{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:11:12Z","timestamp":1788876672049,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"IER Foundation 2025","award":["IERF202502"],"award-info":[{"award-number":["IERF202502"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Funct. Biomater.","JFB"],"abstract":"<jats:p>Objective: This study aimed to evaluate the long-term degradation behavior, biostimulatory effects, and biocompatibility of a novel poly-L-lactic acid-block-polyethylene glycol\/hyaluronic acid (PLLA\u2013b\u2013PEG\/HA) composite filler for soft tissue augmentation. Methods: PLLA\u2013b\u2013PEG\/HA microsphere properties were characterized via scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance hydrogen spectroscopy (1H NMR), thermogravimetry (TG) and differential scanning calorimetry (DSC). A 104-week in vivo rabbit model was established to systematically observe filler degradation and tissue responses. Ultrasound monitoring, histological staining, ELISA and RT-PCR were performed to assess volumetric changes, inflammatory reactions and collagen synthesis-related signaling. Results: Physicochemical property tests demonstrated that PLLA\u2013b\u2013PEG retains the fundamental physicochemical properties of pristine PLLA while exhibiting enhanced hydrophilicity. B-ultrasound demonstrated a presented uniform in vivo distribution without displacement or diffusion over time, confirming steady and predictable degradation. SEM verified progressive morphological degradation and porous evolution of the microspheres. The filler induced a mild, balanced inflammatory microenvironment with early expression of both pro-inflammatory (IL-12, TNF-\u03b1) and anti-inflammatory (IL-4) cytokines, which resolved gradually over time. Sustained TGF-\u03b2 upregulation persisted throughout the 104-week observation period, driving continuous neocollagenesis and prominent neoelastogenesis, thereby achieving favorable and long-term tissue remodeling with excellent biocompatibility. Conclusions: The PLLA\u2013b\u2013PEG\/HA composite filler exhibits controllable degradation properties and homeostatic regulatory effects, along with outstanding long-term biosafety and tissue integration capacity. As an ideal biostimulatory filler for soft tissue augmentation, it can effectively facilitate the regeneration of high-quality functional extracellular matrix rich in collagen fibers and elastic fibers, and holds promising clinical prospects for natural and long-lasting soft tissue filling applications.<\/jats:p>","DOI":"10.3390\/jfb17090460","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:46:33Z","timestamp":1788875193000},"page":"460","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Long-Term In Vivo Biological Performance of PLLA\u2013b\u2013PEG\/HA Filler"],"prefix":"10.3390","volume":"17","author":[{"given":"Shujiang","family":"Zhang","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510182, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1390-8857","authenticated-orcid":false,"given":"Tong","family":"He","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Aging Regulation and Translational Innovation in Skin and Soft Tissue, Beijing 100022, China"},{"name":"Beijing Engineering Lab of Neo-Biodegradable Materials, Beijing 100022, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Shuhan","family":"Wang","sequence":"additional","affiliation":[{"name":"Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Lixin","family":"Yuan","sequence":"additional","affiliation":[{"name":"Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Hongjiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Ruizhi","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Aging Regulation and Translational Innovation in Skin and Soft Tissue, Beijing 100022, China"},{"name":"Beijing Engineering Lab of Neo-Biodegradable Materials, Beijing 100022, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8903-4504","authenticated-orcid":false,"given":"Kun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Aging Regulation and Translational Innovation in Skin and Soft Tissue, Beijing 100022, China"},{"name":"Beijing Engineering Lab of Neo-Biodegradable Materials, Beijing 100022, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1061-6020","authenticated-orcid":false,"given":"Shiwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Aging Regulation and Translational Innovation in Skin and Soft Tissue, Beijing 100022, China"},{"name":"Beijing Engineering Lab of Neo-Biodegradable Materials, Beijing 100022, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Chen","family":"Lai","sequence":"additional","affiliation":[{"name":"Biomedical Engineering Center, Peking University Shenzhen Institute, Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3508","DOI":"10.1111\/jocd.16446","article-title":"Clinical applications of a novel poly-L-lactic acid microsphere and hyaluronic acid suspension for facial depression filling and rejuvenation","volume":"23","author":"Su","year":"2024","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e70003","DOI":"10.1111\/jocd.70003","article-title":"Enhancing Facial Projection: Efficacy and Safety of a Novel Filler Combining Cross-Linked Sodium Hyaluronate Gel With Poly-L-Lactic Acid-b-PEG Microspheres for T-Zone Augmentation","volume":"24","author":"Wang","year":"2025","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e70935","DOI":"10.1111\/jocd.70935","article-title":"Cross-Linked Sodium Hyaluronate Filler Containing Poly-L-Lactic Acid-b-Poly (Ethylene Glycol) Microspheres for Periorbital Rejuvenation: A Multimodal Assessment of Physicochemical, Preclinical, and Clinical Performance","volume":"25","author":"Chen","year":"2026","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3893","DOI":"10.1111\/jocd.16527","article-title":"Safety and effectiveness results of an innovative injectable poly-L-lactic acid-based collagen stimulator (Lanluma\u00ae)-Clinical outcomes at 9 months in a post-market study","volume":"23","author":"Amselem","year":"2024","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1093\/asj\/sjaf121","article-title":"Poly-L-Lactic Acid in Aesthetic Dermatology: A Decade Beyond Volume Restoration Toward Regenerative Biostimulation","volume":"45","author":"Haykal","year":"2025","journal-title":"Aesthet. Surg. J."},{"key":"ref_6","first-page":"s35","article-title":"Understanding, avoiding, and treating potential adverse events following the use of injectable poly-L-lactic acid for facial and nonfacial volumization","volume":"13","author":"Vleggaar","year":"2014","journal-title":"J. Drugs Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1007\/s00266-024-04499-9","article-title":"Injectable Poly-L-Lactic Acid for Body Aesthetic Treatments: An International Consensus on Evidence Assessment and Practical Recommendations","volume":"49","author":"Haddad","year":"2025","journal-title":"Aesthet. Plast. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"110708","DOI":"10.1016\/j.clinimag.2025.110708","article-title":"Ultrasonographic evaluation of cosmetic fillers: Patterns and frequent complications\u2014A literature review","volume":"131","author":"Khorasanizadeh","year":"2026","journal-title":"Clin. Imaging"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1007\/s00266-021-02650-4","article-title":"Clinical Management of Complications Following Filler Injection","volume":"46","author":"Carella","year":"2022","journal-title":"Aesthet. Plast. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e70014","DOI":"10.1111\/srt.70014","article-title":"LC-OCT as a tool to visualize in vivo location of dermal fillers","volume":"30","author":"Musolff","year":"2024","journal-title":"Skin Res. Technol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ijpharm.2010.08.037","article-title":"In vitro degradation behavior of poly(lactide)\u2013poly(ethylene glycol) block copolymer micelles in aqueous solution","volume":"400","author":"Yang","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_12","first-page":"220","article-title":"Degradation Behaviors of Poly(L-lactic acid) Microspheres","volume":"50","author":"Ma","year":"2026","journal-title":"Polymer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e13764","DOI":"10.1111\/srt.13764","article-title":"A morphological analysis of calcium hydroxylapatite and poly-l-lactic acid biostimulator particles","volume":"30","author":"McCarthy","year":"2024","journal-title":"Skin Res. Technol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e70891","DOI":"10.1111\/jocd.70891","article-title":"A Comprehensive Evaluation of Patient Satisfaction and Clinical Outcomes in Poly-L-Lactic Acid Treatments-A Randomized, Interventional, and Comparative Clinical Study","volume":"25","author":"Dias","year":"2026","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.62347\/NFNB7436","article-title":"Poly-L-lactic acid fillers for nasal alar retraction: Safety and effectiveness in 13 cases","volume":"16","author":"Yang","year":"2024","journal-title":"Am. J. Transl. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1021\/acs.biomac.0c01504","article-title":"Poly(Ethylene Glycol) Interacts with Hyaluronan in Aqueous Media","volume":"22","author":"Musatova","year":"2021","journal-title":"Biomacromolecules"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1007\/s10965-010-9463-8","article-title":"Shear induced crystallization of poly(L-lactide) and poly(ethylene glycol) (PLLA-PEG-PLLA) copolymers with different block length","volume":"18","author":"Hu","year":"2011","journal-title":"J. Polym. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e70000","DOI":"10.1111\/jocd.70000","article-title":"Effects of Poly-L-Lactic Acid Fillers on Inflammatory Response and Collagen Synthesis in Different Animal Models","volume":"24","author":"He","year":"2025","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1002\/jbm.a.34599","article-title":"Macrophages-Key cells in the response to wear debris from joint replacements","volume":"101","author":"Nich","year":"2013","journal-title":"J. BioMed. Mater. Res. A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"a022236","DOI":"10.1101\/cshperspect.a022236","article-title":"Regulation of the Immune Response by TGF-\u03b2: From Conception to Autoimmunity and Infection","volume":"9","author":"Sanjabi","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1080\/08830185.2024.2411998","article-title":"Transforming growth factor-\u03b2 in tumor microenvironment: Understanding its impact on monocytes and macrophages for its targeting","volume":"44","author":"Hourani","year":"2025","journal-title":"Int. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E15","DOI":"10.12788\/cutis.0555","article-title":"Nodules on the Anterior Neck Following Poly-L-lactic Acid Injection","volume":"109","author":"Dunn","year":"2022","journal-title":"Cutis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"519","DOI":"10.5021\/ad.2020.32.6.519","article-title":"Late Onset Foreign Body Reaction due to Poly-L-Lactic Acid Facial Injections for Cosmetic Purpose","volume":"32","author":"Jeon","year":"2020","journal-title":"Ann. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"123370","DOI":"10.1016\/j.polymer.2020.123370","article-title":"Confined crystallization of Poly (ethylene glycol) in spherulites of Poly (L-lactic acid) in a PLLA\/PEG blend","volume":"215","author":"Banpean","year":"2021","journal-title":"Polymer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"123720","DOI":"10.1016\/j.polymer.2021.123720","article-title":"Effect of molecular weight of Poly (ethylene glycol) on plasticization of Poly (\u029f-lactic acid)","volume":"223","author":"Guo","year":"2021","journal-title":"Polymer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1093\/rb\/rbx009","article-title":"The effect of mechanical loads on the degradation of aliphatic biodegradable polyesters","volume":"4","author":"Li","year":"2017","journal-title":"Regen. Biomater."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1177\/0885328206065125","article-title":"Long-term in vivo degradation of poly-L-lactide (PLLA) in bone","volume":"21","author":"Walton","year":"2007","journal-title":"J. Biomater. Appl."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Signori, R., Barbosa, A.P., Cezar-Dos-Santos, F., Carbone, A.C., Ventura, S., Nobre, B.B.S., Neves, M.L.B.B., C\u00e2mara-Souza, M.B., Poluha, R.L., and De la Torre Canales, G. (2024). Efficacy and Safety of Poly-l-Lactic Acid in Facial Aesthetics: A Systematic Review. Polymers, 16.","DOI":"10.20944\/preprints202407.1452.v1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3653","DOI":"10.2147\/CCID.S566829","article-title":"Poly-L-Lactic Acid in Facial Rejuvenation: Volumetric Data Supporting Regenerative Outcomes","volume":"18","year":"2025","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"ojae091","DOI":"10.1093\/asjof\/ojae091","article-title":"Comparison of Different Types of Poly-L-Lactic Acid Microspheres In Vitro and In Vivo Studies","volume":"6","author":"Liu","year":"2024","journal-title":"Aesthet. Surg. J. Open Forum"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1039\/C9BM00155G","article-title":"Hyaluronic acid-based extracellular matrix triggers spontaneous M2-like polarity of monocyte\/macrophage","volume":"7","author":"Kim","year":"2019","journal-title":"Biomater. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e00682","DOI":"10.1002\/adbi.202400682","article-title":"The Immobilization of Hyaluronic Acid in 3D Hydrogel Scaffolds Modulates Macrophage Polarization","volume":"9","author":"Oates","year":"2025","journal-title":"Adv. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1021\/acsbiomaterials.5b00181","article-title":"High and low molecular weight hyaluronic acid differentially influence macrophage activation","volume":"1","author":"Rayahin","year":"2015","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_34","first-page":"929","article-title":"Recommendations on the Use of Injectable Poly-L-Lactic Acid for Skin Laxity in Off-Face Areas","volume":"18","author":"Haddad","year":"2019","journal-title":"J. Drugs Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.cps.2016.03.016","article-title":"Hyaluronic Acid Fillers: Science and Clinical Uses","volume":"43","author":"Gutowski","year":"2016","journal-title":"Clin. Plast. Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1080\/14764172.2017.1358459","article-title":"A review of hydrolifting: A new modality for skin rejuvenation","volume":"20","author":"Youn","year":"2018","journal-title":"J. Cosmet. Laser Ther."},{"key":"ref_37","first-page":"s29","article-title":"Composition and mechanism of action of poly-L-lactic acid in soft tissue augmentation","volume":"13","author":"Vleggaar","year":"2014","journal-title":"J. Drugs Dermatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5714","DOI":"10.1039\/D1BM00516B","article-title":"Collagen and the effect of poly-l-lactic acid based materials on its synthesis","volume":"9","author":"Ray","year":"2021","journal-title":"Biomater. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jdermsci.2015.01.012","article-title":"The biological basis for poly-L-lactic acid-induced augmentation","volume":"78","author":"Stein","year":"2015","journal-title":"J. Dermatol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1002\/art.30312","article-title":"Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: A novel mouse model for scleroderma?","volume":"63","author":"Wei","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1038\/jid.2010.15","article-title":"Antagonistic Effect of the Matricellular Signaling Protein CCN3 on TGF-\u03b2- and Wnt-Mediated Fibrillinogenesis in Systemic Sclerosis and Marfan Syndrome","volume":"130","author":"Lemaire","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Oh, S., Lee, J.H., Kim, H.M., Batsukh, S., Sung, M.J., Lim, T.H., Lee, M.H., Son, K.H., and Byun, K. (2023). Poly-L-Lactic Acid Fillers Improved Dermal Collagen Synthesis by Modulating M2 Macrophage Polarization in Aged Animal Skin. Cells, 12.","DOI":"10.3390\/cells12091320"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.immuni.2015.09.005","article-title":"Interleukin-4 Receptor \u03b1 Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair","volume":"43","author":"Knipper","year":"2015","journal-title":"Immunity"}],"container-title":["Journal of Functional Biomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4983\/17\/9\/460\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:53:16Z","timestamp":1788875596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4983\/17\/9\/460"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["jfb17090460"],"URL":"https:\/\/doi.org\/10.3390\/jfb17090460","relation":{},"ISSN":["2079-4983"],"issn-type":[{"value":"2079-4983","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]}}}