the-submerged-printing-cells-onto-modified-surface-using-continuous

The Submerged Printing of Cells onto a Modified Surface Using a Continuous Flow Microspotter

The printing of cells for microarray applications possesses significant challenges including the problem of maintaining physiologically relevant cell ...

WASATCH MICROFLUIDICS

Bone allograft material used for osseous void filling and structural support in skeletal reconstructive surgeries can also be used in combination as a drug carrier. Previous coating methods to load drugs, such as antibiotics and anti-inflammatories, provided an initial burst release, which may not be optimal for combating persistent local implant-associated bacterial infections. Theoretical drug release kinetics can be optimized not only with a clinically relevant drug-to-polymer ratio but also with a robust, effective rate-limiting release coating method. Three coating methods were evaluated in which degradable polycaprolactone (PCL) polymer retains and controls the release of antibiotic tobramycin from commercial, clinically common allograft bone fragments. Methods are based on a common dip-coating of the allograft fragment, with each coating method distinguished by subsequent drying and processing steps. Using a combination of classic polymer coating techniques, dipping and rapid drying, a method has been developed to apply the drug-releasing polymer coating while concurrently maintaining the high surface area, cancellous pore allograft structure. This provides increased local drug loading and controlled release over the clinically relevant six-to-eight week time period. This method offers potential for industrial scale-up as multiple cancellous allograft fragments can be processed batch-wise. Multiple drugs and combination therapies can also be applied in laminate coating designs.

A robust method to coat allograft bone with a drug-releasing polymer shell - biomed 2010.

To address persistent 1-3% infection rates associated with orthopedic implant surgeries, the next generation of bone graft filler materials will no longer pharmacologically silent being endowed as a local drug delivery vehicle to maintain locally high levels of antibiotic. Bone allograft material, used as a structural support to fill the avascular spaces in bone defects, revision surgeries, and traumatic injury, can be used as a drug depot to provide effective antibiotic delivery over the orthopedically relevant six-to-eight week time period. Passive antibiotic coatings, applied in the surgical theater, are quickly depleted from the site, inadvertently promoting the development of drug-resistance. Alternatively, many promising controlled-delivery strategies provide an initial burst release of antibiotic within 24 to 72 hours; however, this remains inadequate to combat the onslaught of ubiquitous pathogens that can persist only to reemerge once drug concentrations fall below the minimal inhibitory concentration (MIC). To improve the longevity of this strategy, a variety of coating techniques were evaluated in which clinically-accepted, FDA-recognized, degradable polycaprolactone (PCL) polymer acts as a rate-controlling membrane to retard the release of the antibiotic tobramycin from allograft bone. Using a combination of dipping and rapid drying, the drug-releasing polymer coating was applied concurrently maintaining the high surface area of the allograft bone; however, SEM imaging reveled an imperfect coating that negatively affected the release kinetics. Altering the drug-containing polymer formulation to incorporate water provided a smoother, more uniform coat and ultimately improved the drug-release profile and longevity out to 5 weeks using both bacteriostatic and bacteriocidal assays. Additionally, drug bioactivity was assessed and confirmed between 2 and 4 weeks in the absence of the water-containing polymer.

Evaluating antibiotic release profiles as a function of polymer coating formulation - biomed 2011.

Osteomyelitis is most commonly caused by Staphylococcus aureus and often sourced during orthopedic surgical intervention. Successful treatment or prevention of this bone penetrating infection requires antibiotics be delivered in excess of the minimal inhibitory concentration to prohibit the growth of the causative organism for sufficient duration. Unfortunately, current standard-of-care antibiotic therapies, administered via intravenous or oral delivery, suffer not only from systemic toxicity and low patient compliance but also provide insufficient local concentrations for therapy. To overcome these clinical inadequacies, a synthetic bone graft material was coated with an antibiotic (tobramycin)-releasing polymer (polycaprolactone) matrix to create a polymer-controlled antibiotic- releasing combination therapy for use as a bone void filler in orthopedic surgeries. Even though this local delivery strategy allows antibiotic delivery over a clinically relevant time frame to prevent infection, complete healing requires the host bone to infiltrate and reabsorb the bone void filler, ultimately replacing the defect with healthy tissue. Unfortunately, the same polymer matrix that allows for controlled local antibiotic delivery may also discourage host bone healing. Efficient orthopedic healing requires the rate of polymer degradation to match the rate of host-bone infiltration. Current imaging techniques, such as histological staining and x-ray imaging, are insufficient to simultaneously assess polymer degradation and host bone integration. Alternative techniques relying on backscatter electron detection during scanning electron microscopy (SEM) imaging may allow a visual differentiation between host bone, synthetic bone, and polymer. Analysis of backscattered SEM images was automated using a custom MATLAB program to determine the ratio of bone to polymer based upon the contrast between the bone (white) and polymer (dark grey). By collecting images of the implant over time, a profile could be created to describe the rate of polymer degradation in conjunction with host-bone infiltration, allowing the intelligent tailoring of infectious osteomyelitis treatment/prevention and host-graft integration.

Scanning electron image analysis to monitor of implant degradation and host healing following implantation of a drug-eluting bone graft void filler - biomed 2013.

Infection remains a significant problem associated with biomedical implants and orthopedic surgeries, especially in revision total joint replacements. Recent advances in antibiotic-releasing bone void fillers (BVF) provide new opportunities to address these types of device-related orthopedic infections that often lead to substantial economic burdens and reduced quality of life. We report improvements made in fabrication and scalability of an antibiotic-releasing polycaprolactone-calcium carbonate/phosphate ceramic composite BVF using a new solvent-free, molten-cast fabrication process. This strategy provides the ability to tailor drug release kinetics from the BVF composite based on modifications of the inorganic substrate and/or the polymeric component, allowing extended tobramycin release at bactericidal concentrations. The mechanical properties of the new BVF composite are comparable to many reported BVFs and validate the relative homogeneity of fabrication. Most importantly, fabrication quality controls are correlated with favorable drug release kinetics, providing bactericidal activity to 10 weeks in vitro when the polycaprolactone component exceeds 98% w/w of the total polymer fraction. Furthermore, in a time kill study, tobramycin-releasing composite fragments inhibited S. aureus growth over 48 h at inoculums as high as 10(9) CFU/mL. This customizable antibiotic-releasing BVF polymer-inorganic biomaterial should provide osseointegrative and osteoconductive properties while contributing antimicrobial protection to orthopedic sites requiring the use of bone void fillers. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013.

Article	Year
A robust method to coat allograft bone with a drug-releasing polymer shell - biomed 2010. Biomedical sciences instrumentation\| PubMed ID: 20467092	2010
Evaluating antibiotic release profiles as a function of polymer coating formulation - biomed 2011. Biomedical sciences instrumentation\| PubMed ID: 21525595	2011
Scanning electron image analysis to monitor of implant degradation and host healing following implantation of a drug-eluting bone graft void filler - biomed 2013. Biomedical sciences instrumentation\| PubMed ID: 23686196	2013
Molded polymer-coated composite bone void filler improves tobramycin controlled release kinetics. Journal of biomedical materials research. Part B, Applied biomaterials\| PubMed ID: 24376164	2013

Sherry N. Davidoff

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