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Sustained low-dose dexamethasone delivery via a PLGA microsphere-embedded agarose implant for enhanced osteochondral repair
Articular cartilage defects are a common source of joint pain and dysfunction. We hypothesized that sustained low-dose dexamethasone (DEX) delivery via an acellular osteochondral implant would have a dual pro-anabolic and anti-catabolic effect, both supporting the functional integrity of adjacent gr...
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| Published in: | Acta biomaterialia 2020-01, Vol.102, p.326-340 |
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| creator | Stefani, Robert M. Lee, Andy J. Tan, Andrea R. Halder, Saiti S. Hu, Yizhong Guo, X. Edward Stoker, Aaron M. Ateshian, Gerard A. Marra, Kacey G. Cook, James L. Hung, Clark T. |
| description | Articular cartilage defects are a common source of joint pain and dysfunction. We hypothesized that sustained low-dose dexamethasone (DEX) delivery via an acellular osteochondral implant would have a dual pro-anabolic and anti-catabolic effect, both supporting the functional integrity of adjacent graft and host tissue while also attenuating inflammation caused by iatrogenic injury. An acellular agarose hydrogel carrier with embedded DEX-loaded poly(lactic-co-glycolic) acid (PLGA) microspheres (DLMS) was developed to provide sustained release for at least 99 days. The DLMS implant was first evaluated in an in vitro pro-inflammatory model of cartilage degradation. The implant was chondroprotective, as indicated by maintenance of Young's modulus (EY) (p = 0.92) and GAG content (p = 1.0) in the presence of interleukin-1β insult. In a subsequent preliminary in vivo experiment, an osteochondral autograft transfer was performed using a pre-clinical canine model. DLMS implants were press-fit into the autograft donor site and compared to intra-articular DEX injection (INJ) or no DEX (CTL). Functional scores for DLMS animals returned to baseline (p = 0.39), whereas CTL and INJ remained significantly worse at 6 months (p |
| doi_str_mv | 10.1016/j.actbio.2019.11.052 |
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Articular cartilage defects are a common source of joint pain and dysfunction. Effective treatment of these injuries may prevent the progression of osteoarthritis and reduce the need for total joint replacement. Dexamethasone, a potent glucocorticoid with concomitant anti-catabolic and pro-anabolic effects on cartilage, may serve as an adjuvant for a variety of repair strategies. Utilizing a dexamethasone-loaded osteochondral implant with controlled release characteristics, we demonstrated in vitro chondroprotection in the presence of IL-1-induced degradation and improved in vivo functional outcomes following osteochondral repair. These improved outcomes were correlated with superior histological cartilage scores and minimal-to-no comorbidity, which is a risk with high dose dexamethasone injections. Using this model of cartilage restoration, we have for the first time shown the application of targeted, low-dose dexamethasone for improved healing in a preclinical model of focal defect repair.
[Display omitted]</description><identifier>ISSN: 1742-7061</identifier><identifier>EISSN: 1878-7568</identifier><identifier>DOI: 10.1016/j.actbio.2019.11.052</identifier><identifier>PMID: 31805408</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Anti-Inflammatory Agents - therapeutic use ; Arthralgia ; Autografts - transplantation ; Biomedical materials ; Bone implants ; Bone Transplantation ; Cartilage ; Cartilage (articular) ; Cartilage, Articular - transplantation ; Cattle ; Chondrocytes ; Collagen ; Controlled release ; Cytokines ; Cytotoxicity ; Degradation ; Delayed-Action Preparations ; Dexamethasone ; Dexamethasone - therapeutic use ; Dogs ; Drug Carriers - chemistry ; Hindlimb - surgery ; Hydrogels ; IL-1β ; Inflammation ; Inflammatory response ; Interleukin 1 ; Knee ; Lymphocytes T ; Mechanical properties ; Microspheres ; Modulus of elasticity ; Osteochondral repair ; Pain ; Polylactic Acid-Polyglycolic Acid Copolymer - chemistry ; Polylactide-co-glycolide ; Preclinical models ; Proteoglycans ; Sepharose - chemistry ; Surgical implants ; Sustained release ; Synovial fluid ; Targeted drug delivery ; Transplants & implants</subject><ispartof>Acta biomaterialia, 2020-01, Vol.102, p.326-340</ispartof><rights>2019</rights><rights>Copyright © 2019. Published by Elsevier Ltd.</rights><rights>Copyright Elsevier BV Jan 15, 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c528t-76f26b7725e7c0ed9214fa72f1cc2369fc263885b79cf9ad742092d5187d2acf3</citedby><cites>FETCH-LOGICAL-c528t-76f26b7725e7c0ed9214fa72f1cc2369fc263885b79cf9ad742092d5187d2acf3</cites><orcidid>0000-0001-9959-1709</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31805408$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stefani, Robert M.</creatorcontrib><creatorcontrib>Lee, Andy J.</creatorcontrib><creatorcontrib>Tan, Andrea R.</creatorcontrib><creatorcontrib>Halder, Saiti S.</creatorcontrib><creatorcontrib>Hu, Yizhong</creatorcontrib><creatorcontrib>Guo, X. Edward</creatorcontrib><creatorcontrib>Stoker, Aaron M.</creatorcontrib><creatorcontrib>Ateshian, Gerard A.</creatorcontrib><creatorcontrib>Marra, Kacey G.</creatorcontrib><creatorcontrib>Cook, James L.</creatorcontrib><creatorcontrib>Hung, Clark T.</creatorcontrib><title>Sustained low-dose dexamethasone delivery via a PLGA microsphere-embedded agarose implant for enhanced osteochondral repair</title><title>Acta biomaterialia</title><addtitle>Acta Biomater</addtitle><description>Articular cartilage defects are a common source of joint pain and dysfunction. We hypothesized that sustained low-dose dexamethasone (DEX) delivery via an acellular osteochondral implant would have a dual pro-anabolic and anti-catabolic effect, both supporting the functional integrity of adjacent graft and host tissue while also attenuating inflammation caused by iatrogenic injury. An acellular agarose hydrogel carrier with embedded DEX-loaded poly(lactic-co-glycolic) acid (PLGA) microspheres (DLMS) was developed to provide sustained release for at least 99 days. The DLMS implant was first evaluated in an in vitro pro-inflammatory model of cartilage degradation. The implant was chondroprotective, as indicated by maintenance of Young's modulus (EY) (p = 0.92) and GAG content (p = 1.0) in the presence of interleukin-1β insult. In a subsequent preliminary in vivo experiment, an osteochondral autograft transfer was performed using a pre-clinical canine model. DLMS implants were press-fit into the autograft donor site and compared to intra-articular DEX injection (INJ) or no DEX (CTL). Functional scores for DLMS animals returned to baseline (p = 0.39), whereas CTL and INJ remained significantly worse at 6 months (p < 0.05). DLMS knees were significantly more likely to have improved OARSI scores for proteoglycan, chondrocyte, and collagen pathology (p < 0.05). However, no significant improvements in synovial fluid cytokine content were observed. In conclusion, utilizing a targeted DLMS implant, we observed in vitro chondroprotection in the presence of IL-1-induced degradation and improved in vivo functional outcomes. These improved outcomes were correlated with superior histological scores but not necessarily a dampened inflammatory response, suggesting a primarily pro-anabolic effect.
Articular cartilage defects are a common source of joint pain and dysfunction. Effective treatment of these injuries may prevent the progression of osteoarthritis and reduce the need for total joint replacement. Dexamethasone, a potent glucocorticoid with concomitant anti-catabolic and pro-anabolic effects on cartilage, may serve as an adjuvant for a variety of repair strategies. Utilizing a dexamethasone-loaded osteochondral implant with controlled release characteristics, we demonstrated in vitro chondroprotection in the presence of IL-1-induced degradation and improved in vivo functional outcomes following osteochondral repair. These improved outcomes were correlated with superior histological cartilage scores and minimal-to-no comorbidity, which is a risk with high dose dexamethasone injections. Using this model of cartilage restoration, we have for the first time shown the application of targeted, low-dose dexamethasone for improved healing in a preclinical model of focal defect repair.
[Display omitted]</description><subject>Animals</subject><subject>Anti-Inflammatory Agents - therapeutic use</subject><subject>Arthralgia</subject><subject>Autografts - transplantation</subject><subject>Biomedical materials</subject><subject>Bone implants</subject><subject>Bone Transplantation</subject><subject>Cartilage</subject><subject>Cartilage (articular)</subject><subject>Cartilage, Articular - transplantation</subject><subject>Cattle</subject><subject>Chondrocytes</subject><subject>Collagen</subject><subject>Controlled release</subject><subject>Cytokines</subject><subject>Cytotoxicity</subject><subject>Degradation</subject><subject>Delayed-Action Preparations</subject><subject>Dexamethasone</subject><subject>Dexamethasone - therapeutic use</subject><subject>Dogs</subject><subject>Drug Carriers - chemistry</subject><subject>Hindlimb - surgery</subject><subject>Hydrogels</subject><subject>IL-1β</subject><subject>Inflammation</subject><subject>Inflammatory response</subject><subject>Interleukin 1</subject><subject>Knee</subject><subject>Lymphocytes T</subject><subject>Mechanical properties</subject><subject>Microspheres</subject><subject>Modulus of elasticity</subject><subject>Osteochondral repair</subject><subject>Pain</subject><subject>Polylactic Acid-Polyglycolic Acid Copolymer - chemistry</subject><subject>Polylactide-co-glycolide</subject><subject>Preclinical models</subject><subject>Proteoglycans</subject><subject>Sepharose - chemistry</subject><subject>Surgical implants</subject><subject>Sustained release</subject><subject>Synovial fluid</subject><subject>Targeted drug delivery</subject><subject>Transplants & implants</subject><issn>1742-7061</issn><issn>1878-7568</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9UU2L1TAUDaI449N_IBJw46Y1SZsm3QjDoKPwQEFdhzS5nebRJjVp3zj450154_ixcJWEe87N-UDoOSUlJbR5fSi1WToXSkZoW1JaEs4eoHMqhSwEb-TDfBc1KwRp6Bl6ktKBkEpSJh-js4pKwmsiz9GPz2tatPNg8RhuChsSYAvf9QTLoFPw22t0R4i3-Og01vjT_uoCT87EkOYBIhQwdWBt5utrHTe6m-ZR-wX3IWLwg_YmD0NaIJgheBv1iCPM2sWn6FGvxwTP7s4d-vru7ZfL98X-49WHy4t9YTiTSyGanjWdEIyDMARsy2jda8F6agyrmrY3rKmk5J1oTd9qm02Tllmek7BMm77aoTenvfPaTWAN-CWLUHN0k463Kmin_p54N6jrcFRNm3PkJC94dbcghm8rpEVNLhkYs00Ia1KsYkxQyZo2Q1_-Az2ENfpsL6N41lVXWe0O1SfUFmOK0N-LoURt7aqDOrWrtnYVpSq3m2kv_jRyT_pV52-nkOM8OogqGQdbAS6CWZQN7v8__ATe5rqF</recordid><startdate>20200115</startdate><enddate>20200115</enddate><creator>Stefani, Robert M.</creator><creator>Lee, Andy J.</creator><creator>Tan, Andrea R.</creator><creator>Halder, Saiti S.</creator><creator>Hu, Yizhong</creator><creator>Guo, X. 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Edward</creatorcontrib><creatorcontrib>Stoker, Aaron M.</creatorcontrib><creatorcontrib>Ateshian, Gerard A.</creatorcontrib><creatorcontrib>Marra, Kacey G.</creatorcontrib><creatorcontrib>Cook, James L.</creatorcontrib><creatorcontrib>Hung, Clark T.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Biotechnology Research Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta biomaterialia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stefani, Robert M.</au><au>Lee, Andy J.</au><au>Tan, Andrea R.</au><au>Halder, Saiti S.</au><au>Hu, Yizhong</au><au>Guo, X. Edward</au><au>Stoker, Aaron M.</au><au>Ateshian, Gerard A.</au><au>Marra, Kacey G.</au><au>Cook, James L.</au><au>Hung, Clark T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sustained low-dose dexamethasone delivery via a PLGA microsphere-embedded agarose implant for enhanced osteochondral repair</atitle><jtitle>Acta biomaterialia</jtitle><addtitle>Acta Biomater</addtitle><date>2020-01-15</date><risdate>2020</risdate><volume>102</volume><spage>326</spage><epage>340</epage><pages>326-340</pages><issn>1742-7061</issn><eissn>1878-7568</eissn><abstract>Articular cartilage defects are a common source of joint pain and dysfunction. We hypothesized that sustained low-dose dexamethasone (DEX) delivery via an acellular osteochondral implant would have a dual pro-anabolic and anti-catabolic effect, both supporting the functional integrity of adjacent graft and host tissue while also attenuating inflammation caused by iatrogenic injury. An acellular agarose hydrogel carrier with embedded DEX-loaded poly(lactic-co-glycolic) acid (PLGA) microspheres (DLMS) was developed to provide sustained release for at least 99 days. The DLMS implant was first evaluated in an in vitro pro-inflammatory model of cartilage degradation. The implant was chondroprotective, as indicated by maintenance of Young's modulus (EY) (p = 0.92) and GAG content (p = 1.0) in the presence of interleukin-1β insult. In a subsequent preliminary in vivo experiment, an osteochondral autograft transfer was performed using a pre-clinical canine model. DLMS implants were press-fit into the autograft donor site and compared to intra-articular DEX injection (INJ) or no DEX (CTL). Functional scores for DLMS animals returned to baseline (p = 0.39), whereas CTL and INJ remained significantly worse at 6 months (p < 0.05). DLMS knees were significantly more likely to have improved OARSI scores for proteoglycan, chondrocyte, and collagen pathology (p < 0.05). However, no significant improvements in synovial fluid cytokine content were observed. In conclusion, utilizing a targeted DLMS implant, we observed in vitro chondroprotection in the presence of IL-1-induced degradation and improved in vivo functional outcomes. These improved outcomes were correlated with superior histological scores but not necessarily a dampened inflammatory response, suggesting a primarily pro-anabolic effect.
Articular cartilage defects are a common source of joint pain and dysfunction. Effective treatment of these injuries may prevent the progression of osteoarthritis and reduce the need for total joint replacement. Dexamethasone, a potent glucocorticoid with concomitant anti-catabolic and pro-anabolic effects on cartilage, may serve as an adjuvant for a variety of repair strategies. Utilizing a dexamethasone-loaded osteochondral implant with controlled release characteristics, we demonstrated in vitro chondroprotection in the presence of IL-1-induced degradation and improved in vivo functional outcomes following osteochondral repair. These improved outcomes were correlated with superior histological cartilage scores and minimal-to-no comorbidity, which is a risk with high dose dexamethasone injections. Using this model of cartilage restoration, we have for the first time shown the application of targeted, low-dose dexamethasone for improved healing in a preclinical model of focal defect repair.
[Display omitted]</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>31805408</pmid><doi>10.1016/j.actbio.2019.11.052</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-9959-1709</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Acta biomaterialia, 2020-01, Vol.102, p.326-340 |
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| source | ScienceDirect Freedom Collection 2022-2024 |
| subjects | Animals Anti-Inflammatory Agents - therapeutic use Arthralgia Autografts - transplantation Biomedical materials Bone implants Bone Transplantation Cartilage Cartilage (articular) Cartilage, Articular - transplantation Cattle Chondrocytes Collagen Controlled release Cytokines Cytotoxicity Degradation Delayed-Action Preparations Dexamethasone Dexamethasone - therapeutic use Dogs Drug Carriers - chemistry Hindlimb - surgery Hydrogels IL-1β Inflammation Inflammatory response Interleukin 1 Knee Lymphocytes T Mechanical properties Microspheres Modulus of elasticity Osteochondral repair Pain Polylactic Acid-Polyglycolic Acid Copolymer - chemistry Polylactide-co-glycolide Preclinical models Proteoglycans Sepharose - chemistry Surgical implants Sustained release Synovial fluid Targeted drug delivery Transplants & implants |
| title | Sustained low-dose dexamethasone delivery via a PLGA microsphere-embedded agarose implant for enhanced osteochondral repair |
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