A multifunctional ionic liquid coating on 3D-Printed prostheses: Combating infection, promoting osseointegration.

Periprosthetic infection and mechanical loosening are two leading causes of implant failure in orthopedic surgery that have devastating consequences for patients both physically and financially. Hence, advanced prostheses to simultaneously prevent periprosthetic infection and promote osseointegration are highly desired to achieve long-term success in orthopedics. In this study, we proposed a multifunctional three-dimensional printed porous titanium alloy prosthesis coated with imidazolium ionic liquid. The imidazolium ionic liquid coating exhibited excellent bacterial recruitment property and near-infrared (NIR) triggered photothermal bactericidal activity, enabling the prosthesis to effectively trap bacteria in its vicinity and kill them remotely via tissue-penetrating NIR irradiation. In vivo anti-infection and osseointegration investigations in infected animal models confirmed that our antibacterial prosthesis could provide long-term and sustainable prevention against periprosthetic infection, while promoting osseointegration simultaneously. It is expected to accelerate the development of next-generation prostheses and improve patient outcomes after prosthesis implantation.

AI energized hydrogel design, optimization and application in biomedicine.

Traditional hydrogel design and optimization methods usually rely on repeated experiments, which is time-consuming and expensive, resulting in a slow-moving of advanced hydrogel development. With the rapid development of artificial intelligence (AI) technology and increasing material data, AI-energized design and optimization of hydrogels for biomedical applications has emerged as a revolutionary breakthrough in materials science. This review begins by outlining the history of AI and the potential advantages of using AI in the design and optimization of hydrogels, such as prediction and optimization of properties, multi-attribute optimization, high-throughput screening, automated material discovery, optimizing experimental design, and etc. Then, we focus on the various applications of hydrogels supported by AI technology in biomedicine, including drug delivery, bio-inks for advanced manufacturing, tissue repair, and biosensors, so as to provide a clear and comprehensive understanding of researchers in this field. Finally, we discuss the future directions and prospects, and provide a new perspective for the research and development of novel hydrogel materials for biomedical applications.

bay/ortho-Octa-substituted Perylene: A Versatile Building Block toward Novel Polycyclic (Hetero)Aromatic Hydrocarbons.

ConspectusPolycyclic (hetero)aromatic hydrocarbons (PAHs) have emerged as a focal point in current interdisciplinary research, spanning the realms of chemistry, physics, and materials science. Possessing distinctive optical, electronic, and magnetic properties, these π-functional materials exhibit significant potential across diverse applications, including molecular electronic devices, organic spintronics, and biomedical functions, among others. Despite the extensive documentation of various PAHs over the decades, the efficient and precise synthesis of π-extended PAHs remains a formidable challenge, hindering their broader application. This challenge is primarily attributed to the intricate and often elusive nature of their synthesis, compounded by issues related to low solubility and unfavored stability.The development of π-building blocks that can be facilely and modularly transformed into diverse π-frameworks constitutes a potent strategy for the creation of novel PAH materials. For instance, based on the classic perylene diimide (PDI) unit, researchers such as Würthner, Wang, and Nuckolls have successfully synthesized a plethora of structurally diverse PAHs, as well as numerous other π-functional materials. However, until now the availability of such versatile building blocks is still severely limited, especially for those simultaneously having a facile preparation process, adequate solubilizing groups, favored material stability, and critically, rich possibilities for structural extension spaces.In this Account, we present an overview of our invention of a highly versatile bay-/ortho-octa-substituted perylene building block, designated as Per-4Br, for the construction of a series of novel PAH scaffolds with tailor-made structures and rich optoelectronic and magnetic properties. First, starting with a brief discussion of current challenges associated with the bottom-up synthesis of π-extended PAHs, we rationalize the key features of Per-4Br that enable facile access to new PAH molecules including its ease of large-scale preparation, favored material stability and solubility, and multiple flexible reaction sites, with a comparison to the PDI motif. Then, we showcase our rational design and sophisticated synthesis of a body of neutral or charged, closed- or open-shell, curved, or planar PAHs via controlled annulative π-extensions in different directions such as peripheral, diagonal, or multiple dimensions of the Per-4Br skeleton. In this part, the fundamental structure-property relationships between molecular conformations, electronic structures, and self-assembly behaviors of these PAHs and their unique physiochemical properties such as unusual open-shell ground states, global aromaticity, state-associated/stimuli-responsive magnetic activity, and charge transport characteristics will be emphatically elaborated. Finally, we offer our perspective on the continued advancement of π-functional materials based on Per-4Br, which, we posit, may stimulate heightened research interest in the versatile structural motifs typified by Per-4Br, consequently catalyzing further progress in the realm of organic π-functional materials.

Dual-network DNA-silk fibroin hydrogels with controllable surface rigidity for regulating chondrogenic differentiation.

Osteoarthritis (OA) is a common joint disease known for cartilage degeneration, leading to a substantial burden on individuals and society due to its high disability rate. However, current clinical treatments for cartilage defects remain unsatisfactory due to the unclear mechanisms underlying cartilage regeneration. Tissue engineering hydrogels have emerged as an attractive approach in cartilage repair. Recent research studies have indicated that stem cells can sense the mechanical strength of hydrogels, thereby regulating their differentiation fate. In this study, we present the groundbreaking construction of dual-network DNA-silk fibroin (SF) hydrogels with controllable surface rigidity. The supramolecular networks, formed through DNA base-pairing, induce the development of ß-sheet structures by constraining and aggregating SF molecules. Subsequently, SF was cross-linked via horseradish peroxidase (HRP)-mediated enzyme reactions to form the second network. Experimental results demonstrated a positive correlation between the surface rigidity of dual-network DNA-SF hydrogels and the DNA content. Interestingly, it was observed that dual-network DNA-SF hydrogels with moderate surface rigidity exhibited the highest effectiveness in facilitating the migration of bone marrow mesenchymal stem cells (BMSCs) and their chondrogenic differentiation. Transcriptome sequencing further confirmed that dual-network DNA-SF hydrogels primarily enhanced chondrogenic differentiation of BMSCs by upregulating the Wnt and TGF-ß signaling pathways while accelerating collagen II synthesis. Furthermore, in vivo studies revealed that dual-network DNA-SF hydrogels with moderate surface rigidity significantly accelerated cartilage regeneration. In summary, the dual-network DNA-SF hydrogels represent a promising and novel therapeutic strategy for cartilage regeneration.

3D-printed PCL scaffolds with anatomy-inspired bionic stratified structures for the treatment of growth plate injuries.

The growth plate is a cartilaginous tissue with three distinct zones. Resident chondrocytes are highly organized in a columnar structure, which is critical for the longitudinal growth of immature long bones. Once injured, the growth plate may potentially be replaced by bony bar formation and, consequently, cause limb abnormalities in children. It is well-known that the essential step in growth plate repair is the remolding of the organized structure of chondrocytes. To achieve this, we prepared an anatomy-inspired bionic Poly(ε-caprolactone) (PCL) scaffold with a stratified structure using three-dimensional (3D) printing technology. The bionic scaffold is engineered by surface modification of NaOH and collagen Ⅰ (COL Ⅰ) to promote cell adhesion. Moreover, chondrocytes and bone marrow mesenchymal stem cells (BMSCs) are loaded in the most suitable ratio of 1:3 for growth plate reconstruction. Based on the anatomical structure of the growth plate, the bionic scaffold is designed to have three regions, which are the small-, medium-, and large-pore-size regions. These pore sizes are used to induce BMSCs to differentiate into similar structures such as the growth plate. Remarkably, the X-ray and histological results also demonstrate that the cell-loaded stratified scaffold can successfully rebuild the structure of the growth plate and reduce limb abnormalities, including limb length discrepancies and angular deformities in vivo. This study provides a potential method of preparing a bioinspired stratified scaffold for the treatment of growth plate injuries.

Bisphosphonate-incorporated coatings for orthopedic implants functionalization.

Bisphosphonates (BPs), the stable analogs of pyrophosphate, are well-known inhibitors of osteoclastogenesis to prevent osteoporotic bone loss and improve implant osseointegration in patients suffering from osteoporosis. Compared to systemic administration, BPs-incorporated coatings enable the direct delivery of BPs to the local area, which will precisely enhance osseointegration and bone repair without the systemic side effects. However, an elaborate and comprehensive review of BP coatings of implants is lacking. Herein, the cellular level (e.g., osteoclasts, osteocytes, osteoblasts, osteoclast precursors, and bone mesenchymal stem cells) and molecular biological regulatory mechanism of BPs in regulating bone homeostasis are overviewed systematically. Moreover, the currently available methods (e.g., chemical reaction, porous carriers, and organic material films) of BP coatings construction are outlined and summarized in detail. As one of the key directions, the latest advances of BP-coated implants to enhance bone repair and osseointegration in basic experiments and clinical trials are presented and critically evaluated. Finally, the challenges and prospects of BP coatings are also purposed, and it will open a new chapter in clinical translation for BP-coated implants.

Biomimetic Nanozyme-Decorated Hydrogels with H2O2-Activated Oxygenation for Modulating Immune Microenvironment in Diabetic Wound.

Diabetic foot ulcers (DFUs) remain a devastating threat to human health. While hydrogels are promising systems for DFU-based wound management, their effectiveness is often hindered by the immune response and hostile wound microenvironment associated with the uncontrollable accumulation of reactive oxygen species and hypoxia. Here, we develop a therapeutic wound dressing using a biomimetic hydrogel system with the decoration of catalase-mimic nanozyme, namely, MnCoO@PDA/CPH. The hydrogel can be designed to match the mechanical and electrical cues of skins simultaneously with H2O2-activated oxygenation ability. As a proof of concept, DFU-based rat models are created to validate the therapeutic efficacy of the MnCoO@PDA/CPH hydrogel in vivo. The results indicate that the developed hydrogel can promote DFU healing and improve the quality of the healed wound as featured by alleviated proinflammatory, increased re-epithelialization, highly ordered collagen deposition, and functional blood vessel growth.

Functionalization of biomimetic mineralized collagen for bone tissue engineering.

Mineralized collagen (MC) is the basic unit of bone structure and function and is the main component of the extracellular matrix (ECM) in bone tissue. In the biomimetic method, MC with different nanostructures of neo-bone have been constructed. Among these, extra-fibrous MC has been approved by regulatory agencies and applied in clinical practice to play an active role in bone defect repair. However, in the complex microenvironment of bone defects, such as in blood supply disorders and infections, MC is unable to effectively perform its pro-osteogenic activities and needs to be functionalized to include osteogenesis and the enhancement of angiogenesis, anti-infection, and immunomodulation. This article aimed to discuss the preparation and biological performance of MC with different nanostructures in detail, and summarize its functionalization strategy. Then we describe the recent advances in the osteo-inductive properties and multifunctional coordination of MC. Finally, the latest research progress of functionalized biomimetic MC, along with the development challenges and future trends, are discussed. This paper provides a theoretical basis and advanced design philosophy for bone tissue engineering in different bone microenvironments.

Nanozyme-reinforced hydrogel as a H2O2-driven oxygenerator for enhancing prosthetic interface osseointegration in rheumatoid arthritis therapy.

Stem cell-based therapy has drawn attention for enhancing the osseointegration efficiency after joint replacement in the rheumatoid arthritis (RA). However, therapeutic efficacy of this approach is threatened by the accumulated reactive oxygen species (ROS) and poor oxygen supply. Herein, we develop a nanozyme-reinforced hydrogel for reshaping the hostile RA microenvironment and improving prosthetic interface osseointegration. The engineered hydrogel not only scavenges endogenously over-expressed ROS, but also synergistically produces dissolved oxygen. Such performance enables the hydrogel to be utilized as an injectable delivery vehicle of bone marrow-derived mesenchymal stem cells (BMSCs) to protect implanted cells from ROS and hypoxia-mediated death and osteogenic limitation. This nanozyme-reinforced hydrogel encapsulated with BMSCs can alleviate the symptoms of RA, including suppression of local inflammatory cytokines and improvement of osseointegration. This work provides a strategy for solving the long-lasting challenge of stem cell transplantation and revolutionizes conventional intervention methods for improving prosthetic interface osseointegration in RA.

A novel AIEgen photosensitizer with an elevated intersystem crossing rate for tumor precise imaging and therapy.

Herein, we have designed and synthesized a quinolinyl-AIE photosensitizer (TPE-4QL+) with an alternative elevated intersystem crossing (ISC) rate, which exhibits not only highly efficient photosensitivity but also high tumor cell specificity and an excellent mitochondrial targeting ability. In vitro experiments indicate that using TPE-4QL+ as a photosensitizer can induce a series of tumor cells to die with a low dose of radiation, but with no obvious toxicity to normal cells. The in vivo studies on a mouse model bearing a subcutaneous 4T1 xenograft also show that TPE-4QL+ can be used with high efficiency as a photosensitizer in PDT.

Temperature-Resistant Intrinsic High Dielectric Constant Polyimides: More Flexibility of the Dipoles, Larger Permittivity of the Materials.

High dielectric constant polymers have been widely studied and concerned in modern industry, and the induction of polar groups has been confirmed to be effective for high permittivity. However, the way of connection of polar groups with the polymer backbone and the mechanism of their effect on the dielectric properties are unclear and rarely reported. In this study, three polyimides (C0-SPI, C1-SPI, and C2-SPI) with the same rigid backbone and different linking groups to the dipoles were designed and synthesized. With their rigid structure, all of the polyimides show excellent thermal stability. With the increase in the flexibility of linking groups, the dielectric constant of C0-SPI, C1-SPI, and C2-SPI enhanced in turn, showing values of 5.6, 6.0, and 6.5 at 100 Hz, respectively. Further studies have shown that the flexibility of polar groups affected the dipole polarization, which was positively related to the dielectric constant. Based on their high permittivity and high temperature resistance, the polyimides exhibited outstanding energy storage capacity even at 200 °C. This discovery reveals the behavior of the dipoles in polymers, providing an effective strategy for the design of high dielectric constant materials.

A Nanozyme-Immobilized Hydrogel with Endogenous ROS-Scavenging and Oxygen Generation Abilities for Significantly Promoting Oxidative Diabetic Wound Healing.

Non-healing wound is a common complication of diabetic patients associated with high morbidity and mortality. Engineered therapeutic hydrogels have enviable advantages in tissue regeneration, however, they are suboptimal for the healing of diabetic wounds characterized by reactive oxygen species (ROS) accumulation and chronic hypoxia. Here, a unique biological metabolism-inspired hydrogel, for ameliorating this hostile diabetic microenvironment, is presented. Consisting of natural polymers (hydrazide modified hyaluronic acid and aldehyde modified hyaluronic acid) and a metal-organic frameworks derived catalase-mimic nanozyme (ε-polylysine coated mesoporous manganese cobalt oxide), the engineered nanozyme-reinforced hydrogels can not only capture the endogenous elevated ROS in diabetic wounds, but also synergistically produce oxygen through the ROS-driven oxygen production ability. These fascinating properties of hydrogels protect skin cells (e.g., keratinocytes, fibroblasts, and vascular endothelial cells) from ROS and hypoxia-mediated death and proliferation inhibition. Diabetic wounds treated with the nanozyme-reinforced hydrogels highlight the potential of inducing the macrophages polarization from pro-inflammatory phenotype (M1) to anti-inflammatory subtype (M2). The hydrogel dressings demonstrate a prominently accelerated healing rate as shown by alleviating the excessive inflammatory, inducing efficiently proliferation, re-epithelialization, collagen deposition, and neovascularization. This work provides an effective strategy based on nanozyme-reinforced hydrogel as a ROS-driven oxygenerator for enhancing diabetic wound healing.

A smart hydrogel patch with high transparency, adhesiveness and hemostasis for all-round treatment and glucose monitoring of diabetic foot ulcers.

The treatment and management of diabetic foot ulcers (DFUs) is a pretty intractable problem for clinical nursing. Urgently, the "Black Box" status of the healing process prevents surgeons from providing timely analysis for more effective diagnosis and therapy of the wound. Herein, we designed a transparent monitoring system to treat and manage the DFUs with blood oozing and hard-healing, which resolved the problem of blind management for the other conductive patches. This system was prepared from a conductive hydrogel patch with ultra-high transparence (up to 93.6%), adhesiveness and hemostasis, which is engineered by assembling in situ formed poly(tannic acid) (PTA)-doped polypyrrole (PPy) nanofibrils in the poly(acrylamide-acrylated adenine) (P(AM-Aa)) polymer networks. Significantly, the high transparent conductive hydrogel patch can monitor the wound-healing status visually and effectively promote the healing of DFUs by accelerating hemostasis, improving communication between cells, preventing wound infection, facilitating collagen deposition, and promoting angiogenesis. In addition, the versatile hydrogel patch could realize indirect blood glucose monitoring by detecting the glucose levels on wounds, and further sense the movements with different magnitudes of human body timely. This research may provide a novel strategy in the design of chronic wound dressings for monitoring and treating the wounds synergistically.

Lotus Seedpod-Inspired Crosslinking-Assembled Hydrogels Based on Gold Nanoclusters for Synergistic Osteosarcoma Multimode Imaging and Therapy.

Osteosarcoma is difficult to be resected through surgical operations without damage to the bone matrix, while chemotherapy and radiotherapy induce inevitable systemic injury. It is still a major challenge to develop a novel treatment suitable for the complex anatomical structure of the bone. Herein, inspired by lotus seedpods, injectable hydrogels with long-term retention for synergistic osteosarcoma treatment were developed. Gold nanoclusters (GNCs) with strong fluorescence (FL) and computed tomography (CT) imaging effects represented the lotus seeds. The oxidized hyaluronic acid (HA-ALD) chain resembled the stem. HA-ALD and GNCs form crosslinking-assembled hydrogels abbreviated as HG-CAHs through dynamic amide bonds. Compared with DNA-, pH-, and light-mediated assembly, this in situ method induces enhanced photothermal therapy (PTT) ability, ensures high biocompatibility, and retains the imaging function of GNCs, which contribute to lighting up osteosarcoma persistently for further diagnosis and treatment. In addition, the HG-CAHs with outstanding mechanical properties are similar to the lotus seedpods with supportive force and a typical porous structure. They are favorable for the local pH- and near-infrared (NIR)-responsive release of doxorubicin (Dox) owing to the acidic osteosarcoma microenvironment and the Brownian movement. The HG-CAHs ablate osteosarcoma efficiently and reduce metabolic toxicity significantly, which will aid in the development of a new generation of osteosarcoma treatments.

Biomaterials for Interbody Fusion in Bone Tissue Engineering.

In recent years, interbody fusion cages have played an important role in interbody fusion surgery for treating diseases like disc protrusion and spondylolisthesis. However, traditional cages cannot achieve satisfactory results due to their unreasonable design, poor material biocompatibility, and induced osteogenesis ability, limiting their application. There are currently 3 ways to improve the fusion effect, as follows. First, the interbody fusion cage is designed to facilitate bone ingrowth through the preliminary design. Second, choose interbody fusion cages made of different materials to meet the variable needs of interbody fusion. Finally, complete post-processing steps, such as coating the designed cage, to achieve a suitable osseointegration microstructure, and add other bioactive materials to achieve the most suitable biological microenvironment of bone tissue and improve the fusion effect. The focus of this review is on the design methods of interbody fusion cages, a comparison of the advantages and disadvantages of various materials, the influence of post-processing techniques and additional materials on interbody fusion, and the prospects for the future development of interbody fusion cages.

Icariin-Loaded Hydrogel Regulates Bone Marrow Mesenchymal Stem Cell Chondrogenic Differentiation and Promotes Cartilage Repair in Osteoarthritis.

Intra-articular injection of mesenchymal stem cells is a potential therapeutic strategy for cartilage protection and symptom relief for osteoarthritis (OA). However, controlling chondrogenesis of the implanted cells in the articular cavity remains a challenge. In this study, hydrogels containing different concentrations of icariin were prepared by in situ crosslinking of hyaluronic acid and Poloxamer 407. This injectable and thermoresponsive hydrogel, as a 3D cell culture system, showed good biocompatibility with chondrocytes and bone marrow mesenchymal stem cells (BMSCs), as well as promoted proliferation and chondrogenesis of BMSCs through the Wnt/ß-catenin signaling pathway. Intra-articular injection of this kind of BMSC-loaded composite hydrogel can significantly prevent cartilage destruction by inducing chondrogenic differentiation of BMSCs, and relieve pain through regulating the expression of inflammatory cytokines (e.g., IL-10 and MMP-13) in the OA model. Incorporating BMSCs into this novel icariin-loaded hydrogel indicates a more superior efficacy than the single BMSC injection, which suggests a great potential for its application in OA.

Engineering Multifunctional Hydrogel-Integrated 3D Printed Bioactive Prosthetic Interfaces for Osteoporotic Osseointegration.

3D printed porous titanium alloy implants is an advanced orthopedic material for joint replacement. However, the high risk of aseptic loosening and periprosthetic infection is difficult to avoid, and the declined autophagy of osteoporosis-derived bone marrow mesenchymal stem cells (OP-BMSCs) further severely impairs the osseointegration under the osteoporotic circumstance. It is thus becoming urgently significant to develop orthopedic materials with autophagy regulation and antibacterial bioactivity. In this regard, a novel class of multifunctional hydrogel-integrated 3D printed bioactive prosthetic interfaces is engineered for in situ osseointegration in osteoporosis. The hydrogel is fabricated from the dynamic crosslinking of synthetic polymers, natural polymers, and silver nanowires to deliver autophagy-regulated rapamycin. Therefore, the resultant soft material exhibits antibacterial ability, biocompatibility, degradability, conductive, self-healing, and stimuli-responsive abilities. In vitro experiments demonstrate that the hydrogel-integrated 3D printed bioactive prosthetic interfaces can restore the declined cellular activities of OP-BMSCs by upregulating the autophagy level and show excellent antibacterial activity against S. aureus and MRSA. More remarkably, the multifunctional 3D printed bioactive prosthetic interfaces significantly improve osseointegration and inhibit infection in osteoporotic environment in vivo. This study provides an efficient strategy to develop novel prosthetic interfaces to reduce complications after arthroplasty for patients with osteoporosis.

Fabrication of Stable MIL-53(Al) for Excellent Removal of Rhodamine B.

Adsorptive purification of organic dyes in wastewater is significant to protect the water environment. Herein, MIL-53(Al) was successfully fabricated through a facile and versatile solvothermal strategy. The stability of MIL-53(Al) under high temperature, acid, base, and peroxide conditions was investigated. The porous MIL-53(Al) had high chemical stability, and the thermal stability reached up to 500 °C, which provided a good foundation for dye removal. MIL-53(Al) showed excellent adsorption performance. The maximum adsorption capacity of MIL-53(Al) for rhodamine B (RhB) can reach 1547 mg g-1 under 303 K, and the corresponding removal efficiency exceeded 90% at the equilibrium time (120 min). The Langmuir model and pseudo-second-order model can well fit RhB adsorption on MIL-53(Al). Thermodynamic study and activation energy values over the range of 298-323 K revealed that the adsorption of RhB was a spontaneous and endothermic physical process in nature. The batch experimental results, X-ray photoelectron spectroscopy (XPS), and Fourier-transform infrared (FTIR) spectroscopy analyses suggested that the hydrogen bonding and electrostatic interactions between the hydroxyl/carboxyl groups of MIL-53(Al) and RhB were the primary adsorption mechanisms. Besides, MIL-53(Al) had a higher selectivity to RhB than the coexisting ions in aqueous solution and a superior adsorption performance after five cycles.

Instructive cartilage regeneration modalities with advanced therapeutic implantations under abnormal conditions.

The development of interdisciplinary biomedical engineering brings significant breakthroughs to the field of cartilage regeneration. However, cartilage defects are considerably more complicated in clinical conditions, especially when injuries occur at specific sites (e.g., osteochondral tissue, growth plate, and weight-bearing area) or under inflammatory microenvironments (e.g., osteoarthritis and rheumatoid arthritis). Therapeutic implantations, including advanced scaffolds, developed growth factors, and various cells alone or in combination currently used to treat cartilage lesions, address cartilage regeneration under abnormal conditions. This review summarizes the strategies for cartilage regeneration at particular sites and pathological microenvironment regulation and discusses the challenges and opportunities for clinical transformation.

Incorporation of Bone Morphogenetic Protein-2 and Osteoprotegerin in 3D-Printed Ti6Al4V Scaffolds Enhances Osseointegration Under Osteoporotic Conditions.

Osteoporosis is an age-related metabolic disease that results in limited bone regeneration capacity and excessive osteoclast activity. After arthroplasty in patients with osteoporosis, poor interface osseointegration resulting from insufficient bone regeneration ability often leads to catastrophic complications such as prosthesis displacement and loosening and periprosthetic fractures. In this study, we prepared a thermosensitive hydrogel loaded with bone morphogenetic protein-2 (BMP-2) to promote osteogenesis and osteoprotegerin (OPG) to inhibit excessive osteoclast activity. To construct three-dimensional (3D)-printed composite scaffolds for implantation, a hydrogel loaded with drugs was injected into porous Ti6Al4V scaffolds. The 3D-printed composite scaffolds showed good biocompatibility and sustained release of BMP-2 and OPG for more than 20 days. In vitro experiments indicated that composite scaffolds promoted osteogenic differentiation and reduced the osteoclastic activation simultaneously. Remarkably, immunofluorescence staining, micro-CT, histological, and biomechanical tests demonstrated that the sustained release of both BMP-2 and OPG from composite scaffolds significantly improved bone ingrowth and osseointegration in osteoporotic defects. In conclusion, this study demonstrated that the BMP-2- and OPG-loaded 3D-printed composite scaffolds can potentially promote osseointegration for osteoporotic patients after joint replacement.