Biomedical subjects

Michael J Cima

Publications and source records attributed to Michael J Cima.

At least 19 recordsLinked to original sources

PubMed2007

Combination of automated high throughput platforms, flow cytometry, and hierarchical clustering to detect cell state.

BACKGROUND: This study examined whether hierarchical clustering could be used to detect cell states induced by treatment combinations that were generated through automation and high-throughput (HT) technology. Data-mining techniques were used to analyze the large experimental data sets to determine whether nonlinear, non-obvious responses could be extracted from the data. METHODS: Unary, binary, and ternary combinations of pharmacological factors (examples of stimuli) were used to induce differentiation of HL-60 cells using a HT automated approach. Cell profiles were analyzed by incorporating hierarchical clustering methods on data collected by flow cytometry. Data-mining techniques were used to explore the combinatorial space for nonlinear, unexpected events. Additional small-scale, follow-up experiments were performed on cellular profiles of interest. RESULTS: Multiple, distinct cellular profiles were detected using hierarchical clustering of expressed cell-surface antigens. Data-mining of this large, complex data set retrieved cases of both factor dominance and cooperativity, as well as atypical cellular profiles. Follow-up experiments found that treatment combinations producing "atypical cell types" made those cells more susceptible to apoptosis. CONCLUSIONS Hierarchical clustering and other data-mining techniques were applied to analyze large data sets from HT flow cytometry. From each sample, the data set was filtered and used to define discrete, usable states that were then related back to their original formulations. Analysis of resultant cell populations induced by a multitude of treatments identified unexpected phenotypes and nonlinear response profiles.

Algorithms↗

PubMed2006

Orientation dependence of the isoelectric point of TiO2 (rutile) surfaces.

The electroosmotic behavior of the rutile polymorph of titanium dioxide was explored as a function of the crystallographic orientation. Atomic force microscopy (AFM) was employed to make high-resolution force spectroscopy measurements between a silica sphere attached to a traditional, contact-mode AFM cantilever and TiO2(110), TiO2(100), and TiO2(001) surfaces in aqueous solutions. Measurements were taken in multiple solution conditions across a broad range of pH values, and the resultant force-distance curves were used to deduce relative behaviors of each orientation of rutile, with particular interest in changes of the isoelectric point (iep). Differences in the iep as a function of orientation are explained in terms of differences in both the coordination number and density of acidic and basic sites on the surface. The results were supported by angle-resolved X-ray photoelectron spectroscopy (XPS) measurements of a nominal monolayer of palladium metal deposited on each of the three orientations studied. The palladium monolayer served as a means of probing the relative electron affinities of the three surfaces studied, which were exhibited in shifts of the palladium XPS peak that corresponded to differences in the binding energy as a function of the substrate orientation. The correlation between the rutile orientation and the shift in the palladium binding energy corresponded directly to the relationship between the isoelectric point and the orientation, with the surface of lowest isoelectric point exhibiting the highest Pd binding energy.

Journal Article↗

PubMed2006

Application of micro- and nano-electromechanical devices to drug delivery.

Micro- and nano-electromechanical systems (MEMS and NEMS)-based drug delivery devices have become commercially-feasible due to converging technologies and regulatory accommodation. The FDA Office of Combination Products coordinates review of innovative medical therapies that join elements from multiple established categories: drugs, devices, and biologics. Combination products constructed using MEMS or NEMS technology offer revolutionary opportunities to address unmet medical needs related to dosing. These products have the potential to completely control drug release, meeting requirements for on-demand pulsatile or adjustable continuous administration for extended periods. MEMS or NEMS technologies, materials science, data management, and biological science have all significantly developed in recent years, providing a multidisciplinary foundation for developing integrated therapeutic systems. If small-scale biosensor and drug reservoir units are combined and implanted, a wireless integrated system can regulate drug release, receive sensor feedback, and transmit updates. For example, an "artificial pancreas" implementation of an integrated therapeutic system would improve diabetes management. The tools of microfabrication technology, information science, and systems biology are being combined to design increasingly sophisticated drug delivery systems that promise to significantly improve medical care.

Administration, Cutaneous↗

PubMed2005

In vivo delivery of BCNU from a MEMS device to a tumor model.

A drug delivery micrcoelectromechanical systems (MEMS) device was used to locally deliver a chemotherapeutic agent (BCNU) to an experimental tumor in rats. This MEMS device consists of an array of reservoirs etched into the silicon substrate. The drug release is achieved by the electrochemical dissolution of the gold membranes covering the reservoirs. A new Pyrex package was developed to improve the BCNU release kinetics and enhance device capacity. Co-formulation of BCNU with polyethylene glycol (PEG) led to complete and rapid release of drug in vivo. BCNU delivered from the MEMS device showed dose-dependent inhibiting effect on the tumor growth in the BCNU dosage range of 0.67 approximately 2 mg. BCNU delivered from the activated devices was as effective as equipotent subcutaneous injections of BCNU in inhibiting tumor growth. Further optimization using this MEMS device to deliver BCNU in combination with other therapeutic agents against the tumor challenge is possible because of the unique capability of the device to precisely control the temporal release profiles of multiple substances.

Animals↗

PubMed2005

Size and temperature effects on poly(lactic-co-glycolic acid) degradation and microreservoir device performance.

The component materials of controlled-release drug delivery systems are often selected based on their degradation rates. The release time of a drug from a system will strongly depend on the degradation rates of the component polymers. We have observed that some poly(lactic-co-glycolic acid) polymers (PLGA) exhibit degradation rates that depend on the size of the polymer object and the temperature of the surrounding environment. In vitro degradation studies of four different PLGA polymers showed that 150 microm thick membranes degraded more rapidly than 50 microm thick membranes, as characterized by gel permeation chromatography and mass loss measurements. Faster degradation was observed at 37 degrees C than 25 degrees C, and when the saline media was not refreshed. A biodegradable polymeric microreservoir device that we have developed relies on the degradation of polymeric membranes to deliver pulses of molecules from reservoirs on the device. Earlier molecular release was seen from devices having thicker PLGA membranes. Comparison of an in vitro release study from these devices with the degradation study suggests that reservoir membranes rupture and drug release occurs when a membrane threshold molecular weight of 5000-15000 is reached.

Absorbable Implants↗

PubMed2004

Repeated in vivo electrochemical activation and the biological effects of microelectromechanical systems drug delivery device.

The repeated activation of a microelectromechanical systems (MEMS) drug delivery device was studied in vivo in rats to examine the effect of implantation on the device operation and the effect of electrochemical activation on the inflammatory and wound-healing response. The MEMS devices were fabricated from a silicon wafer into which reservoirs were etched and covered with gold membranes. The membranes were electrochemically removed when an anodic voltage was applied. Devices were implanted subcutaneously both with and without stainless steel mesh cages for 4, 7, 14, 21, or 28 days before activation. Devices were activated every other day for five activations. Leukocyte concentrations indicated that both the application of voltage and the gold corrosion products elevated the inflammatory response which was resolved within 48 h after each activation. The efficiency of gold membrane removal was not impaired throughout the implantation, although a bimodal distribution of background current densities was observed after long implantation times. The thickness of the fibrous capsule surrounding the MEMS devices was similar between activated and control devices explanted at each time point. It was concluded that the repeated activation of MEMS drug delivery devices was successful and the activation produced an acceptable biological response that resolved promptly.

Animals↗

PubMed2004

In vivo release from a drug delivery MEMS device.

A drug delivery microelectromechanical systems (MEMS) device was designed to release complex profiles of multiple substances in order to maximize the effectiveness of drug therapies. The device is based on micro-reservoirs etched into a silicon substrate that contain individual doses of drug. Each dose is released by the electrochemical dissolution of the gold membrane that covers the reservoir. The first in vivo operation of this device was reported in this study. Subcutaneous release was demonstrated in rats using two tracer molecules, fluorescein dye and radiolabeled mannitol, and one radiolabeled chemotherapeutic agent, carmustine (BCNU). BCNU was chosen because of the need to improve the direct delivery of chemotherapy to malignant tumors. The spatial profile of fluorescein dye release from the drug delivery device was evaluated by fluorimetry, the temporal profile of 14C labeled mannitol release was evaluated by liquid scintillation counting, and the temporal profile of 14C labeled BCNU release was evaluated by accelerator mass spectrometry (AMS). Release profiles obtained from injected controls were compared with those from activated devices. The in vivo dye release results showed high concentration of fluorescein in the flank tissue surrounding the devices 1 h after activation. The 14C labeled mannitol released from the drug delivery devices was rapidly cleared (1 day) from the rat urine. In vivo release of 14C labeled BCNU from activated devices showed slightly slower kinetics than the injected and in vitro controls, and the time to reach the steady-state plasma 14C concentration was on the order of 1 h. All these results demonstrated the capability of this drug delivery device to achieve localized delivery of various compounds with well-defined temporal profiles.

Animals↗

PubMed2004

The role of electrochemical reactions during electrophoretic particle deposition.

Platinum microelectrodes were fabricated on a sapphire substrate by lithographic patterning and used to manipulate 1.58 microm silica particles in the plane of the substrate. A digital video system captured the motion of particles far from the electrodes and their deposition onto the working electrode during application of a DC potential. The role of electrode reversibility was investigated by comparing as-deposited electrodes with electrodes modified by electrolytic plating of platinum. Particles were also observed adhering to the substrate before reaching the electrode. The zeta potential of the particles and substrate was measured. The differing surface chemistry of the two systems and a local reduction in pH due to the production of hydrogen ion at the anode can explain the adhesion phenomena. Force distance curves were recorded using a colloid probe atomic force microscopy technique to directly measure the interaction of the silica particles with the sapphire substrate. These data validated the observed adhesion at the electrode and provided further support for the temporal and spatial reduction in pH. The role of Faradaic processes and the diffusion of potential determining ions in electrophoretic deposition were also considered.

Aluminum Oxide↗

PubMed2004

Molecular release from a polymeric microreservoir device: Influence of chemistry, polymer swelling, and loading on device performance.

A polymeric microreservoir device for controlled-release drug delivery relies on the degradation of thin poly(lactic-co-glycolic acid) membranes that seal each reservoir to achieve pulsatile drug delivery. In vitro release studies in which the swelling of the reservoir membranes was measured indicate a correlation between the release times of various radiolabeled molecules from the devices and the time at which the maximum membrane swelling was observed. Varying the chemistry (lipophilicity/hydrophilicity) or molecular weight of the molecules loaded into the devices did not appear to affect the degree of membrane swelling that was observed, or the time at which the molecules were released from the devices. The amount of drug that was loaded into the reservoirs also did not appear to affect the observed release time of the drug from the device, a significant departure from the behavior of many matrix-type polymeric drug delivery systems.

Biocompatible Materials↗

PubMed2004

Zeta potential orientation dependence of sapphire substrates.

The zeta potential of planar sapphire substrates for three different crystallographic orientations was measured by a streaming potential technique in the presence of KCl and (CH3)4NCl electrolytes. The streaming potential was measured for large single crystalline C-plane (0001), A-plane (1120), and R-plane (1102) wafers over a full pH range at three or more ionic strengths ranging from 1 to 100 mM. The roughness of the epi-polished wafers was verified using atomic force microscopy to be on the order of atomic scale, and X-ray photoelectron spectroscopy (XPS) was used to ensure that the samples were free of silica and other contaminants. The results reveal a shift in the isoelectric point (iep) of the three samples by as much as two pH units, with the R-plane surface exhibiting the most acidic behavior and the C-plane samples having the highest iep. The iep at all ionic strengths was tightly centered around a single pH for each wafer. These values of iep are substantially different from the range of pH 8-10 consistently reported in the literature for alpha-Al2O3 particles. Particle zeta potential measurements were performed on a model powder using phase analysis light scattering, and the iep was confirmed to occur at pH 8. Modified Auger parameters (MAP) were calculated from XPS spectra of a monolayer of iridium metal deposited on the sapphire by electron beam deposition. A shift in MAP consistent with the observed differences in iep of the surfaces confirms the effect of surface structure on the transfer of charge between the Ir and sapphire, hence accounting for the changes in acidity as a function of crystallographic orientation.

Journal Article↗

PubMed2004

High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids.

The concepts of high-throughput (HT) screening and combinatorial synthesis have been integrated into the pharmaceutical discovery process, but are not yet commonplace in the pharmaceutical development arena. Emerging strategies to speed pharmaceutical development and capture solid form diversity of pharmaceutical substances have resulted in the emergence of HT crystallization technologies. The primary type of diversity often refers to polymorphs, which are different crystal forms of the same chemical composition. However, diverse salt forms, co-crystals, hydrates and solvates are also amenable to study in HT crystallization systems. The impact of form diversity encompasses issues of stability and bioavailability, as well as development considerations such as process definition, formulation design, patent protection and regulatory control. This review highlights the opportunities and challenges of HT crystallization technologies as they apply to pharmaceutical research and development.

Chemistry, Pharmaceutical↗

PubMed2004

Electronic MEMS for triggered delivery.

Implantable electronic devices such as pacemakers and neural implants are often used for electrical stimulation. The usage of microfabrication techniques to produce microelectromechanical systems (MEMS) has allowed engineers to address a wider range of clinical indications. A new direction in the area of MEMS technology is the goal of achieving pulsatile drug delivery. The digital capabilities of MEMS may allow greater temporal control over drug release compared to traditional polymer-based systems, while the batch-processing techniques used in the microelectronics industry can lead to greater device uniformity and reproducibility than is currently available to the pharmaceutical industry. A repertoire of structures, including microreservoirs, micropumps, valves, and sensors, is being developed that will provide a strong foundation for the design of integrated, responsive MEMS for drug delivery.

Electronics↗

PubMed2004

Nondestructive and on-line monitoring of tablets using light-induced fluorescence technology.

A system using light-induced fluorescence (LIF) technology was developed for rapid and nondestructive analysis of active pharmaceutical ingredients on tablet surfaces. Nonhomogeneous tablets with defined layer of active ingredients were made by 3-Dimensional Printing technology to determine penetration depths of the light source and the resultant fluorescence responses. The LIF method of analysis showed penetration to depths of up to 3 mm into tablets. A correlation between LIF signals from analysis of tablet surfaces and the total drug content of the respective tablets was established. This method of surface analysis was verified with UV spectrometric methods for the total drug content of each respective tablet. The results from a small sample population of tablets made from both homogeneous and nonhomogeneous powder mixtures established good correlation between LIF surface monitoring and total tablet content. The use of on-line monitoring of the individual tablet for surface content demonstrated consistent LIF profiles from simulated production rates up to 3000 tablets a minute. The instrument was also field tested successfully on a tablet analyzer.

Chemistry, Pharmaceutical↗

PubMed2004

In vivo inflammatory and wound healing effects of gold electrode voltammetry for MEMS micro-reservoir drug delivery device.

The in vivo biocompatibility and biofouling of gold electrodes for a microelectromechanical systems drug delivery device were investigated in a rodent model. The role of the applied voltage and gold electrolysis products in modulating the inflammatory response (biocompatibility), and the temporal adhesion of cellular populations onto macroscopic gold film electrodes (biofouling) were analyzed in reference to two controls, devices to which voltage was not applied (uncorroded) or voltage was applied to inert platinum electrodes (electrical controls). Voltammetry was applied to the gold surfaces once (day 4, 7, 14, 21, 28, 35, 42, or 49), while voltage of identical magnitude was applied to the electrical controls. An inflammatory response characterized by a rapid decrease of leukocyte concentration to control levels was observed 48 h following voltage application with no significant cell concentration difference (p > 0.05) between the corroded devices and electrical controls. The histological evaluation of the direct implant fibrous capsule showed comparable thickness of voltage applied and control specimens. The gold corrosion peak current showed no significant difference (p > 0.05) among peak values at all time points. It was concluded that gold electrode corrosion was biocompatible and its electrochemical performance was not hindered by fibrous capsule formation.

Animals↗

PubMed2004

Differential degradation rates in vivo and in vitro of biocompatible poly(lactic acid) and poly(glycolic acid) homo- and co-polymers for a polymeric drug-delivery microchip.

The biocompatibility and biodegradation rate of component materials are critical when designing a drug-delivery device. The degradation products and rate of degradation may play important roles in determining the local cellular response to the implanted material. In this study, we investigated the biocompatibility and relative biodegradation rates of PLA, PGA and two poly(lactic-co-glycolic acid) (PLGA) polymers of 50:50 mol ratio, thin-film component materials of a drug-delivery microchip developed in our laboratory. The in vivo biocompatibility and both in vivo and in vitro degradation of these materials were characterized using several techniques. Total leukocyte concentration measurements showed normal acute and chronic inflammatory responses to the PGA and low-molecular-weight PLGA that resolved by 21 days, while the normal inflammatory responses to the PLA and high-molecular-weight PLGA were resolved but at slower rates up to 21 days. These results were paralleled by thickness measurements of fibrous capsules surrounding the implants, which showed greater maturation of the capsules for the more rapidly degrading materials after 21 days, but less mature capsules of sustained thicknesses for the PLA and high-molecular-weight PLGA up to 49 days. Gel-permeation chromatography of residual polymer samples confirmed classification of the materials as rapidly or slowly degrading. These materials showed thinner fibrous capsules than have been reported for other materials by our laboratory and have suitable biocompatibility and biodegradation rates for an implantable drug-delivery device.

Biocompatible Materials↗

PubMed2003

Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization.

Pharmaceutical compounds are molecular solids that frequently exhibit polymorphism of crystal form. One high profile case of polymorphism was ritonavir, a peptidomimetic drug used to treat HIV-1 infection and introduced in 1996. In 1998, a lower energy, more stable polymorph (form II) appeared, causing slowed dissolution of the marketed dosage form and compromising the oral bioavailability of the drug. This event forced the removal of the oral capsule formulation from the market. We have carried out high-throughput crystallization experiments to comprehensively explore ritonavir form diversity. A total of five forms were found: both known forms and three previously unknown forms. The novel forms include a metastable polymorph, a hydrate phase, and a formamide solvate. The solvate was converted to form I via the hydrate phase by using a simple washing procedure, providing an unusual route to prepare the form I "disappearing polymorph" [Dunitz, J. D. & Bernstein, J. (1995) Acc. Chem. Res. 28, 193-200]. Crystals of form I prepared by using this method retained the small needle morphology of the solvate and thus offer a potential strategy for particle size and morphology control.

Crystallography, X-Ray↗

PubMed2003

Biocompatibility and biofouling of MEMS drug delivery devices.

The biocompatibility and biofouling of the microfabrication materials for a MEMS drug delivery device have been evaluated. The in vivo inflammatory and wound healing response of MEMS drug delivery component materials, metallic gold, silicon nitride, silicon dioxide, silicon, and SU-8(TM) photoresist, were evaluated using the cage implant system. Materials, placed into stainless-steel cages, were implanted subcutaneously in a rodent model. Exudates within the cage were sampled at 4, 7, 14, and 21 days, representative of the stages of the inflammatory response, and leukocyte concentrations (leukocytes/microl) were measured. Overall, the inflammatory responses elicited by these materials were not significantly different than those for the empty cage controls over the duration of the study. The material surface cell density (macrophages or foreign body giant cells, FBGCs), an indicator of in vivo biofouling, was determined by scanning electron microscopy of materials explanted at 4, 7, 14, and 21 days. The adherent cellular density of gold, silicon nitride, silicon dioxide, and SU-8(TM) were comparable and statistically less (p<0.05) than silicon. These analyses identified the MEMS component materials, gold, silicon nitride, silicon dioxide, SU-8(TM), and silicon as biocompatible, with gold, silicon nitride, silicon dioxide, and SU-8(TM) showing reduced biofouling.

Animals↗

PubMed2003

Multi-pulse drug delivery from a resorbable polymeric microchip device.

Controlled-release drug delivery systems have many applications, including treatments for hormone deficiencies and chronic pain. A biodegradable device that could provide multi-dose drug delivery would be advantageous for long-term treatment of conditions requiring pulsatile drug release. In this work, biodegradable polymeric microchips were fabricated that released four pulses of radiolabelled dextran, human growth hormone or heparin in vitro. Heparin that was released over 142 days retained on average 96 +/- 12% of its bioactivity. The microchips were 1.2 cm in diameter, 480-560 microm thick and had 36 reservoirs that could each be filled with a different chemical. The devices were fabricated from poly(L-lactic acid) and had poly(D,L-lactic-co-glycolic acid) membranes of different molecular masses covering the reservoirs. A drug delivery system can be designed with the potential to release pulses of different drugs at intervals after implantation in a patient by using different molecular masses or materials for the membrane.

Absorbable Implants↗