A passive biodegradable implant for subcutaneous soft-tissue trauma monitoring

In-body medical devices can play an important role in clinical monitoring and diagnosis of diseases. Wireless devices implanted within a patient have to be physically small, and must overcome the challenges of having a little or no onboard electrical power and the highly attenuating electromagnetic propagation environment which is the human body. In this paper, we investigate the use of biodegradable implant to monitor the healing of soft-tissue trauma and to allow early stage diagnosis of infection. The implantable tag is designed to degrade in a predetermined and controlled method, the stage of which can be measured from outside the body without the need for further surgical intervention. The speed of degradation of the tag depends on the temperature and acidity of the subcutaneous tissue in which the tag is implanted. We show that as the electrical length of the tag pattern increases due to degradation, the resonant frequency changes significantly, and this change in resonant frequency can be detected from outside the patient. Results are presented showing the tag's performance at normal and oblique incidence, and techniques for miniaturizing and enhancing the tag's response sensitivity are given. As the entire tag is biodegradable, there is no need for further postoperative surgery to remove it from the patient at the end of its useful life

Beyond Tissue replacement: The Emerging role of smart implants in healthcare

Smart implants are increasingly used to treat various diseases, track patient status, and restore tissue and organ function. These devices support internal organs, actively stimulate nerves, and monitor essential functions. With continuous monitoring or stimulation, patient observation quality and subsequent treatment can be improved. Additionally, using biodegradable and entirely excreted implant materials eliminates the need for surgical removal, providing a patient-friendly solution. In this review, we classify smart implants and discuss the latest prototypes, materials, and technologies employed in their creation. Our focus lies in exploring medical devices beyond replacing an organ or tissue and incorporating new functionality through sensors and electronic circuits. We also examine the advantages, opportunities, and challenges of creating implantable devices that preserve all critical functions. By presenting an in-depth overview of the current state-of-the-art smart implants, we shed light on persistent issues and limitations while discussing potential avenues for future advancements in materials used for these devices

Doctor of Philosophy

dissertationDiabetes mellitus affects 5% of the world's population and requires constant monitoring to avoid fatality. Tight control of blood glucose levels has shown to reduce the long-term effects of diabetes. Finger-stick blood glucose measurements are the gold standard for glucose monitoring that are painful and only provide intermittent glucose values. Continuous glucose monitoring (CGM) is an improvement in this technology but is severely limited in its performance abilities beyond the currently approved implantation time lasting up to a week. CGM is still performed as an adjunct to finger-stick measurements since they are unreliable even during the approved usage durations. Implantation of a biomaterial induces a wound (catheter, hernia meshes, etc.) or disturbance in local tissue (contact lens, etc.). Wound healing response in the host mediates the formation of scar tissue and healing of the injury site. Host foreign body response (FBR) deviates from its healing response in the presence of a foreign body i.e, an implant, and tries to isolate it from the host via fibrous encapsulation. FBR is considered as one of the primary reasons for CGM sensor failure. FBR encapsulates the sensor implant, creating a barrier between the sensing electrode and essential analytes (glucose, oxygen, etc.) required for measuring glucose levels. This phenomenon results in painful and expensive CGM sensor replacements. Work described in this dissertation focuses on improving the clinical performance of CGM sensors by extending their functional lifetimes. Combination device strategies involving the use of a drug (dexamethasone, etc.), or a biologic (VEGF, siRNA, etc.), or a combination of these have been studied to reduce implant-associated FBR. In this dissertation, we targeted mast cells that are believed to orchestrate the FBR by secreting several key granules containing inflammatory cytokines, vasodilators, chemokines, etc. that result in an increased influx of inflammatory cells to the wound site. A novel tyrosine kinase inhibitor- masitinib was used to target the c-KIT receptor on the cell surface of mast cells. Stem cell factor and its ligand c-KIT are considered critical for mast cell survival, proliferation, and degranulation and the hypothesis driving this research is that targeting mast cell degranulation via the c-KIT pathway results in a reduced foreign body response. To test our hypothesis, we developed a local drug delivery formulation comprised of PLGA microsphere drug carriers embedded in a PEG matrix around implants. The effect of the drug was initially evaluated in wild-type (mast cell competent) and sash (mast cell-deficient) mice for up to 28 days. The results from these studies confirmed previous claims that mast cells play an important role in mediating FBR-associated fibrosis around implanted biomaterials and that the use of a mast cell stabilizing tyrosine kinase inhibitor reduced fibrous capsule thickness around implants in wild-type mice but had no effect in sash mice. The drug-releasing coating was then tested in CGM sensors in a wild-type murine percutaneous model for 21 days. Results from the CGM study indicate that drug-releasing coated sensors exhibit relatively stable response compared to control implants, suggesting that reduced fibrosis resulting from stabilizing mast cells results in improving CGM performance. The translation of these results to human subjects would enable better control of diabetes and provide the ability to better diagnose long-term effects of diabetes through long-term continuous glucose monitoring

Osseointegration for Amputees: Past, Present and Future: Basic Science, Innovations in Surgical Technique, Implant Design and Rehabilitation Strategies

Loss of a leg or arm is a tremendous disability. Immediate and obvious impairments are decreased mobility or diminished functional capacity. Not quite as obvious are the difficulties associated with activities of daily living, quality of life impairments, sometimes loss of independence or employment, and the mental health issues which often accompany limb loss. The interface between native tissue and the prosthetic limb presents the greatest challenge to amputee rehabilitation. Computer-controlled robotic limbs have been widely available since the 1990s. However, the weight of prosthetic limbs, coupled with the difficulty of where to locate the components, requires substantial loads to be transferred through the humanimplant interface. This interface has always been a skin-squeezing mechanism which results in repetitive soft-tissue loading and trauma, in both compression and shear, which inevitably causes multiple problems (pain, skin breakdown and infection, hyperhidrosis, allergic reaction to the material) leading to periodic or prolonged prosthesis disuse. So unfortunately, despite all the effort and expense invested in the prosthetic limb itself, patients often were unable to benefit. Percutaneous EndoProsthetic Osseointegration for Limbs (PEPOL) is a revolutionary technique that involves anchoring a metal implant directly to a patient’s skeleton, then permanently passed through the patient’s skin, and attached to a prosthetic limb. By doing this, the weight of the prosthesis is borne by the patient’s skeleton and is directly powered by muscles, leading to a lighter and more native experience. The skin is no longer compressed and traumatised, eliminating the aforementioned issues. Since learning about this technology in the mid-2000s and performing my first independent procedure in 2009, I have investigated and pioneered the world’s leading surgical techniques and rehabilitative methods for PEPOL. Treating nearly 1000 amputees via the Osseointegration Group of Australia and the MQ Health Limb Reconstruction Centre at Macquarie University has allowed research to be performed on this technology, documented, and discussed in the 2 Body of Work. Patients almost always improve their objective and assessed mobility performance (Overall 38.6% distance improvement on the 6MWT), they wear their prosthetic limb more (Overall 38.1% increase in the Q-TFA Prosthetic Use Score), and they are subjectively more satisfied with their condition as an amputee (Overall 41.1% increase in the Q-TFA Global Score) . While these benefits are consistent, my research has also identified the fortunately limited problems with infection and soft tissue management (29% of all patients required re-operations due to direct or indirect complications). PEPOL clearly provides excellent improvement for the vast majority of patients, and the continued investigation of this technology should lead to even greater improvements in progressing from what is already successful, make it more readily available, and ameliorate its existing challenges

Design and clinical application of injectable hydrogels for musculoskeletal therapy

Musculoskeletal defects are an enormous healthcare burden and source of pain and disability for individuals. With an ageing population, the proportion living with these medical indications will increase. Simultaneously, there is pressure on healthcare providers to source efficient solutions, which are cheaper and less invasive than conventional technology. This has led to an increased research focus on hydrogels as highly biocompatible biomaterials that can be delivered through minimally invasive procedures. This review will discuss how hydrogels can be designed for clinical translation, particularly in the context of the new European Medical Device Regulation (MDR). We will then do a deep dive into the clinically used hydrogel solutions that have been commercially approved or have undergone clinical trials in Europe or the US. We will discuss the therapeutic mechanism and limitations of these products. Due to the vast application areas of hydrogels, this work focuses only on treatments of cartilage, bone, and the nucleus pulposus. Lastly, the main steps towards clinical translation of hydrogels as medical devices are outlined. We suggest a framework for how academics can assist small and medium MedTech enterprises conducting the initial clinical investigation and Post-Market Clinical Follow-up (PMCF) required in the MDR. It is evident that the successful translation of hydrogels is governed by acquiring high-quality pre-clinical and clinical data confirming the device mechanism of action and safety

The Synthesis, Characterization, and Cell Seeding of a Collagen/Hydroxyapatite Porous Scaffold for Treatment of Osseous Defects

The need for finding a bone graft substitute stems from the fact that approximately 200,000 bone grafting procedures are performed annually in the U.S. alone. Although biological grafting options (i.e. autografts & allografts) exist, they do suffer from inherent problems. These include limited resources, costly processing, and potential for pathogen transfer. Thus, investigators have sought synthetic alternatives. The objective of this research was to utilize hydroxyapatite (HA) and collagen, both analogues to the major constituents of bone, to fabricate an optimal synthetic osteoconductive/osteoinductive bone scaffold. Current attempts by other investigators to combine the two materials have been met with some difficulties, resulting in free or loosely bound particulate HA within the collagen matrix. This may ultimately result in a foreign body response to the disseminated crystals. Yet, this study revealed that through manipulation of the collagen\u27s collodial chemistry, it could be made into a more effective carrier medium for particulate HA. It was found that treating the collagen with either IOOmM NaOH or hydrochloric acid followed by titration with 1 N NaOH to a basic pH ( approximately 11 . 8) would yield an adhesive, paste-like matrix capable of incorporating the HA, following lyophilization of the matrix. Composites made under acidic, neutral, and conditions correlating to pH values below 11 .8 were found to possess free HA particulates and loose, friable collagen fibers. The composites were also frozen at two different temperatures to study their effects on microporosity formation. Porosity is an essential characteristic given that it serves as 111 pathways by which vasculature is established, cellular elements may infiltrate; and by which nutrients are supplied to the graft. It was found that porosity of the composite could be controlled by regulating the ice crystal formation prior to lyophilization of the material. Micron size pores were achieved by freezing the composite to -l 5°C and controlling the amount of particulate HA added to the system. TGF-β 1 was also studied for its efficacy in serving as an osteoinductive catalyst with the collagen/HA composite. It was chosen due to its ability to modulate the growth and differentiation of osteoblast precursor cells. Utilizing 1125 as a tracer, release kinetics of the adsorbed polypeptide from the composite were evaluated. Elution was rapid, with approximately 56 ± 3.5% of the theoretical load release following 24 hours incubation. Improved methods by which to prolong the release of the growth factor may be needed in order to provide for optimal inductive properties. Last, the cytocompatibility of the composite was evaluated. Primary cultures of adult, rabbit and fetal bovine osteoblasts were seeded into two formulations of the collagen/HA composite. Following three days of culture, an acid-to-base titrated composite formulation grafted with fetal bovine cells was the only combination which exhibited the presence of adherent cells. The lack of fetal cells upon a base-only treated collagen/HA composite was speculated to be a result of modifications to the collagen due to processing. Seeding technique and cell donor age were also suggested as possible reasons for the absence of cells utilizing adult rabbit cells on either composite formulation. Together, the findings suggest that the composite could serve as a suitable, porous bone scaffold. Due to its compressive strength values, it would best be reserved for non-load-bearing applications, such as an osseous filler material used, for example, in IV conjunction with plated fractures. Improved TGF-β1 incorporation, in-depth in vitro studies, as well as an in vivo model will need to be assessed to determine the true effectiveness of the composite to replace existing biological sources

Landmarks in vaginal mesh development: polypropylene mesh for treatment of SUI and POP

Vaginal meshes used in the treatment of stress urinary incontinence (SUI) and pelvic organ prolapse (POP) have produced highly variable outcomes, causing life-changing complications in some patients while providing others with effective, minimally invasive treatments. The risk:benefit ratio when using vaginal meshes is a complex issue in which a combination of several factors, including the inherent incompatibility of the mesh material with some applications in pelvic reconstructive surgeries and the lack of appropriate regulatory approval processes at the time of the premarket clearance of these products, have contributed to the occurrence of complications caused by vaginal mesh. Surgical mesh used in hernia repair has evolved over many years, from metal implants to knitted polymer meshes that were adopted for use in the pelvic floor for treatment of POP and SUI. The evolution of the material and textile properties of the surgical mesh was guided by clinical feedback from hernia repair procedures, which were also being modified to obtain the best outcomes with use of the mesh. Current evidence shows how surgical mesh fails biomechanically when used in the pelvic floor and materials with improved performance can be developed using modern material processing and tissue engineering techniques

Role of Sustained Nitric Oxide Release on the In Vivo Analytical Performance of Glucose Biosensors

Optimal management of diabetes is best achieved through the use of continuous glucose monitors (CGMs). However, the accurate lifetime of these medical devices is severely limited by the host-mounted foreign body response (FBR). Efforts to extend the lifetime of CGMs must focus on strategies to mitigate the FBR at the tissue-sensor interface. Sensor coatings capable of extended NO release represent a promising strategy to improve tissue integration and long-term accuracy of CGMs. To achieve extended NO-release profiles, mesoporous silica nanoparticles (MSNs) functionalized with S-nitrosothiol (RSNO) functional groups were doped into polyurethane (PU) coatings. Mesoporous particles were characterized as having larger NO payloads and longer NO-release durations than those of nonporous particles, a feature attributed to the recombination of the NO radical in confined intraporous microenvironments. Nitric oxide-release kinetics, particle leaching, and thermal stability of the RSNO-modified MSNs dispersed in PU toward device-coating applications. The NO-release kinetics from the PUs proved to be long in duration (>30 d) and consistent over a range of PU properties. Furthermore, the RSNO-modified MSNs were not observed to leach from the PUs. Analytical performance and tissue interactions of NO-releasing continuous glucose sensors were evaluated over a 28-d study in a diabetic swine model. Two NO-release durations were achieved by doping sensor membranes with nonporous (14-d release) or porous (30-d release) RSNO-modified silica nanoparticles. Numerical and clinical accuracy of the sensors were assessed at 1, 3, 7, 10, 14, 21, 28 d following implantation. Nitric oxide-releasing sensors demonstrated accurate glucose detection and low tissue inflammation over a time period directly correlated with active NO release. Membranes that released NO for 30 d showed standard-compliant accuracy (i.e., mean absolute relative difference ≤ 15%) for >3 wks post-implantation. Tissue response to PU-coated implants employing active (NO release) and/or passive (textured topcoats) was also evaluated over a 28-d study in a diabetic swine model. Topcoats were designed to minimally impact the NO-release kinetics and to possess topographical features known to mitigate the FBR (foam topcoats with 50 µm pores and fiber topcoats with <1 µm fiber diameters). Inflammatory cell density and collagen density at the implant-tissue interface were evaluated at 7, 14, 21, 28 d following implantation. Active NO release lowered both inflammatory cell density and collagen density, while the textured topcoats only lowered collagen density. When combined, the NO-releasing textured implant showed the greatest potential for eventual application in future sensor studies.Doctor of Philosoph