Calcium (Hydroxyapatite)

BACKGROUND: Calcium hydroxyapatite (CaHA) is a well-established biostimulatory filler approved for hand rejuvenation. Recent approaches have explored dilution with polymicronutrient (PMN) solutions to enhance cellular metabolism and extracellular matrix (ECM) regeneration. AIMS: To evaluate the biological and clinical effects of CaHA diluted in a PMN solution (CaHA + PMN) compared with the conventional CaHA diluted in saline solution (CaHA + SS) for hand rejuvenation. METHODS: An in vitro study was conducted to assess fibroblast proliferation and gene expression of ECM components (COL1A1, COL3A1, and ELN) after exposure to CaHA diluted with PMN or SS. A prospective, split-hand, double-blind clinical trial (n = 22) compared both formulations regarding Hand Grading Scale (HGS), Global Aesthetic Improvement Scale (GAIS), skin hydration (corneometry), and dermal thickness (ultrasound imaging) at baseline, 15 and 90 days after treatment. RESULTS: In vitro, CaHA + PMN induced greater fibroblast proliferation and upregulated COL1A1 and ELN gene expression compared to CaHA + SS. Clinically, both treatments led to significant improvement from baseline in HGS (p < 0.001), skin hydration and dermal/hypodermal thickness, with no statistically significant differences between-group. Investigator-assessed GAIS and patient-reported satisfaction on a 5-point Likert scale also showed improvement in both groups. CONCLUSION: Both treatments demonstrated comparable clinical outcomes, suggesting that the strong biostimulating effect of CaHA may have overshadowed potential additive effects of PMN. Nonetheless, in vitro findings confirmed enhanced biological activity with CaHA + PMN, supporting its investigation as a complementary strategy in future studies. © 2026 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

OBJECTIVE: The current study aims to investigate the safety and efficacy of using calcium hydroxyapatite (CaHA) versus CaHA associated with hyaluronic acid (HA) for forehead volume replacement and contour restoration without forehead irregularities. METHODS: This interventional study involved 132 participants in a two-arm, parallel, double-blind trial for forehead treatment using the supraperiosteal technique. Group A received CaHA, and Group B received a combination of CaHA and HA as filler materials. Follow-up assessments occurred at 30 and 180 days, incorporating the 5-point Global Aesthetic Improvement Scale (GAIS) and photographic analysis for forehead volume replacement, contour restoration, and without forehead irregularities. Safety assessments included monitoring adverse events, particularly nodules. RESULTS: The study included all 132 enrolled patients who completed the trial. Applying CaHA in combination with HA resulted in a statistically significant improvement in both GAIS scale scores and the reduction of forehead irregularities. The total incidence of nodules was 3.7%. Group A had four times more occurrences of nodules than Group B. Furthermore, Group B exhibited lower rates of forehead irregularities following the treatment compared to Group A. CONCLUSION: The supraperiosteal application of CaHA and HA for forehead treatment demonstrates superior efficacy in addressing signs of aging compared to the isolated use of CaHA. © 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

BACKGROUND: Calcium hydroxyapatite (CaHA)-carboxymethylcellulose (CMC)+ has unique properties that make it optimal for lifting, contouring, and defining the jawline. This long-term follow-up of a randomized, multicenter, rater-blinded trial reports efficacy and safety of CaHA-CMC(+) through 48 and up to 60 weeks post-treatment. METHODS: Eligible patients were randomized (2:1) to the treatment or the control/delayed treatment group to receive CaHA-CMC(+) injections in both jawlines. While touch-ups were permitted 4 weeks post-treatment for both groups, only the treatment group was eligible for optional retreatment after 48 weeks. The primary outcome was ≥1-point improvement on both jawlines on the Merz Jawline Assessment Scale (MJAS); secondary endpoints included the Subject Global Aesthetic Improvement Scale (SGAIS) among others. Post hoc analysis included pooling up to 48-week data from the combined treatment and control/delayed groups and 60-week data for the treatment group. RESULTS: Overall, 175 received treatment. MJAS responder rates were 77.9%, 78.7%, and 62.9% at 12, 24, and 48 weeks post-treatment, respectively. Responder rate on the MJAS at 60 weeks was 74.6% for those who received retreatment and 43.5% for those patients who received only the initial and touchup treatments. SGAIS scores demonstrated 93.4%, 85.6%, and 68.5% of patients rated themselves very much improved after 12, 24, and 48 weeks, respectively. Adverse events consisted of procedure or CaHA-CMC(+)-related events that were mostly resolved and overwhelmingly mild. CONCLUSIONS: CaHA-CMC(+) produced clinically meaningful and long-lasting improvements in jawline contour and was well tolerated in patients through 60 weeks. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03583359. © 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

INTRODUCTION: Hand aging is a prevalent concern characterized by the atrophy of local soft tissues and increased visibility of vessels and tendons. Hyaluronic acid (HA) and calcium hydroxyapatite (CaHA) are well-established treatments for addressing this issue. While hybrid filler containing HA and CaHA has been proposed for facial rejuvenation, studies investigating its efficacy for hand rejuvenation are lacking. OBJECTIVE: This study aims to assess the safety and efficacy of a premixed hybrid filler containing calcium hydroxyapatite (CaHA) and hyaluronic acid (HA) for hand rejuvenation. METHODS: A prospective, double-blind, controlled trial was conducted. The control arm (CA) received conventional subdermal treatment with CaHA at a 1:1 dilution. The intervention arm (IA) underwent hybrid treatment, consisting of CaHA at a 1:1 dilution combined with 1 ml of low-density HA. Evaluation was performed subjectively using the Global Aesthetic Improvement Scale (GAIS) and the Manchester Hand Grading System (MHGS), and objectively using cutometry, corneometry, and ultrasound. RESULTS: Both the CA and the IA exhibited high rates of patient satisfaction and satisfaction as assessed by blinded evaluators. Although numerical superiority was observed in the IA, no statistical difference was found between the two groups. Significant improvements in hydration, elasticity, and skin thickness were observed in both arms, with no discernible difference between them. Greater ultrasound echogenicity was noted in the IA, which, as indicated by existing literature, may suggest enhanced biostimulation. No adverse effects were reported in either arm. CONCLUSION: Premixed filler containing HA and CaHA for hand rejuvenation appears to be a safe and effective approach. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . © 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.

PURPOSE: The study aimed to evaluate and compare the efficacy and safety of treating atrophied labia majora with hyaluronic acid (HA) and calcium hydroxyapatite (CaHA). METHODS: Ten participants complaining of sagging or loss of volume in the labia majora were evaluated and randomly assigned to two groups-treated with CaHA or AH. Photographic documentation was taken and appreciated by the participants and by blind observers. RESULTS: The study showed an improvement in labia majora regarding volumization and flaccidity that was more significant after 90 days of treatment in both treatments. Besides flaccidity, volume replacement resulted in better balance and proportion between the labia majora and labia minora. The evaluators, independent and blind, judged that in 80% of the cases of the HA group and in 50% of cases of the CaHA group, there was an excellent improvement. CONCLUSION: CaHA and HA are both effective and safe for treating the intimate region, and this study cannot prove the superiority of one over the other. An appropriate assessment involving the analysis of sagging and/or volume loss and the creation of a sequential treatment protocol, involving CaHA and HA, seems to be the best solution. LEVEL OF EVIDENCE I: Evidence obtained from at least one properly designed randomized controlled trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . © 2023. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.

OBJECTIVE: The objective of this in vitro study was to compare two 5% sodium fluoride varnishes, each containing different sources of calcium and phosphate, for their ability to deliver fluoride into treated sound tooth enamel and adjacent, but untreated demineralized enamel. METHODS: Six sets of 12 bovine enamel cores were mounted in plexiglass rods and the exposed surfaces were polished. Synthetic lesions were formed in the surface of three sets by soaking in thickened, pH 5.0, 1M lactic acid, 50% saturated with calcium hydroxyapatite. A fluoride varnish containing tri-calcium phosphate (TCP) was applied to one set of sound enamel cores, and a second, delivering amorphous calcium phosphate (ACP), was applied to another. A third set of sound enamel cores was water-treated. Each treated sound core was paired with an untreated lesioned core, and the pairs were soaked in artificial saliva for 24 hours at 37 degrees C. The treated cores, but not their lesioned counterparts, were initially soaked in 1.0 N KOH saturated with calcium phosphate for 18 hours. Each core was separately etched with 1.0 N perchloric acid for exactly 15 seconds, and fluoride measured by an ion-sensitive electrode after neutralizing with NaOH and buffering in TISAB II. The amount of calcium extracted was also determined by atomic absorption spectrophotometry as a measure of etch depth. RESULTS: Fluoride uptake average was 1677 +/- 193 ppm, 455 + 38 ppm, and 44 +/- 5 ppm for the sound enamel cores treated with ACP varnish, TCP varnish, and water treatment, respectively. Fluoride uptake into the demineralized enamel averaged 5567 +/- 460 ppm, 2126 +/-126 ppm, and 49 -/+ 4 ppm for demineralized enamel paired with the sound cores treated with ACP varnish, TCP varnish, and water, respectively. The differences between the ACP varnish, the TCP varnish, and the water treatments were statistically significant (p < 0.05). CONCLUSION: The ACP varnish formulation delivers statistically significantly more fluoride to both intact and demineralized enamel than the formulation containing TCP.

BACKGROUND: Collagen biostimulators, such as poly-L-lactic acid (PLLA) and calcium hydroxyapatite (CaHA), are widely used in facial esthetic treatments to improve skin quality, restore volume, and stimulate neocollagenesis. OBJECTIVE: This study aimed to evaluate the efficacy, durability, and safety of PLLA- and CaHA-based collagen biostimulators in facial esthetic treatments. METHODS: A systematic literature review was conducted following PRISMA 2020 guidelines. The PICO strategy guided the research question. Searches were performed in April 2024 in the BVS, Medline (via PubMed), and Scopus databases, using standardized descriptors and Boolean operators. Studies published between 2010 and 2024, available in full text in Portuguese, English, or Spanish, were included. Screening was conducted using the Rayyan platform, and the quality of included studies was assessed with the ROB2 tool. RESULTS: Fourteen studies met the eligibility criteria. Both PLLA and CaHA demonstrated significant improvements in skin elasticity, wrinkle reduction, and increased facial volume. PLLA maintained its effects for up to 25 months, while CaHA offered results lasting 12 to 18 months. The most frequent adverse effects were mild, including pain and swelling at the injection site. One serious case of compression necrosis was reported with CaHA. CONCLUSION: Both PLLA and CaHA are effective and safe biostimulators for facial rejuvenation. However, further research is needed to standardize techniques and assess long-term safety. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . © 2025. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.

63. Aesthet Surg J. 2025 Nov 17;45(12):1278-1284. doi: 10.1093/asj/sjaf142. Biostimulants in Aesthetic Medicine: A Systematic Review and Meta-analysis of Efficacy, Safety, and Patient Satisfaction. Smith L, Rahmati M, Pizzol D, López-Sánchez GF, Boyer L, Fond G, Tran BX, Gawronska J, Yon DK, Ravindran R. Biostimulants, including calcium hydroxyapatite, poly-L-lactic acid, and polycaprolactone, have become popular in aesthetic medicine as they lead to long-term tissue rejuvenation. However, their efficacy (eg, dermal, volume, and anatomic outcomes), patient satisfaction, and safety remain unclear. This systematic review and meta-analysis collates and appraises the available data on biostimulants, examining their efficacy, adverse events, and patient satisfaction. A comprehensive search was conducted in PubMed/Medline (National Library of Medicine, Bethesda, MD), Scopus (Elsevier, Amsterdam, the Netherlands), Embase (Elsevier), and Web of Science (Clarivate, Philadelpha, PA), up to January 14, 2025. Studies were included that assessed the effects of biostimulants on efficacy, adverse events, and patient satisfaction in observational studies. Meta-analyses using random-effects models were performed on individual proportions and applied to 7 outcomes (satisfaction, bruising, ecchymosis, edema, erythema, nodule development, pain). A total of 197 articles were screened, and 25 studies were included in the systematic review. The results of meta-analyses indicate that the pooled satisfaction rate of biostimulants was estimated to be 91% (95% CI, 67%-98%; I2 = 87.3%), with the following adverse event rates: bruising, 27% (95% CI, 12%-50%; I2 = 96%); ecchymosis, 22% (95% CI, 11%-40%; I2 = 95.5%); edema, 5% (95% CI, 1%-18%; I2 = 93.6%); erythema, 16% (95% CI, 4%-47%; I2 = 94.3%); nodule development, 5% (95% CI, 2%-10%; I2 = 85.5%); pain, 92% (95% CI, 63%-99%; I2 = 87.7%). Among studies not included in the meta-analysis, all parameters studied showed significant improvements in terms of dermal, volume, anatomic, and satisfaction outcomes. Biostimulants demonstrate clinical promise and a favorable tolerability profile in aesthetic medicine despite the common occurrence of

OBJECTIVE: This study aimed to evaluate the effectiveness of various alloplastic facial implants in correcting facial defects based on post-operative complications and failure rates in patients who underwent facial skeletal augmentation. METHOD: A comprehensive search for articles reporting relevant articles was using Google Scholar and PubMed databases. Data from publications that satisfied the predefined inclusion criteria were synthesized and analyzed using OpenMeta [Analyst] software. RESULTS: A total of 48 studies with a population size of 3701 patients who received 4139 alloplastic facial implants were included in this analysis. The complication rate was 10.7% (95% confidence intervals [CI] [8.3%, 13.2%], and I2 =89.35%). Paranasal implants had the highest rate of complications of 15.1% (95% CI [7.8%, 22.3%], and malar implants had the lowest complication rate of 7.4% (95% CI 3.8%, 11.1%]) I2 = 72.62%). In 15 studies that had malar implants, 853/1788 (45.8%) of the patients received malar implants (95% CI [0.356, 0.561]). In 8 studies that included mandibular implants, 265 (56%) of 508 patients received mandibular implants (95% CI [0.474, 0.645]); in 11 studies, 371/489 (76.1%) received nasal or paranasal implants (95% CI of [0.565, 0.912]), while in 3 studies, 14/15 (85.5%) received frontal implant (95% CI of [0.645, 0.997]). In 17 studies that investigated the use of chin implants, 1366/1366 (100%) of the eligible patients received chin implants (95% CI [0.995, 1.000], I2 = 0%). The complication rate was 2.78% for silicone, 1.02% for calcium hydroxyapatite, and 2.48 for Medpor. CONCLUSION: Alloplastic facial implants are a viable alternative to enhancing facial beauty and performing facial skeletal augmentation with a relatively lower risk of complications associated with all facial implants. Crown Copyright © 2025. Published by Elsevier Ltd. All rights reserved.

BACKGROUND: For patients looking for temporary results or who do not want surgery, nonsurgical rhinoplasty using filler injections has become increasingly popular. Filler materials and surgical techniques have improved in recent years, but serious complications remain. Therefore, the aim of this systematic review is to summarize the common types of fillers and injection techniques, complications, and treatment to help clinicians perform in a safer and more effective way. METHODS: A systematic review was performed using keywords and Medical Subject Headings search terms. PubMed, Embase, and the Cochrane Library were searched using the appropriate search terms. Data collected from each study included injection materials, location, technique, patient satisfaction and complications, and treatment. RESULTS: From the 1812 studies identified, 30 were included in the systematic review. A total of 9657 patients underwent nonsurgical rhinoplasty, most commonly with hyaluronic acid (HA) (96.76%), followed by calcium hydroxyapatite (CaHA) (1.22%). Overall satisfaction was 99.08%. The overall incidence of complications was 39.11%, with the highest incidence of erythema and swelling (27.95%). Most of the complications are mild, but there are still 0.27% of the patients who have undergone severe complication-an arterial occlusion. CONCLUSIONS: Nonsurgical rhinoplasty is an effective and relatively safe option for improving the profile of the nose, with a short operative time and high patient satisfaction. Most of the complications were mild, but still serious vascular complications such as blindness, skin necrosis, and stroke were as high as 0.27%. A thorough understanding of the anatomy of the nasal vessels and a precise surgical technique is an important basis for prevention. A BULLET POINT LIST: (1) We summarize the common types of fillers and injection techniques, complications, and treatment of complications to guide physicians to perform nonsurgical rhinoplasty in a safer and more effective manner. (2) Out of 1812 studies through the search strategy, 30 articles were included in the systematic review. A total of 9657 patients underwent nonsurgical rhinoplasty. (3) Nonsur

Hydroxyapatite (HA) is a biomaterial widely used in clinical applications and pharmaceuticals. The literature on HA-based materials studies is focused on chemical characterization and biocompatibility. Generally, biocompatibility is analyzed through adhesion, proliferation, and differentiation assays. Fewer studies are looking for genotoxic events. Thus, although HA-based biomaterials are widely used as biomedical devices, there is a lack of literature regarding their genotoxicity. This systematic review was carried out following the PRISMA statement. Specific search strategies were developed and performed in four electronic databases (PubMed, Science Direct, Scopus, and Web of Science). The search used "Hydroxyapatite OR Calcium Hydroxyapatite OR durapatite AND genotoxicity OR genotoxic OR DNA damage" and "Hydroxyapatite OR Calcium Hydroxyapatite OR durapatite AND mutagenicity OR mutagenic OR DNA damage" as keywords and articles published from 2000 to 2022, after removing duplicate studies and apply include and exclusion criteria, 53 articles were identified and submitted to a qualitative descriptive analysis. Most of the assays were in vitro and most of the studies did not show genotoxicity. In fact, a protective effect was observed for hydroxyapatites. Only 20 out of 71 tests performed were positive for genotoxicity. However, no point mutation-related mutagenicity was observed. As the genotoxicity of HA-based biomaterials observed was correlated with its nanostructured forms as needles or rods, it is important to follow their effect in chronic exposure to guarantee safe usage in humans.

The treatment of facial asymmetry in patients with microphthalmos or acquired anophthalmic sockets usually requires aggressive reconstructive surgeries. In recent years, studies have been published on the use of fillers to optimize orbital tissue symmetry, as minimally invasive techniques. For this reason, we performed a systematic review of the literature published to date on the use of fillers for the treatment of volume loss in acquired anophthalmic or microphthalmic cavities. Fourteen articles were reviewed in which the material used, the injection technique, the anatomical study of the patients before the procedure and the presence of associated complications were analyzed. Various materials have been used as fillers, including autologous fat, calcium hydroxyapatite, collagen, hyaluronic acid, or polyacrylamide gel. Standard peribulbar and retrobulbar injection techniques were applied, with few associated complications, the most serious being the development of vasovagal symptoms. Patient follow-up is usually limited in most studies to 12 months. In Conclusion, the use of fillers seems to be a safe practice, with good results and few complications, although studies with longer follow-up times than those published to date would be required.

BACKGROUND: Injection treatments have been proposed as novel treatment options for Vulvovaginal Atrophy of Menopause (VVA) also known as Genitourinary Syndrome of Menopause (GSM). However, to date data about these treatments are poor. OBJECTIVE: To assess all available injection treatments for VVA. METHODS: A systematic review was performed by searching five electronic databases for peer-reviewed studies that assessed injection treatments for VVA. RESULTS: Eight studies (7 observational and 1 randomized) with 236 women were included. Assessed injection materials were: autologous platelet-rich plasma (PRP) + hyaluronic acid (HA), not cross-linked HA plus calcium hydroxyapatite (NCLHA + CaHA), micro-fragmented adipose tissue (MFAT), hyaluronan hybrid cooperative complexes (HCC), crosslinked HA, microfat and nanofat grafting + PRP, and PRP alone. Improvement in GSM symptoms after treatment was assessed through Visual Analogic Scale (VAS) for GSM symptoms or patient satisfaction, several validated questionnaires (FSFI, VHI, FSD, SF12, ICIQ UI SF, PGI-I, FSDS-R, VSQ), symptoms severity, changes in vaginal mucosa thickness, flora, pH, and expression on vaginal mucosal biopsies of Procollagen I and III and ki67 immunofluorescence or COL1A1 and COL3A1 mRNA. Injection treatments showing significant improvement in GSM-related symptoms were: (i) HCC in terms of VAS for GSM symptoms and FSFI score; (ii) Crosslinked HA in terms of VAS for GSM symptoms, FSFI and VHI score, COL1A1 and COL3A1 mRNA expression on vaginal mucosal biopsies; (iii) NCLHA + CaHA in terms of FSFI score; (iv) PRP + HA in terms of VHI, FSD and SF12 score; (v) microfat and nanofat grafting + PRP in terms of VHI score and FSDS-R score; (vi) PRP alone in terms of VHI and VSQ scores. CONCLUSIONS: All assessed injection treatments except for MFAT seem to lead to significant improvement in VVA symptoms on validated questionnaires. Further studies are necessary in the field. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Author

BACKGROUND: Injectable laryngoplasty with hydroxyapatite and hyaluronic acid is frequently used for the treatment of glottic incompetence. The effectiveness of these substances is controversial due to the heterogeneity of studies. OBJECTIVES: To evaluate the effectiveness of the treatment for glottic incompetence using hydroxyapatite and hyaluronic acid. STUDY DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, PUBMED, LILACS, SCOPUS, EMBASE, Cochrane, clinicaltrials.gov, published and unpublished trials, Web of Science. ELIGIBILITY CRITERIA: Studies that evaluated vocal fold function before and after 4-6 weeks and 6 months of hydroxyapatite and hyaluronic acid injection in adults with glottic incompetence. EXCLUSION CRITERIA: studies with outcome, follow-up time or type of intervention outside the predetermined pattern or systematic review and meta-analysis. SYNTHESIS OF METHODS: Primary outcome - Maximum Phonation Time. Secondary outcomes - Voice Handicap Index (VHI)-30, Parameters G and B of GRBAS Scale. Outcomes were analyzed for mean differences with the corresponding 95% CI. RESULTS: Six hundred forty-four studies identified, 12 included (5 CaHA; 6 HA; 1 HA and CaHA). After 4-6 weeks the mean difference were: MPT (+5.86), IDV (-39.32), G (-1.14), and B (-1.46). After 6 months: MPT (+5.97), IDV (-30.13), G (-1.33), and B (-1.33). LIMITATIONS: Studies comparing injectable drugs are small, as well as the number of patients in each one, making the isolated comparison of substances difficult. CONCLUSIONS AND IMPLICATIONS: There is an evidence that the injectable substances HA and CaHA are effective in the treatment of glottic incompetence, however, it is important that more studies are carried out comparing the two substances.

Tear trough deformity is a popular target for the treatment with filler injections. The side effects are generally mild and transient. However, delayed complications may occur. We aim to perform a thorough systematic review of the published literature related to delayed complications after tear trough filler injections. A search of published literature was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in June 2021 and included PubMed, ScienceDirect, and Embase databases. The Medical Subject Headings (MeSH) terms used included the following terms: delayed complications, nodules, granulomas, swelling, discoloration, dermal filler, hyaluronic acid (HA), polyacrylamide, calcium hydroxyapatite (CaHA), poly-L-lactic acid (PLLA), eyelid, periorbital, periocular, and tear trough. Twenty-eight articles consisting of 52 individual cases were included in the final analysis. 98% (51/52) of patients were female and had an average age of 48.3 years. HA was the most reported product (71.2%, 37/52), followed by PLLA (4/52, 7.7%), and CaHA (4/52, 7.7%). The most common delayed complication with any dermal filler was swelling (42.3%, 22/52) followed by lumps or nodules (25.0%, 13/52). Xanthelasma-like reaction (17.3%, 9/52), migration (7.7%, 4/52), discoloration (3%, 3/52) also occurred. The average time of onset of any complication was 16.8 months with xanthelasma-like reaction appearing soonest (mean: 10 months) and discoloration appearing latest (mean: 52 months). Most swelling cases were caused by HA. Semi-permanent fillers such as PMMA and synthetic fillers such as PLLA were more likely to be associated with lumps and nodules than other complications. It is important that clinicians who perform tear trough augmentation with dermal fillers have a thorough understanding of the risks of the procedure to diagnose and manage them promptly as well as provide patients with accurate information regarding the potential adverse effects. Thieme. All rights reserved.

BACKGROUND: In recent years, there has been a rise in non-surgical rhinoplasty (NSR) due to its minimally invasive approach. As with all procedures, NSR can result in complications. Although rare, the consequences of complications can result in a devastating outcome and therefore an evidence-based approach to enable the recognition and management of NSR complications is required. AIMS: This paper aims to review and appraise current literature to determine the evidence base for complications experienced with NSR including their causes and management. METHODS: A systematic review was conducted using a PRISMA methodology. The PubMed and WebofScience databases were queried. Papers relating to the three most commonly used filler materials; hyaluronic acid (HA), calcium hydroxyapatite and collagen were collated. RESULTS: Four hundred and ninety studies were identified in the initial literature search and after applying an inclusion and exclusion criteria, 12 papers were included. CONCLUSION: The results of this literature review showed a paucity of high-level evidence which may indicate underreporting of NSR complications. Although treatment is not always effective, it is clear that early recognition and treatment favors better outcomes with the potential for complete resolution in some cases. Immediate availability of hyaluronidase is important when undertaking NSR with HA as this review showed early use was critical in the management of serious complications such as vascular occlusion. © 2021 Wiley Periodicals LLC.

The development of sustainable biomaterials for bone regeneration represents a current challenge in tissue engineering. In this study, microcrystalline cellulose (MCC) aerogels were developed, to which fish scale particles (FSP) were added; these particles contain collagen and hydroxyapatite in their structure, with the aim of increasing the bioactivity of the aerogels. The results confirmed the incorporation of FSP into the cellulose matrix, modifying the material's physicochemical and mechanical properties. Biological evaluation using human fetal osteoblasts showed that the leachates exhibited no cytotoxicity and that the aerogels containing FSP promoted greater cell viability compared to the cellulose aerogel. Furthermore, the Alizarin Red assay revealed an increase in mineral deposition after 7 and 14 days of culture. These results suggest that the incorporation of FSP provides a surface with altered wettability and chemical composition due to the presence of amino, carboxyl, calcium, and phosphate groups derived from the collagen and hydroxyapatite rich FSP, which may contribute to cell/material interactions. Overall, the developed aerogels represent a waste-derived alternative with potential for applications in bone tissue regeneration.

In vitro tests of glass, glass-ceramic, or ceramic biomaterials such as synthetic hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP) are performed using simulated body fluid (SBF), in which the pH is maintained using TRIS buffer (ISO standard 23317:2014; recently updated as ISO standard 23317:2025). When evaluating the experiments, we not only looked at the tested material itself but also analyzed the SBF leachate. We have found out that TRIS buffer, as well as other tested buffers (Good's buffers), actively interacts with glass and ceramic materials. They significantly accelerate their dissolution (up to 3× higher compared to unbuffered SBF). This increases the local supersaturation of biogenic ions near the surface and promotes the formation of the expected hydroxyapatite (the newly formed hydroxyapatite layer is labeled as HAp). In this work, we focused on bioglass 45S5 to observe the corrosion rate of the glass surface on samples in the form of bulk, in SBF solutions buffered with (i) TRIS and (ii) HEPES, and we used (iii) SBF without any buffer for comparison. The glass corrosion rate and the growth kinetics of the new HAp layer (SEM/EDS, XRD, FTIR) were compared with the results of the leachate analyses (pH, ICP-OES). The concentration of SiIV in the leachates showed the corrosive effects of each of the solutions, while the concentrations of Ca2+ and (PO4)3- confirmed precipitation of a new Ca-P phase. The results confirmed earlier findings and showed that the TRIS and HEPES buffering systems are not inert and are strongly corrosive to bioglass 45S5. Moreover, their parts incorporate into the newly formed Ca-P layer and change its quality and crystallinity. These findings suggest that the current approach to in vitro testing of these materials requires reconsideration. © 2026 The Authors. Published by American Chemical Society.

Rapid caries progression occurs even when salivary flow and calcium phosphate availability are preserved, suggesting a knowledge gap in how available minerals are used for repair. Early-stage Sjögren's syndrome was examined as a clinical model of this condition. Salivary citrate was markedly lower in the disease cohort and was inversely associated with caries burden, whereas salivary flow and the major mineral ions did not differ from healthy controls. In mineralization systems with matched calcium and phosphate concentrations, the disease-associated citrate concentration reduced intrafibrillar mineral deposition, disrupted hydroxyapatite organization, and limited structural and mechanical recovery of demineralized dentin. Human salivary gland tissue, an immunization-induced rat model, and primary salivary gland epithelial cells showed a similar metabolic pattern: increased metallothionein 1/2 (MT1/2), reduced labile Zn2+, increased aconitase 2 (ACO2) activity, and citrate depletion. ZnSO4 repletion increased intracellular Zn2+, reduced ACO2 activity, restored citrate toward control levels, and improved the mineralization activity of epithelial-cell supernatants. The data indicate that citrate availability influences dentin mineral utilization and associate citrate depletion with glandular MT1/2-Zn2+-ACO2 dysregulation. These findings support an association between glandular zinc-citrate dysregulation and impaired remineralization, suggesting that this mechanism may account for impaired endogenous remineralization despite preserved availability of the major mineral ions. © 2026 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

BACKGROUND Extreme lateral lumbar interbody fusion (XLIF) requires reliable graft material for arthrodesis. Bone morphogenetic protein-2 (BMP-2) is osteoinductive but costly and may cause complications. ß-Tricalcium phosphate (ß-TCP) combined with iliac crest bone graft (ICBG) may provide an alternative. This study compared the radiographic and clinical outcomes of BMP-2 versus ß-TCP+ICBG in single-level XLIF. MATERIAL AND METHODS This ambidirectional observational cohort included 79 consecutive patients who underwent single-level XLIF from 2014 to 2024 (BMP-2, 45; ß-TCP + ICBG, 34). The Oswestry Disability Index (ODI), EuroQol 5-Dimension 5-Level (EQ-5D-5L), and EuroQol Visual Analog Scale (EQ-VAS) were assessed preoperatively and at 24 months. Radiographic alignment was evaluated preoperatively and at 24 months. Fusion was assessed at 12 and 24 months using computed tomography-supported criteria supplemented by dynamic radiographs. RESULTS Baseline characteristics and surgical indications were similar between groups. Fusion rates at 12 months were 75.6% with BMP-2 and 55.9% with ß-TCP+ICBG (P=0.065), increasing to 100% and 97.1%, respectively, at 24 months (P=0.247). Both groups showed substantial improvements in ODI and EQ-5D-5L, without significant between-group differences at 24 months. Intervertebral disc height significantly increased in both groups, whereas foraminal height was maintained. Complication rates were comparable. CONCLUSIONS Both grafting strategies produced favorable radiographic and clinical outcomes at 24 months. BMP-2 showed a numerically higher 12-month fusion rate, whereas ß-TCP+ICBG achieved a similar final fusion rate. Given the observational design and limited sample size, these findings support ß-TCP+ICBG as a potential alternative but do not establish equivalence.

Alloplastic bone grafting has become one of the fastest-moving areas of research in craniomaxillofacial reconstruction. Over the past decade, the field has expanded from a small set of biocompatible fillers into a broad design space encompassing calcium phosphate ceramics, bioactive glass, resorbable polymers, hybrid composite scaffolds, and custom three-dimensionally printed constructs. This is further accelerated by a large body of work on ionic doping, antimicrobial modification, and biological payloads such as bone morphogenetic protein and stem cell-derived exosomes. This pace, however, has not been matched clinically. Current practice still rests largely on hydroxyapatite cements, demineralized bone matrices, and inert patient-specific implants, while functionalized scaffolds that dominate the literature remain confined to bench-top and small-animal models. This article reviews the materials and design principles that define modern regenerative alloplastic grafts, covering the fundamentals of bioceramics, composites, scaffold architecture and manufacturing, and biological augmentation. It then examines the current state of clinical applications of regenerative grafts across craniomaxillofacial reconstruction relative to other alloplastic options, and concludes with frontier developments expected to define the future of the field.

Surgical site infection remains a critical barrier to successful bone tissue engineering, and silk fibroin (SF)-based scaffolds, despite their excellent biocompatibility, lack intrinsic antibacterial activity. Here, we report a multifunctional biohybrid nanocomposite hydrogel that integrates methacrylated silk fibroin (SFMA) with an antibacterial imidazolium-based ionic liquid monomer, 1-vinyl-3-hexylimidazolium bromide ([C6VIm]Br), fabricated via a bioinspired bidirectional freeze-casting strategy followed by in situ biomineralization with hydroxyapatite (HAp). Successful methacrylation (degree of substitution = 35%) and ionic liquid synthesis were confirmed by NMR spectroscopy, while FT-IR, TGA/DTG, and XRD analyses verified the formation of the interpenetrating SF/IL network and progressive HAp deposition, with mineral content rising from 12.1 to 32.9 wt % over successive mineralization cycles. SEM imaging and elemental mapping revealed a highly interconnected, anisotropic porous architecture with uniform calcium/phosphorus distribution, closely emulating native bone microstructure, and mineralization enhanced the swelling capacity to approximately 170%. Biologically, the ionic liquid component conferred potent, additive-free antibacterial activity against both Staphylococcus aureus and Escherichia coli, while HAp incorporation improved MG-63 osteoblast-like cell adhesion and the viability of mesenchymal stem cells (MSCs), with MSC viability exceeding 120% of the control in the mineralized sample. All formulations exhibited hemolysis well below accepted safety limits, confirming excellent hemocompatibility. By combining intrinsic antibacterial function, bioinspired anisotropic architecture, and biomimetic mineralization within a single platform, this work offers a promising, metal- and antibiotic-free strategy for infection-resistant scaffolds for bone tissue engineering, with significant potential for advancing bone tissue engineering and regenerative medicine. © 2026 American Chemical Society.

Background/Objectives: Estrogen deficiency is associated with impaired bone mineralization and deterioration of bone quality. Protein-polysaccharide nanostructures have attracted interest as food-grade formulations because their physicochemical properties can be modified by the nature and organization of their constituent biopolymers. This study evaluated the effects of whey protein-polysaccharide nanocomplex formulations on bone-related outcomes in ovariectomized female Wistar rats. Methods: Whey protein nanocomplexes containing either Opuntia ficus-indica mucilage or Tamarindus indica xyloglucan were produced by complex coacervation and ultrasonication. The nanocomplexes were characterized in terms of particle size, polydispersity index, ζ-potential, and morphology. Ovariectomized rats received the nanostructured formulations, their corresponding physical mixtures, the individual ingredients, or control diets for 12 weeks. Femoral bone quality was evaluated through biomechanical testing, calcium and phosphorus content, Ca/P ratio, bone mineral density, scanning electron microscopy and histomorphometry, and X-ray diffraction analysis. Results: The developed nanocomplexes exhibited particle sizes below 500 nm and polydispersity indices of approximately 0.3. Their physicochemical characteristics and morphology differed according to the polysaccharide incorporated. Ovariectomy was associated with unfavorable changes in bone mineralization, microarchitecture, crystallographic characteristics, and biomechanical competence. Among the evaluated treatments, the whey protein-O. ficus-indica mucilage nanostructured formulation (LMCC) showed the most favorable overall pattern across most bone-related outcomes, including bone mineral density, femoral calcium content, microarchitecture, hydroxyapatite crystallite size, and biomechanical properties. However, the response to nanostructuring was not uniform across the two polysaccharide systems, and the xyloglucan-based formulations exhibited parameter-dependent responses. Conclusions: The biological response to whey protein-polysaccharide formulations was associated with polysaccharide type and physicochemical organization. T

Dysfunction of bone marrow mesenchymal stem cells (BMSCs) and impaired exosome-mediated intercellular communication are recognized as critical contributors to the pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH), although the underlying mechanisms remain incompletely understood. Moreover, the development of novel biomaterials and therapeutic strategies capable of improving SONFH treatment remains an urgent clinical priority. Previous studies have demonstrated that LNC000133-modified exosomes derived from human BMSCs (hBMSCs) promote osteoblastic differentiation and enhance exosome uptake by osteoblasts, thereby exerting therapeutic effects in SONFH. Building on these findings, we developed a 3D-printed biphasic calcium phosphate (BCP)/poly (lactic-co-glycolic acid) (PLGA)- polyethylene glycol (PEG)-PLGA scaffold loaded with LNC000133-modified hBMSC-derived exosomes (LNC000133-Exos) to facilitate the clinical translation of this gene-based therapeutic approach for SONFH. The biological effects of this composite scaffold on hBMSCs were subsequently evaluated in vitro. Furthermore, the BCP/PLGA-PEG-PLGA scaffold loaded with LNC000133-Exos was applied for the treatment of SONFH in a rabbit model. Our results demonstrated that transplantation of the LNC000133-Exos-loaded BCP/PLGA-PEG-PLGA scaffold markedly enhanced bone repair and structural reconstruction within the necrotic region of the femoral head in vivo. Collectively, these findings indicate that the BCP/PLGA-PEG-PLGA scaffold and LNC000133 synergistically promote hBMSC proliferation and osteogenic differentiation while suppressing adipogenic differentiation, providing a strong theoretical foundation and a promising therapeutic strategy for targeted SONFH treatment.

Background/Objectives: This descriptive pilot documented preparation-related, microscopic, and aqueous-exposure appearances of nine injectable biostimulator products spanning poly-L-lactic acid (PLLA), poly-D,L-lactic acid (PDLLA), polycaprolactone (PCL), and calcium hydroxyapatite (CaHA). Methods: Nine products were examined (one unit per product). Five reconstitution-required products underwent manufacturer-specified dilution and mixing, a study-defined 120-min observation period, and re-agitation; this interval is not clinical preparation guidance. Four products were assessed as supplied. Following baseline sampling, the remaining material underwent product-specific introduction into dishes initially containing 15 mL of sterile 0.9% NaCl and incubation for 72 h at 37 °C. Three random fields were photographed and assessed per product, stage, and magnification. Fields were unpaired; no statistical analysis was performed. Results: Four reconstituted samples had a single-phase appearance and one a liquid-foam appearance; both PDLLA samples appeared visually thick/cohesive. Immediate bulk patterns comprised homogeneous dispersion (two samples), non-homogeneous dispersion (four), and retained rod-like extrusion (three). Microscopy showed spherical, ovoid, and irregular particles and spindle-like microstructures. After 72 h, dominant morphology categories corresponded to baseline, while additional appearances and aggregation categories differed between unpaired fields for some samples. Conclusions: The examined samples showed features not uniformly aligned with material platform. The images provide a preliminary reference for further physicochemical and in vivo histopathological studies. This single-unit study does not establish reproducibility, chemical stability, or clinical performance.

Bone metastasis remains a major clinical challenge in advanced breast cancer because therapeutic efficacy is limited by poor lesion targeting and systemic toxicity. Moreover, the hypoxic bone microenvironment induces protective autophagy in tumor cells, which maintains metabolic homeostasis and limits therapeutic efficacy. Herein, we develop a bone metastasis-targeted micellar system (AD/R) to overcome this protective autophagy "shield". Based on the low crystallinity of pathological hydroxyapatite (HAP) and the hypoxic bone microenvironment, a pathological HAP-targeting polymer (DSPE-PEG-ALN, DPA) and a hypoxia-responsive polymer (DSPE-AZO-PEG, DAP) are coassembled into micelles encapsulating the oxidative phosphorylation inhibitor resveratrol (RES). Following selective accumulation in bone-metastatic lesions, AD/R undergoes hypoxia-triggered disassembly. The released DPA induces calcium-mediated membrane mineralization to restrict oxygen and nutrient supply, whereas RES suppresses oxidative phosphorylation and ATP production. This "external blockade" and "internal disruption" synergistically aggravate metabolic stress, activate AMPK-dependent autophagy, and impair lysosomal degradation through lysosomal membrane permeabilization, ultimately inducing autophagy dysfunction and autophagy-associated tumor cell death. In murine breast cancer bone metastasis models, AD/R effectively suppresses bone and secondary lung metastases and restores bone homeostasis. This work establishes a "turn shield into sword" paradigm by converting protective autophagy into metabolic stress-induced autophagy dysfunction for the treatment of bone metastasis. © 2026 American Chemical Society.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been clinically used for fracture healing in many countries for more than two decades; however, no BMP product has been approved in Japan. To obtain the first regulatory approval of BMP therapy in Japan, a phase I/II clinical trial was conducted to evaluate the safety and efficacy of Escherichia coli-derived rhBMP-2 combined with β-tricalcium phosphate (β-TCP) granules for long-bone nonunion. METHODS: This prospective, single-center, exploratory phase I/II study enrolled adults with femoral, tibial, or humeral noninfected nonunion. β-TCP granules soaked with rhBMP-2 were implanted into the nonunion site instead of autologous bone grafting. Patients were followed for 9 months. Primary safety outcomes included local findings, serum rhBMP-2 levels, and anti-rhBMP-2 antibody formation. Primary efficacy outcomes were radiographic union and restoration of limb function. RESULTS: Eight patients (six femoral and two humeral nonunions) completed follow-up. No adverse events related to rhBMP-2/β-TCP were observed. Serum rhBMP-2 levels remained below the limit of detection postoperatively in five patients, suggesting no systemic absorption. Anti-rhBMP-2 antibodies appeared in two patients, peaked at 3-6 months, and declined without clinical effect. Radiographic union occurred in seven of eight patients at 9 months; the remaining case could not be definitively assessed because of double-plate instrumentation, although bridging callus was present. All patients achieved functional improvement, including full weight-bearing or recovery of upper-limb motion. CONCLUSIONS: E. coli-derived rhBMP-2 combined with β-TCP granules demonstrated acceptable safety and potential efficacy in long-bone nonunion. These findings support further clinical investigation toward potential regulatory approval.

Among the biomaterials used in grafting techniques for bone rehabilitation and subsequent dental implant placement, biphasic ceramics have emerged as promising alternatives, prompting investigations into their structural and biological properties. The objective of this study was to evaluate bone repair in critical-size calvarial defects in rats using two particulate biphasic ceramics composed of micro- or nano-hydroxyapatite associated with βtricalcium phosphate in different proportions. Seventy-two Wistar rats were used, distributed into four groups: blood clot (BC); GenPhos® 70/30 (GP), containing micro-HA; Blue Bone® 80/20 (BB), containing nano-HA; and Bio-Oss® (BO). In each rat, a critical defect was created in the calvaria, filled according to the group and covered with a collagen membrane. The animals were euthanized at 7, 14, and 28 days. Histomorphometric analysis was performed, quantifying newly formed bone, biomaterial, and connective tissue, in addition to microcomputed tomography (Micro-CT), adopting p < 0.05, and qualitative histological analysis. In the Micro-CT analysis, no significant differences in bone volume were observed among the groups, although the BB group exhibited a more pronounced trabecular microarchitecture. Histomorphometrically, all biomaterial groups were superior to BC (p < 0.001). The BB group showed similar mean new bone formation (45.03%) compared to the BO group (46.62%), at 28 days, with no statistically significant difference, exhibiting an intraparticular osteoconduction pattern. The GP group demonstrated greater resorption dynamics (17.22%), whereas BO remained the most stable (44.22%). The BC group showed the highest connective tissue persistence (68.07%). It is concluded that the biphasic ceramics and the xenogeneic biomaterial promoted defect closure, with nano-hydroxyapatite (BB) demonstrating great qualitative performance in trabecular organization and initial vascularization, indicating that the nanometric scale and the bioactivity of β-TCP favor a dynamic tissue replacement in critical defects.

This in vitro study compared enamel surface microhardness responses to sodium fluoride (NaF), tricalcium phosphate (TCP), and calcium glycerophosphate (CaGP) in an olive leaf extract-containing artificial saliva carrier and to the unsupplemented carrier. A total of 131 human premolars were randomly allocated to NaF (n = 40), TCP (n = 40), CaGP (n = 40), or carrier (n = 11). After 96 h of demineralization, specimens underwent continuous immersion for 28 days. The primary outcome was surface microhardness recovery (ΔVHN), calculated as post-treatment minus post-demineralization Vickers hardness number (VHN). Scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDX) was exploratory (n = 14). Surface hardness increased in all groups. Mean ΔVHN was 105.00 ± 53.00, 138.11 ± 50.40, 102.81 ± 48.46, and 116.98 ± 39.71 for NaF, TCP, CaGP, and carrier, respectively. The TCP formulation showed greater ΔVHN than the NaF and CaGP formulations (Bonferroni-adjusted p = 0.027 and 0.009), but no supplemented formulation showed significantly greater recovery than the carrier after multiplicity correction. Supplementary analysis likewise did not demonstrate a TCP-carrier difference (adjusted p = 0.117). No corrected SEM-EDX stage contrast was significant. These results describe surface mechanical responses of specific formulations at unequal doses under prolonged laboratory exposure. They do not establish incremental benefit over the calcium/phosphate-containing carrier or superior remineralizing efficacy of TCP; complete lesion repair cannot be inferred.

Peri-implantitis is a plaque-associated inflammatory condition characterized by progressive loss of supporting peri-implant bone and remains one of the most challenging biological complications in implant dentistry. Although reconstructive procedures are increasingly used, the relative effectiveness of different regenerative biomaterials and biologically enhanced strategies remains uncertain. This structured narrative review critically evaluates current clinical evidence for regenerative biomaterials used in peri-implantitis treatment and places emerging biological and cell-based approaches within their appropriate translational context. A structured literature search was conducted in PubMed/MEDLINE. Particular emphasis was placed on direct human evidence concerning enamel matrix derivative, porous titanium granules, deproteinized bovine bone mineral (DBBM), hydroxyapatite, biphasic calcium phosphate, and platelet-rich fibrin, while periodontal, endodontic, and preclinical studies were considered indirect or translational evidence where relevant. Available clinical studies indicate that reconstructive procedures can improve radiographic defect fill and selected peri-implant clinical parameters; however, radiographic improvement does not necessarily correspond to complete disease resolution or true re-osseointegration. Among currently evaluated grafting materials, DBBM, porous titanium granules, and hydroxyapatite are supported by direct human clinical evidence, although heterogeneity in HA formulations and accompanying treatment protocols limits material-specific conclusions. BCP-containing reconstructive protocols have also been evaluated clinically, but the independent contribution of BCP remains difficult to isolate. Enamel matrix derivative and platelet-rich fibrin may provide biologically active adjunctive effects, although their independent contribution within multimodal regenerative protocols remains difficult to determine. Emerging cell-based and cell-derived strategies offer additional regenerative potential but remain predominantly supported by preclinical or translational evidence. No single biomaterial has demonstrated universal superiority. Future s

Hydroxyapatite (HAp) possesses exceptional compositional flexibility, allowing for extensive cationic, anionic, and coupled substitutions that can modify its structural, mechanical, electronic, magnetic, catalytic, and biological properties. However, experimental identification of dopant locations and charge-compensation mechanisms remains challenging, particularly in nanocrystalline, calcium-deficient, and multiphase materials. This review evaluates first-principles studies of ion-substituted HAp, with particular emphasis on substitution-site preferences, defect association, charge compensation, thermodynamic stability, configurational effects, surfaces, hydration, and comparison with experimental observables. Unlike earlier reviews that primarily catalogued individual dopants and their calculated effects, the present work critically examines the methodological and defect-chemical assumptions underlying reported substitution mechanisms, including charge compensation, configurational sampling, chemical-potential definitions, hydration, finite-temperature effects, and experimental validation. The literature demonstrates that dopant site preference is not an intrinsic and concentration-independent property of an element. Instead, it depends on supercell size, dopant concentration, hydroxyl ordering, oxidation and spin states, compensating defects, chemical potentials, hydration, temperature, and the presence of other impurities. Many apparent discrepancies between studies arise from small simulation cells, incomplete configurational sampling, inconsistent formation-energy definitions, or calculations performed for assumed compositions without explicit charge compensation. The strongest structural assignments combine defect energetics with directly calculated spectroscopic parameters. Future predictive models should treat substituted HAp as a condition-dependent ensemble of interacting defects and integrate large-scale configurational sampling, finite-temperature methods, hydrated surfaces, machine learning, and advanced spectroscopic validation.

Critical-sized bone defects remain a major clinical challenge because of their limited regenerative capacity and the high incidence of delayed healing and non-union. Biomorphic calcium phosphate scaffolds have emerged as promising bone tissue engineering (BTE) platforms owing to their ability to reproduce the hierarchical architecture of trabecular bone while providing a bioactive environment for bone regeneration. In the present study, the early osteogenic transcriptional response of biomorphic magnesium-doped hydroxyapatite (HA)/β-tricalcium phosphate (β-TCP) scaffolds obtained through biomorphic transformation of a rattan wood template was investigated to evaluate their ability to support the early osteogenic response of pre-osteoblastic cells. Porous scaffolds preserving the hierarchical architecture of the rattan template and exhibiting different HA/β-TCP phase compositions were obtained through a multistep biomorphic transformation process followed by controlled magnesium incorporation. Cytocompatibility was assessed using MC3T3-E1 pre-osteoblastic cells by evaluating cell viability, adhesion and proliferation. The early osteogenic response was investigated by analyzing the expression of representative osteogenic marker genes in cells cultured on the scaffolds under basal and osteogenic conditions. All scaffold formulations were cytocompatible and supported cell adhesion and proliferation. Culture on biomorphic Mg2+-doped HA/β-TCP scaffolds promoted the expression of osteogenic marker genes, and this response was further enhanced following osteogenic stimulation. No statistically significant differences among the investigated formulations were detected in cell viability or osteogenic marker gene expression. Overall, these findings demonstrate that biomorphic Mg2+-doped HA/β-TCP scaffolds provide a favorable microenvironment for pre-osteoblastic cell growth and early osteogenic transcriptional commitment. The present work also establishes a simplified experimental model for investigating the contribution of magnesium to the early osteogenic transcriptional response of biomorphic calcium phosphate scaffolds, providing a rational basis for the development of

INTRODUCTION: Teriparatide (TPTD) is an established osteoanabolic agent for the treatment of osteoporosis; however, its short circulating half-life necessitates repeated administration, while limited skeletal selectivity may reduce delivery efficiency. To address these limitations, we developed an Asp6-functionalized, bone-targeting exosome system carrying TPTD mRNA (Asp6-Exo@TPTD). An Exo-Motif sequence was incorporated into the TPTD mRNA construct to facilitate hnRNPA2B1-associated enrichment of the transcript in exosomes, while surface modification with the hydroxyapatite-binding peptide Asp6 was used to enhance skeletal affinity. BMSC-derived exosomes may additionally provide intrinsic regenerative signals that complement the osteoanabolic activity of TPTD. METHODS: Mouse bone marrow mesenchymal stromal cells (BMSCs) were incubated with different exosome formulations to evaluate intracellular TPTD mRNA transfer, TPTD protein production, CRE-dependent reporter activity, and osteogenic differentiation. Free TPTD was included as a pharmacological reference in the functional, osteogenic, and animal efficacy experiments. The bone-binding properties of the engineered exosomes were assessed using hydroxyapatite-containing bone samples and ex vivo bone tissues. In vivo biodistribution was evaluated by fluorescence imaging after intravenous administration. Therapeutic efficacy was investigated in an ovariectomy-induced osteoporosis mouse model by assessing trabecular microarchitecture, histological changes, serum bone-formation markers, and dynamic bone formation. Preliminary tolerability was evaluated by major-organ histology and serum biochemical analyses, including serum calcium and hepatic and renal function indices. RESULTS: Asp6-Exo@TPTD increased intracellular TPTD mRNA levels and TPTD secretion in recipient BMSCs and enhanced CRE-dependent luciferase activity, osteogenic gene expression, alkaline phosphatase staining, and extracellular matrix mineralization. Asp6-Exo@TPTD exhibited greater binding to bone tissues than both unloaded Exo and non-targeted Exo@TPTD in vitro and ex vivo. Following systemic administration, bone-associated fluorescence remained dete

A cardinal feature of nonexudative age-related macular degeneration (AMD) is the accumulation of drusen between the retinal pigment epithelium (RPE) and Bruch's membrane, yet the mechanisms that initiate and promote drusen formation remain to be fully understood. Hydroxyapatite (HAP), a calcium-phosphate mineral identified within human drusen, has been proposed to contribute to drusen nucleation and is associated with increased likelihood of RPE atrophy. However, mechanistic studies providing insight into RPE-associated mineralization have been limited by a lack of easy-to-use and manipulatable culture models. Here, we established a rapid, inducible ARPE-19-based model of HAP mineralization. We found that ARPE-19 cells cultured in minimum essential media (MEM) supplemented with nicotinamide (NIC), sodium phosphate, and ascorbic acid (NaPAA) reproducibly formed HAP positive deposits, whereas mineralization was not observed while using standard DMEM/F12 medium, DMEM/F12 with NaPAA, MEM-NIC medium, or MEM-NIC medium with alternative osteogenic supplements (such as β-glycerophosphate, ascorbic acid, and dexamethasone). Scanning electron microscopy with energy dispersive X ray spectroscopy demonstrated that the formed deposits were enriched in calcium (Ca) and phosphorus (P) with Ca/P ratios comparable to drusen-associated HAP deposits from AMD donor tissue. ARPE-19-based HAP deposits were also closely associated with neutral lipid-rich material, staining positive for BODIPY around their core structure. Bulk RNA sequencing of mineralized ARPE-19 cells revealed extracellular matrix, angiogenic, inflammatory, and metabolic transcriptional changes in the absence of strong enrichment of canonical osteogenic pathways. Co-treatment of mineralizing cells with either pyrophosphate, EDTA, or sodium citrate significantly reduced mineral deposition, but these approaches were not able to reverse it. Together, these findings establish a tractable RPE mineralization model that recapitulates key features of AMD-associated HAP and provides a platform for investigating mechanisms of drusen-associated mineral formation.

Dental calculus is a mineralized oral biofilm widely occurring in domestic dogs, yet its mineralogical variability and chemical evolution remain insufficiently defined. Here, we investigate dental calculus collected as biological waste material during routine professional dental cleaning from twenty-eight indoor pet dogs of different breeds, ages, and clinical backgrounds. X-ray powder diffraction, vibrational spectroscopy, and elemental analysis were combined to determine the crystalline phase assemblage, phosphate and carbonate spectral signatures, and major-element composition of the deposits. The crystalline fraction is dominated by hydroxyapatite and magnesian-calcite, which occur over a broad compositional range from calcite-rich to apatite-rich deposits. Raman analysis of selected apatite-rich samples further indicates the presence of structurally disordered phosphate contributions compatible with amorphous calcium phosphate, while quantitative phase analysis of a representative apatite-rich sample reveals a substantial amorphous fraction. Elemental data show that phosphorus increases monotonically with the crystalline hydroxyapatite fraction, whereas calcium and magnesium remain comparatively constant across the sample set. The Ca/P ratio is markedly higher than that of stoichiometric hydroxyapatite and decreases nonlinearly with increasing hydroxyapatite fraction, supporting the presence of calcium-bearing nonapatitic components and confirming major-element chemistry as an independent descriptor of the calcite-apatite balance. Correlation and exploratory multivariate analyses indicate that hydroxyapatite enrichment is moderately associated with dog age, ablated calculus mass, and estimated accumulation time, defining an age- and accumulation-associated mineralization continuum rather than a fixed calculus composition. These results provide a mineralogical and chemical framework for canine dental calculus as a heterogeneous biomineral system and suggest that its composition records coupled processes of biofilm mineralization, deposit accumulation, and mineral maturation. The study is cross-sectional and does not validate diagnostic use, but establishes a

Dental bleaching with 35% hydrogen peroxide (HP) can cause deleterious effects on the mineral content of enamel. In this regard, remineralizing submicroparticles of calcium polyphosphate (CaPP) have been investigated for their ability to deposit calcium ions into enamel's hydroxyapatite. Thus, this study aimed to evaluate the effects of commercial toothpastes with or without the addition of CaPP submicroparticles after in-office bleaching treatment with 35% HP regarding color (ΔE, ΔE00 and WID), microhardness (KHN), and surface roughness (Ra). MATERIAL AND METHODS: Eighty bovine incisors were randomly divided into eight groups (n = 10): NC (negative control); HP (Whiteness HP 35%-FGM); HP + CT12 (HP + Colgate Total 12); HP + CMP (HP + Colgate Máxima Proteção Anticáries); HP + CPA (HP + Colgate Sensitive Pró-Alívio); HP + SRP (HP + Sensodyne Repair and Protect); HP + CT12 + CaPP (HP + Colgate Total 12 with 1% CaPP); HP + CMP + 1% CaPP (HP + Colgate Máxima Proteção Anticáries with 1% CaPP). All samples were subjected to the mechanical brushing protocol with 825 cycles and kept in artificial saliva with daily exchanges. ΔE, ΔE00, and WID were analyzed through generalized linear models fitted for the group effect. KHN and Ra were analyzed through mixed linear models for repeated measures over time. All analysis was performed in R* software at the 5% significance level. RESULTS: Color variation (ΔE and ΔE00) was higher in the HP + SRP group compared to NC and HP (p < 0.0001). At T1, the NC group had a lower WID than other groups (p < 0.0001). Surface microhardness (KHN) analyses showed a significant group-time interaction (p = 0.04). At T1, the HP + CPA and HP + CT12 + 1% CaPP groups showed significantly higher median KHN values than the NC, HP, HP + CT12, and HP + CMP + 1% CaPP groups (p < 0.05). Surface roughness (Ra) increased significantly after the first bleaching session, regardless of the experimental group (p = 0.002). CONCLUSION: The whitening effectiveness of 35% HP was maintained across the evaluated toothpaste formulations. Colgate Total 12 supplemented with 1% CaPP resulted in higher enamel microhardness than the corresponding formulation without CaPP, w

Amelogenin is a major component in developing enamel protein matrix and plays a key role in regulating enamel mineral morphology. However, intrinsic disorder encoded in amelogenin's low-complexity regions leads to structural heterogeneity, thereby evading high-resolution characterization under physiological conditions. We hypothesize that amelogenin undergoes domain-specific rather than uniform structural and dynamic remodeling in regulating enamel apatite formation. Solid-state NMR (SSNMR), coupled with complementary techniques including scanning electron microscopy (SEM), AFM-based nano-scale Infrared Spectroscopy (AFM-NanoIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), was employed to correlate amelogenin structural transitions with the mineral morphological changes across atomic to microscale resolutions at near physiological conditions in this study. Both cross-polarization and J-coupling based magic-angle-spinning (MAS) SSNMR experiments delineated an assembly landscape comprising rigid and dynamic components during calcium phosphate mineralization. Time-resolved tracking revealed distinct, stage-specific domain behaviors: the N-terminal domain partially adopts a β-strand secondary conformation with amyloid properties and gradually gains ordering towards the late-stage biomineralization, coinciding with HAP crystal elongation; the C-terminal domain maintains structurally rigidity but with structural reorganization during the mineralization; the central domain becomes increasingly dynamic as mineralization progresses, indicated by J-coupling-based 3D NMR experiments (HNCA, HNcoCA, HNCO, and CBCAcoNH), suggesting interactions with the minerals earlier, but later weakened protein-mineral contacts. These domain-specific, spatiotemporal roles collectively may contribute to the hierarchical mineralization process, providing insight into enamel formation. STATEMENT OF SIGNIFICANCE: Understanding how nature builds complex materials like tooth enamel requires tracking the dynamic role of proteins, which are often transient in nature. By integrating advanced solid-state NMR with high-resolution imaging, we captured, for the first time, how the

Treatment of 99Tc in contaminated environments remains an important challenge in the remediation of legacy nuclear sites, including Hanford (USA) and Sellafield (UK). The highly mobile pertechnetate anion (Tc(VII)O4-) dominates in oxic shallow subsurface environments. Immobilization driven by biogeochemical reduction of Tc(VII)O4- to poorly soluble Tc(IV) species has been a key focus for remediation approaches. Here, we explore a novel 99Tc remediation strategy employing bisphosphonate ligands (e.g., medronic acid, MDP), which form soluble 99Tc(IV)-phosphate complexes that can subsequently be incorporated into calcium (Ca)-phosphate phases. We explored this MDP ligand-based approach in batch experiments containing 99Tc, hydroxyapatite, sediment, and synthetic groundwater representative of key nuclear sites. 99Tc concentration and speciation were tracked using a multitechnique approach including X-ray absorption spectroscopy. Additionally, we explored MDP-enhanced Tc scavenging in the column experiments. Here, in situ planar and tomographic gamma imaging employing 99mTc as a radiotracer showed enhanced removal of MDP-ligated 99mTc(IV) under dynamic flow conditions and field-relevant 99mTc concentrations. Finally, the feasibility of microbially mediated transformations to form MDP-ligated Tc(IV) was examined to explore the potential for this approach to support in situ bioremediation of technetium contamination. Here, 99Tc(VII) was bioreduced in the presence of MDP using the metal-reducing bacteria Shewanella oneidensis MR-1 to form the Tc(IV)-MDP precursor for enhanced removal by Ca phosphate. Overall, these findings demonstrate that 99Tc(VII) (bio)reduction and complexation with Tc(IV)-MDP enhanced 99Tc scavenging by Ca-phosphate phases. © 2026 American Chemical Society.

Synthesis and characterization of calcium-based materials (CBMs) such as calcium pyrophosphate and hydroxyapatite activated with Er(III)-Yb(III) and Eu(III), respectively, are reported to establish their utility as markers for dosimetry and biological imaging. Under 980 and 246 nm excitation, these phosphors produce distinct emissions through 2H11/2 to 4I15/2 and 5D0 to 7F4 Er(III) and Eu(III) transitions, respectively. Despite the promising optical performance of these materials, there is a notable lack of toxicological data regarding lanthanides such as Er(III), Yb(III), and Eu(III) when utilized as dopants. To address this knowledge gap, a chronic toxicity study was performed by using the Daphnia magna model at 300 mg/L. The results indicate that although CBMs do not cause significant mortality, they can produce significant physiological changes, such as delaying sexual maturity from 9.6 to 13 days and reducing the number of neonates per female (around 50%) in the Eu(III)-doped samples (the most critical case). Survival rates also showed a decrease, from 95% to near 70%, in doped hydroxyapatite. These findings suggest that CBMs are suitable for biomedical applications because they cannot produce either highly toxic or fatal effects at these levels. Nevertheless, their eventual implementation could require careful concentration management to protect the organism's suitability. This work provides an assessment of the environmental impact of these dopants and supports their responsible integration into future device development and diagnostic biological imaging applications. © 2026 American Chemical Society.

Investigating the effect of amino acids, which are the building blocks of proteins, in biomineralization is beneficial to provide deeper insight into the function that protein exerts in mineralization. In this work, we tethered different amino acids to a single layer of two-dimensional polymer so that the density and spatial dispersion of amino acids could be controlled, and we studied the structural dependence of amino acids in inducing hydroxyapatite (HAp) mineralizaion. FTIR, Raman, X-ray photoelectric spectroscopy, and scanning electron microscopy were utilized to explore the morphological characteristics, chemical components, and crystallinity of the mineral layers. The results demonstrated that aspartate had stronger effectiveness in mineralization compared with serine, which can be rationalized by the difference in carboxyl group density and surface potential between these two materials. Our strategy provides a possible path for the decoupling of complex influencing factors in biomimic mineralization so that it gives more detailed insight into the structure-performance relationship. © 2026 American Chemical Society.

The Masquelet technique is widely used for reconstructing critical-sized bone defects; however, autologous bone grafting (ABG) is associated with donor-site morbidity such as pain and bleeding. Bone morphogenetic protein-2 (BMP-2) has attracted attention as a potential alternative strategy for promoting bone regeneration. Studies on direct comparisons between BMP-2 and autologous bone grafting within the context of the Masquelet technique are limited. The purpose of this study was to establish a novel rabbit femoral Masquelet model and compare the bone regenerative capacity of ABG with β-tricalcium phosphate (β-TCP) loaded with BMP-2. A 20-mm segmental defect was created in the femur of 24-week-old New Zealand White rabbits and stabilized with a locking plate. The defect was filled with polymethyl methacrylate cement, which was removed four weeks later to induce membrane formation. The defect was subsequently filled with autologous iliac bone (ABG group) or β-TCP granules containing BMP-2 (BMP-2 group). Bone regeneration was evaluated 12 weeks after the second surgery using radiographic, histological, micro-computed tomography (μCT), and biomechanical analyses. Radiographic evaluation demonstrated satisfactory bone union in both groups, without substantial difference in union rate. Histological analysis showed cortical continuity and new bone formation in both groups. μ-CT revealed that the bone volume/tissue volume ratio of total calcified callus was significantly higher in the ABG group, whereas the tissue mineral density was significantly higher in the BMP-2 group. Biomechanical testing showed no significant differences in ultimate stress, extrinsic stiffness, or failure energy between the two groups. In this rabbit femoral Masquelet model, BMP-2 delivered with β-TCP achieved bone regeneration comparable to that of autologous bone grafting. These findings suggest that BMP-2 may represent a promising option for bone reconstruction using the Masquelet technique.