Diaphyseal bone defect represents a significant problem for orthopaedic surgeons and patients. In order to improve and fasten bone regenerating process we implanted HA biodegradable magnetized scaffolds in a large animal model critical bone defect. A critical long bone defect was created in 6 sheep metatarsus diaphysis; then we implanted a novel porous ceramic composite scaffold (20.0 mm in length; 6.00 mm inner diameter and 17.00 mm outer diameter), made of Hydroxyapatite that incorporates magnetite (HA/Mgn 90/10), proximally fixated by two small cylindrical permanent parylene coated NdFeB magnets (one 6.00 mm diameter magnetic rod firmly incorporated into the scaffold and one 8.00 mm diameter magnetic rods fitted into proximal medullary canal, both 10.00 mm long); to give stability to the complex bone-scaffold-bone, screws and plate was used as a bridge. Scaffolds biocompatibility was previously assessed in vitro using human osteoblast-like cells. Magnetic forces through scaffold were calculated by finite element software (COMSOL Multiphysics, AC/DC Model). One week after surgery, magnetic nanoparticles functionalized with vascular endothelial growth factor (VEGF) were injected at the mid portion of the scaffold using a cutaneous marker positioned during surgery as reference point. After sixteen weeks, sheep were sacrificed to analyze metatarsi. Macroscopical, radiological and microCT examinations were performed. Macroscopical examination shows bone tissue formation inside scaffold pores and with complete coverage of scaffolds, in particular at magnetized bone-scaffold interface. X-rays show a good integration of the scaffold with a good healing process of critical bone defect, and without scaffolds mobilization. These datas were confirmed by the microCT that shown new formation of bone inside the scaffolds, in particular at magnetized bone-scaffold interface. These preliminary results lead our research to exploiting magnetic forces to stimulate bone formation, as attested in both in vitro and in vivo models and to improve fixation at bone scaffold interface, as calculated by finite element software, and moreover to guide targeted drug delivery without functionalized magnetic nanoparticles dissemination in all body. Histological analysis will be performed to confirm and quantify bone tissue regeneration at both interfaces.

Nowadays, magnetic materials are receiving special attention due to their potential applications in different fields and in particular in medicine. Magnetic micro-nano-particles have been progressively employed as support materials for enzyme immobilization, and have been used as drug-delivery vehicles, contrast agents for magnetic resonance imaging as well as heat mediators for hyperthermia-based anti-cancer treatments and many other exciting biomedical applications. Magnetic materials have also attracted a big interest in the field of bone tissue regeneration because it has been demonstrated that magnetic nanoparticles have effect of osteoinduction even without external magnetic force. Therefore, one of the most big challenge in this field is the production of magnetic materials with good biocompatibility and biodegradability. In fact, the long-term effects in the human body of iron oxide (maghemite or magnetite), the most popular magnetic phase used in medicine and biotechnology, are not yet completely assessed. To this aim, in this work we developed an innovative biocompatible and bioresorbable superparamagnetic-like phase by doping nano-hydroxyapatite with Fe 2+ /Fe 3+ ions (FeHA). Moreover the same magnetic nanoparticles were used as nano-particulate emulsifier for the preparation of hollow hybrid Fe-HA-poly(L-lactic) acid (PLLA) micro-nano-spheres. PLLA has been used because poly(α-hydroxy-esters) are the most frequently used synthetic polymers for biomedical applications owing to their biocompatibility, hydrolytic degradation process and proper mechanical properties. These micro-nanospheres could be used as new type of scaffold for hard tissue regeneration. In fact, spherical scaffold display several advantages respect to the monolithic counterpart e.g., (i) improving control over sustained delivery of therapeutic agents, signalling biomolecules and even pluripotent stem cells, (ii) serving as stimulus-sensitive delivery vehicles for triggered release, (iii) introducing porosity and/or improve the mechanical properties of bulk scaffolds by acting as porogen or reinforcement phase, (iv) supplying compartmentalized micro-reactors for dedicated biochemical processes, (v) functioning as cell delivery vehicle, and, finally, (vi) giving possibility of preparing injectable and/or mouldable formulations to be applied by using minimally invasive surgery. Moreover, the same magnetic materials could find applications in nanomedicine as a multifunctional carrier. Their magnetic functionality could be utilized to move them into the body towards target organs by an external magnetic field. Furthermore, the superparamagnetic feature of the nanoparticles could allow to tailor the release of the therapeutic agent by switching (on-off) the external magnetic field and/or to treat cancer cells by hyperthermia.

Based on the American Cancer Society’s report at 2004, after 50-year’s efforts in bio-chemical medicine development, the U.S.A. cancer mortality is 193.9 per 100,000 persons, which is not significantly reduced from that at 1950, 185.8 per 100,000 persons. One critical reason for the clinical inefficacy is that it is not identified what signals trigger the onset of metastasis. 90% of cancer deaths are caused by metastases (1–6). During metastasis, malignant cancer cells detach from the parent cancer tumor to invade new organs (5–7). Although the primary tumor can be readily removed by surgery if detected in time, metastasis cannot be cured effectively due to the presence of numerous secondary tumors. Here we present, for the first time, that cancer cells can exhibit metastasis like phenotype (MLP) in vitro when they are experiencing appropriate mechanical stimuli.

Hydrocephalus is a brain disease characterized by abnormalities in the cerebrospinal fluid (CSF) circulation. The treatment is surgical in nature and continues to suffer of poor outcomes. The first mathematical model for studying the CSF pressure-volume relationship in hydrocephalus was proposed by Marmarou in the 1970s. However, the model fails to fully capture the complex CSF dynamics controlled by CSF-brain tissue interactions. In this paper we use fractional calculus to introduce multiscaling effects in Marmarou’s model. We solve our fractional order non-linear differential equation analytically using a modified Adomian decomposition method.

Anterior cruciate ligament (ACL) reconstructive surgery is a major health concern world-wide because of a large aging population and increased occurrence of sport-related injuries. Tissue engineering is a rapidly growing interdisciplinary field that offers a promising new approach for ACL repair. The aim of this project is to explore novel “smart” surgical fixation devices that not only secure a graft in place without strength failure, but also incorporate and release bioactive materials, intended to promote bone tissue growth. In order to facilitate bioactive reagent release, biopolymeric scaffolds with continuous micro-porous structure were developed. The morphology of the porous structures in the poly-L-lactic acid (PLLA) matrix reflects the differential influence of the concentration of sacrificial material (PS-polystyrene), phase separation levels of the immiscible polymers (PLLA and PS), and melt-blending conditions (Fig. 1) [1]. During removal of the sacrificial material, the chemical solvent might introduce some chemical reactant into the scaffolds. In order to assess the feasibility of using the micro-porous structures for medical applications, 7F2 osteoblasts were cultured on these scaffolds for 7 days. The attachment and proliferation of 7F2 cells on all scaffolds were assessed by fluorescent nuclear staining with Hoechst 33258 and phalloidin. The morphology of 7F2 osteoblasts on solid PLLA and PLLA/HA with 40% porous structure scaffolds till the 7 days pos-seeding was observed under confocal microscopy (Fig. 2A and B). The results showed that removal of the sacrificial material does not influence cell growth and the composites are biocompatible. Besides in vitro cytotoxicity test, in vivo test of all the micro-porous structural scaffolds was performed through rat subcutaneous surgery. Histological analysis (H&E staining) of the porous PLLA/HA with 40% pores retrieved from rat subcutaneous tissue 4 weeks postimplantation show that cells start to grow inside the porous scaffold (Fig. 3A). The morphology of surrounding extracellular matrix (ECM) growing on the scaffolds was observed under SEM. Figure 3B shows soft tissue attached onto PLLA/HA porous scaffold after 1 month post implantation time point, which indicates the good biocompatibility of the scaffolds. Based on these data we predict that these scaffolds will be suitable for inducing and sustaining bone tissue regeneration, and will be feasible for ACL repair.

Glioblastoma multiforme is the most common and aggressive primary brain tumor, with median survival of approximately 10 months and only 5% of patients surviving greater than 5 years after treatment (1). Surgery and radiotherapy are the main treatment modalities for primary brain tumors, but the associated risks are high when infiltrative tumors are positioned near sensitive regions in the brain. Nanoshells, nanoparticles characterized by a spherical silica core and a gold shell, may provide the opportunity to treat brain tumors in a minimally invasive manner, reducing the risk associated with treatment. Upon exposure to a near-infrared laser, nanoshells convert light energy into heat that can thermally ablate cancerous cells (2). Targeted photothermal ablation of human glioma and medulloblastoma cells has already been demonstrated with this technique in vitro (3).

A drug delivery system utilizing nanodiamonds has been proposed for the controlled release of the chemotherapeutic doxorubicin (DOX) [1,2]. The drug delivery system consists of a patch which is envisioned to be implanted immediately after a tumor removal surgery to target residual cancerous cells such that tumor reoccurrence can be effectively prevented. Therefore, long release times are desired for the patch to prevent any new cancerous tissue from forming. The patch is to be assembled in three different layers beginning with a bottom layer comprised of nonporous parylene. A layer of DOX loaded nanodimonds is deposited onto the base layer. Then a porous layer of parylene is accumulated on top of the nanodimonds. Nanodimonds are utilized because their release rates are based on pH, which changes near cancerous cells. Due to the complexity of the drug delivery system, models are created at several different scales.

Atherosclerosis is the leading cause of morbidity and mortality in the developed world. A common treatment option is arterial bypass surgery, which requires the use of a vascular graft. Autologous vein is the current gold standard for use as a vascular graft; however, donor site morbidity and inconsistent availability have provided an impetus to explore alternative graft sources.

Micro swimming robots that mimic the motion of micro organisms can carry out a variety of medical tasks including drug delivery, micro surgery and minimally invasive diagnostic tasks. Micro organisms such as spermatozoa and bacteria use their flagella to propel themselves. The artificial micro swimmer presented in this study is composed of a body that carries a medical payload, and one wave propagating tail attached to it. In this study, forces and torques exerted on the tail structure by the surrounding fluid are computed with the help of corresponding force coefficients. Rigid body dynamics computations are carried out by four-dimensional quaternion configuration to eliminate numerical error accumulation during matrix integrations, and, hence, instantaneous rotation matrix for rigid body rotation is extracted from the quaternion. Propulsive force obtained by waving tail is balanced by the drag force on the micro swimmers’ total wet surface and dynamic behavior of the micro swimmer is obtained as a rigid body motion. The effect of swimmer and waving geometry is parameterized to study the swimming behavior. Simulations carried out to explore the effect of wave length, wave amplitude, driving frequency. Translational and rotational velocities and hydrodynamic power requirements are presented for each individual set of design parameters. Validity of the model is tested by comparing the numerical results and finite element simulation results. Lastly, the model is modified to utilize the mobility matrix coefficients obtained from inertia eliminated finite element simulations governed by time dependent Navier-Stokes equations.

Primary brain tumors are treated surgically or with stereotactic radiation but often residual positive margins lead to recurrence. While these approaches have success, recurrences have more limited options. These approaches also cause serious functional impairment, and treatment of a recurrent tumor in a previously irradiated or post-surgical fibrosed field is a difficult problem [1]. A controlled minimally invasive alternative is the proposed treatment of nanoshell mediated heating with intratumoral fiber placement to overcome the light penetration limitation of surface illumination.

This talk is aimed at presenting novel solutions developed recently by the author’s group for many neurological disorders including Parkinson’s disease, Alzheimer’s disease, depression, anxiety, sleep apnea and sleep disorders using the fundamental research and developments in nanotechnologies and wireless sensor network. Point-of-care (POC) diagnostics promises to bring diagnostic testing out of the laboratory directly to patients and the general public wherever they may be. The key to POC diagnostics is capable of bringing immediate answers so that health care professionals can make rapid and accurate diagnosis of disease so as to ensure the effectiveness of therapy and early detection for preventive therapy. Selected movies illustrating the applications of both invasive and non-invasive wireless nanosensor systems to patients and surgical procedures will be shown at the talk.

Every year, there are roughly 8 million bone fractures in United States [1]. In addition, approximately 2300 new cases of primary bone cancer are diagnosed each year [2]. Yet, the number of people suffering from bone disease is significantly greater; about 10 million people in the U.S. alone suffer from osteoporosis [3]. Consequently, surgeons perform nearly 500,000 bone graft operations annually making bone grafts the second most frequently transplanted materials [4]. Although there is an extremely high demand for treatment of bone abnormalities, the current grafting methods fail to meet these demands due to several limitations. Autografting has the fewest problems with rejection and pathogen transmission, however in some cases the availability may be limited or not be possible (e.g., genetic diseases). With other methods of transplantation such as allogafting and xenografting where tissue is acquired from other humans or species, respectively, the receptor’s immune system causes an increased risk of chronic rejection [5]. Notably, the major drawback with all these methods is that they often require multiple painful and invasive surgeries.

While cancers have no known cure, some of them can be successfully treated with the combination of surgery and systematic therapy. In general, systemic/widespread chemotherapy is usually injected into the bloodstream to attempt to target cancer cells. Such procedure often imparts devastating side effects because cancer drugs are nonspecific in activity, and transporting them throughout the bloodstream further reduces their ability to target the right region. This means that they kill both healthy and unhealthy cells. It has been observed that the physiological conditions of the fluids around living cells can be characterized by p H , and the magnitude of p H around a living cell is different from cancerous cells. Moreover, a multiscale anatomy of carcinoma will reveal that the microstructure of cancer cells contains some characteristic elements such as specific biomarker receptors and DNA molecules that exclusively differentiate them from healthy cells. If these cancer specific ligands can be intercalated by some functional molecules supplied from an implantable patch, then the patch can be envisioned to serve as a complementary technology with current systemic therapy to enhance localized treatment efficiency, minimize excess injections/surgeries, and prevent tumor recurrence. The broader objective of our current research is to capture some fundamental insights of such drug delivery patch system. It is envisioned that the essential components of the device is nanodiamonds (ND), parylene buffer layer and doxorubicin (DOX) drugs. In its simplest form, self-assembled nanodiamonds - functionalized or pristine, and DOX molecules are contained inside parylene capsule. The efficient functioning of the device is characterized by its ability to precisely detect targets (cancer cells) and then to release drugs at a controlled manner. The fundamental science issues concerning the development of the ND-based device include: 1. A precise identification of the equilibrium structure and self assembled morphology of nanodiamonds, 2. Fundamental understanding of the drug adsorption and desorption process to and from NDs, and 3. The rate of drug release through the parylene buffers. The structure of the nanodiamond (ND) is crucial to the adsorption and desorption of drug molecules because it not only changes the self-assembly configuration but also alters the surface electrostatics. To date, the structure and electrostatics of NDs are not yet well understood. A density functional tight binding theory (DFTB) study on smaller [2] NDs suggests a facet dependent charge distributions on ND surfaces. These charges are estimated by Mulliken Analysis [1]. Using the charges for smaller NDs (∼valid for 1–3.3 nm dia ND) we first projected surface charges for larger (4–10 nm) truncated octahedral nanodiamonds (TOND), and it has been found that the [100] face and the [111] face contain positively and negatively charged atoms, respectively. These projected charges are then utilized to obtain the self assembled structure of pristine TONDs from Molecular Dynamics (MD) simulations [4] as shown in Fig. 1. The opposite charges on the [100] and [111] face invoked electrostatic attractions among the initially isolated NDs and a network of nanodiamond agglutinates are formed as evidenced in Fig. 1(b). This study confirms why as manufactured NDs are found in agglomerated form. The study also suggests that a large fraction of ND surfaces become unavailable for drug absorption as many of the [100] faces are coherently connected to [111] faces. As a result, it can be perceived that effective area for drug adsorption on ND surfaces will be less compared to theoretical prediction which suggests that a 4nm TOND may contain as high 360 drug molecules on its surface [5]. It has been observed that as manufactured NDs may contain a variety of functional groups, and currently, we are studying the mechanism of self-assembly for functionalized nanodiamonds so that we understand the role of functional groups. The next phase of calculation involves binding of the DOX to the NDs. Essentially, the understanding of drug absorption and desorption profile at a controlled rate to and from NDs is the most critical part of the device design. Some recent quantum calculation suggests that part of NDs and drug molecules contain opposite charges at their surfaces; it has been a natural interpretation that interactions between ND and drug molecules should be straight-forward — NDs should attract to drugs as soon as they come closure. Recent experiments [6], however, suggest that NDs usually do not interact with drug molecules in the presence of neutral solutions. Addition of NaCl in the solution improves the interaction dramatically. In the first part of the study, we [3–5] have studied the interaction of single DOX molecules with TOND surfaces via MD simulation. As shown in Fig. 2, this study suggests that DOX molecules first arrange them around the preferential sites on nanodiamonds (e.g. around the [111] face) and then spontaneously attach on the surface. It is also observed that only DOX molecule is attached per facets of TONDs. It can be noted that each TOND has 6 [100] face and 8 [111] faces. Figure 3 shows the energy minimization process during the DOX-ND interaction. It can be noted that these simulations have been performed in vacuum environment. In order to see how DOX interacts in solution media, another set of simulations have been conducted where “vacuum” environment have been replaced with solution media of different pH. Moreover, functionalization on the ND surfaces will create a different environment for the DOX molecules. Research is underway to capture the fundamental physics on the DOX loading and release to and from functionalized nanodiamonds. Once we understand the essential physics of drug loading and unloading, in the future we plan to model diffusion controlled drug release through ND coated film device by incorporating the multiscale science learned from the current study. Results from this study will provide fundamental insight on the definitive targeting of infected cells and high resolution controlling of drug molecules.