of Simvastatin Enabled Osteogenic Differentiation

Abstract

Sim, a potent HMG-CoA reductase inhibitor, exhibits notable anabolic effects on bone and can upregulate osteogenic genes such as BMP-2, thereby promoting bone formation. An ideal drug delivery system for Sim involves its controlled and sustained release at the defect site to minimize adverse side effects. In this study, Sim was first modified via HP-γ-CD to form a hydrophilic Sim/HP-γ-CD inclusion complex, thereby improving drug solubility and dispersion in aqueous systems. A gelatin–sodium alginate (Gel/SA) hydrogel was then employed as the drug delivery matrix to construct a Gel-SA-Sim/HP-γ-CD hydrogel sustained release system. This hydrogel system exhibited a high water content (82%), along with enhanced mechanical properties, including a compressive strength of 0.284 MPa and a compressive modulus of 0.277 MPa, suggesting strong load-bearing capacity and favorable stiffness. Importantly, Sim was released in a controlled and sustained manner over 7 days, without exhibiting burst release behavior. In vitro osteogenic differentiation assays demonstrated that optimal concentrations of Sim effectively enhanced cellular bioactivity and osteoinductive performance, offering a promising approach to enhance the bioactivity, osteogenesis, and osseointegration of orthopedic implants.

1. Introduction

Joint implants often exhibit limited capacity to promote bone regeneration due to their chemically homogeneous composition and lack of bioactive factors [1,2]. Well-established osteoinductive growth factors, including transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), and insulin-like growth factor (IGF), play critical roles in regulating bone formation [3,4]. However, their clinical application is constrained by high cost, short half-lives, and challenges in dosage control. For example, excessive administration of bone morphogenetic protein-2 (BMP-2) may cause adverse effects such as ectopic ossification, inflammation, and nerve compression [5], while overexpression of vascular endothelial growth factor (VEGF) may lead to pathological angiogenesis, raising concerns about tumorigenicity [6].

Statins have long been prescribed for cholesterol management and cardiovascular risk reduction. Although accumulating evidence suggests that statins can stimulate bone formation both in vitro and in vivo [7,8], their osteogenic efficacy remains controversial [9], largely due to the low bioavailability of systemic oral administration. Simvastatin (Sim), a naturally derived statin and potent inhibitor of HMG-CoA reductase, has demonstrated promising effects on localized bone regeneration [10]. When locally delivered via poly(lactic acid)-based systems, Sim has been shown to accelerate bone formation and repair [11]. Furthermore, single-dose administration of Sim using Pluronic F127, a thermosensitive hydrogel with low toxicity and immunogenicity, promoted endogenous BMP-2 and VEGF expression and enhanced osteogenesis in ovariectomized miniature pigs [12]. Extensive studies have confirmed the osteoinductive potential of Sim. For instance, Nantavisai et al. [13] found that low-dose Sim enhanced angiogenesis and osteogenic differentiation of bone marrow mesenchymal stem cells, expediting bone regeneration. Deng et al. [14] developed a porous PLA–hyaluronic acid hydrogel coating on PEEK implants to deliver Sim, achieving superior cytocompatibility and osteoinduction in vitro. ALP activity, calcium deposition, and osteogenic gene expression further confirmed the enhanced osteogenic differentiation conferred by Sim-loaded hydrogel surfaces. Similarly, Biouki et al. [15] encapsulated Sim in a PLGA scaffold, demonstrating sustained drug release over 80 days and favorable ALP activity and mineralization outcomes. Zhang et al. [16] incorporated Sim into a biomimetic calcium phosphate system, enabling controlled release and promoting osteogenesis of adipose-derived stem cells. Although Sim exhibits strong anabolic effects on bone by inducing endogenous BMP-2 and VEGF and also possesses anti-inflammatory, osteogenic, and anticancer properties [17], its clinical application is hindered by its poor aqueous solubility as a hydrophobic drug. Efficient drug loading and release strategies remain key challenges for clinical translation.

Hydrogels, a solid–liquid biphasic material with three-dimensional porous networks, are widely used in drug delivery, tissue engineering, and cell culture due to their high biocompatibility [18,19,20]. Gelatin-based hydrogels, in particular, offer low cost, biodegradability, and excellent cytocompatibility, making them attractive for medical applications, including capsules, sponges, scaffolds, and smart hydrogels [21,22,23], and are considered promising carriers for Sim. However, gelatin (Gel) suffers from low mechanical strength and rapid degradation, which limits its capacity to provide sustained drug release. Sodium alginate (SA), a naturally derived linear polysaccharide, possesses excellent biocompatibility and ionically crosslinkable functionality [24]. It mimics the negatively charged glycosaminoglycan microenvironment and complements Gel’s limitations, such as brittleness in pure SA and fast degradation in pure gelatin. In bone regeneration, the Gel-SA composite can effectively emulate the collagen–glycosaminoglycan structure of the natural bone matrix. Nevertheless, the hydrophobicity of Sim often leads to aggregation or precipitation in the hydrophilic hydrogel matrix, compromising its release profile. To overcome this, hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclodextrin derivative with a hydrophilic outer shell and hydrophobic inner cavity, was employed to encapsulate Sim. This inclusion complex enhances Sim’s solubility and stability by accommodating the hydrophobic moiety of Sim inside the cyclodextrin cavity, while its polar groups form hydrogen bonds with HP-γ-CD, further stabilizing the complex [25,26].

In this study, Sim was first modified via HP-γ-CD to form a hydrophilic Sim/HP-γ-CD inclusion complex, thereby improving drug solubility and dispersion in aqueous systems. A gelatin–sodium alginate (Gel/SA) hydrogel was then employed as the drug delivery matrix to construct a Gel-SA-Sim/HP-γ-CD hydrogel sustained release system. The osteogenic potential of this hydrogel system was evaluated in vitro using MC3T3-E1 preosteoblasts. This strategy enables the formation of a bioactive osteoinductive coating at the implant bone interface, offering a promising avenue for enhancing the bioactivity and osteointegration of orthopedic implants.

2. Experiment

2.1. Preparation of the Sim/HP-γ-CD Inclusion Complex

To prepare the Sim/HP-γ-CD inclusion complexes (Figure 1), 1 mg of Sim was added to a glass vial, followed by 1 mL of aqueous HP-γ-CD solution at varying concentrations (0, 4, 6, 8, 10, 12, and 14 mM). The mixture was vigorously shaken at 37 °C for 24 h to facilitate complexation. After incubation, the resulting solution was filtered through a 1 μm PVDF membrane to remove undissolved Sim. The filtrate containing the Sim/HP-γ-CD inclusion complex was collected. To assess the formation efficiency, 100 μL of the filtrate was diluted with 900 μL of methanol, and the absorbance was measured using a UV–visible spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA, Evolution 300).

2.2. Fabrication of the Gel-SA-Sim/HP-γ-CD Sustained Release System

A hydrogel matrix was prepared by dissolving 10 wt% Gel and varying amounts of SA (1, 2, 3, 4, or 5 wt%) in the Sim/HP-γ-CD solution (Figure 2). The mixture was stirred in a water bath at 50 °C for 12 h to ensure homogeneity, followed by ultrasonication to remove air bubbles. The resulting Gel-SA-Sim/HP-γ-CD solution was cast either into molds or directly onto the surface of implant substrates (e.g., sulfonated polyetheretherketone, SPEEK), and incubated at −20 °C for 30 min to solidify. Cross-linking was then performed by immersing the hydrogel in 3 wt% calcium chloride solution for 30 min, yielding Gel-SA-Sim/HP-γ-CD composite hydrogels with different formulations or biofunctionalized implant interfaces coated with the hydrogel.

2.3. Basic Property Characterization

The phase analysis and crystalline state analysis of the Sim/HP-γ-CD inclusion complexes and the Gel-SA-Sim/HP-γ-CD hydrogels were carried out by X-ray diffraction (XRD, D8 ADVANCE, Bruker, Karlsruhe, Germany). The Fourier transform infrared spectroscopy (FT-IR, VTRTEX 80v, Bruker, Ettlingen, Germany) was used to characterize the functional groups of the Sim/HP-γ-CD inclusion complexes and the Gel-SA-Sim/HP-γ-CD hydrogels. The water content and swelling ratio of the hydrogels were measured by weighing.

2.4. Degradation Behavior of Hydrogels

The degradation performance of the hydrogel was assessed by monitoring its mass loss over time under physiological conditions. Fully swollen hydrogel samples were first prepared by incubating them in phosphate-buffered saline (PBS) at 37 °C until equilibrium swelling was achieved. The surface water was then gently removed using filter paper, and the initial wet weight was recorded as W. Subsequently, the hydrogels were immersed in fresh PBS and incubated at 37 °C. At predetermined time points (e.g., days 1, 2, 3, 4, etc.), the samples were retrieved, surface PBS was blotted off, and the weight at each time point was measured and recorded as W_t. The degradation ratio (DR) was calculated according to the following equation: DR = (W − W_t)/W.

2.5. Mechanical Properties

The compression test was carried out by a WDW-2 microcomputer-controlled electronic universal testing machine. A 10 mm × 10 mm × 4 mm cubic hydrogel was used as the compression specimen. In the compression test, the speed of the load was 2 mm/min, and the compressive strength was defined as the stress when the compressive strain reached 50%. The compressive modulus was calculated from the straight-line region of the stress–strain curve where the strain is in the range of 20%–30%.

2.6. Cell Biocompatibility

MC3T3E1 cells were used to evaluate the cytocompatibility of the Gel-SA-Sim/HP-γ-CD hydrogel sustained release system. The CCK-8 test was used to quantitatively analyze the cytotoxicity and proliferation ability of the hydrogels to MC3T3E1 cells. A live/dead staining test was used to observe the growth of cells.

2.7. In Vitro Osteogenic Differentiation

2.7.1. ALP Staining

MC3T3-E1 cells at a concentration of 2 × 104 cells/mL were co-cultured with the Gel-SA-Sim/HP-γ-CD hydrogels for 24 h. The growth medium was replaced with osteogenic induction medium, and after 7 days of induction, cells adhered to the hydrogels were lysed using Western and IP cell lysis buffer (without inhibitors). An alkaline phosphatase assay kit (Beyotime, Haimen, China) was used to evaluate the ALP activity in the cell lysates.

2.7.2. ARS Staining

MC3T3-E1 cells were co-cultured with the Gel-SA-Sim/HP-γ-CD hydrogels in osteogenic induction medium for 21 days. Cells were then removed from the hydrogels, gently washed twice with PBS buffer, fixed with 4% paraformaldehyde for 20 min, washed three times with PBS buffer again, and stained using Alizarin red S (ARS) staining solution with a PH of 4.2.

2.8. Osteogenic Gene Expression

In the process of natural bone formation, ALP, RUNX2, and OPN are genes closely related to osteogenic differentiation, and their expression reflects the degree of osteoblast differentiation. The samples were co-cultured with MC3T3E1 cells in vitro for 1, 2, 3, and 4 weeks and then removed, and the expression of osteogenic genes (ALP, RUNX2, OPN) of MC3T3E1 on the PEEK materials was quantitatively analyzed using real-time quantitative polymerase chain reaction (RT-qPCR).

3. Results and Discussion

3.1. Characterization and Optimization of the Sim/HP-γ-CD Inclusion Complexes

Figure 3a presents the FT-IR spectra of Sim, HP-γ-CD, and Sim/HP-γ-CD inclusion complex. Characteristic absorption bands of pure Sim were observed at approximately 3520 cm⁻¹ and 3541 cm⁻¹, corresponding to hydroxyl groups (–OH), 2900 cm⁻¹ and 2967 cm⁻¹, corresponding to alkyl groups (C–H), 1698 cm⁻¹, indicating a strong carbonyl group (C=O), and at 1170 cm⁻¹ and 1263 cm⁻¹, representing ester groups (C–O). HP-γ-CD exhibited distinct absorption peaks at 3420 cm⁻¹, corresponding to –OH, 2920 cm⁻¹, attributed to C–H, and strong peaks at 1026 cm⁻¹ and 1160 cm⁻¹ related to the cyclodextrin backbone (C–O–C). The FT-IR spectrum of the Sim/HP-γ-CD inclusion complex (1632 cm⁻¹) showed shifts and changes in the hydroxyl peaks of both Sim (1638 cm⁻¹) and HP-γ-CD (1640 cm⁻¹), suggesting hydrogen bonding interactions between them. Additionally, the intensity of the C=O of Sim was reduced, indicating interaction and encapsulation within HP-γ-CD. Moreover, spectral changes and shifts observed in peaks of 500–1500 cm⁻¹ imply alterations in the chemical environment due to intermolecular interactions.

Figure 3b shows the XRD patterns of Sim, HP-γ-CD, and the Sim/HP-γ-CD inclusion complex. Sim exhibited distinct crystalline diffraction peaks of 5–30°, characterized by multiple sharp peaks. HP-γ-CD displayed characteristic diffraction peaks around 10° and 20°. However, in the XRD pattern of the Sim/HP-γ-CD complex, the crystalline peaks of Sim disappeared entirely, indicating that Sim transitioned from a crystalline to an amorphous form upon encapsulation within the HP-γ-CD cavity. Furthermore, the diffraction peaks of the inclusion complex exhibited positional shifts relative to pure HP-γ-CD. Collectively, these observations confirm the successful formation of the inclusion complex, with HP-γ-CD effectively disrupting the crystalline structure of Sim.

The optimal inclusion ratio between Sim and HP-γ-CD was investigated by preparing Sim/HP-γ-CD inclusion complexes through a saturated aqueous solution method with varying concentrations of HP-γ-CD (0, 4, 6, 8, 10, 12, and 14 mM). Figure 4a demonstrates the changes in Sim absorbance at different HP-γ-CD concentrations. The absorbance indirectly reflects the inclusion efficiency and host–guest binding ratio, where higher absorbance indicates stronger inclusion interactions and improved solubility of Sim. Figure 4a indicates a significant increase in Sim absorbance as the HP-γ-CD concentration rose from 0 to 8 mM, peaking at 8 mM, which suggests the formation of optimal inclusion complexes and maximum efficiency at this concentration. The enhanced absorbance at 8 mM is likely due to the near-stoichiometric 1:1 host–guest ratio, enabling efficient encapsulation of Sim molecules within the cyclodextrin cavity, thereby substantially enhancing the apparent solubility of Sim. Conversely, absorbance decreased with further increases in HP-γ-CD concentration beyond 8 mM, possibly due to competitive cavity binding or aggregation phenomena among excess cyclodextrin molecules. Thus, 8 mM HP-γ-CD was identified as the optimal concentration, maximizing Sim encapsulation efficiency while preventing unnecessary material waste.

Based on the absorbance data, Figure 4b shows the fitted solubility of Sim at varying HP-γ-CD concentrations, providing a reference for subsequent biological evaluations. The results demonstrate that at 0 mM HP-γ-CD, Sim exhibited minimal solubility (approximately 0.02 mg/mL), and Sim solubility increased significantly with rising HP-γ-CD concentration, reaching a maximum at 8 mM. Beyond this concentration, Sim solubility approached saturation, showing negligible further improvement, suggesting a threshold to the solubility-enhancing capacity of HP-γ-CD. The substantial increase in Sim solubility achieved by HP-γ-CD inclusion may improve its bioavailability and therapeutic efficacy.

3.2. Optimization of the Gel-SA-Sim/HP-γ-CD Hydrogel Sustained Release System

The Gel-SA-Sim/HP-γ-CD hydrogel sustained release system was prepared by combining 8 μM HP-γ-CD with Sim, Gel, and varying concentrations of SA, with SA content optimized based on degradation performance. Figure 5a shows the FT-IR spectra of the Gel-SA-Sim/HP-γ-CD hydrogels. For the Sim/HP-γ-CD inclusion complex, a broad absorption band at 3250 cm⁻¹ corresponds to –OH, peaks at 2935 cm⁻¹ are attributed to C–H stretching, strong peaks at 1748 cm⁻¹ and 1630 cm⁻¹ arise from C=O groups, and absorption at 1148 cm⁻¹ and 1028 cm⁻¹ reflects C–O–C bonds from the cyclodextrin skeleton and ester bonds of Sim. In the FT-IR spectrum of Gel, bands at 3281 cm⁻¹, 2918 cm⁻¹, 1617 cm⁻¹, and 1540 cm⁻¹ correspond to amide A (N–H stretching), C–H stretching, amide I (C=O stretching), and amide II (N–H bending) vibrations, respectively. The FT-IR spectrum of SA shows a broad –OH peak at 3300 cm⁻¹, a carboxylate (COO⁻) peak at 1580 cm⁻¹, and a C–O–C stretching peak at 1016 cm⁻¹. Moreover, the FT-IR spectrum of the Gel-SA-Sim/HP-γ-CD hydrogels exhibits a broadened –OH peak at 3250 cm⁻¹ and 1630 cm⁻¹, suggesting hydrogen bonding among Sim, HP-γ-CD, Gel, and SA. The observed shifts in the amide I and II bands (1538 and 1630 cm⁻¹) further indicate molecular interactions between Gel and the other components. The variation in the carboxylate peak at 1580 cm⁻¹ reflects ionic cross-linking of SA with Ca²⁺ ions.

Figure 5b displays the XRD patterns of the Gel-SA-Sim/HP-γ-CD hydrogels. The inclusion complex shows a sharp diffraction peak around 2θ = 20°, indicating that Sim transitions from a crystalline to an amorphous state upon encapsulation within HP-γ-CD cavities. Gel presents a broad halo around 2θ = 20°, while SA shows a similar diffuse peak near 10°. In the composite hydrogel, only a broad amorphous peak near 25° remains, with the disappearance of Sim’s sharp crystalline peaks, confirming uniform dispersion of Sim within the hydrogel matrix.

Figure 5c illustrates the degradation profiles of Gel/SA hydrogels (with 10 wt% Gel) containing varying SA concentrations. Hydrogels with 1% SA fully degraded by day 4, 2% SA by day 6, and 3% SA by day 7. These differences are attributed to cross-linking density: at low SA content, the hydrogel network is loose and degrades rapidly due to gelatin enzymolysis. At moderate SA content, both ionic exchange of SA and enzymatic degradation of Gel contribute to a balanced degradation rate. At high SA concentrations, the hydrogel exhibits dense cross-linking and slow degradation, primarily governed by ionic exchange of SA. To achieve the target degradation period of 7 days, 3% SA was selected for the preparation of Gel-SA-Sim/HP-γ-CD hydrogels in subsequent experiments.

3.3. Characterization of the Gel-SA-Sim/HP-γ-CD Hydrogel Sustained Release System

Figure 6a–c present the compressive performance of the Gel-SA-Sim/HP-γ-CD hydrogels. The hydrogel containing 0.1 μM Sim exhibits the higher compressive strength (0.284 MPa) and compressive modulus (0.277 MPa), suggesting stronger load-bearing capacity and greater stiffness, whereas the 1.0 μM Sim hydrogel demonstrates the lower compressive strength and modulus. Generally, higher cross-linking density in hydrogels corresponds to enhanced mechanical properties. The hydrophobicity of Sim reduces the hydrogel’s cross-linking density and significantly affects compressive performance. At 0.1 μM, Sim concentration is low and exerts minimal influence on cross-linking density. Thus, the mechanical behavior is primarily governed by Gel and SA components, resulting in high compressive strength and modulus. However, at 1.0 μM, increased hydrophobicity leads to decreased cross-linking density and diminished mechanical performance. Therefore, 0.1 μM Sim hydrogels are better suited for load-bearing bone tissue repair, whereas 1.0 μM Sim hydrogels may be more applicable as soft tissue scaffolds or drug delivery vehicles.

Figure 6d,e show the swelling behavior and the water content of the Gel-SA-Sim/HP-γ-CD hydrogels. Sim content does not significantly affect either swelling or water retention. During the first 1000 min, hydrogels undergo a rapid swelling phase due to the hydrophilic components Gel and SA. After 1000 min, the swelling rate slows, indicating that the hydrogels are approaching equilibrium, largely influenced by the internal network structure. At around 2000 min, swelling reaches equilibrium with stable water content at approximately 82%, demonstrating excellent water retention.

Figure 6f displays the release profile of Sim from the Gel-SA-Sim/HP-γ-CD hydrogels, which shows a stable and sustained drug release over 168 h, with no evidence of burst release. The Sim release process can be divided into three stages: an initial burst release stage (0–20 h), which surface-bound Sim is rapidly released, reaching 35.54% cumulative release, a slow-release stage (20–120 h), which Sim diffuses through the hydrogel matrix and HP-γ-CD, achieving 92.91% cumulative release, and a final plateau stage (120–168 h), where the release rate declines and the drug is completely released.

The release mechanism of the Gel-SA-Sim/HP-γ-CD hydrogel sustained release system is governed by a combination of diffusion, swelling, and degradation. Diffusion enables Sim transport through hydrogel pores, swelling increases permeability as the network relaxes, and degradation contributes by breaking down the matrix in physiological conditions. Encapsulation within HP-γ-CD not only enhances Sim dispersion within the hydrogel but also mitigates localized high concentrations, thereby improving bioavailability.

3.4. Cell Biocompatibility of the Gel-SA-Sim/HP-γ-CD Hydrogel Sustained Release System

Figure 7 evaluates the cell biocompatibility of the Gel-SA-Sim/HP-γ-CD hydrogel sustained release system loaded with 0.1 μM and 1.0 μM Sim. Figure 7a shows that the OD values increase with time, and proliferation accelerates significantly after 4 days. Hydrogels with 0.1 μM Sim promote notable cell proliferation, whereas 1.0 μM Sim reduces proliferation, possibly due to inhibition of HMG-CoA reductase, which affects membrane formation and post-translational protein modification. Thus, 0.1 μM Sim appears to provide the most favorable bioactivity for supporting MC3T3-E1 adhesion and growth.

Figure 7b further verifies cell viability through live/dead staining after 7 days of co-culture. All samples support significant cell adhesion, with the majority being live cells (green fluorescence) and negligible cell death (red fluorescence). As culture time increases, cell density rises, with the 0.1 μM Sim group showing the highest density of viable cells. These results confirm that moderate Sim levels (0.1 μM) promote osteoblast proliferation, while higher concentrations (1.0 μM) may be cytotoxic and inhibit growth.

3.5. In Vitro Osteogenic Differentiation of the Gel-SA-Sim/HP-γ-CD Hydrogel Sustained Release System

Figure 8 shows the ALP staining results after 14 days of co-culture between MC3T3-E1 cells and the Gel-SA-SIM/HP-γ-CD hydrogels loaded with 0.1 μM and 1.0 μM Sim. ALP activity of the Gel-SA-SIM/HP-γ-CD hydrogel with 0.1 μM Sim increased from 5.39 to 6.25, representing a 15.96% enhancement compared to the control group with 0 μM Sim, which exhibited the strongest enzymatic activity, with dense cellular distribution and intense staining. However, when the Sim concentration was increased to 1.0 μM, ALP activity dropped markedly to 4.76, with reduced cell density and lighter staining, indicating that Sim at 0.1 μM optimally promotes osteogenic differentiation by enhancing ALP activity.

Figure 9 presents the Alizarin red S staining of MC3T3-E1 cells cultured with the Gel-SA-SIM/HP-γ-CD hydrogels for 14 days. The 0.1 μM Sim-loaded hydrogel group demonstrated the most abundant and deeply stained orange-red mineralized nodules, indicating enhanced osteogenic capacity. In contrast, the group with 1.0 μM Sim exhibited fewer mineralized nodules and lighter staining, suggesting an inhibitory effect at higher Sim concentrations.

Figure 10 illustrates the expression levels of osteogenic genes (ALP, OPN, and RUNX2) after 1, 2, 3, and 4 weeks of culture with the hydrogel system. In the group loaded with 0.1 μM Sim, gene expression levels were significantly upregulated: ALP by 3.87%, OPN by 6.08%, and RUNX2 by 17.92% compared to the control group with 0 μM Sim. However, increasing Sim concentration to 1.0 μM led to a decrease in the expression of all three osteogenic markers, indicating a dose-dependent suppression of gene expression at higher concentrations.

On the one hand, Sim promotes osteoblast differentiation by upregulating BMP-2, a key regulator of osteogenesis. BMP-2 activates Runx2, a critical transcription factor that drives osteoblast maturation and bone formation. On the other hand, Sim also facilitates mesenchymal stem cell (MSC) differentiation into osteoblasts via activation of the Wnt/β-catenin signaling pathway, thereby increasing osteoblast numbers. Moreover, Sim enhances matrix mineralization by stimulating ALP activity and upregulating osteocalcin (OCN), collectively promoting extracellular matrix mineralization and bone regeneration.

4. Conclusions

In this study, Sim was first modified via HP-γ-CD to form a hydrophilic Sim/HP-γ-CD inclusion complex, thereby improving drug solubility and dispersion in aqueous systems. A gelatin–sodium alginate (Gel/SA) hydrogel was then employed as the drug delivery matrix to construct a Gel-SA-Sim/HP-γ-CD hydrogel sustained release system. This hydrogel system exhibited a high water content (82%), along with enhanced mechanical properties, including a compressive strength of 0.284 MPa and a compressive modulus of 0.277 MPa, suggesting strong load-bearing capacity and favorable stiffness. Importantly, Sim was released in a controlled and sustained manner over 7 days, without exhibiting burst release behavior. In vitro osteogenic differentiation assays demonstrated that optimal concentrations of Sim effectively enhanced cellular bioactivity and osteoinductive performance. Specifically, ALP activity increased by 15.96%, the formation of mineralized nodules was significantly promoted, and the expression of osteogenic genes ALP, OPN, and RUNX2 was upregulated by 3.87%, 6.08%, and 17.92%, respectively.