Three-dimensional printing of antibiotics-loaded poly-ε-caprolactone/poly(lactic-co-glycolic acid) scaffolds for treatment of chronic osteomyelitis

Osteomyelitis, an infection and inflammation of bone marrow, often progresses to chronic stage because of delay in diagnosis and treatment. Once it becomes chronic, intravenous antibiotics therapy is no longer effective as swollen surrounding tissue interrupts blood flow into the infected tissue. In severe cases, debridement of the necrotic tissue becomes necessary to prevent further infection. In this study, for the first time, we produced three-dimensional (3D) printed antibiotics-loaded biodegradable poly-e-caprolactone/poly(lactic-co-glycolic acid) scaffold for treatment of chronic osteomyelitis. Subsequent bone regeneration in debrided site was also observed with the customized scaffolds fabricated using 3D printing. Tobramycin, one of the most widely used antibiotics in orthopedic surgery, was chosen due to its thermostable nature compliant to the heat-based fabrication conditions. In in vitro tests, antibacterial and anti-inflammatory effects and release profile of tobramycin from the scaffold were evaluated to verify the potential of our scaffold as a drug delivery system. In addition, in vivo efficacy of the developed drug loaded scaffolds for treatment of chronic osteomyelitis was also examined in a rat model.

[1]  J. Chevalier,et al.  Evaluation of a new press-fit in situ setting composite porous scaffold for cancellous bone repair: towards a "surgeon-friendly" bone filler? , 2010, Acta biomaterialia.

[2]  Dong-Woo Cho,et al.  Solid freeform fabrication technology applied to tissue engineering with various biomaterials , 2012 .

[3]  D. Cho,et al.  Bioprinting of a mechanically enhanced three-dimensional dual cell-laden construct for osteochondral tissue engineering using a multi-head tissue/organ building system , 2012 .

[4]  Gang Chai,et al.  Rapid prototyped PGA/PLA scaffolds in the reconstruction of mandibular condyle bone defects , 2010, The international journal of medical robotics + computer assisted surgery : MRCAS.

[5]  Syngcuk Kim,et al.  The fabrication of rapid prototype based 3D PCL and PLGA scaffolds using precision deposition system , 2008 .

[6]  Carla Renata Arciola,et al.  Antibiotic-loaded biomaterials and the risks for the spread of antibiotic resistance following their prophylactic and therapeutic clinical use. , 2010, Biomaterials.

[7]  Dong-Woo Cho,et al.  Projection image-generation algorithm for fabrication of a complex structure using projection-based microstereolithography , 2012 .

[8]  Ken Chen,et al.  Three‐dimensional ultrasound image‐guided robotic system for accurate microwave coagulation of malignant liver tumours , 2010, The international journal of medical robotics + computer assisted surgery : MRCAS.

[9]  Sean Molloy,et al.  Temperature Measurement During Polymerization of Polymethylmethacrylate Cement Used for Vertebroplasty , 2003, Spine.

[10]  H. C. van der Mei,et al.  Biodegradable vs non-biodegradable antibiotic delivery devices in the treatment of osteomyelitis , 2013, Expert opinion on drug delivery.

[11]  B. Gander,et al.  Gentamicin encapsulation in PLA/PLGA microspheres in view of treating Brucella infections. , 2000, International journal of pharmaceutics.

[12]  C. Papasian,et al.  The Immunoproteasomes Regulate LPS-Induced TRIF/TRAM Signaling Pathway in Murine Macrophages , 2011, Cell Biochemistry and Biophysics.

[13]  D. Cho,et al.  Bone regeneration using a microstereolithography-produced customized poly(propylene fumarate)/diethyl fumarate photopolymer 3D scaffold incorporating BMP-2 loaded PLGA microspheres. , 2011, Biomaterials.

[14]  Benjamin Wu,et al.  Customized biomimetic scaffolds created by indirect three-dimensional printing for tissue engineering , 2013, Biofabrication.

[15]  M. McKee,et al.  A Prospective, Randomized Clinical Trial Comparing an Antibiotic-Impregnated Bioabsorbable Bone Substitute With Standard Antibiotic-Impregnated Cement Beads in the Treatment of Chronic Osteomyelitis and Infected Nonunion , 2010, Journal of orthopaedic trauma.

[16]  Matti J. Peltola,et al.  Novel composite implant in craniofacial bone reconstruction , 2011, European Archives of Oto-Rhino-Laryngology.

[17]  T. Hansen,et al.  Osteonecrosis of the jaws in patients treated with bisphosphonates - histomorphologic analysis in comparison with infected osteoradionecrosis. , 2006, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[18]  C. Zalavras,et al.  Chronic Posttraumatic Osteomyelitis and Infected Nonunion of the Tibia: Current Management Concepts , 2005, The Journal of the American Academy of Orthopaedic Surgeons.

[19]  Y. Sogo,et al.  Gatifloxacine-loaded PLGA and β-tricalcium phosphate composite for treating osteomyelitis. , 2011, Dental materials journal.

[20]  A. Yamazaki,et al.  Antibiotic-loaded poly-ε-caprolactone and porous β-tricalcium phosphate composite for treating osteomyelitis , 2008 .

[21]  J. Knuuti,et al.  Efficacy of Ciprofloxacin-Releasing Bioabsorbable Osteoconductive Bone Defect Filler for Treatment of Experimental Osteomyelitis Due to Staphylococcus aureus , 2005, Antimicrobial Agents and Chemotherapy.

[22]  Swee Hin Teoh,et al.  Evaluation of polycaprolactone scaffold degradation for 6 months in vitro and in vivo. , 2009, Journal of biomedical materials research. Part A.

[23]  F. Oner,et al.  Re: Belkoff SM, Molloy S. Temperature measurement during polymerization of polymethyl methacrylate cement used for vertebroplasty. Spine. 2003; 28:1555-9. , 2004, Spine.

[24]  J. Ryan.  Colorimetric determination of gentamicin, kanamycin, tobramycin, and amikacin aminoglycosides with 2,4-dinitrofluorobenzene. , 1984, Journal of pharmaceutical sciences.

[25]  H. Merkle,et al.  Hydrophilic poly(DL-lactide-co-glycolide) microspheres for the delivery of DNA to human-derived macrophages and dendritic cells. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[26]  Dong-Woo Cho,et al.  Evaluating cell proliferation based on internal pore size and 3D scaffold architecture fabricated using solid freeform fabrication technology , 2010, Journal of materials science. Materials in medicine.

[27]  폴리머 적층 시스템을 이용한 중공축 형상 인공지지체의 제작 및 비교 분석 , 2015, Tissue Engineering and Regenerative Medicine.

[28]  Bill Bynum,et al.  Lancet , 2015, The Lancet.

[29]  Jaesung Park,et al.  Development of a hybrid scaffold with synthetic biomaterials and hydrogel using solid freeform fabrication technology , 2011, Biofabrication.

[30]  J. V. van Horn,et al.  Residual gentamicin-release from antibiotic-loaded polymethylmethacrylate beads after 5 years of implantation. , 2003, Biomaterials.

[31]  L. Massari,et al.  Osteomyelitis: clinical update for practical guidelines , 2006, Nuclear medicine communications.

[32]  Weiwei Jiang,et al.  Triptolide suppresses lipopolysaccharide-induced activity of toll-like receptor 4 in mouse macrophage cell line RAW 264.7 , 2011, Medicinal Chemistry Research.

[33]  E. Strauss,et al.  Surgical management of chronic osteomyelitis. , 2004, American journal of surgery.

[34]  J. V. van Horn,et al.  Biomaterial-associated infection of gentamicin-loaded PMMA beads in orthopaedic revision surgery. , 2001, The Journal of antimicrobial chemotherapy.

[35]  David J Mooney,et al.  Engineering vascular networks in porous polymer matrices. , 2002, Journal of biomedical materials research.

[36]  D. Day,et al.  Novel borate glass/chitosan composite as a delivery vehicle for teicoplanin in the treatment of chronic osteomyelitis. , 2010, Acta biomaterialia.

[37]  A. Yamazaki,et al.  Antibiotic-loaded poly-epsilon-caprolactone and porous beta-tricalcium phosphate composite for treating osteomyelitis. , 2008, Biomaterials.