1
|
Salehi Moghaddam A, Bahrami M, Sarikhani E, Tutar R, Ertas YN, Tamimi F, Hedayatnia A, Jugie C, Savoji H, Qureshi AT, Rizwan M, Maduka CV, Ashammakhi N. Engineering the Immune Response to Biomaterials. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2414724. [PMID: 40232044 PMCID: PMC12097135 DOI: 10.1002/advs.202414724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/29/2025] [Indexed: 04/16/2025]
Abstract
Biomaterials are increasingly used as implants in the body, but they often elicit tissue reactions due to the immune system recognizing them as foreign bodies. These reactions typically involve the activation of innate immunity and the initiation of an inflammatory response, which can persist as chronic inflammation, causing implant failure. To reduce these risks, various strategies have been developed to modify the material composition, surface characteristics, or mechanical properties of biomaterials. Moreover, bioactive materials have emerged as a new class of biomaterials that can induce desirable tissue responses and form a strong bond between the implant and the host tissue. In recent years, different immunomodulatory strategies have been incorporated into biomaterials as drug delivery systems. Furthermore, more advanced molecule and cell-based immunomodulators have been developed and integrated with biomaterials. These emerging strategies will enable better control of the immune response to biomaterials and improve the function and longevity of implants and, ultimately, the outcome of biomaterial-based therapies.
Collapse
Affiliation(s)
- Abolfazl Salehi Moghaddam
- Department of BioengineeringP.C. Rossin College of Engineering & Applied ScienceLehigh UniversityBethlehemPA18015USA
| | - Mehran Bahrami
- Department of Mechanical Engineering & MechanicsLehigh UniversityBethlehemPA18015USA
| | - Einollah Sarikhani
- Department of Nano and Chemical EngineeringUniversity of California San DiegoLa JollaCA92093USA
| | - Rumeysa Tutar
- Department of ChemistryFaculty of Engineering, Istanbul University‐CerrahpaşaIstanbul, Avcılar34320Turkey
| | - Yavuz Nuri Ertas
- Department of Biomedical EngineeringErciyes UniversityKayseri38039Turkey
- ERNAM – Nanotechnology Research and Application CenterErciyes UniversityKayseri38039Turkey
| | - Faleh Tamimi
- College of Dental MedicineQatar University HealthQatar UniversityP.O. Box 2713DohaQatar
| | - Ali Hedayatnia
- Azrieli Research CenterCentre Hospitalier Universitaire Sainte‐JustineMontrealQCH3T 1C5Canada
- Institute of Biomedical Engineering, Department of Pharmacology and PhysiologyFaculty of MedicineMontrealQuebecH3T 1J4Canada
- Montreal TransMedTech InstituteiTMTMontrealQuebecH3T 1J4Canada
| | - Clotilde Jugie
- Azrieli Research CenterCentre Hospitalier Universitaire Sainte‐JustineMontrealQCH3T 1C5Canada
- Montreal TransMedTech InstituteiTMTMontrealQuebecH3T 1J4Canada
| | - Houman Savoji
- Azrieli Research CenterCentre Hospitalier Universitaire Sainte‐JustineMontrealQCH3T 1C5Canada
- Institute of Biomedical Engineering, Department of Pharmacology and PhysiologyFaculty of MedicineMontrealQuebecH3T 1J4Canada
- Montreal TransMedTech InstituteiTMTMontrealQuebecH3T 1J4Canada
| | - Asma Talib Qureshi
- Department of Biomedical EngineeringMichigan Technological UniversityHoughtonMI49931USA
| | - Muhammad Rizwan
- Department of Biomedical EngineeringMichigan Technological UniversityHoughtonMI49931USA
- Health Research InstituteMichigan Technological UniversityHoughtonMI49931USA
| | - Chima V. Maduka
- BioFrontiers InstituteUniversity of ColoradoBoulderCO80303USA
| | - Nureddin Ashammakhi
- Institute for Quantitative Health Science and Engineering (IQ) and Department of Biomedical Engineering (BME)Colleges of Engineering and Human MedicineMichigan State UniversityEast LansingMI48824USA
- Department of BioengineeringSamueli School of EngineeringUniversity of California Los AngelesLos AngelesCA90095USA
| |
Collapse
|
2
|
Omidian H, Wilson RL. PLGA Implants for Controlled Drug Delivery and Regenerative Medicine: Advances, Challenges, and Clinical Potential. Pharmaceuticals (Basel) 2025; 18:631. [PMID: 40430452 PMCID: PMC12114454 DOI: 10.3390/ph18050631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/23/2025] [Accepted: 04/25/2025] [Indexed: 05/29/2025] Open
Abstract
Poly(lactide-co-glycolide) (PLGA) implants have become a cornerstone in drug delivery and regenerative medicine due to their biocompatibility, tunable degradation, and capacity for sustained, localized therapeutic release. Recent innovations in polymer design, fabrication methods, and functional modifications have expanded their utility across diverse clinical domains, including oncology, neurology, orthopedics, and ophthalmology. This review provides a comprehensive analysis of PLGA implant properties, fabrication strategies, and biomedical applications, while addressing key challenges such as burst release, incomplete drug release, manufacturing complexity, and inflammatory responses. Emerging solutions-such as 3D printing, in situ forming systems, predictive modeling, and patient-specific customization-are improving implant performance and clinical translation. Emphasis is placed on scalable production, long-term biocompatibility, and personalized design to support the next generation of precision therapeutics.
Collapse
Affiliation(s)
- Hossein Omidian
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | | |
Collapse
|
3
|
Villa J, Cury J, Kessler L, Tan X, Richter CP. Enhancing biocompatibility of the brain-machine interface: A review. Bioact Mater 2024; 42:531-549. [PMID: 39308547 PMCID: PMC11416625 DOI: 10.1016/j.bioactmat.2024.08.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 08/05/2024] [Accepted: 08/27/2024] [Indexed: 09/25/2024] Open
Abstract
In vivo implantation of microelectrodes opens the door to studying neural circuits and restoring damaged neural pathways through direct electrical stimulation and recording. Although some neuroprostheses have achieved clinical success, electrode material properties, inflammatory response, and glial scar formation at the electrode-tissue interfaces affect performance and sustainability. Those challenges can be addressed by improving some of the materials' mechanical, physical, chemical, and electrical properties. This paper reviews materials and designs of current microelectrodes and discusses perspectives to advance neuroprosthetics performance.
Collapse
Affiliation(s)
- Jordan Villa
- Northwestern University-Feinberg School of Medicine, Department of Otolaryngology, USA
| | - Joaquin Cury
- Northwestern University-Feinberg School of Medicine, Department of Otolaryngology, USA
| | - Lexie Kessler
- Northwestern University-Feinberg School of Medicine, Department of Otolaryngology, USA
| | - Xiaodong Tan
- Northwestern University-Feinberg School of Medicine, Department of Otolaryngology, USA
- The Hugh Knowles Center, Department of Communication Sciences and Disorders, Northwestern University, USA
| | - Claus-Peter Richter
- Northwestern University-Feinberg School of Medicine, Department of Otolaryngology, USA
- The Hugh Knowles Center, Department of Communication Sciences and Disorders, Northwestern University, USA
- Department of Communication Sciences and Disorders, Northwestern University, USA
- Department of Biomedical Engineering, Northwestern University, USA
| |
Collapse
|
4
|
Morand J, McClellan P, Isali I, Dikici Y, Fan D, Li L, Shoffstall AJ, Akkus O, Weidenbecher M. Dexamethasone eluting polydopaminated polycaprolactone-poly (lactic-co-glycolic) acid for treatment of tracheal stenosis. J Biomed Mater Res A 2024; 112:781-792. [PMID: 38204293 DOI: 10.1002/jbm.a.37659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 12/06/2023] [Accepted: 12/08/2023] [Indexed: 01/12/2024]
Abstract
Tracheal stenosis is commonly caused by injury, resulting in inflammation and fibrosis. Inhibiting inflammation and promoting epithelization can reduce recurrence after initial successful treatment of tracheal stenosis. Steroids play an important role in tracheal stenosis management. This study in vitro evaluated effectiveness of a polydopaminated polycaprolactone stent coated with dexamethasone-eluting poly(lactic-co-glycolic) acid microparticles (μPLGA) for tracheal stenosis management. Polydopamination was characterized by Raman spectroscopy and promoted epithelialization while dexamethasone delivery reduced macrophage activity, assessed by individual cell area measurements and immunofluorescent staining for inducible nitric oxide synthase (iNOS). Dexamethasone release was quantified by high-performance liquid chromatography over 30 days. Activation-related increase in cell area and iNOS production by RAW 264.7 were both reduced significantly (p < .05) through dexamethasone release. Epithelial cell spreading was higher on polydopaminated polycaprolactone (PCL) than PCL-alone (p < .05). Force required for stent migration was measured by pullout tests of PCL-μPLGA stents from cadaveric rabbit and porcine tracheas (0.425 ± 0.068 N and 1.082 ± 0.064 N, respectively) were above forces estimated to occur during forced respiration. Biomechanical support provided by stents to prevent airway collapse was assessed by comparing compressive circumferential stiffness, and stiffness of the stent was about 1/10th of the rabbit trachea (0.156 ± 0.023 N/mm vs. 1.420 ± 0.194 N/mm, respectively). A dexamethasone-loaded PCL-μPLGA stent platform can deliver dexamethasone and exhibits sufficient mechanical properties to anchor within the trachea and polydopamination of PCL is conducive to epithelial layer formation. Therefore, a polydopaminated PCL-μPLGA stent is a promising candidate for in vivo evaluation for treatment of tracheal restenosis.
Collapse
Affiliation(s)
- Jacob Morand
- Advanced Platform Center, Louis Stokes Cleveland Veteran Affairs Medical Center, Cleveland, Ohio, USA
| | - Phillip McClellan
- Department of Urology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Ilaha Isali
- Department of Urology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Yusuf Dikici
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Di Fan
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Longshun Li
- Advanced Platform Center, Louis Stokes Cleveland Veteran Affairs Medical Center, Cleveland, Ohio, USA
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Andrew J Shoffstall
- Advanced Platform Center, Louis Stokes Cleveland Veteran Affairs Medical Center, Cleveland, Ohio, USA
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Ozan Akkus
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Orthopedic Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Mark Weidenbecher
- Advanced Platform Center, Louis Stokes Cleveland Veteran Affairs Medical Center, Cleveland, Ohio, USA
- Department of Otolaryngology, Case Western Reserve University, Cleveland, Ohio, USA
| |
Collapse
|
5
|
Chen K, Cambi F, Kozai TDY. Pro-myelinating clemastine administration improves recording performance of chronically implanted microelectrodes and nearby neuronal health. Biomaterials 2023; 301:122210. [PMID: 37413842 PMCID: PMC10528716 DOI: 10.1016/j.biomaterials.2023.122210] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 06/08/2023] [Accepted: 06/19/2023] [Indexed: 07/08/2023]
Abstract
Intracortical microelectrodes have become a useful tool in neuroprosthetic applications in the clinic and to understand neurological disorders in basic neurosciences. Many of these brain-machine interface technology applications require successful long-term implantation with high stability and sensitivity. However, the intrinsic tissue reaction caused by implantation remains a major failure mechanism causing loss of recorded signal quality over time. Oligodendrocytes remain an underappreciated intervention target to improve chronic recording performance. These cells can accelerate action potential propagation and provides direct metabolic support for neuronal health and functionality. However, implantation injury causes oligodendrocyte degeneration and leads to progressive demyelination in surrounding brain tissue. Previous work highlighted that healthy oligodendrocytes are necessary for greater electrophysiological recording performance and the prevention of neuronal silencing around implanted microelectrodes over the chronic implantation period. Thus, we hypothesize that enhancing oligodendrocyte activity with a pharmaceutical drug, Clemastine, will prevent the chronic decline of microelectrode recording performance. Electrophysiological evaluation showed that the promyelination Clemastine treatment significantly elevated the signal detectability and quality, rescued the loss of multi-unit activity, and increased functional interlaminar connectivity over 16-weeks of implantation. Additionally, post-mortem immunohistochemistry showed that increased oligodendrocyte density and myelination coincided with increased survival of both excitatory and inhibitory neurons near the implant. Overall, we showed a positive relationship between enhanced oligodendrocyte activity and neuronal health and functionality near the chronically implanted microelectrode. This study shows that therapeutic strategy that enhance oligodendrocyte activity is effective for integrating the functional device interface with brain tissue over chronic implantation period.
Collapse
Affiliation(s)
- Keying Chen
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA
| | - Franca Cambi
- Veterans Administration Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Takashi D Y Kozai
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA; McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA; NeuroTech Center, University of Pittsburgh Brain Institute, Pittsburgh, PA, USA.
| |
Collapse
|
6
|
Imaichi-Kobayashi S, Kassab R, Piersigilli A, Robertson R, Leonard C, Long N, Dean B, Phaneuf M, Ling V. An electrospun macrodevice for durable encapsulation of human cells with consistent secretion of therapeutic antibodies. Biomaterials 2023; 298:122123. [PMID: 37172505 DOI: 10.1016/j.biomaterials.2023.122123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 03/31/2023] [Accepted: 04/08/2023] [Indexed: 05/15/2023]
Abstract
Frequent subcutaneous or intravenous administrations of therapeutic biomolecules can be costly and inconvenient for patients. Implantation of encapsulated recombinant cells represents a promising approach for the sustained delivery of biotherapeutics. However, foreign body and fibrotic response against encapsulation materials results in drastically reduced viability of encapsulated cells, presenting a major engineering challenge for biocompatibility. Here, we show that the multi-laminate electrospun retrievable macrodevice (Bio-Spun) protects genetically modified human cells after subcutaneous implant in mice. We describe here a biocompatible nanofiber device that limits fibrosis and extends implant survival. For more than 150 days, these devices supported human cells engineered to secrete the antibodies: vedolizumab, ustekinumab, and adalimumab, while eliciting minimal fibrotic response in mice. The porous electrospun cell chamber allowed secretion of the recombinant antibodies into the host bloodstream, and prevented infiltration of host cells into the chamber. High plasma levels (>50 μg/mL) of antibody were maintained in the optimized devices for more than 5 months. Our findings demonstrate that macrodevices constructed from electrospun materials are effective in protecting genetically engineered cells for the sustained administration of recombinant therapeutic antibodies.
Collapse
Affiliation(s)
| | | | - Alessandra Piersigilli
- Department of Drug Safety Research and Evaluation, Takeda Pharmaceuticals, Cambridge, MA, USA
| | | | - Christopher Leonard
- Department of Drug Safety Research and Evaluation, Takeda Pharmaceuticals, Cambridge, MA, USA
| | | | | | | | - Vincent Ling
- Department of Pharmaceutical Science, Takeda Pharmaceuticals, Cambridge, MA, USA.
| |
Collapse
|
7
|
Chen K, Cambi F, Kozai TDY. Pro-myelinating Clemastine administration improves recording performance of chronically implanted microelectrodes and nearby neuronal health. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.31.526463. [PMID: 36778360 PMCID: PMC9915570 DOI: 10.1101/2023.01.31.526463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Intracortical microelectrodes have become a useful tool in neuroprosthetic applications in the clinic and to understand neurological disorders in basic neurosciences. Many of these brain-machine interface technology applications require successful long-term implantation with high stability and sensitivity. However, the intrinsic tissue reaction caused by implantation remains a major failure mechanism causing loss of recorded signal quality over time. Oligodendrocytes remain an underappreciated intervention target to improve chronic recording performance. These cells can accelerate action potential propagation and provides direct metabolic support for neuronal health and functionality. However, implantation injury causes oligodendrocyte degeneration and leads to progressive demyelination in surrounding brain tissue. Previous work highlighted that healthy oligodendrocytes are necessary for greater electrophysiological recording performance and the prevention of neuronal silencing around implanted microelectrodes over chronic implantation. Thus, we hypothesize that enhancing oligodendrocyte activity with a pharmaceutical drug, Clemastine, will prevent the chronic decline of microelectrode recording performance. Electrophysiological evaluation showed that the promyelination Clemastine treatment significantly elevated the signal detectability and quality, rescued the loss of multi-unit activity, and increased functional interlaminar connectivity over 16-weeks of implantation. Additionally, post-mortem immunohistochemistry showed that increased oligodendrocyte density and myelination coincided with increased survival of both excitatory and inhibitory neurons near the implant. Overall, we showed a positive relationship between enhanced oligodendrocyte activity and neuronal health and functionality near the chronically implanted microelectrode. This study shows that therapeutic strategy that enhance oligodendrocyte activity is effective for integrating the functional device interface with brain tissue over chronic implantation period. Abstract Figure
Collapse
|
8
|
Controlled release of low-molecular weight, polymer-free corticosteroid coatings suppresses fibrotic encapsulation of implanted medical devices. Biomaterials 2022; 286:121586. [DOI: 10.1016/j.biomaterials.2022.121586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 05/12/2022] [Accepted: 05/15/2022] [Indexed: 11/23/2022]
|
9
|
Muddineti OS, Omri A. Current trends in PLGA based long-acting injectable products: The industry perspective. Expert Opin Drug Deliv 2022; 19:559-576. [PMID: 35534912 DOI: 10.1080/17425247.2022.2075845] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Poly (lactic-co-glycolic acid) (PLGA) has been used in many long-acting drug formulations, which have been approved by the US Food and Drug Administration (FDA). PLGA has unique physicochemical properties, which results in complexities in the formulation, characterization, and evaluation of generic products. To address the challenges of generic development of PLGA-based products, the FDA has established an extensive research program to investigate novel methods and tools to aid product development and regulatory review. AREAS COVERED This review article intends to provide a comprehensive review on physicochemical properties of PLGA polymer, characterization, formulation, and analytical aspects, manufacturing conditions on product performance, in-vitro release testing, and bioequivalence. Current research on formulation development as per QbD in vitro release testing methods, regulatory research outcomes, and bioequivalence. EXPERT OPINION The development of PLGA based long-acting injectables is promising and challenging when considering the numerous interrelated delivery-related factors. Achieving a successful formulation requires a thorough understanding of the critical interactions between polymer/drug properties, release profiles over time, up-to-date knowledge on regulatory guidance, and elucidation of the impact of multiple in vivo conditions to methodically evaluate the eventual clinical efficacy.
Collapse
Affiliation(s)
- Omkara Swami Muddineti
- Formulation Research & Development, Vimta Labs Limited, Plot No.5, M N Park, Genome Valley, Shameerpet, Hyderabad, Telangana, 500101, India
| | - Abdelwahab Omri
- The Novel Drug & Vaccine Delivery Systems Facility, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, ON, Canada
| |
Collapse
|
10
|
Nash KE, Ong KG, Guldberg RE. Implantable biosensors for musculoskeletal health. Connect Tissue Res 2022; 63:228-242. [PMID: 35172654 PMCID: PMC8977250 DOI: 10.1080/03008207.2022.2041002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE A healthy musculoskeletal system requires complex functional integration of bone, muscle, cartilage, and connective tissues responsible for bodily support, motion, and the protection of vital organs. Conditions or injuries to musculoskeeltal tissues can devastate an individual's quality of life. Some conditions that are particularly disabling include severe bone and muscle injuries to the extremities and amputations resulting from unmanageable musculoskeletal conditions or injuries. Monitoring and managing musculoskeletal health is intricate because of the complex mechanobiology of these interconnected tissues. METHODS For this article, we reviewed literature on implantable biosensors related to clinical data of the musculoskeletal system, therapeutics for complex bone injuries, and osseointegrated prosthetics as example applications. RESULTS As a result, a brief summary of biosensors technologies is provided along with review of noteworthy biosensors and future developments needed to fully realize the translational benefit of biosensors for musculoskeletal health. CONCLUSIONS Novel implantable biosensors capable of tracking biophysical parameters in vivo are highly relevant to musculoskeletal health because of their ability to collect clinical data relevant to medical decisions, complex trauma treatment, and the performance of osseointegrated prostheses.
Collapse
Affiliation(s)
- Kylie E. Nash
- Phil and Penny Knight Campus for Accelerating Scientific Impact Department of Bioengineering, University of Oregon, Eugene, OR 97403
| | - Keat Ghee Ong
- Phil and Penny Knight Campus for Accelerating Scientific Impact Department of Bioengineering, University of Oregon, Eugene, OR 97403
| | - Robert E. Guldberg
- Phil and Penny Knight Campus for Accelerating Scientific Impact Department of Bioengineering, University of Oregon, Eugene, OR 97403,Corresponding Author: Robert E. Guldberg, Ph.D., 3231 University of Oregon, Eugene OR, 97403,
| |
Collapse
|
11
|
Bhave G, Chen JC, Singer A, Sharma A, Robinson JT. Distributed sensor and actuator networks for closed-loop bioelectronic medicine. MATERIALS TODAY (KIDLINGTON, ENGLAND) 2021; 46:125-135. [PMID: 34366697 PMCID: PMC8336425 DOI: 10.1016/j.mattod.2020.12.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Designing implantable bioelectronic systems that continuously monitor physiological functions and simultaneously provide personalized therapeutic solutions for patients remains a persistent challenge across many applications ranging from neural systems to bioelectronic organs. Closed-loop systems typically consist of three functional blocks, namely, sensors, signal processors and actuators. An effective system, that can provide the necessary therapeutics, tailored to individual physiological factors requires a distributed network of sensors and actuators. While significant progress has been made, closed-loop systems still face many challenges before they can truly be considered as long-term solutions for many diseases. In this review, we consider three important criteria where materials play a critical role to enable implantable closed-loop systems: Specificity, Biocompatibility and Connectivity. We look at the progress made in each of these fields with respect to a specific application and outline the challenges in creating bioelectronic technologies for the future.
Collapse
|
12
|
Didyuk O, Econom N, Guardia A, Livingston K, Klueh U. Continuous Glucose Monitoring Devices: Past, Present, and Future Focus on the History and Evolution of Technological Innovation. J Diabetes Sci Technol 2021; 15:676-683. [PMID: 31931614 PMCID: PMC8120065 DOI: 10.1177/1932296819899394] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The concept of implantable glucose sensors has been promulgated for more than 40 years. It is now accepted that continuous glucose monitoring (CGM) increases quality of life by allowing informed diabetes management decisions as a result of more optimized glucose control. The focus of this article is to provide a brief overview of the CGM market history, emerging technologies, and the foreseeable challenges for the next CGM generations as well as proposing possible solutions in an effort to advance the next generation of implantable sensor.
Collapse
Affiliation(s)
- Olesya Didyuk
- Department of Biological Sciences, IBio
(Integrative Biosciences Center), Wayne State University, Detroit, MI, USA
| | - Nicolas Econom
- Biomedical Engineering, IBio
(Integrative Biosciences Center), Wayne State University, Detroit, MI, USA
| | - Angelica Guardia
- Biomedical Engineering, IBio
(Integrative Biosciences Center), Wayne State University, Detroit, MI, USA
| | - Kelsey Livingston
- Biomedical Engineering, IBio
(Integrative Biosciences Center), Wayne State University, Detroit, MI, USA
| | - Ulrike Klueh
- Biomedical Engineering, IBio
(Integrative Biosciences Center), Wayne State University, Detroit, MI, USA
- Ulrike Klueh, PhD, Department of Biomedical
Engineering, Wayne State University, 263 Farmington Avenue, Detroit, MI 48202,
USA.
| |
Collapse
|
13
|
Reich KM, Viitanen P, Apu EH, Tangl S, Ashammakhi N. The Effect of Diclofenac Sodium-Loaded PLGA Rods on Bone Healing and Inflammation: A Histological and Histomorphometric Study in the Femur of Rats. MICROMACHINES 2020; 11:mi11121098. [PMID: 33322731 PMCID: PMC7764049 DOI: 10.3390/mi11121098] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 12/03/2022]
Abstract
Implants made of poly(lactide-co-glycolide) (PLGA) are biodegradable and frequently provoke foreign body reactions (FBR) in the host tissue. In order to modulate the inflammatory response of the host tissue, PLGA implants can be loaded with anti-inflammatory drugs. The aim of this study was to analyze the impact of PLGA 80/20 rods loaded with the diclofenac sodium (DS) on local tissue reactions in the femur of rats. Special emphasis was put on bone regeneration and the presence of multinucleated giant cells (MGCs) associated with FBR. PLGA 80/20 alone and PLGA 80/20 combined with DS was extruded into rods. PLGA rods loaded with DS (PLGA+DS) were implanted into the femora of 18 rats. Eighteen control rats received unloaded PLGA rods. The follow-up period was of 3, 6 and 12 weeks. Each group comprised of six rats. Peri-implant tissue reactions were histologically and histomorphometrically evaluated. The implantation of PLGA and PLGA+DS8 rods induced the formation of a layer of newly formed bone islands parallel to the contour of the implants. PLGA+DS rods tended to reduce the presence of multi-nucleated giant cells (MGCs) at the implant surface. Although it is known that the systemic administration of DS is associated with compromised bone healing, the local release of DS via PLGA rods did not have negative effects on bone regeneration in the femora of rats throughout 12 weeks.
Collapse
Affiliation(s)
- Karoline M. Reich
- Karl Donath Laboratory for Hard Tissue and Biomaterial Research, Division of Oral Surgery, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria;
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Petrus Viitanen
- Institute of Biomaterials, Tampere University of Technology, 33101 Tampere, Finland;
| | - Ehsanul Hoque Apu
- Laboratory of Developmental Biology, Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90220 Oulu, Finland;
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Stefan Tangl
- Karl Donath Laboratory for Hard Tissue and Biomaterial Research, Division of Oral Surgery, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria;
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- Correspondence: (S.T.); (N.A.)
| | - Nureddin Ashammakhi
- Division of Plastic Surgery, Department of Surgery, Oulu University Hospital, 90220 Oulu, Finland
- Center for Minimally Invasive Therapeutics (C-MIT), University of California, Los Angeles, CA 90095, USA
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA
- Correspondence: (S.T.); (N.A.)
| |
Collapse
|
14
|
Jaquins-Gerstl A, Michael AC. Dexamethasone-Enhanced Microdialysis and Penetration Injury. Front Bioeng Biotechnol 2020; 8:602266. [PMID: 33364231 PMCID: PMC7752925 DOI: 10.3389/fbioe.2020.602266] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/11/2020] [Indexed: 01/25/2023] Open
Abstract
Microdialysis probes, electrochemical microsensors, and neural prosthetics are often used for in vivo monitoring, but these are invasive devices that are implanted directly into brain tissue. Although the selectivity, sensitivity, and temporal resolution of these devices have been characterized in detail, less attention has been paid to the impact of the trauma they inflict on the tissue or the effect of any such trauma on the outcome of the measurements they are used to perform. Factors affecting brain tissue reaction to the implanted devices include: the mechanical trauma during insertion, the foreign body response, implantation method, and physical properties of the device (size, shape, and surface characteristics. Modulation of the immune response is an important step toward making these devices with reliable long-term performance. Local release of anti-inflammatory agents such as dexamethasone (DEX) are often used to mitigate the foreign body response. In this article microdialysis is used to locally deliver DEX to the surrounding brain tissue. This work discusses the immune response resulting from microdialysis probe implantation. We briefly review the principles of microdialysis and the applications of DEX with microdialysis in (i) neuronal devices, (ii) dopamine and fast scan cyclic voltammetry, (iii) the attenuation of microglial cells, (iv) macrophage polarization states, and (v) spreading depolarizations. The difficulties and complexities in these applications are herein discussed.
Collapse
|
15
|
Welch NG, Winkler DA, Thissen H. Antifibrotic strategies for medical devices. Adv Drug Deliv Rev 2020; 167:109-120. [PMID: 32553685 DOI: 10.1016/j.addr.2020.06.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 06/02/2020] [Accepted: 06/08/2020] [Indexed: 12/13/2022]
Abstract
A broad range of medical devices initiate an immune reaction known as the foreign body response (FBR) upon implantation. Here, collagen deposition at the surface of the implant occurs as a result of the FBR, ultimately leading to fibrous encapsulation and, in many cases, reduced function or failure of the device. Despite significant efforts, the prevention of fibrotic encapsulation has not been realized at this point in time. However, many next-generation medical technologies including cellular therapies, sensors and devices depend on the ability to modulate and control the FBR. For these technologies to become viable, significant advances must be made in understanding the underlying mechanism of this response as well as in the methods modulating this response. In this review, we highlight recent advances in the development of materials and coatings providing a reduced FBR and emphasize key characteristics of high-performing approaches. We also provide a detailed overview of the state-of-the-art in strategies relying on controlled drug release, the surface display of bioactive signals, materials-based approaches, and combinations of these approaches. Finally, we offer perspectives on future directions in this field.
Collapse
|
16
|
Chen K, Wellman SM, Yaxiaer Y, Eles JR, Kozai TD. In vivo spatiotemporal patterns of oligodendrocyte and myelin damage at the neural electrode interface. Biomaterials 2020; 268:120526. [PMID: 33302121 DOI: 10.1016/j.biomaterials.2020.120526] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 11/07/2020] [Accepted: 11/10/2020] [Indexed: 12/26/2022]
Abstract
Intracortical microelectrodes with the ability to detect intrinsic electrical signals and/or deliver electrical stimulation into local brain regions have been a powerful tool to understand brain circuitry and for therapeutic applications to neurological disorders. However, the chronic stability and sensitivity of these intracortical microelectrodes are challenged by overwhelming biological responses, including severe neuronal loss and thick glial encapsulation. Unlike microglia and astrocytes whose activity have been extensively examined, oligodendrocytes and their myelin processes remain poorly studied within the neural interface field. Oligodendrocytes have been widely recognized to modulate electrical signal conductance along axons through insulating myelin segments. Emerging evidence offers an alternative perspective on neuron-oligodendrocyte coupling where oligodendrocytes provide metabolic and neurotrophic support to neurons through cytoplasmic myelin channels and monocarboxylate transporters. This study uses in vivo multi-photon microscopy to gain insights into the dynamics of oligodendrocyte soma and myelin processes in response to chronic device implantation injury over 4 weeks. We observe that implantation induces acute oligodendrocyte injury including initial deformation and substantial myelinosome formation, an early sign of myelin injury. Over chronic implantation periods, myelin and oligodendrocyte soma suffer severe degeneration proximal to the interface. Interestingly, wound healing attempts such as oligodendrogenesis are initiated over time, however they are hampered by continued degeneration near the implant. Nevertheless, this detailed characterization of oligodendrocyte spatiotemporal dynamics during microelectrode-induced inflammation may provide insights for novel intervention targets to facilitate oligodendrogenesis, enhance the integration of neural-electrode interfaces, and improve long-term functional performance.
Collapse
Affiliation(s)
- Keying Chen
- Department of Bioengineering, University of Pittsburgh, USA; Center for the Neural Basis of Cognition, University of Pittsburgh and Carnegie Mellon University, USA
| | - Steven M Wellman
- Department of Bioengineering, University of Pittsburgh, USA; Center for the Neural Basis of Cognition, University of Pittsburgh and Carnegie Mellon University, USA
| | - Yalikun Yaxiaer
- Eberly College of Science, Pennsylvania State University, University Park, USA
| | - James R Eles
- Department of Bioengineering, University of Pittsburgh, USA; Center for the Neural Basis of Cognition, University of Pittsburgh and Carnegie Mellon University, USA
| | - Takashi Dy Kozai
- Department of Bioengineering, University of Pittsburgh, USA; Center for the Neural Basis of Cognition, University of Pittsburgh and Carnegie Mellon University, USA; Center for Neuroscience, University of Pittsburgh, USA; McGowan Institute of Regenerative Medicine, University of Pittsburgh, USA; NeuroTech Center, University of Pittsburgh Brain Institute, USA.
| |
Collapse
|
17
|
Stefani RM, Lee AJ, Tan AR, Halder SS, Hu Y, Guo XE, Stoker AM, Ateshian GA, Marra KG, Cook JL, Hung CT. Sustained low-dose dexamethasone delivery via a PLGA microsphere-embedded agarose implant for enhanced osteochondral repair. Acta Biomater 2020; 102:326-340. [PMID: 31805408 PMCID: PMC6956850 DOI: 10.1016/j.actbio.2019.11.052] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 12/16/2022]
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. STATEMENT OF SIGNIFICANCE: 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.
Collapse
Affiliation(s)
- Robert M Stefani
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 1210 Amsterdam Avenue, New York 10027, NY United States
| | - Andy J Lee
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 1210 Amsterdam Avenue, New York 10027, NY United States
| | - Andrea R Tan
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 1210 Amsterdam Avenue, New York 10027, NY United States
| | - Saiti S Halder
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 1210 Amsterdam Avenue, New York 10027, NY United States
| | - Yizhong Hu
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 1210 Amsterdam Avenue, New York 10027, NY United States
| | - X Edward Guo
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 1210 Amsterdam Avenue, New York 10027, NY United States
| | - Aaron M Stoker
- Missouri Orthopaedic Institute, University of Missouri, 1100 Virginia Avenue, Columbia 65212, MO, United States
| | - Gerard A Ateshian
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 1210 Amsterdam Avenue, New York 10027, NY United States; Department of Mechanical Engineering, Columbia University, 500 West 120th Street, 220 S.W. Mudd, New York 10027, NY, United States
| | - Kacey G Marra
- University of Pittsburgh, Biomedical Science Tower, 200 Lothrop Street, Pittsburgh 15213, PA, United States
| | - James L Cook
- Missouri Orthopaedic Institute, University of Missouri, 1100 Virginia Avenue, Columbia 65212, MO, United States
| | - Clark T Hung
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 1210 Amsterdam Avenue, New York 10027, NY United States.
| |
Collapse
|
18
|
Synthesis Strategies for Biomedical Grade Polymers. MATERIALS HORIZONS: FROM NATURE TO NANOMATERIALS 2020. [DOI: 10.1007/978-981-15-1251-3_1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
|
19
|
Park E, Lee J, Huh KM, Lee SH, Lee H. Toxicity-Attenuated Glycol Chitosan Adhesive Inspired by Mussel Adhesion Mechanisms. Adv Healthc Mater 2019; 8:e1900275. [PMID: 31091015 DOI: 10.1002/adhm.201900275] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 04/25/2019] [Indexed: 01/04/2023]
Abstract
Chitosan-catechol, inspired from mussel-adhesive-proteins, is characterized by the formation of an adhesive membrane complex through instant bonding with serum proteins not found in chitosan. Using this intrinsic property, chitosan-catechol is widely applied for hemostatic needles, general hemostatic materials, nanoparticle composites, and 3D printing. Despite its versatility, the practical use of chitosan-catechol in the clinic is limited due to its undesired immune responses. Herein, a catechol-conjugated glycol chitosan is proposed as an alternative hemostatic hydrogel with negligible immune responses enabling the replacement of chitosan-catechol. Comparative cellular toxicity and in vivo skin irritation between chitosan-catechol and glycol chitosan-catechol are evaluated. Their immune responses are also assessed using histological analysis after subcutaneous implantation into mice. The results show that glycol chitosan-catechol significantly attenuates the immune response compared with chitosan-catechol; this finding is likely due to the antibiofouling effect of ethylene glycol groups and the reduced adhesion of immune cells. Finally, the tissue adhesion and hemostatic ability of glycol chitosan-catechol hydrogels reveal that these ethylene glycol groups do not dramatically modify the adhesiveness and hemostatic ability compared with nonglycol chitosan-catechol. This study suggests that glycol chitosan-catechol can be a promising alternative to chitosan-catechol in various biomedical fields such as hemostatic agents.
Collapse
Affiliation(s)
- Eunsook Park
- Department of ChemistryKorea Advanced Institute of Science and Technology (KAIST) 291 University Rd Yuseong‐gu Daejeon 34141 Republic of Korea
| | - Jeehee Lee
- Biomedical Science and Engineering Interdisciplinary ProgramKorea Advanced Institute of Science and Technology (KAIST) 291 University Rd Yuseong‐gu Daejeon 34141 Republic of Korea
| | - Kang Moo Huh
- Department of Polymer Science and EngineeringChungnam National University 99 University Rd Yuseong‐gu Daejeon 34134 Republic of Korea
| | - Soo Hyeon Lee
- Department of ChemistryKorea Advanced Institute of Science and Technology (KAIST) 291 University Rd Yuseong‐gu Daejeon 34141 Republic of Korea
| | - Haeshin Lee
- Department of ChemistryKorea Advanced Institute of Science and Technology (KAIST) 291 University Rd Yuseong‐gu Daejeon 34141 Republic of Korea
| |
Collapse
|
20
|
Synthesis, physicochemical, rheological and in-vitro characterization of double-crosslinked hyaluronic acid hydrogels containing dexamethasone and PLGA/dexamethasone nanoparticles as hybrid systems for specific medical applications. Int J Biol Macromol 2019; 126:193-208. [DOI: 10.1016/j.ijbiomac.2018.12.181] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 12/14/2018] [Accepted: 12/20/2018] [Indexed: 12/22/2022]
|
21
|
Abstract
The human body is endowed with an uncanny ability to distinguish self from foreign. The implantation of a foreign object inside a mammalian host activates complex signaling cascades, which lead to biological encapsulation of the implant. This reaction by the host system to a foreign object is known as foreign body response (FBR). Over the last few decades, it has been increasingly important to have a deeper insight into the mechanisms of FBR is needed to develop biomaterials for better integration with living systems. In the light of recent advances in tissue engineering and regenerative medicine, particularly in the field of biosensors and biodegradable tissue engineering scaffolds, the classical concepts related to the FBR have acquired new dimensions. The aim of this review is to provide a holistic view of the FBR, while critically analyzing the challenges, which need to be addressed in the future to overcome this innate response. In particular, this review discusses the relevant experimental methodology to assess the host response. The role of erosion and degradation behavior on FBR with biodegradable polymers is largely explored. Apart from the discussion on temporal progression of FBR, an emphasis has been given to the design of next-generation biomaterials with favorable host response.
Collapse
|
22
|
Scholten K, Meng E. A review of implantable biosensors for closed-loop glucose control and other drug delivery applications. Int J Pharm 2018; 544:319-334. [DOI: 10.1016/j.ijpharm.2018.02.022] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 01/30/2018] [Accepted: 02/15/2018] [Indexed: 12/19/2022]
|
23
|
Immunomodulation of Biomaterials by Controlling Macrophage Polarization. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1064:197-206. [PMID: 30471034 DOI: 10.1007/978-981-13-0445-3_12] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Macrophages are key players in innate immune responses to foreign substances. They participate in the phagocytosis of biomaterial-derived particles, angiogenesis, recruitment of fibroblasts, and formation of granulation tissues. Most macrophage functions are achieved through the release of various cytokines and chemokines; the release profile of cytokines is dependent on the phenotype of macrophages, namely proinflammatory M1 or antiinflammatory M2. M1 and M2 macrophages coexist during an inflammatory phase, and the M1/M2 ratio is considered to be an important factor for wound-healing or tissue regeneration. This ratio depends on the chemical and physical properties of biomaterials. To obtain a favorable foreign body reaction to biomaterials, the phenotypes of the macrophages can be modulated by cytokines, antibodies, small chemicals, and microRNAs. Geometrical surface fabrication of biomaterials can also be used for modulating the phenotype of macrophages.
Collapse
|
24
|
Monomer sequence in PLGA microparticles: Effects on acidic microclimates and in vivo inflammatory response. Acta Biomater 2018; 65:259-271. [PMID: 29101019 DOI: 10.1016/j.actbio.2017.10.043] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 10/24/2017] [Accepted: 10/30/2017] [Indexed: 01/12/2023]
Abstract
Controlling the backbone architecture of poly(lactic-co-glycolic acid)s (PLGAs) is demonstrated to have a strong influence on the production and release of acidic degradation by-products in microparticle matrices. Previous efforts for controlling the internal and external accumulation of acidity for PLGA microparticles have focused on the addition of excipients including neutralization and anti-inflammatory agents. In this report, we utilize a sequence-control strategy to tailor the microstructure of PLGA. The internal acidic microclimate distributions within sequence-defined and random PLGA microparticles were monitored in vitro using a non-invasive ratiometric two-photon microscopy (TPM) methodology. Sequence-defined PLGAs were found to have minimal changes in pH distribution and lower amounts of percolating acidic by-products. A parallel scanning electron microscopy study further linked external morphological events to internal degradation-induced structural changes. The properties of the sequenced and random copolymers characterized in vitro translated to differences in in vivo behavior. The sequence alternating copolymer, poly LG, had lower granulomatous foreign-body reactions compared to random racemic PLGA with a 50:50 ratio of lactic to glycolic acid. STATEMENT OF SIGNIFICANCE This paper demonstrates that changing the monomer sequence in poly(lactic-co-glycolic acid)s (PLGAs) leads to dramatic differences in the rate of degradation and the internal acidic microclimate of microparticles degrading in vitro. We note that the acidic microclimates within these particles were imaged for the first time with two-photon microscopy, which gives an extremely clear and detailed picture of the degradation process. Importantly, we also document that the observed sequence-controlled in vitro processes translate into differences in the in vivo behavior of polymers which have the same L to G composition but differing microstructures. These data, placed in the context of our prior studies on swelling, erosion, and MW loss (Biomaterials2017, 117, 66 and other references cited within the manuscript), provide significant insight not only about sequence effects in PLGAs but into the underlying mechanisms of PLGA degradation in general.
Collapse
|
25
|
Lafuente JV, Requejo C, Carrasco A, Bengoetxea H. Nanoformulation: A Useful Therapeutic Strategy for Improving Neuroprotection and the Neurorestorative Potential in Experimental Models of Parkinson's Disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2017; 137:99-122. [PMID: 29132545 DOI: 10.1016/bs.irn.2017.09.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder, but current therapies are only symptomatic. Experimental models are necessary to go deeper in the comprehension of pathophysiological mechanism and to assess new therapeutic strategies. The unilateral 6-hydroxydopamine (6-OHDA) lesion either in medial forebrain bundle (MFB) or into the striatum in rats affords to study various stages of PD depending on the evolution time lapsed. A promising alternative to address the neurodegenerative process is the use of neurotrophic factors; but its clinical use has been limited due to its short half-life and rapid degradation after in vivo administration, along with difficulties for crossing the blood-brain barrier (BBB). Tyrosine hydroxylase (TH) immunostaining revealed a significant decrease of the TH-immunopositive striatal volume in 6-OHDA group from rostral to caudal one. The loss of TH-ir neurons and axodendritic network (ADN) was higher in caudal sections showing a selective vulnerability of the topological distributed dopaminergic system. In addition to a remarkable depletion of dopamine in the nigrostriatal system, the administration of 6-OHDA into MFB induces some other neuropathological changes such as an increase of glial fibrillary acidic protein (GFAP) positive cells in substantia nigra (SN) as well as in striatum. Intrastriatal implantation of micro- or nanosystems delivering neurotrophic factor in parkinsonized rats for bypassing BBB leads to a significative functional and morphological recovery. Neurorestorative morphological changes (preservation of the TH-ir cells and ADN) along the rostrocaudal axis of caudoputamen complex and SN have been probed supporting a selective recovering after the treatment as well. Others innovative therapeutic strategies, such as the intranasal delivery, have been recently assessed in order to search the NTF effects. In addition some others methodological key points are reviewed.
Collapse
Affiliation(s)
- Jose V Lafuente
- Laboratory of Clinical and Experimental Neuroscience (LaNCE), University of the Basque Country UPV/EHU, Leioa, Vizcaya, Spain.
| | - Catalina Requejo
- Laboratory of Clinical and Experimental Neuroscience (LaNCE), University of the Basque Country UPV/EHU, Leioa, Vizcaya, Spain
| | - Alejandro Carrasco
- Group Nanoneurosurgery, Institute of Health Research Biocruces, Barakaldo, Spain; Service Neurosurgery, Cruces University Hospital, Barakaldo, Spain
| | - Harkaitz Bengoetxea
- Laboratory of Clinical and Experimental Neuroscience (LaNCE), University of the Basque Country UPV/EHU, Leioa, Vizcaya, Spain
| |
Collapse
|
26
|
Morris AH, Mahal RS, Udell J, Wu M, Kyriakides TR. Multicompartment Drug Release System for Dynamic Modulation of Tissue Responses. Adv Healthc Mater 2017. [PMID: 28636088 DOI: 10.1002/adhm.201700370] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Pharmacological modulation of responses to injury is complicated by the need to deliver multiple drugs with spatiotemporal resolution. Here, a novel controlled delivery system containing three separate compartments with each releasing its contents over different timescales is fabricated. Core-shell electrospun fibers create two of the compartments in the system, while electrosprayed spheres create the third. Utility is demonstrated by targeting the foreign body response to implants because it is a dynamic process resulting in implant failure. Sequential delivery of a drug targeting nuclear factor-κB (NF-κB) and an antifibrotic is characterized in in vitro experiments. Specifically, macrophage fusion and p65 nuclear translocation in the presence of releasate or with macrophages cultured on the surfaces of the constructs are evaluated. In addition, releasate from pirfenidone scaffolds is shown to reduce transforming growth factor-β (TGF-β)-induced pSMAD3 nuclear localization in fibroblasts. In vivo, drug eluting constructs successfully mitigate macrophage fusion at one week and fibrotic encapsulation in a dose-dependent manner at four weeks, demonstrating effective release of both drugs over different timescales. Future studies can employ this system to improve and prolong implant lifetimes, or load it with other drugs to modulate other dynamic processes.
Collapse
Affiliation(s)
- Aaron H. Morris
- Department of Biomedical Engineering, Vascular Biology and Therapeutics Program Yale University New Haven CT 06519 USA
| | - Rajwant S. Mahal
- Department of Biomedical Engineering Yale University New Haven CT 06519 USA
| | - Jillian Udell
- Department of Biomedical Engineering Yale University New Haven CT 06519 USA
| | - Michelle Wu
- Department of Biomedical Engineering Yale University New Haven CT 06519 USA
| | - Themis R. Kyriakides
- Department of Biomedical Engineering Department of Pathology, Vascular Biology and Therapeutics Program Yale University New Haven CT 06519 USA
| |
Collapse
|
27
|
Klueh U, Ludzinska I, Czajkowski C, Qiao Y, Kreutzer DL. Crosslinked basement membrane-based coatings enhance glucose sensor function and continuous glucose monitoring in vivo. J Biomed Mater Res A 2017; 106:7-16. [PMID: 28875571 DOI: 10.1002/jbm.a.36206] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 08/16/2017] [Accepted: 08/30/2017] [Indexed: 01/17/2023]
Abstract
Overcoming sensor-induced tissue reactions is an essential element of achieving successful continuous glucose monitoring (CGM) in the management of diabetes, particularly when used in closed loop technology. Recently, we demonstrated that basement membrane (BM)-based glucose sensor coatings significantly reduced tissue reactions at sites of device implantation. However, the biocompatible BM-based biohydrogel sensor coating rapidly degraded over a less than a 3-week period, which effectively eliminated the protective sensor coating. In an effort to increase the stability and effectiveness of the BM coating, we evaluated the impact of crosslinking BM utilizing glutaraldehyde as a crosslinking agent, designated as X-Cultrex. Sensor performance (nonrecalibrated) was evaluated for the impact of these X-Cultrex coatings in vitro and in vivo. Sensor performance was assessed over a 28-day time period in a murine CGM model and expressed as mean absolute relative difference (MARD) values. Tissue reactivity of Cultrex-coated, X-Cultrex-coated, and uncoated glucose sensors was evaluated over a 28-day time period in vivo using standard histological techniques. These studies demonstrated that X-Cultrex-based sensor coatings had no effect on glucose sensor function in vitro. In vivo, glucose sensor performance was significantly enhanced following X-Cultrex coating throughout the 28-day study. Histological evaluations of X-Cultrex-treated sensors demonstrated significantly less tissue reactivity when compared to uncoated sensors. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 7-16, 2018.
Collapse
Affiliation(s)
- Ulrike Klueh
- Department of Biomedical Engineering, School of Engineering, Wayne State University, Detroit, Michigan, 48202.,Department of Surgery, School of Medicine, University of Connecticut, Farmington, Connecticut, 06030
| | - Izabela Ludzinska
- Department of Surgery, School of Medicine, University of Connecticut, Farmington, Connecticut, 06030
| | - Caroline Czajkowski
- Department of Surgery, School of Medicine, University of Connecticut, Farmington, Connecticut, 06030
| | - Yi Qiao
- Department of Surgery, School of Medicine, University of Connecticut, Farmington, Connecticut, 06030
| | - Donald L Kreutzer
- Department of Surgery, School of Medicine, University of Connecticut, Farmington, Connecticut, 06030
| |
Collapse
|
28
|
Hou Y, Jiang N, Zhang L, Li Y, Meng Y, Han D, Chen C, Yang Y, Zhu S. Oppositely Charged Polyurethane Microspheres with Tunable Zeta Potentials as an Injectable Dual-Loaded System for Bone Repair. ACS APPLIED MATERIALS & INTERFACES 2017; 9:25808-25817. [PMID: 28704028 DOI: 10.1021/acsami.7b06673] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
To effectively repair irregular shaped bone defects by a minimally invasive procedure, the exploration of an injectable gel to fill the defect is desirable. Herein, positively and negatively charged polyurethane microspheres (PU-A and PU-B) with adjustable zeta potentials as well as the hydroxyapatite-loaded PU microsphere (PU-A/HA) and the dexamethasone-loaded PU microsphere (PU-B/Dex) were successfully prepared, and the oppositely charged microspheres could self-assemble into injectable gels with 3D structures by a mutually electrostatic attraction. The self-assembly PU-A/HA+PU-B/Dex gel exhibited a much higher elastic modulus (about 0.20 MPa) and excellent shear-thinning and self-recovery behaviors, which would allow the gel to be injected through a fine syringe to fill the irregular defect. The in vitro and in vivo experiments demonstrated that the coexistence of HA and Dex in PU-A/HA+PU-B/Dex gel had a synergistic effect on cell differentiation and accelerating new bone formation, displaying a good prospect as an injectable gel for bone repair in minimally invasive surgery.
Collapse
Affiliation(s)
- Yi Hou
- Analytical & Testing Center, Sichuan University , Chengdu, Sichuan 610064, PR China
| | - Nan Jiang
- State Key Laboratory of Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, PR China
| | - Li Zhang
- Analytical & Testing Center, Sichuan University , Chengdu, Sichuan 610064, PR China
| | - Yubao Li
- Analytical & Testing Center, Sichuan University , Chengdu, Sichuan 610064, PR China
| | - Yuezhong Meng
- The Key Laboratory of Low-carbon Chemistry & Energy Conservation of Guangdong Province/State Key Laboratory of Optoelectronic Materials and Technologies, School of Materials Science and Engineering, Sun Yat-sen University , Guangzhou, Guangdong 510275, PR China
| | - Dongmei Han
- The Key Laboratory of Low-carbon Chemistry & Energy Conservation of Guangdong Province/State Key Laboratory of Optoelectronic Materials and Technologies, School of Materials Science and Engineering, Sun Yat-sen University , Guangzhou, Guangdong 510275, PR China
| | - Chen Chen
- Analytical & Testing Center, Sichuan University , Chengdu, Sichuan 610064, PR China
| | - Yuan Yang
- Institute of Biomaterials and Biomedical Engineering, University of Toronto , Toronto, Ontario M5S 3E3, Canada
| | - Songsong Zhu
- State Key Laboratory of Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, PR China
| |
Collapse
|
29
|
Boehler C, Kleber C, Martini N, Xie Y, Dryg I, Stieglitz T, Hofmann U, Asplund M. Actively controlled release of Dexamethasone from neural microelectrodes in a chronic in vivo study. Biomaterials 2017; 129:176-187. [DOI: 10.1016/j.biomaterials.2017.03.019] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 03/08/2017] [Accepted: 03/12/2017] [Indexed: 10/20/2022]
|
30
|
Morphological, thermal and drug release studies of poly (methacrylic acid)-based molecularly imprinted polymer nanoparticles immobilized in electrospun poly (ε-caprolactone) nanofibers as dexamethasone delivery system. KOREAN J CHEM ENG 2017. [DOI: 10.1007/s11814-017-0078-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
31
|
Catt K, Li H, Hoang V, Beard R, Cui XT. Self-powered therapeutic release from conducting polymer/graphene oxide films on magnesium. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2017; 14:2495-2503. [PMID: 28571834 DOI: 10.1016/j.nano.2017.02.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 01/07/2017] [Accepted: 02/07/2017] [Indexed: 10/19/2022]
Abstract
Magnesium's complete in vivo degradation is appealing for medical implant applications. Rapid corrosion and hydrogen bubble generation along with inflammatory host tissue response have limited its clinical use. Here we electropolymerized a poly (3,4-ethylenedioxythiophene) (PEDOT) and graphene oxide (GO) film directly on Mg surface. GO acted as nano-drug carrier to carry anti-inflammatory drug dexamethasone (Dex). PEDOT/GO/Dex coatings improved Mg corrosion resistance and decreased the rate of hydrogen production. Dex could be released driven by the electrical current generated from Mg corrosion. The anti-inflammatory activity of the released Dex was confirmed in microglia cultures. This PEDOT/GO/Dex film displayed the ability to both control Mg corrosion and act as an on demand release coating that delivers Dex at the corrosion site to minimize detrimental effects of corrosion byproducts. Such multi-functional smart coating will improve the clinical use of Mg implants. Furthermore, the PEDOT/GO/Drug/Mg system may be developed into self-powered implantable drug delivery devices.
Collapse
Affiliation(s)
- Kasey Catt
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - Huaxiu Li
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - Victor Hoang
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - Roland Beard
- Department of Mechanical Engineering and Materials Science, University of Pittsburgh, Pittsburgh, PA, USA
| | - X Tracy Cui
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
| |
Collapse
|
32
|
Chen E, Chu S, Gov L, Kim Y, Lodoen M, Tenner A, Liu W. CD200 modulates macrophage cytokine secretion and phagocytosis in response to poly(lactic co-glycolic acid) microparticles and films. J Mater Chem B 2017; 5:1574-1584. [PMID: 28736613 PMCID: PMC5515357 DOI: 10.1039/c6tb02269c] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Biocompatibility is a major concern for developing biomaterials used in medical devices, tissue engineering and drug delivery. Poly(lactic-co-glycolic acid) (PLGA) is one of the most widely used biodegradable materials, yet still triggers a significant foreign body response that impairs healing. Immune cells including macrophages respond to the implanted biomaterial and mediate the host response, which can eventually lead to device failure. Previously in our laboratory, we found that CD200, an immunomodulatory protein, suppressed macrophage inflammatory activation in vitro and reduced local immune cell infiltration around a biomaterial implant. While in our initial study we used polystyrene as a model material, here we investigate the effect of CD200 on PLGA, a commonly used biomaterial with many potential clinical applications. We fabricated PLGA with varied geometries, modified their surfaces with CD200, and examined macrophage cytokine secretion and phagocytosis. We found that CD200 suppressed secretion of the pro-inflammatory cytokine TNF-α and enhanced secretion of the anti-inflammatory cytokine IL-10, suggesting a role for CD200 in promoting wound healing and tissue remodeling. In addition, we found that CD200 increased phagocytosis in both murine macrophages and human monocytes. Together, these data suggest that modification with CD200 leads to a response that simultaneously prevents inflammation and enhances phagocytosis. This immunomodulatory feature may be used as a strategy to mitigate inflammation or deliver drugs or anti-inflammatory agents targeting macrophages.
Collapse
Affiliation(s)
- E.Y. Chen
- Department of Chemical Engineering and Materials Science, University of California, Irvine
- The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine
| | - S. Chu
- Department of Molecular Biology and Biochemistry, University of California, Irvine
| | - L. Gov
- Department of Molecular Biology and Biochemistry, University of California, Irvine
| | - Y.K. Kim
- Department of Chemical Engineering and Materials Science, University of California, Irvine
- The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine
- Department of Biomedical Engineering, University of California, Irvine
| | - M.B. Lodoen
- Department of Molecular Biology and Biochemistry, University of California, Irvine
| | - A.J. Tenner
- Department of Molecular Biology and Biochemistry, University of California, Irvine
| | - W.F. Liu
- Department of Chemical Engineering and Materials Science, University of California, Irvine
- The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine
- Department of Biomedical Engineering, University of California, Irvine
| |
Collapse
|
33
|
Bensiamar F, Olalde B, Cifuentes SC, Argarate N, Atorrasagasti G, González-Carrasco JL, García-Rey E, Vilaboa N, Saldaña L. Bioactivity of dexamethasone-releasing coatings on polymer/magnesium composites. Biomed Mater 2016; 11:055011. [DOI: 10.1088/1748-6041/11/5/055011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|
34
|
Neural Probes for Chronic Applications. MICROMACHINES 2016; 7:mi7100179. [PMID: 30404352 PMCID: PMC6190051 DOI: 10.3390/mi7100179] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Revised: 09/12/2016] [Accepted: 09/26/2016] [Indexed: 12/11/2022]
Abstract
Developed over approximately half a century, neural probe technology is now a mature technology in terms of its fabrication technology and serves as a practical alternative to the traditional microwires for extracellular recording. Through extensive exploration of fabrication methods, structural shapes, materials, and stimulation functionalities, neural probes are now denser, more functional and reliable. Thus, applications of neural probes are not limited to extracellular recording, brain-machine interface, and deep brain stimulation, but also include a wide range of new applications such as brain mapping, restoration of neuronal functions, and investigation of brain disorders. However, the biggest limitation of the current neural probe technology is chronic reliability; neural probes that record with high fidelity in acute settings often fail to function reliably in chronic settings. While chronic viability is imperative for both clinical uses and animal experiments, achieving one is a major technological challenge due to the chronic foreign body response to the implant. Thus, this review aims to outline the factors that potentially affect chronic recording in chronological order of implantation, summarize the methods proposed to minimize each factor, and provide a performance comparison of the neural probes developed for chronic applications.
Collapse
|
35
|
Synergistic Effect of Mesoporous Silica and Hydroxyapatite in Loaded Poly(DL-lactic-co-glycolic acid) Microspheres on the Regeneration of Bone Defects. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9824827. [PMID: 27652269 PMCID: PMC5019907 DOI: 10.1155/2016/9824827] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 06/26/2016] [Accepted: 06/29/2016] [Indexed: 02/06/2023]
Abstract
A microsphere composite made of poly(DL-lactic-co-glycolic acid) (PLGA), mesoporous silica nanoparticle (MSN), and nanohydroxyapatite (nHA) (PLGA-MSN/nHA) was prepared and evaluated as bone tissue engineering materials. The objective of this study was to investigate the synergistic effect of MSN/nHA on biocompatibility as well as its potential ability for bone formation. First, we found that this PLGA-MSN/nHA composite performed good characteristics on microstructure, mechanical strength, and wettability. By cell culture experiments, the adhesion and proliferation rate of the cells seeded on PLGA-MSN/nHA composite was higher than those of the controls and high levels of osteogenetic factors such as ALP and Runx-2 were detected by reverse transcriptase polymerase chain reaction. Finally, this PLGA-MSN/nHA composite was implanted into the femur bone defect in a rabbit model, and its ability to induce bone regeneration was observed by histological examinations. Twelve weeks after implantation, the bone defects had significantly more formation of mature bone and less residual materials than in the controls. These results demonstrate that this PLGA-MSN/nHA composite, introducing both MSN and nHA into PLGA microspheres, can improve the biocompatibility and osteoinductivity of composite in vitro and in vivo and had potential application in bone regeneration.
Collapse
|
36
|
Price CF, Burgess DJ, Kastellorizios M. l -DOPA as a small molecule surrogate to promote angiogenesis and prevent dexamethasone-induced ischemia. J Control Release 2016; 235:176-181. [DOI: 10.1016/j.jconrel.2016.05.065] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Revised: 05/11/2016] [Accepted: 05/31/2016] [Indexed: 12/19/2022]
|
37
|
Roach BL, Kelmendi-Doko A, Balutis EC, Marra KG, Ateshian GA, Hung CT. Dexamethasone Release from Within Engineered Cartilage as a Chondroprotective Strategy Against Interleukin-1α. Tissue Eng Part A 2016; 22:621-32. [PMID: 26956216 DOI: 10.1089/ten.tea.2016.0018] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
While significant progress has been made toward engineering functional cartilage constructs with mechanical properties suitable for in vivo loading, the impact on these grafts of inflammatory cytokines, chemical factors that are elevated with trauma or osteoarthritis, is poorly understood. Previous work has shown dexamethasone to be a critical compound for cultivating cartilage with functional properties, while also providing chondroprotection from proinflammatory cytokines. This study tested the hypothesis that the incorporation of poly(lactic-co-glycolic acid) (PLGA) (75:25) microspheres that release dexamethasone from within chondrocyte-seeded agarose hydrogel constructs would promote development of constructs with functional properties and protect constructs from the deleterious effects of interleukin-1α (IL-1α). After 28 days of growth culture, experimental groups were treated with IL-1α (10 ng/mL) for 7 days. Reaching native equilibrium moduli and proteoglycan levels, dexamethasone-loaded microsphere constructs exhibited tissue properties similar to microsphere-free control constructs cultured in dexamethasone-supplemented culture media and were insensitive to IL-1α exposure. These findings are in stark contrast to constructs containing dexamethasone-free microspheres or no microspheres, cultured without dexamethasone, where IL-1α exposure led to significant tissue degradation. These results support the use of dexamethasone delivery from within engineered cartilage, through biodegradable microspheres, as a strategy to produce mechanically functional tissues that can also combat the deleterious effects of local proinflammatory cytokine exposure.
Collapse
Affiliation(s)
- Brendan L Roach
- 1 Department of Biomedical Engineering, Columbia University , New York, New York
| | - Arta Kelmendi-Doko
- 2 Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Elaine C Balutis
- 3 Department of Orthopedics and Sports Medicine, Mount Sinai Health System , New York, New York
| | - Kacey G Marra
- 2 Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania.,4 McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.,5 Department of Plastic Surgery, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Gerard A Ateshian
- 1 Department of Biomedical Engineering, Columbia University , New York, New York.,6 Department of Mechanical Engineering, Columbia University , New York, New York
| | - Clark T Hung
- 1 Department of Biomedical Engineering, Columbia University , New York, New York
| |
Collapse
|
38
|
Santos TC, Reis RL, Marques AP. Can host reaction animal models be used to predict and modulate skin regeneration? J Tissue Eng Regen Med 2016. [DOI: 10.1002/term.2128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- T. C. Santos
- 3Bs Research Group - Biomaterials, Biodegradables and Biomimetics; University of Minho, Taipas, and ICVS-3Bs - PT Government Associate Laboratory; Braga/Guimarães Portugal
| | - R. L. Reis
- 3Bs Research Group - Biomaterials, Biodegradables and Biomimetics; University of Minho, Taipas, and ICVS-3Bs - PT Government Associate Laboratory; Braga/Guimarães Portugal
| | - A. P. Marques
- 3Bs Research Group - Biomaterials, Biodegradables and Biomimetics; University of Minho, Taipas, and ICVS-3Bs - PT Government Associate Laboratory; Braga/Guimarães Portugal
| |
Collapse
|
39
|
Andhariya JV, Burgess DJ. Recent advances in testing of microsphere drug delivery systems. Expert Opin Drug Deliv 2016; 13:593-608. [PMID: 26828874 DOI: 10.1517/17425247.2016.1134484] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
INTRODUCTION This review discusses advances in the field of microsphere testing. AREAS COVERED In vitro release-testing methods such as sample and separate, dialysis membrane sacs and USP apparatus IV have been used for microspheres. Based on comparisons of these methods, USP apparatus IV is currently the method of choice. Accelerated in vitro release tests have been developed to shorten the testing time for quality control purposes. In vitro-in vivo correlations using real-time and accelerated release data have been developed, to minimize the need to conduct in vivo performance evaluation. Storage stability studies have been conducted to investigate the influence of various environmental factors on microsphere quality throughout the product shelf life. New tests such as the floating test and the in vitro wash-off test have been developed along with advancement in characterization techniques for other physico-chemical parameters such as particle size, drug content, and thermal properties. EXPERT OPINION Although significant developments have been made in microsphere release testing, there is still a lack of guidance in this area. Microsphere storage stability studies should be extended to include microspheres containing large molecules. An agreement needs to be reached on the use of particle sizing techniques to avoid inconsistent data. An approach needs to be developed to determine total moisture content of microspheres.
Collapse
Affiliation(s)
- Janki V Andhariya
- a School of Pharmacy , University of Connecticut , Storrs , CT , USA
| | - Diane J Burgess
- a School of Pharmacy , University of Connecticut , Storrs , CT , USA
| |
Collapse
|
40
|
Vallejo-Heligon SG, Brown NL, Reichert WM, Klitzman B. Porous, Dexamethasone-loaded polyurethane coatings extend performance window of implantable glucose sensors in vivo. Acta Biomater 2016; 30:106-115. [PMID: 26537203 DOI: 10.1016/j.actbio.2015.10.045] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 10/07/2015] [Accepted: 10/28/2015] [Indexed: 10/22/2022]
Abstract
Continuous glucose sensors offer the promise of tight glycemic control for insulin dependent diabetics; however, utilization of such systems has been hindered by issues of tissue compatibility. Here we report on the in vivo performance of implanted glucose sensors coated with Dexamethasone-loaded (Dex-loaded) porous coatings employed to mediate the tissue-sensor interface. Two animal studies were conducted to (1) characterize the tissue modifying effects of the porous Dex-loaded coatings deployed on sensor surrogate implants and (2) investigate the effects of the same coatings on the in vivo performance of Medtronic MiniMed SOF-SENSOR™ glucose sensors. The tissue response to implants was evaluated by quantifying macrophage infiltration, blood vessel formation, and collagen density around implants. Sensor function was assessed by measuring changes in sensor sensitivity and time lag, calculating the Mean Absolute Relative Difference (MARD) for each sensor treatment, and performing functional glucose challenge test at relevant time points. Implants treated with porous Dex-loaded coatings diminished inflammation and enhanced vascularization of the tissue surrounding the implants. Functional sensors with Dex-loaded porous coatings showed enhanced sensor sensitivity over a 21-day period when compared to controls. Enhanced sensor sensitivity was accompanied with an increase in sensor signal lag and MARD score. These results indicate that Dex-loaded porous coatings were able to elicit an attenuated tissue response, and that such tissue microenvironment could be conducive towards extending the performance window of glucose sensors in vivo. STATEMENT OF SIGNIFICANCE In the present article, a coating to extend the functionality of implantable glucose sensors in vivo was developed. Our study showed that the delivery of an anti-inflammatory agent with the presentation of micro-sized topographical cues from coatings may lead to improved long-term glucose sensor function in vivo. We believe that improved function of sensors treated with the novel coatings was a result of the observed decreases in inflammatory cell density and increases in vessel density of the tissue adjacent to the devices. Furthermore, extending the in vivo functionality of implantable glucose sensors may lead to greater adoption of these devices by diabetic patients.
Collapse
|
41
|
Hur W, Park M, Lee JY, Kim MH, Lee SH, Park CG, Kim SN, Min HS, Min HJ, Chai JH, Lee SJ, Kim S, Choi TH, Choy YB. Bioabsorbable bone plates enabled with local, sustained delivery of alendronate for bone regeneration. J Control Release 2016; 222:97-106. [DOI: 10.1016/j.jconrel.2015.12.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 11/27/2015] [Accepted: 12/08/2015] [Indexed: 11/15/2022]
|
42
|
Avula M, Jones D, Rao AN, McClain D, McGill LD, Grainger DW, Solzbacher F. Local release of masitinib alters in vivo implantable continuous glucose sensor performance. Biosens Bioelectron 2015; 77:149-56. [PMID: 26402593 DOI: 10.1016/j.bios.2015.08.059] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Revised: 08/24/2015] [Accepted: 08/25/2015] [Indexed: 11/25/2022]
Abstract
Continuous glucose monitoring (CGM) sensors are often advocated as a clinical solution to improve long-term glycemic control in the context of diabetes. Subcutaneous sensor inflammatory response, fouling and fibrous encapsulation resulting from the host foreign body response (FBR) reduce sensor sensitivity to glucose, eventually resulting in sensor performance compromise and device failure. Several combination device strategies load CGM sensors with drug payloads that release locally to tissue sites to mitigate FBR-mediated sensor failure. In this study, the mast cell-targeting tyrosine kinase inhibitor, masitinib, was released from degradable polymer microspheres delivered from the surfaces of FDA-approved human commercial CGM needle-type implanted sensors in a rodent subcutaneous test bed. By targeting the mast cell c-Kit receptor and inhibiting mast cell activation and degranulation, local masitinib penetration around the CGM to several hundred microns sought to reduce sensor fibrosis to extend CGM functional lifetimes in subcutaneous sites. Drug-releasing and control CGM implants were compared in murine percutaneous implant sites for 21 days using direct-wire continuous glucose reporting. Drug-releasing implants exhibited no significant difference in CGM fibrosis at implant sites but showed relatively stable continuous sensor responses over the study period compared to blank microsphere control CGM implants.
Collapse
Affiliation(s)
- M Avula
- Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA
| | - D Jones
- Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA
| | - A N Rao
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA
| | - D McClain
- Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA
| | - L D McGill
- Associated Regional and University Pathologist Laboratories, University of Utah, Salt Lake City, UT 84112, USA
| | - D W Grainger
- Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
| | - F Solzbacher
- Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Department of Electrical and Computer Engineering, University of Utah, Salt Lake City, UT 84112, USA
| |
Collapse
|
43
|
Kastellorizios M, Tipnis N, Papadimitrakopoulos F, Burgess DJ. Drug Distribution in Microspheres Enhances Their Anti-Inflammatory Properties in the Gottingen Minipig. Mol Pharm 2015; 12:3332-8. [PMID: 26237140 DOI: 10.1021/acs.molpharmaceut.5b00326] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The foreign body reaction (FBR), one of the body's defense mechanisms against foreign materials, results in loss of implant biocompatibility. A popular strategy to prevent FBR is the constant release of dexamethasone in the tissue surrounding the implant. However, FBR prevention has not been sufficiently studied in large animal models, which offer a better representation of the human subcutaneous tissue physiology. Accordingly, a long-term strategy to prevent FBR to subcutaneous implants in a large animal model is necessary to translate the existing research for clinical applications. Here, a poly(lactic-co-glycolic) (PLGA) microsphere/poly(vinyl alcohol) (PVA) hydrogel composite coating for one-month prevention of FBR in Gottingen minipigs was developed. A modified PLGA microsphere formulation process is presented, that utilizes coprecipitation of dexamethasone and PLGA. Traditional methods result in heterogeneous distribution of large drug crystals in the microsphere matrix, which in turn results in low drug loading since the drug crystal size is close to that of the microspheres. The modified microsphere preparation method showed homogeneous distribution of dexamethasone, which in turn gave rise to increased drug loading, low burst release, and minimal lag phase. Elimination of the lag phase was dictated from previous work that compared FBR between rats and minipigs. The ability of the coatings to improve implant biocompatibility was successfully tested in vivo via histological examination of explanted tissue from the area surrounding the implants. The biocompatible coatings presented here are suitable for miniaturized implantable devices, such as biosensors, that require constant communication with the local microenvironment.
Collapse
Affiliation(s)
- Michail Kastellorizios
- Department of Pharmaceutical Sciences and ‡Department of Chemistry and Institute of Materials Science, University of Connecticut , Storrs, Connecticut 06269, United States
| | - Namita Tipnis
- Department of Pharmaceutical Sciences and ‡Department of Chemistry and Institute of Materials Science, University of Connecticut , Storrs, Connecticut 06269, United States
| | - Fotios Papadimitrakopoulos
- Department of Pharmaceutical Sciences and ‡Department of Chemistry and Institute of Materials Science, University of Connecticut , Storrs, Connecticut 06269, United States
| | - Diane J Burgess
- Department of Pharmaceutical Sciences and ‡Department of Chemistry and Institute of Materials Science, University of Connecticut , Storrs, Connecticut 06269, United States
| |
Collapse
|
44
|
Multiple tissue response modifiers to promote angiogenesis and prevent the foreign body reaction around subcutaneous implants. J Control Release 2015. [PMID: 26216396 DOI: 10.1016/j.jconrel.2015.07.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Dexamethasone-releasing PLGA poly(lactic-co-glycolic acid) microsphere/PVA (polyvinyl alcohol) hydrogel composite coatings have been shown to prevent the foreign body reaction (FBR) to subcutaneous implants in small and large animal models. Such coatings were developed to extend the lifetime of implantable biosensors. However, long-term exposure of tissue to low levels of dexamethasone results in a reduction in blood vessel density due to the anti-angiogenic effect of dexamethasone. This mild effect, while not threatening to the subject's health, may interfere with analyte detection and the sensor response time over the long-term. The present work is focused on the development of coatings that deliver combinations of three tissue response modifiers (TRMs): dexamethasone, VEGF (vascular endothelial growth factor) and PDGF (platelet derived growth factor). Dexamethasone, VEGF and PDGF prevent the FBR, increase angiogenesis and promote blood vessel maturation (which increases blood flow), respectively. To minimize any potential interference among these three TRMs (for example, PDGF increases fibrosis), the relative doses of dexamethasone, VEGF and PDGF were adjusted. It was determined that: a) all three TRMs are required for maximum promotion of angiogenesis, blood vessel maturation and prevention of the FBR; b) VEGF has to be administered at higher doses than PDGF; c) an increase in dexamethasone dosing must be accompanied by a proportional increase in growth factor dosing; and d) modification of the TRM ratio can achieve a constant capillary density throughout the implantation period which is important for applications such as biosensors to maintain sensitivity and a stable sensor baseline. Moreover, an osmosis-driven process for encapsulation of proteins in PLGA microspheres that showed low burst release was developed.
Collapse
|
45
|
Continuous metabolic monitoring based on multi-analyte biomarkers to predict exhaustion. Sci Rep 2015; 5:10603. [PMID: 26028477 PMCID: PMC4450587 DOI: 10.1038/srep10603] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 04/21/2015] [Indexed: 12/03/2022] Open
Abstract
This work introduces the concept of multi-analyte biomarkers for continuous metabolic monitoring. The importance of using more than one marker lies in the ability to obtain a holistic understanding of the metabolism. This is showcased for the detection and prediction of exhaustion during intense physical exercise. The findings presented here indicate that when glucose and lactate changes over time are combined into multi-analyte biomarkers, their monitoring trends are more sensitive in the subcutaneous tissue, an implantation-friendly peripheral tissue, compared to the blood. This unexpected observation was confirmed in normal as well as type 1 diabetic rats. This study was designed to be of direct value to continuous monitoring biosensor research, where single analytes are typically monitored. These findings can be implemented in new multi-analyte continuous monitoring technologies for more accurate insulin dosing, as well as for exhaustion prediction studies based on objective data rather than the subject’s perception.
Collapse
|
46
|
Kastellorizios M, Papadimitrakopoulos F, Burgess DJ. Prevention of foreign body reaction in a pre-clinical large animal model. J Control Release 2015; 202:101-7. [DOI: 10.1016/j.jconrel.2015.01.038] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 01/14/2015] [Accepted: 01/29/2015] [Indexed: 10/24/2022]
|
47
|
Chandorkar Y, Bhaskar N, Madras G, Basu B. Long-term sustained release of salicylic acid from cross-linked biodegradable polyester induces a reduced foreign body response in mice. Biomacromolecules 2015; 16:636-49. [PMID: 25559641 DOI: 10.1021/bm5017282] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
There has been a continuous surge toward developing new biopolymers that exhibit better in vivo biocompatibility properties in terms of demonstrating a reduced foreign body response (FBR). One approach to mitigate the undesired FBR is to develop an implant capable of releasing anti-inflammatory molecules in a sustained manner over a long time period. Implants causing inflammation are also more susceptible to infection. In this article, the in vivo biocompatibility of a novel, biodegradable salicylic acid releasing polyester (SAP) has been investigated by subcutaneous implantation in a mouse model. The tissue response to SAP was compared with that of a widely used biodegradable polymer, poly(lactic acid-co-glycolic acid) (PLGA), as a control over three time points: 2, 4, and 16 weeks postimplantation. A long-term in vitro study illustrates a continuous, linear (zero order) release of salicylic acid with a cumulative mass percent release rate of 7.34 × 10(-4) h(-1) over ∼1.5-17 months. On the basis of physicochemical analysis, surface erosion for SAP and bulk erosion for PLGA have been confirmed as their dominant degradation modes in vivo. On the basis of the histomorphometrical analysis of inflammatory cell densities and collagen distribution as well as quantification of proinflammatory cytokine levels (TNF-α and IL-1β), a reduced foreign body response toward SAP with respect to that generated by PLGA has been unambiguously established. The favorable in vivo tissue response to SAP, as manifest from the uniform and well-vascularized encapsulation around the implant, is consistent with the decrease in inflammatory cell density and increase in angiogenesis with time. The above observations, together with the demonstration of long-term and sustained release of salicylic acid, establish the potential use of SAP for applications in improved matrices for tissue engineering and chronic wound healing.
Collapse
Affiliation(s)
- Yashoda Chandorkar
- Laboratory for Biomaterials, Materials Research Centre, ‡Department of Chemical Engineering, §Bioengineering Program, Indian Institute of Science , Bangalore 560012, India
| | | | | | | |
Collapse
|
48
|
Li YF, Rubert M, Yu Y, Besenbacher F, Chen M. Delivery of dexamethasone from electrospun PCL–PEO binary fibers and their effects on inflammation regulation. RSC Adv 2015. [DOI: 10.1039/c5ra03099d] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Differences in surface topography, chemical composition, wettability and release kinetics of the anti-inflammatory drug dexamethasone among different PCL–PEO fibers collectively affected the regulation of inflammatory related gene expression.
Collapse
Affiliation(s)
- Yan-Fang Li
- Interdisciplinary Nanoscience Center (iNANO)
- Aarhus University
- DK-8000 Aarhus C
- Denmark
- Institute of Nanoscience and Nanotechnology
| | - Marina Rubert
- Interdisciplinary Nanoscience Center (iNANO)
- Aarhus University
- DK-8000 Aarhus C
- Denmark
| | - Ying Yu
- Institute of Nanoscience and Nanotechnology
- Central China Normal University
- Wuhan 430079
- China
| | - Flemming Besenbacher
- Interdisciplinary Nanoscience Center (iNANO)
- Aarhus University
- DK-8000 Aarhus C
- Denmark
| | - Menglin Chen
- Interdisciplinary Nanoscience Center (iNANO)
- Aarhus University
- DK-8000 Aarhus C
- Denmark
| |
Collapse
|
49
|
Vallejo-Heligon SG, Klitzman B, Reichert WM. Characterization of porous, dexamethasone-releasing polyurethane coatings for glucose sensors. Acta Biomater 2014; 10:4629-4638. [PMID: 25065548 PMCID: PMC4186909 DOI: 10.1016/j.actbio.2014.07.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Revised: 07/15/2014] [Accepted: 07/18/2014] [Indexed: 10/25/2022]
Abstract
Commercially available implantable needle-type glucose sensors for diabetes management are robust analytically but can be unreliable clinically primarily due to tissue-sensor interactions. Here, we present the physical, drug release and bioactivity characterization of tubular, porous dexamethasone (Dex)-releasing polyurethane coatings designed to attenuate local inflammation at the tissue-sensor interface. Porous polyurethane coatings were produced by the salt-leaching/gas-foaming method. Scanning electron microscopy and micro-computed tomography (micro-CT) showed controlled porosity and coating thickness. In vitro drug release from coatings monitored over 2 weeks presented an initial fast release followed by a slower release. Total release from coatings was highly dependent on initial drug loading amount. Functional in vitro testing of glucose sensors deployed with porous coatings against glucose standards demonstrated that highly porous coatings minimally affected signal strength and response rate. Bioactivity of the released drug was determined by monitoring Dex-mediated, dose-dependent apoptosis of human peripheral blood derived monocytes in culture. Acute animal studies were used to determine the appropriate Dex payload for the implanted porous coatings. Pilot short-term animal studies showed that Dex released from porous coatings implanted in rat subcutis attenuated the initial inflammatory response to sensor implantation. These results suggest that deploying sensors with the porous, Dex-releasing coatings is a promising strategy to improve glucose sensor performance.
Collapse
Affiliation(s)
| | - Bruce Klitzman
- Department of Biomedical Engineering, Duke University, Durham, NC 27708-0281, USA; Kenan Plastic Surgery Research Labs, Duke University Medical Center, Durham, NC 27710, USA
| | - William M Reichert
- Department of Biomedical Engineering, Duke University, Durham, NC 27708-0281, USA.
| |
Collapse
|
50
|
Sidney LE, Heathman TRJ, Britchford ER, Abed A, Rahman CV, Buttery LDK. Investigation of localized delivery of diclofenac sodium from poly(D,L-lactic acid-co-glycolic acid)/poly(ethylene glycol) scaffolds using an in vitro osteoblast inflammation model. Tissue Eng Part A 2014; 21:362-73. [PMID: 25104438 DOI: 10.1089/ten.tea.2014.0100] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Nonunion fractures and large bone defects are significant targets for osteochondral tissue engineering strategies. A major hurdle in the use of these therapies is the foreign body response of the host. Herein, we report the development of a bone tissue engineering scaffold with the ability to release anti-inflammatory drugs, in the hope of evading this response. Porous, sintered scaffolds composed of poly(D,L-lactic acid-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) were prepared with and without the anti-inflammatory drug diclofenac sodium. Analysis of drug release over time demonstrated a profile suitable for the treatment of acute inflammation with ∼80% of drug released over the first 4 days and a subsequent release of around 0.2% per day. Effect of drug release was monitored using an in vitro osteoblast inflammation model, comprised of mouse primary calvarial osteoblasts stimulated with proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Levels of inflammation were monitored by cell viability and cellular production of nitric oxide (NO) and prostaglandin E2 (PGE2). The osteoblast inflammation model revealed that proinflammatory cytokine addition to the medium reduced cell viability to 33%, but the release of diclofenac sodium from scaffolds inhibited this effect with a final cell viability of ∼70%. However, releasing diclofenac sodium at high concentrations had a toxic effect on the cells. Proinflammatory cytokine addition led to increased NO and PGE2 production; diclofenac-sodium-releasing scaffolds inhibited NO release by ∼64% and PGE2 production by ∼52%, when the scaffold was loaded with the optimal concentration of drug. These observations demonstrate the potential use of PLGA/PEG scaffolds for localized delivery of anti-inflammatory drugs in bone tissue engineering applications.
Collapse
Affiliation(s)
- Laura E Sidney
- 1 Division of Drug Delivery and Tissue Engineering, School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham , Nottingham, United Kingdom
| | | | | | | | | | | |
Collapse
|