Smart Thin Porous Calcium Phosphate Coatings for Local Antibiotic Delivery

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V. Le, Maria Carolina Lanzino, Anika Höppel, Mirjam Rech, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6887301/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Sep, 2025 Read the published version in BMC Research Notes → Version 1 posted 10 You are reading this latest preprint version Abstract Implant failure after arthroplasty due to aseptic loosening or periprosthetic joint infections remains a serious clinical challenge. To avoid these complications, bioactive ceramic coatings e.g., β-tricalcium phosphate (β-TCP) can be used to improve the osseointegration of the prosthesis, thereby reducing the risk of aseptic loosening. Simultaneously, local antibiotic delivery from the implant surface offers a promising strategy to prevent early bacterial colonization and infection. In this study, we evaluated the feasibility of incorporating the heat-sensitive antibiotic vancomycin (VAN) into β-TCP coatings using high‐velocity suspension flame spraying (HVSFS). For this, β-TCP suspensions containing VAN-loaded supraparticles were used as feedstock. In our study, we were able to show that VAN can successfully be integrated into a β-TCP-coating using the described technique. Analysis by high-performance liquid chromatography confirmed that VAN did not undergo thermal decomposition during the coating process, and the resulting spectra corresponded to those of the untreated controls. These findings establish that HVSFS can successfully embed heat‐labile antibiotics within β-TCP matrices, yielding a multifunctional implant surface that promotes bone integration while delivering localized antimicrobial therapy. coatings HVSFS β-TCP Vancomycin supraparticles Figures Figure 1 Figure 2 Figure 3 Figure 4 1 Introduction Implant failure after arthroplasty remains a major clinical challenge, primarily due to inadequate bonding between the implant and surrounding bone tissue, as well as complications such as bacterial contamination and biofilm formation [ 1 – 3 ]. Overcoming these problems requires a combined approach: improving osseointegration while preventing bacterial infections. Recent research has demonstrated the potential of biocompatible materials to improve implant-bone integration [ 4 , 5 ]. In thin calcium phosphate (CaP) coatings, the balance between the degradation rate of the coating and the kinetics of bone regeneration is crucial. In resorbable ceramics, this process should be synchronized - ideally, the coating is gradually resorbed by the body and replaced by newly formed bone [ 6 , 7 ]. The study is part of the project “Thin resorbable coatings for optimizing osteointegration while preventing infection”. The focus is on the development of thin, porous, and bioresorbable CaP coatings with antibacterial properties, which are applied using high-velocity suspension flame spraying (HVSFS) [ 8 , 9 ]. An important strategy for increasing porosity and functionality is the incorporation of supraparticles into the layer matrix [ 10 ]. These supraparticles, made of nanoparticle (NP) building blocks and loaded with Copper (Cu) as in our previous works [ 8 , 11 , 12 ] as in the present case, with antibiotics, serve as both structural and antibacterial components. To incorporate supraparticles into the matrix, the radial injection of the suspension right after the nozzle can be used, as described in [ 11 ]. This allows thermally sensitive materials to be sprayed because their dwell time in the flame is reduced, meaning the material particles are exposed to less thermal stress. After implantation, the embedded supraparticles gradually release Vancomycin (VAN) as the coating degrades. This design aims to achieve high initial VAN release to prevent biofilm formation at an early stage, followed by sustained antibacterial activity throughout the healing phase - until the coating is completely replaced by new bone tissue. Stigter et al. [ 13 ] have also produced CaP layers with antibiotics on titanium plates, but using precipitation. Schmidmaier et al. [ 14 ] coated K-wires made of titanium using dip coating with poly(D,L-lactide) and growth factors or antibiotics [ 15 ]. This study addressed the question whether VAN is chemically or biologically degraded by the HVSFS used to deposit β-tricalcium phosphate (β-TCP) coatings. VAN is loaded into β-TCP supraparticles and radially co-deposited with the axial injected β-TCP feedstock. This should provide protection from high temperatures during the coating process and ensures a sustained release of VAN over the long term, thereby preventing infections. The outcome of these investigations provides a rational basis for tailoring HVSFS-derived β-TCP coatings that unite rapid osseointegration with long-term antibacterial protection, thereby addressing major factors of implant failure. 2 Materials and Methods The supraparticles were produced and the titanium plates coated in the same way as described in our previous work [ 8 , 10 , 11 , 16 ]. The only difference is the use of Vancomycin instead of Cu ions. 2.1 VAN-Doped Supraparticles 2.1.1 Materials for Supraparticle Synthesis and Coating Process β-TCP, 97.2%, Chemical Specialist Budenheim, Budenheim, Germany), solution styrene-butadiene rubber (SSBR, 15 wt.% in H 2 O, Targray, Kirkland, QC, Canada), phosphonate based dispersion agent (Zschimmer and Schwarz, Lahnstein, Germany) and hydrocolloid (Zschimmer and Schwarz, Lahnstein, Germany). Vancomycin hydrochloride was purchased from Hikma Pharma GmbH (Martinsried, Germany). 2.1.2 Preparation of VAN-Doped β-TCP Supraparticles (TCPVAN Particles) For spray-drying preparation, commercial β-tricalciumphosphate microparticles (TCP) were initially milled in deionized (DI) water at a 1:1 ratio for 1 hour at 700 rpm using a planetary micro mill (PULVERISETTE 7 premium line, FRITSCH, Idar-Oberstein, Germany). Subsequently, an aqueous suspension was prepared containing 30 wt.% of the milled TCP and 0.25 wt.% vancomycin (VAN), relative to the β-TCP content. To this suspension, solution-styrene butadiene rubber (SSBR) was added as a binder at 10 wt.% relative to the total TCP + VAN mass. The resulting mixture was stirred for 1 hour and then spray-dried under the following conditions: inlet temperature (T inlet ) of 130°C, aspirator setting at 100%, and pump rate at 15%. 2.2 Suspensions and Coating Deposition Subsequently, upon the identification of optimal parameters, as shown in previous works [ 8 , 11 ], VAN-doped β-TCP coatings were applied to titanium (Ti) grade 2 substrates (10x10x3 mm, ARA-T Advance GmbH, Dinslaken, Germany). While the β-TCP serves as the primary constituent for forming the matrix of the resulting coating, the VAN-doped supraparticles, acting as secondary phase, are meant to confer antibacterial properties to the coatings. Additionally, they are expected to increase the microporosity of the coatings. In fact, the supraparticles are not expected to be completely molten during the HVSFS process. As a result, the space between the nanoparticles (NPs) will be retained, creating micro- or nanoporosity [ 8 , 11 ]. 2.2.1 Suspensions Water-based suspensions were employed for the deposition of bioconductive coatings via spraying. β-tricalcium phosphate (β-TCP) raw powder was gradually introduced into a mixture of deionized (DI) water containing two stabilizing agents: 2 wt.% of a hydrocolloid and 3 wt.% (solid content) of a phosphonate-based dispersing agent, under continuous stirring. For initial optimization trials, β-TCP concentrations of 5 wt.% and 10 wt.% were tested to modulate the coating porosity. The β-TCP powder used had a particle size distribution with d50 ≤ 10 µm. For the final vancomycin (VAN)-doped coatings, two separate suspensions were prepared: one for the matrix layer, containing only β-TCP, and another for the secondary phase. The matrix suspension was composed of 5 wt.% β-TCP prepared as described above. For the secondary phase, 3 wt.% VAN-loaded supraparticles were dispersed in DI water with the same stabilizing agents and concentrations as used in the β-TCP suspension. 2.2.2 Coating Deposition The coating deposition was carried out as described elsewhere with a radial injection [ 8 , 11 , 12 ]. A modified Top Gun G system (GTV wear protection, Luckenbach, Germany) was used for this purpose. The spray gun was mounted on a six-axis robot to perform a controlled meandering motion with an offset of 3 mm and a spray distance of 120 mm. Ethylene (C 2 H 4 ) and oxygen (O 2 ) were used for combustion. The coatings were applied to Ti grade 2 substrates. All substrates were sandblasted with F60 corundum at a pressure of 4 bar prior to coating. For the coating process, the suspensions previously described were used as feedstock material. The matrix material was β-TCP, which was injected axially into the combustion chamber. The VAN-doped supraparticles suspension was instead injected radially into the flame right after the nozzle of the spray gun, as described in previous works [ 11 , 17 ]. 2.3 VAN Release The VAN-coated titanium samples were incubated in a release test with 5 ml of bidestilled water at 37°C in an incubator. After 2 weeks, the solutions were removed and analyzed using HPLC (Shimadzu CBM-20A, CTO-20AC, DGU-20A5R, LC-20ADXR, Reservoir Tray, RF-20A, SIL-30AC, SPD-M20A IVDD, Kyoto, Japan; Macherey-Nagel precolumn EC 4/3 Nucleodur 300-5 C4ec, column EC 250/3 Nucleodur 300-5 C4ec, Duren, Germany). A calibration curve of 1–50 µg/ml was prepared and examined together with the released vancomycin. Before measurement, all samples underwent sterile filtration with a 0.2 µm pore size. For VAN analysis, HPLC was conducted at a temperature of 25°C, with a running time of 10 min and a flow rate of 0.66 mL/min. The mobile phase consisted of ACN and 10 mM NH 4 H 2 PO 4 (Sigma-Aldrich, now Merck, Darmstadt, Germany), pH 2.2, adjusted with phosphoric acid, in a ratio of 12:88. The area under the curve was measured at a wavelength of 198 nm. The aim was to clarify if the vancomycin is damaged by the coating process. 3 Results VAN-doped β-TCP coatings with a thickness of 50.98 ± 5.91 µm and a porosity of 11.5 ± 0.9% were fabricated by HCSFS process (see Fig. 1 ). HPLC analysis revealed no thermal decomposition of VAN attributable to the HVSFS process. The VAN protected by the supraparticles showed no signs of decomposition. The peaks were identical to those of the calibration curve. The only difference is due to the different VAN concentrations, which are reflected in different peak heights (see Fig. 2 ). No additional peaks were detected in the spectra either. Figure 3 shows a comparison of the VAN spectra: fresh versus released from coating after 2 weeks incubating in double dest. water. Again, the only difference is the peak height/area due to the different concentrations. After incubation for 2 weeks at 37°C, the release of VAN from the supraparticles within the β-TCP coating was 24.04 ± 0.40 µg/mL. The release of VAN from the coating itself was 24.21 ± 0.5 µg/mL. No significant difference was found between the two different releases. The p-value determined by the Tukey test was 0.642. Figure 4 shows the box plots for both VAN releases after 14 days. 4 Discussion The spectra from the HPLC measurements clearly show that VAN can withstand the temperatures in the flame during the HVSFS process. Ensom et al. [18] described in their work, that after 18 hours at 100°C, only 58% of the VAN was detectable by HPLC. They also impressively demonstrated degradation peaks of VAN that occurred before and after the main peak. Dolete et al. [19] refer to oxidative decomposition of VAN after reaching a temperature of 150°C. No degradation peaks were observed in our experiments. However, this is probably due to the very short residence time in the flame. Buss et al. [20] support this theory by demonstrating that the particle residence time (PRT) can be influenced by the geometry of the reaction chamber and the rate of coaxial gas flow. At a temperature of 1000K and a flow rate of > 400 L/min, the PRT was 0.03 s, and only by increasing the temperature to 1500K was the PRT reduced to 0.001 s. We assume that the VAN in the supraparticles did not reach these temperatures at all in the HVSFS and 100% of VAN survived the processing. This is also shown by the unchanged peaks and spectra. Limitations Until now, these coatings have only been made with VAN. This is relatively temperature stable, at least for the short time it spends in the flame of the HVSFS process. Other antibiotics, such as clindamycin, might behave differently and possibly yield different results with/without supraparticles. In addition, this question was investigated at the end of an ongoing project as a pure feasibility study. Antimicrobial efficacy was not the primary focus, and will be the focus of a follow-up project. 5 Conclusion We were able to confirm that the supraparticles are suitable as carriers for antibiotics and can therefore be used to incorporate temperature-protected drugs into implant coatings. We were also able to show that VAN survives the HVSFS process unscathed, and that there is some protection against the high temperatures of the flame. Declarations Acknowledgement s The authors would like to thank Melanie Lynn Hart for proofreading of this article. Author contributions LQL and BR analyzed the samples by HPLC; AH prepared the supraparticles; MCL and MR coated the samples; SD, AK, and MS acquired the funds and supervised the project; LQL and MS drafted and revised the manuscript; all authors read and approved the manuscript. Funding This research is funded by the German Research Foundation (DFG) grant number: 240897167. Open Access funding enabled and organized by Albert-Ludwigs-University of Freiburg and Project DEAL. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request Clinical Trial number not applicable Ethics approval and consent to participate Not applicable Consent for Publication Not applicable Competing interests The authors declare that they have no competing interests References Hodges, N.A.; Sussman, E.M.; Stegemann, J.P. 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Cite Share Download PDF Status: Published Journal Publication published 01 Sep, 2025 Read the published version in BMC Research Notes → Version 1 posted Editorial decision: Revision requested 11 Aug, 2025 Reviews received at journal 07 Aug, 2025 Reviews received at journal 02 Aug, 2025 Reviewers agreed at journal 29 Jul, 2025 Reviewers agreed at journal 18 Jul, 2025 Reviewers invited by journal 07 Jul, 2025 Editor assigned by journal 28 Jun, 2025 Editor invited by journal 17 Jun, 2025 Submission checks completed at journal 17 Jun, 2025 First submitted to journal 17 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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V.","lastName":"Le","suffix":""},{"id":483132268,"identity":"ddad618b-0b1c-460d-b738-3be1ece8f4c9","order_by":1,"name":"Maria Carolina Lanzino","email":"","orcid":"","institution":"Institute for Ceramic Materials and Technologies (IKMT), University of Stuttgart","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Carolina","lastName":"Lanzino","suffix":""},{"id":483132269,"identity":"ceee5c3b-21af-4ec1-84fb-e0d1befa8c5b","order_by":2,"name":"Anika Höppel","email":"","orcid":"","institution":"Department for Functional Materials in Medicine and Dentistry, University of Würzburg","correspondingAuthor":false,"prefix":"","firstName":"Anika","middleName":"","lastName":"Höppel","suffix":""},{"id":483132270,"identity":"f3807790-76ad-4c44-851c-1465797a8034","order_by":3,"name":"Mirjam Rech","email":"","orcid":"","institution":"Institute for Ceramic Materials and Technologies (IKMT), University of Stuttgart","correspondingAuthor":false,"prefix":"","firstName":"Mirjam","middleName":"","lastName":"Rech","suffix":""},{"id":483132271,"identity":"03c763e0-e87e-446e-a625-0c58221e23fd","order_by":4,"name":"Sofia Dembski","email":"","orcid":"","institution":"Department for Functional Materials in Medicine and Dentistry, University of Würzburg","correspondingAuthor":false,"prefix":"","firstName":"Sofia","middleName":"","lastName":"Dembski","suffix":""},{"id":483132272,"identity":"7a426257-e70c-4274-aba0-2616ac01c955","order_by":5,"name":"Andreas Killinger","email":"","orcid":"","institution":"Institute for Ceramic Materials and Technologies (IKMT), University of Stuttgart","correspondingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Killinger","suffix":""},{"id":483132273,"identity":"e49bb9f0-9068-47b9-9f19-e1047ceb50dc","order_by":6,"name":"Bianca Riedel","email":"","orcid":"","institution":"G.E.R.N. Center of Tissue Replacement, Regeneration \u0026 Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Albert-Ludwigs-University of Freiburg Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Bianca","middleName":"","lastName":"Riedel","suffix":""},{"id":483132274,"identity":"ab594a49-4ed6-45ad-8a1d-be0371df074a","order_by":7,"name":"Michael Seidenstuecker","email":"data:image/png;base64,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","orcid":"","institution":"G.E.R.N. Center of Tissue Replacement, Regeneration \u0026 Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Albert-Ludwigs-University of Freiburg Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Michael","middleName":"","lastName":"Seidenstuecker","suffix":""}],"badges":[],"createdAt":"2025-06-13 10:23:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6887301/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6887301/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13104-025-07453-3","type":"published","date":"2025-09-01T15:57:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86502727,"identity":"37414f5e-760f-447e-943c-c22e355ee763","added_by":"auto","created_at":"2025-07-11 11:25:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":182550,"visible":true,"origin":"","legend":"\u003cp\u003eScanninc electron microscopy (SEM) image showing the VAN-doped β-TCP coating; including information on thickness and porosity of the coating.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6887301/v1/6a49bbf64aac58172833ef58.png"},{"id":86501994,"identity":"51776fbf-7607-4d47-9d8a-0f9b62efec4c","added_by":"auto","created_at":"2025-07-11 11:17:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":10142,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of VAN peaks by HPLC: left: freshly applied calibration curve; right: release test after HVSFS and 2 weeks incubation.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6887301/v1/e47315600aebccb64a0639a7.png"},{"id":86502725,"identity":"76478a27-ee20-4943-96ff-438e1194b089","added_by":"auto","created_at":"2025-07-11 11:25:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":14722,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of the VAN spectra from HPLC: fresh (left) versus originating from HVSFS (right).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6887301/v1/26b33f29c4e72c72e43c9947.png"},{"id":86501997,"identity":"cf3d5c55-7eb5-4607-a699-8aa8d40f9a8d","added_by":"auto","created_at":"2025-07-11 11:17:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":5758,"visible":true,"origin":"","legend":"\u003cp\u003eBox plot of VAN releases for different types of coating after 2 weeks by HPLC.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6887301/v1/e3d898e56cabe5c153fa6047.png"},{"id":90828028,"identity":"d0aca47b-603a-4b2c-82d7-360e99cce35e","added_by":"auto","created_at":"2025-09-08 16:05:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":782721,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6887301/v1/734f5979-6ca6-4017-b298-00a9fc2eec73.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Smart Thin Porous Calcium Phosphate Coatings for Local Antibiotic Delivery","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eImplant failure after arthroplasty remains a major clinical challenge, primarily due to inadequate bonding between the implant and surrounding bone tissue, as well as complications such as bacterial contamination and biofilm formation [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Overcoming these problems requires a combined approach: improving osseointegration while preventing bacterial infections. Recent research has demonstrated the potential of biocompatible materials to improve implant-bone integration [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In thin calcium phosphate (CaP) coatings, the balance between the degradation rate of the coating and the kinetics of bone regeneration is crucial. In resorbable ceramics, this process should be synchronized - ideally, the coating is gradually resorbed by the body and replaced by newly formed bone [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The study is part of the project \u0026ldquo;Thin resorbable coatings for optimizing osteointegration while preventing infection\u0026rdquo;. The focus is on the development of thin, porous, and bioresorbable CaP coatings with antibacterial properties, which are applied using high-velocity suspension flame spraying (HVSFS) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. An important strategy for increasing porosity and functionality is the incorporation of supraparticles into the layer matrix [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These supraparticles, made of nanoparticle (NP) building blocks and loaded with Copper (Cu) as in our previous works [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] as in the present case, with antibiotics, serve as both structural and antibacterial components. To incorporate supraparticles into the matrix, the radial injection of the suspension right after the nozzle can be used, as described in [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This allows thermally sensitive materials to be sprayed because their dwell time in the flame is reduced, meaning the material particles are exposed to less thermal stress. After implantation, the embedded supraparticles gradually release Vancomycin (VAN) as the coating degrades. This design aims to achieve high initial VAN release to prevent biofilm formation at an early stage, followed by sustained antibacterial activity throughout the healing phase - until the coating is completely replaced by new bone tissue. Stigter et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] have also produced CaP layers with antibiotics on titanium plates, but using precipitation. Schmidmaier et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] coated K-wires made of titanium using dip coating with poly(D,L-lactide) and growth factors or antibiotics [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis study addressed the question whether VAN is chemically or biologically degraded by the HVSFS used to deposit β-tricalcium phosphate (β-TCP) coatings. VAN is loaded into β-TCP supraparticles and radially co-deposited with the axial injected β-TCP feedstock. This should provide protection from high temperatures during the coating process and ensures a sustained release of VAN over the long term, thereby preventing infections. The outcome of these investigations provides a rational basis for tailoring HVSFS-derived β-TCP coatings that unite rapid osseointegration with long-term antibacterial protection, thereby addressing major factors of implant failure.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cp\u003eThe supraparticles were produced and the titanium plates coated in the same way as described in our previous work [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The only difference is the use of Vancomycin instead of Cu ions.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 VAN-Doped Supraparticles\u003c/h2\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003ch2\u003e2.1.1 Materials for Supraparticle Synthesis and Coating Process\u003c/h2\u003e\u003cp\u003eβ-TCP, 97.2%, Chemical Specialist Budenheim, Budenheim, Germany), solution styrene-butadiene rubber (SSBR, 15 wt.% in H\u003csub\u003e2\u003c/sub\u003eO, Targray, Kirkland, QC, Canada), phosphonate based dispersion agent (Zschimmer and Schwarz, Lahnstein, Germany) and hydrocolloid (Zschimmer and Schwarz, Lahnstein, Germany). Vancomycin hydrochloride was purchased from Hikma Pharma GmbH (Martinsried, Germany).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\u003ch2\u003e2.1.2 Preparation of VAN-Doped β-TCP Supraparticles (TCPVAN Particles)\u003c/h2\u003e\u003cp\u003eFor spray-drying preparation, commercial β-tricalciumphosphate microparticles (TCP) were initially milled in deionized (DI) water at a 1:1 ratio for 1 hour at 700 rpm using a planetary micro mill (PULVERISETTE 7 premium line, FRITSCH, Idar-Oberstein, Germany). Subsequently, an aqueous suspension was prepared containing 30 wt.% of the milled TCP and 0.25 wt.% vancomycin (VAN), relative to the β-TCP content. To this suspension, solution-styrene butadiene rubber (SSBR) was added as a binder at 10 wt.% relative to the total TCP\u0026thinsp;+\u0026thinsp;VAN mass. The resulting mixture was stirred for 1 hour and then spray-dried under the following conditions: inlet temperature (T\u003csub\u003einlet\u003c/sub\u003e) of 130\u0026deg;C, aspirator setting at 100%, and pump rate at 15%.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Suspensions and Coating Deposition\u003c/h2\u003e\u003cp\u003eSubsequently, upon the identification of optimal parameters, as shown in previous works [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], VAN-doped β-TCP coatings were applied to titanium (Ti) grade 2 substrates (10x10x3 mm, ARA-T Advance GmbH, Dinslaken, Germany). While the β-TCP serves as the primary constituent for forming the matrix of the resulting coating, the VAN-doped supraparticles, acting as secondary phase, are meant to confer antibacterial properties to the coatings. Additionally, they are expected to increase the microporosity of the coatings. In fact, the supraparticles are not expected to be completely molten during the HVSFS process. As a result, the space between the nanoparticles (NPs) will be retained, creating micro- or nanoporosity [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e2.2.1 Suspensions\u003c/h2\u003e\u003cp\u003eWater-based suspensions were employed for the deposition of bioconductive coatings via spraying. β-tricalcium phosphate (β-TCP) raw powder was gradually introduced into a mixture of deionized (DI) water containing two stabilizing agents: 2 wt.% of a hydrocolloid and 3 wt.% (solid content) of a phosphonate-based dispersing agent, under continuous stirring. For initial optimization trials, β-TCP concentrations of 5 wt.% and 10 wt.% were tested to modulate the coating porosity. The β-TCP powder used had a particle size distribution with d50\u0026thinsp;\u0026le;\u0026thinsp;10 \u0026micro;m. For the final vancomycin (VAN)-doped coatings, two separate suspensions were prepared: one for the matrix layer, containing only β-TCP, and another for the secondary phase. The matrix suspension was composed of 5 wt.% β-TCP prepared as described above. For the secondary phase, 3 wt.% VAN-loaded supraparticles were dispersed in DI water with the same stabilizing agents and concentrations as used in the β-TCP suspension.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\u003ch2\u003e2.2.2 Coating Deposition\u003c/h2\u003e\u003cp\u003eThe coating deposition was carried out as described elsewhere with a radial injection [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A modified Top Gun G system (GTV wear protection, Luckenbach, Germany) was used for this purpose. The spray gun was mounted on a six-axis robot to perform a controlled meandering motion with an offset of 3 mm and a spray distance of 120 mm. Ethylene (C\u003csub\u003e2\u003c/sub\u003eH\u003csub\u003e4\u003c/sub\u003e) and oxygen (O\u003csub\u003e2\u003c/sub\u003e) were used for combustion. The coatings were applied to Ti grade 2 substrates. All substrates were sandblasted with F60 corundum at a pressure of 4 bar prior to coating. For the coating process, the suspensions previously described were used as feedstock material. The matrix material was β-TCP, which was injected axially into the combustion chamber. The VAN-doped supraparticles suspension was instead injected radially into the flame right after the nozzle of the spray gun, as described in previous works [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.3 VAN Release\u003c/h2\u003e\u003cp\u003eThe VAN-coated titanium samples were incubated in a release test with 5 ml of bidestilled water at 37\u0026deg;C in an incubator. After 2 weeks, the solutions were removed and analyzed using HPLC (Shimadzu CBM-20A, CTO-20AC, DGU-20A5R, LC-20ADXR, Reservoir Tray, RF-20A, SIL-30AC, SPD-M20A IVDD, Kyoto, Japan; Macherey-Nagel precolumn EC 4/3 Nucleodur 300-5 C4ec, column EC 250/3 Nucleodur 300-5 C4ec, Duren, Germany). A calibration curve of 1\u0026ndash;50 \u0026micro;g/ml was prepared and examined together with the released vancomycin. Before measurement, all samples underwent sterile filtration with a 0.2 \u0026micro;m pore size. For VAN analysis, HPLC was conducted at a temperature of 25\u0026deg;C, with a running time of 10 min and a flow rate of 0.66 mL/min. The mobile phase consisted of ACN and 10 mM NH\u003csub\u003e4\u003c/sub\u003eH\u003csub\u003e2\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e (Sigma-Aldrich, now Merck, Darmstadt, Germany), pH 2.2, adjusted with phosphoric acid, in a ratio of 12:88. The area under the curve was measured at a wavelength of 198 nm. The aim was to clarify if the vancomycin is damaged by the coating process.\u003c/p\u003e\u003c/div\u003e"},{"header":"3 Results","content":"\u003cp\u003eVAN-doped β-TCP coatings with a thickness of 50.98\u0026thinsp;\u0026plusmn;\u0026thinsp;5.91 \u0026micro;m and a porosity of 11.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9% were fabricated by HCSFS process (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eHPLC analysis revealed no thermal decomposition of VAN attributable to the HVSFS process. The VAN protected by the supraparticles showed no signs of decomposition. The peaks were identical to those of the calibration curve. The only difference is due to the different VAN concentrations, which are reflected in different peak heights (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNo additional peaks were detected in the spectra either. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows a comparison of the VAN spectra: fresh versus released from coating after 2 weeks incubating in double dest. water. Again, the only difference is the peak height/area due to the different concentrations.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAfter incubation for 2 weeks at 37\u0026deg;C, the release of VAN from the supraparticles within the β-TCP coating was 24.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.40 \u0026micro;g/mL. The release of VAN from the coating itself was 24.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 \u0026micro;g/mL. No significant difference was found between the two different releases. The p-value determined by the Tukey test was 0.642. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the box plots for both VAN releases after 14 days.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThe spectra from the HPLC measurements clearly show that VAN can withstand the temperatures in the flame during the HVSFS process. Ensom et al. [18] described in their work, that after 18 hours at 100\u0026deg;C, only 58% of the VAN was detectable by HPLC. They also impressively demonstrated degradation peaks of VAN that occurred before and after the main peak. Dolete et al. [19] refer to oxidative decomposition of VAN after reaching a temperature of 150\u0026deg;C. No degradation peaks were observed in our experiments. However, this is probably due to the very short residence time in the flame. Buss et al. [20] support this theory by demonstrating that the particle residence time (PRT) can be influenced by the geometry of the reaction chamber and the rate of coaxial gas flow. At a temperature of 1000K and a flow rate of \u0026gt; 400 L/min, the PRT was 0.03 s, and only by increasing the temperature to 1500K was the PRT reduced to 0.001 s. We assume that the VAN in the supraparticles did not reach these temperatures at all in the HVSFS and 100% of VAN survived the processing. This is also shown by the unchanged peaks and spectra.\u003c/p\u003e\n\u003cp\u003eLimitations\u003c/p\u003e\n\u003cp\u003eUntil now, these coatings have only been made with VAN. This is relatively temperature stable, at least for the short time it spends in the flame of the HVSFS process. Other antibiotics, such as clindamycin, might behave differently and possibly yield different results with/without supraparticles. In addition, this question was investigated at the end of an ongoing project as a pure feasibility study. Antimicrobial efficacy was not the primary focus, and will be the focus of a follow-up project.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eWe were able to confirm that the supraparticles are suitable as carriers for antibiotics and can therefore be used to incorporate temperature-protected drugs into implant coatings. We were also able to show that VAN survives the HVSFS process unscathed, and that there is some protection against the high temperatures of the flame.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003cstrong\u003es\u003cbr\u003e\u003c/strong\u003eThe authors would like to thank Melanie Lynn Hart for proofreading of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLQL and BR analyzed the samples by HPLC; AH prepared the supraparticles; MCL and MR coated the samples; SD, AK, and MS acquired the funds and supervised the project; LQL and MS drafted and revised the manuscript; all authors read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research is funded by the German Research Foundation (DFG) grant number: 240897167. Open Access funding enabled and organized by Albert-Ludwigs-University of Freiburg and Project DEAL.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003enot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eHodges, N.A.; Sussman, E.M.; Stegemann, J.P. 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Synergistic antimicrobial activity of magnetite and vancomycin-loaded mesoporous silica embedded in alginate films. \u003cem\u003eGels\u0026nbsp;\u003c/em\u003e\u003cstrong\u003e2023\u003c/strong\u003e, \u003cem\u003e9\u003c/em\u003e, 295.https://doi.org/10.3390/gels9040295\u003c/li\u003e\n \u003cli\u003eBuss, L.; Noriler, D.; Fritsching, U. Impact of reaction chamber geometry on the particle-residence-time in flame spray process. \u003cem\u003eFlow, Turbulence and Combustion\u0026nbsp;\u003c/em\u003e\u003cstrong\u003e2020\u003c/strong\u003e, \u003cem\u003e105\u003c/em\u003e, 1055-1086.https://doi.org/10.1007/s10494-020-00187-1\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"coatings, HVSFS, β-TCP, Vancomycin, supraparticles","lastPublishedDoi":"10.21203/rs.3.rs-6887301/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6887301/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eImplant failure after arthroplasty due to aseptic loosening or periprosthetic joint infections remains a serious clinical challenge. To avoid these complications, bioactive ceramic coatings e.g., β-tricalcium phosphate (β-TCP) can be used to improve the osseointegration of the prosthesis, thereby reducing the risk of aseptic loosening. Simultaneously, local antibiotic delivery from the implant surface offers a promising strategy to prevent early bacterial colonization and infection. In this study, we evaluated the feasibility of incorporating the heat-sensitive antibiotic vancomycin (VAN) into β-TCP coatings using high‐velocity suspension flame spraying (HVSFS). For this, β-TCP suspensions containing VAN-loaded supraparticles were used as feedstock. In our study, we were able to show that VAN can successfully be integrated into a β-TCP-coating using the described technique. Analysis by high-performance liquid chromatography confirmed that VAN did not undergo thermal decomposition during the coating process, and the resulting spectra corresponded to those of the untreated controls. These findings establish that HVSFS can successfully embed heat‐labile antibiotics within β-TCP matrices, yielding a multifunctional implant surface that promotes bone integration while delivering localized antimicrobial therapy.\u003c/p\u003e","manuscriptTitle":"Smart Thin Porous Calcium Phosphate Coatings for Local Antibiotic Delivery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-11 11:16:56","doi":"10.21203/rs.3.rs-6887301/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-11T08:18:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-07T10:52:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-02T07:58:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"181624781471051254483525442622170432933","date":"2025-07-29T16:17:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"277294431458813491243157417013409231001","date":"2025-07-18T08:38:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-07T18:44:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-28T05:42:13+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-17T13:24:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-17T12:05:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Research Notes","date":"2025-06-17T12:02:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4ee167da-b465-42a9-9b21-f0685a2beeeb","owner":[],"postedDate":"July 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-08T16:02:37+00:00","versionOfRecord":{"articleIdentity":"rs-6887301","link":"https://doi.org/10.1186/s13104-025-07453-3","journal":{"identity":"bmc-research-notes","isVorOnly":false,"title":"BMC Research Notes"},"publishedOn":"2025-09-01 15:57:34","publishedOnDateReadable":"September 1st, 2025"},"versionCreatedAt":"2025-07-11 11:16:56","video":"","vorDoi":"10.1186/s13104-025-07453-3","vorDoiUrl":"https://doi.org/10.1186/s13104-025-07453-3","workflowStages":[]},"version":"v1","identity":"rs-6887301","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6887301","identity":"rs-6887301","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}