Reversible dougong structured receptor-ligand recognition for building dynamic extracellular matrix mimics.

Dynamic biomaterials excel at recapitulating the reversible interlocking and remoldable structure of the extracellular matrix (ECM), particularly in manipulating cell behaviors and adapting to tissue morphogenesis. While strategies based on dynamic chemistries have been extensively studied for ECM-mimicking dynamic biomaterials, biocompatible molecular means with biogenicity are still rare. Here, we report a nature-derived strategy for fabrication of dynamic biointerface as well as a three-dimensional (3D) hydrogel structure based on reversible receptor-ligand interaction between the glycopeptide antibiotic vancomycin and dipeptide d-Ala-d-Ala. We demonstrate the reversible regulation of multiple cell types with the dynamic biointerface and successfully implement the dynamic hydrogel as a functional antibacterial 3D scaffold to treat tissue repair. In view of the biogenicity and high applicability, this nature-derived reversible molecular strategy will bring opportunities for malleable biomaterial design with great potential in biomedicine.

Mussel-Derived and Bioclickable Peptide Mimic for Enhanced Interfacial Osseointegration via Synergistic Immunomodulation and Vascularized Bone Regeneration.

Inadequate osseointegration at the interface is a key factor in orthopedic implant failure. Mechanistically, traditional orthopedic implant interfaces fail to precisely match natural bone regeneration processes in vivo. In this study, a novel biomimetic coating on titanium substrates (DPA-Co/GFO) through a mussel adhesion-mediated ion coordination and molecular clicking strategy is engineered. In vivo and in vitro results confirm that the coating exhibits excellent biocompatibility and effectively promotes angiogenesis and osteogenesis. Crucially, the biomimetic coating targets the integrin α2ß1 receptor to promote M2 macrophage polarization and achieves a synergistic effect between immunomodulation and vascularized bone regeneration, thereby maximizing osseointegration at the interface. Mechanical push-out tests reveal that the pull-out strength in the DPA-Co/GFO group is markedly greater than that in the control group (79.04 ± 3.20 N vs 31.47 ± 1.87 N, P < 0.01) and even surpasses that in the sham group (79.04 ± 3.20 N vs 63.09 ± 8.52 N, P < 0.01). In summary, the novel biomimetic coating developed in this study precisely matches the natural process of bone regeneration in vivo, enhancing interface-related osseointegration and showing considerable potential for clinical translation and applications.

Rational integration of defense and repair synergy on PEEK osteoimplants via biomimetic peptide clicking strategy.

Polyetheretherketone (PEEK) has been widely used as orthopedic and dental materials due to excellent mechanical and physicochemical tolerance. However, its biological inertness, poor osteoinduction, and weak antibacterial activity make the clinical applications in a dilemma. Inspired by the mussel adhesion mechanism, here we reported a biomimetic surface strategy for rational integration and optimization of anti-infectivity and osteo-inductivity onto PEEK surfaces using a mussel foot proteins (Mfps)-mimic peptide with clickable azido terminal. The peptide enables mussel-like adhesion on PEEK biomaterial surfaces, leaving azido groups for the further steps of biofunctionalizations. In this study, antimicrobial peptide (AMP) and osteogenic growth peptide (OGP) were bioorthogonally clicked on the azido-modified PEEK biomaterials to obtain a dual-effect of host defense and tissue repair. Since bioorthogonal clicking allows precise collocation between AMP and OGP through changing their feeding molar ratios, an optimal PEEK surface was finally obtained in this research, which could long-term inhibit bacterial growth, stabilize bone homeostasis and facilitate interfacial bone regeneration. In a word, this upgraded mussel surface strategy proposed in this study is promising for the surface bioengineering of inert medical implants, in particular, achieving rational integration of multiple biofunctions to match clinical requirements.

Facile and Versatile Surface Functional Polyetheretherketone with Enhanced Bacteriostasis and Osseointegrative Capability for Implant Application.

Implant-associated infections and inadequate osseointegration are two challenges of implant materials in orthopedics. In this study, a lithium-ion-loaded (Li+)/mussel-inspired antimicrobial peptide (AMP) designed to improve the osseointegration and inhibit bacterial infections effectively is prepared on a polyetheretherketone (PEEK) biomaterial surface through the combination of hydrothermal treatment and mussel-inspired chemistry. The results illustrate that the multifunctional PEEK material demonstrated a great inhibitory effect on Escherichia coli and Staphylococcus aureus, which was attributed to irreversible bacterial membrane damage. In addition, the multifunctional PEEK can simultaneously upregulate the expression of osteogenesis-associated genes/proteins via the Wnt/ß-catenin signaling pathway. Furthermore, an in vivo assay of an infection model revealed that the multifunctional PEEK implants killed bacteria with an efficiency of 95.03%. More importantly, the multifunctional PEEK implants accelerated the implant-bone interface osseointegration compared with pure PEEK implants in the noninfection model. Overall, this work provides a promising strategy for improving orthopedic implant materials with ideal osseointegration and infection prevention simultaneously, which may have broad application clinical prospects.

Sustained Release of Melatonin from GelMA Liposomes Reduced Osteoblast Apoptosis and Improved Implant Osseointegration in Osteoporosis.

A reduction in bone mass around an implant is the main cause of implant loosening, especially in postmenopausal osteoporosis patients. In osteoporosis, excessive oxidative stress, resulting in osteoblast apoptosis, largely contributes to abnormal bone remodeling. Melatonin (MT) synthesized by the pineal gland promotes osteoblast differentiation and bone formation and has been effectively used to combat oxidative stress. Therefore, we hypothesized that MT attenuates osteoblast apoptosis induced by oxidative stress, promotes osteogenesis in osteoporosis, and improves bone mass around prostheses. Moreover, considering the distribution and metabolism of MT, its systemic administration would require a large amount of MT, increasing the probability of drug side effects, so the local administration of MT is more effective than its systemic administration. In this study, we constructed a composite adhesive hydrogel system (GelMA-DOPA@MT) to bring about sustained MT release in a local area. Additionally, MT-reduced apoptosis caused by hydrogen peroxide- (H2O2-) induced oxidative stress and restored the osteogenic potential of MC3T3-E1 cells. Furthermore, apoptosis in osteoblasts around the implant was significantly attenuated, and increased bone mass around the implant was observed in ovariectomized (OVX) rats treated with this composite system. In conclusion, our results show that GelMA-DOPA@MT can inhibit osteoblast apoptosis caused by oxidative stress, thereby promoting osteogenesis and improving bone quality around a prosthesis. Therefore, this system of local, sustained MT release is a suitable candidate to address implant loosening in patients with osteoporosis.

Biomimetic osteogenic peptide with mussel adhesion and osteoimmunomodulatory functions to ameliorate interfacial osseointegration under chronic inflammation.

Bone endoprosthesis in patients with systemic chronic inflammation frequently leads to poor osseointegration after implantation mainly due to the increase in pro-inflammatory cytokines that induce bone resorption and impair bone formation. In this work, peptide-coated implants are designed to create a beneficial bone immune microenvironment around prostheses to promote interfacial osteogenesis. By taking advantage of the spontaneous and stable coordination chemistry, Ti-based implants are coated with the mussel-inspired peptide to mitigate lipopolysaccharide (LPS)-induced inflammation by up-regulating the M2 phenotype of macrophages. In addition, the peptide coating increases the bone-implant contact (BIC) by nearly 3 times resulting in suppressed osteoclastogenesis and promoted osteogenesis by inhibiting the nuclear factor kappa-B (NF-κB) signalling pathway. Our findings indicate that biomimetic peptides with osteoimmunomodulatory bioactivity can be incorporated into Ti-based prostheses to facilitate bone regeneration in patients with chronic inflammatory diseases.

Efficient Inhibition of Wear-Debris-Induced Osteolysis by Surface Biomimetic Engineering of Titanium Implant with a Mussel-Derived Integrin-Targeting Peptide.

Wear-debris-induced osteolysis and subsequent aseptic loosening of the prosthesis are the main reasons for failed arthroplasty. Inhibition of wear-debris-induced osteoclastogenesis is thus a promising method to prolong the lifetime of prostheses. In this work, a mussel-derived peptide, capped with an integrin-targeting RGD tripeptide and a titanium (Ti)-affinity tetrapeptide with catechol groups at each end is biomimetically designed. The RGD peptide can interfere with integrin αv ß3 to affect the cytoskeletal organization and functions of osteoclasts and subsequently inhibit osteoclast hyperactivation and osteoclastogenesis in vitro and in vivo, while the catechol groups could easily adhere to the TiO2 layer of the Ti implant via Ti-catechol coordination. This design thus enables the stable immobilization of the RGD peptide on Ti implants to inhibit osteoclast formation and reduce osteolysis in vivo, even with the existence of Ti wear particles. Further study reveals that the suppression of osteoclastogenesis and osteoclast polarization on the peptide coating is regulated by blocking the PI3K/AKT and NF-κB signal pathways. Considering the simplicity in the surface engineering, the highly biomimetic nature of the bioactive peptide, and efficient inhibition of wear-debris-caused osteolysis, this work thus presents a simple and efficient strategy to improve clinical outcome of prosthesis implantation in challenging conditions.