# Optimizing Titanium Osseointegration through Thermally Modified Co-Doped Monetite Coatings

**Authors:** Gerson Santos de Almeida, Maria Gabriela Jacheto Carra, Matheus Luquirini Penteado dos Santos, Julia Bucci, Luisa Camilo Suter, Diego Rafael Nespeque Corrêa, Pascale Chevalier, Margarida Juri Saeki, Diego Mantovani, Willian Fernando Zambuzzi

PMC · DOI: 10.1021/acsbiomaterials.5c01648 · 2026-02-16

## TL;DR

This study shows that Co-doped monetite coatings on titanium implants improve bone integration by enhancing cell adhesion and promoting blood vessel growth.

## Contribution

The paper introduces thermally modified Co-doped monetite coatings that address both osteogenesis and angiogenesis for better implant integration.

## Key findings

- Co-monetite coatings showed superhydrophilic properties and enhanced preosteoblast adhesion and spreading.
- Gene expression revealed upregulation of osteogenic markers and increased MMP-2/9 activity for extracellular matrix remodeling.
- Cobalt doping induced a pro-angiogenic response through HIF-1α stabilization, supporting vascularization.

## Abstract

Although Ti implants
have been used clinically for decades, their
osseointegration is still a major concern in aged, diseased and osteoporotic
patients. Using a hydrothermal synthesis approach, monetite (CaHPO4) and Co-monetite coatings with controlled crystallinity and
surface topography were designed and produced. Structural characterization
via X-ray diffraction (XRD) confirmed the formation of phase-pure
monetite (triclinic) with homogeneous cobalt distribution, while scanning
electron microscopy (SEM) and profilometry revealed microstructured
surfaces featuring peaks and valleys, mimicking native bone morphology.
Remarkably, the coatings exhibited superhydrophilic properties for
Co-monetite versus uncoated Ti. Biological assessments demonstrated
excellent cytocompatibility using preosteoblasts, with MTT assays
showing higher metabolic activity in Co-monetite groups compared to
control. SEM analysis revealed enhanced preosteoblast adhesion and
spreading on Co-monetite surfaces by day 7. Gene expression profiling
uncovered significant upregulation of osteogenic markers, while zymography
further demonstrated increased both MMP-2/9 activity, indicating active
extracellular matrix remodeling. Altogether, these findings highlight
the dual functionality of Co-monetite coatings toward (1) the physicochemical
properties that promote osteoblast adhesion and early differentiation,
and (2) cobalt doping, that induces a pro-angiogenic response through
HIF-1α stabilization. By addressing both osteogenesis and vascularization,
two critical challenges in implant integration, this research provides
a foundation for the rational design of multifunctional biomaterial
coatings for orthopedic and dental applications. The results suggest
that Co-monetite coatings are a promising strategy to enhance the
osseointegration of bone implants, warranting further preclinical
investigation.

## Linked entities

- **Genes:** HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091]
- **Proteins:** MMP2 (matrix metallopeptidase 2), MMP9 (matrix metallopeptidase 9)
- **Chemicals:** CaHPO4 (PubChem CID 24441), cobalt (PubChem CID 104730)
- **Diseases:** osteoporosis (MONDO:0005298)

## Full-text entities

- **Genes:** Ptk2 (PTK2 protein tyrosine kinase 2) [NCBI Gene 14083] {aka FADK 1, FAK, FRNK, Fadk, p125FAK}, Vtn (vitronectin) [NCBI Gene 22370] {aka Vn}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, Fn1 (fibronectin 1) [NCBI Gene 14268] {aka E330027I09, Fn, Fn-1}, Cdk4 (cyclin dependent kinase 4) [NCBI Gene 12567] {aka Crk3}, Bmp2 (bone morphogenetic protein 2) [NCBI Gene 12156] {aka Bmp2a}, Cpt1b (carnitine palmitoyltransferase 1b, muscle) [NCBI Gene 12895] {aka Cpt1, Cpt1-m, Cpti, Cpti-m, M-cpti}, Mmp2 (matrix metallopeptidase 2) [NCBI Gene 17390] {aka Clg4a, GelA, MMP-2}, Actb (actin, beta) [NCBI Gene 11461] {aka Actx, E430023M04Rik, beta-actin}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, Mmp9 (matrix metallopeptidase 9) [NCBI Gene 17395] {aka B/MMP9, Clg4b, Gel B, MMP-9, pro-MMP-9}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, Cdk6 (cyclin dependent kinase 6) [NCBI Gene 12571] {aka Crk2}, Src (src proto-oncogene, non-receptor tyrosine kinase) [NCBI Gene 20779] {aka pp60c-src}, RUNX2 (RUNX family transcription factor 2) [NCBI Gene 860] {aka AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, Itga1 (integrin alpha 1) [NCBI Gene 109700] {aka CD49A, E130012M19Rik, Vla1}, Dnase1 (deoxyribonuclease I) [NCBI Gene 13419] {aka DNaseI, Dnl1}, Sp7 (Sp7 transcription factor 7) [NCBI Gene 170574] {aka 6430578P22Rik, C22, Osx}, COL1A1 (collagen type I alpha 1 chain) [NCBI Gene 1277] {aka CAFYD, EDSARTH1, EDSC, OI1, OI2, OI3}, Cdk2 (cyclin dependent kinase 2) [NCBI Gene 12566] {aka A630093N05Rik}, Itgb1 (integrin beta 1 (fibronectin receptor beta)) [NCBI Gene 16412] {aka 4633401G24Rik, CD29, Fnrb, Gm9863, gpIIa}, Hif1a (hypoxia inducible factor 1, alpha subunit) [NCBI Gene 15251] {aka HIF-1-alpha, HIF1-alpha, HIF1alpha, MOP1, bHLHe78}, COL3A1 (collagen type III alpha 1 chain) [NCBI Gene 1281] {aka EDS4A, EDSVASC, PMGEDSV}, Nos3 (nitric oxide synthase 3, endothelial cell) [NCBI Gene 18127] {aka 2310065A03Rik, Nos-3, eNOS, ecNOS}
- **Diseases:** hypoxic (MESH:D002534), CaP (MESH:D002128), hypoxia (MESH:D000860), inflammation (MESH:D007249), osteoporotic (MESH:D058866), Cytotoxicity (MESH:D064420)
- **Chemicals:** TRIzol (MESH:C411644), CaPs (MESH:C097300), CO2 (MESH:D002245), Co (MESH:D003035), water (MESH:D014867), apatite (MESH:D001031), Ca (MESH:D002118), DMSO (MESH:D004121), nitric oxide (MESH:D009569), Cu (MESH:D003300), acetic acid (MESH:D019342), ascorbic acid (MESH:D001205), SDS (MESH:D012967), HCl (MESH:D006851), CaP (MESH:C020243), CaCl2 (MESH:D002122), alpha-MEM (MESH:C420642), O (MESH:D010100), penicillin (MESH:D010406), PTFE (MESH:D011138), formazan (MESH:D005562), P (MESH:D010758), methanol (MESH:D000432), crystal violet (MESH:D005840), Coomassie Blue R-250 (MESH:C024757), NO (MESH:D009614), Co-monetite (-), streptomycin (MESH:D013307), polyacrylamide (MESH:C016679), Triton X-100 (MESH:D017830), HA (MESH:D017886), Ti (MESH:D014025), MTT (MESH:C070243), dexamethasone (MESH:D003907), beta-glycerophosphate (MESH:C031463), CaHPO4 (MESH:C485829)
- **Species:** Mycoplasma (genus) [taxon 2093], Homo sapiens (human, species) [taxon 9606]
- **Cell lines:** MC3T3-E1 — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0409), ATCC CRL-2593 — Homo sapiens (Human), Xeroderma pigmentosum variant type, Transformed cell line (CVCL_ZS46)

## Figures

11 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12976997/full.md

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Source: https://tomesphere.com/paper/PMC12976997