Injectable and biodegradable piezoelectric hydrogel for osteoarthritis treatment.

Osteoarthritis affects millions of people worldwide but current treatments using analgesics or anti-inflammatory drugs only alleviate symptoms of this disease. Here, we present an injectable, biodegradable piezoelectric hydrogel, made of short electrospun poly-L-lactic acid nanofibers embedded inside a collagen matrix, which can be injected into the joints and self-produce localized electrical cues under ultrasound activation to drive cartilage healing. In vitro, data shows that the piezoelectric hydrogel with ultrasound can enhance cell migration and induce stem cells to secrete TGF-ß1, which promotes chondrogenesis. In vivo, the rabbits with osteochondral critical-size defects receiving the ultrasound-activated piezoelectric hydrogel show increased subchondral bone formation, improved hyaline-cartilage structure, and good mechanical properties, close to healthy native cartilage. This piezoelectric hydrogel is not only useful for cartilage healing but also potentially applicable to other tissue regeneration, offering a significant impact on the field of regenerative tissue engineering.

Automatic detection of foreign body objects in neurosurgery using a deep learning approach on intraoperative ultrasound images: From animal models to first in-human testing.

Objects accidentally left behind in the brain following neurosurgical procedures may lead to life-threatening health complications and invasive reoperation. One of the most commonly retained surgical items is the cotton ball, which absorbs blood to clear the surgeon's field of view yet in the process becomes visually indistinguishable from the brain parenchyma. However, using ultrasound imaging, the different acoustic properties of cotton and brain tissue result in two discernible materials. In this study, we created a fully automated foreign body object tracking algorithm that integrates into the clinical workflow to detect and localize retained cotton balls in the brain. This deep learning algorithm uses a custom convolutional neural network and achieves 99% accuracy, sensitivity, and specificity, and surpasses other comparable algorithms. Furthermore, the trained algorithm was implemented into web and smartphone applications with the ability to detect one cotton ball in an uploaded ultrasound image in under half of a second. This study also highlights the first use of a foreign body object detection algorithm using real in-human datasets, showing its ability to prevent accidental foreign body retention in a translational setting.

Exercise-induced piezoelectric stimulation for cartilage regeneration in rabbits.

More than 32.5 million American adults suffer from osteoarthritis, and current treatments including pain medicines and anti-inflammatory drugs only alleviate symptoms but do not cure the disease. Here, we have demonstrated that a biodegradable piezoelectric poly(L-lactic acid) (PLLA) nanofiber scaffold under applied force or joint load could act as a battery-less electrical stimulator to promote chondrogenesis and cartilage regeneration. The PLLA scaffold under applied force or joint load generated a controllable piezoelectric charge, which promoted extracellular protein adsorption, facilitated cell migration or recruitment, induced endogenous TGF-ß via calcium signaling pathway, and improved chondrogenesis and cartilage regeneration both in vitro and in vivo. Rabbits with critical-sized osteochondral defects receiving the piezoelectric scaffold and exercise treatment experienced hyaline-cartilage regeneration and completely healed cartilage with abundant chondrocytes and type II collagen after 1 to 2 months of exercise (2 to 3 months after surgery including 1 month of recovery before exercise), whereas rabbits treated with nonpiezoelectric scaffold and exercise treatment had unfilled defect and limited healing. The approach of combining biodegradable piezoelectric tissue scaffolds with controlled mechanical activation (via physical exercise) may therefore be useful for the treatment of osteoarthritis and is potentially applicable to regenerating other injured tissues.

Transdermal microneedles for the programmable burst release of multiple vaccine payloads.

Repeated bolus injections are associated with higher costs and poor compliance and can hinder the implementation of global immunization campaigns. Here, we report the development and preclinical testing of patches of transdermal core-shell microneedles-which were fabricated by the micromoulding and alignment of vaccine cores and shells made from poly(lactic-co-glycolic acid) with varying degradability kinetics-for the preprogrammed burst release of vaccine payloads over a period of a few days to more than a month from a single administration. In rats, microneedles loaded with a clinically available vaccine (Prevnar-13) against the bacterium Streptococcus pneumoniae induced immune responses that were similar to immune responses observed after multiple subcutaneous bolus injections, and led to immune protection against a lethal bacterial dose. Microneedle patches delivering preprogrammed doses may offer an alternative strategy to prophylactic and therapeutic protocols that require multiple injections.

Biodegradable Nanofiber Bone-Tissue Scaffold as Remotely-Controlled and Self-Powering Electrical Stimulator.

Electrical stimulation (ES) has been shown to induce and enhance bone regeneration. By combining this treatment with tissue-engineering approaches (which rely on biomaterial scaffolds to construct artificial tissues), a replacement bone-graft with strong regenerative properties can be achieved while avoiding the use of potentially toxic levels of growth factors. Unfortunately, there is currently a lack of safe and effective methods to induce electrical cues directly on cells/tissues grown on the biomaterial scaffolds. Here, we present a novel bone regeneration method which hybridizes ES and tissue-engineering approaches by employing a biodegradable piezoelectric PLLA (Poly(L-lactic acid)) nanofiber scaffold which, together with externally-controlled ultrasound (US), can generate surface-charges to drive bone regeneration. We demonstrate that the approach of using the piezoelectric scaffold and US can enhance osteogenic differentiation of different stem cells in vitro, and induce bone growth in a critical-sized calvarial defect in vivo. The biodegradable piezoelectric scaffold with applied US could significantly impact the field of tissue engineering by offering a novel biodegradable, battery-free and remotely-controlled electrical stimulator.

Biodegradable nanofiber-based piezoelectric transducer.

Piezoelectric materials, a type of "smart" material that generates electricity while deforming and vice versa, have been used extensively for many important implantable medical devices such as sensors, transducers, and actuators. However, commonly utilized piezoelectric materials are either toxic or nondegradable. Thus, implanted devices employing these materials raise a significant concern in terms of safety issues and often require an invasive removal surgery, which can damage directly interfaced tissues/organs. Here, we present a strategy for materials processing, device assembly, and electronic integration to 1) create biodegradable and biocompatible piezoelectric PLLA [poly(l-lactic acid)] nanofibers with a highly controllable, efficient, and stable piezoelectric performance, and 2) demonstrate device applications of this nanomaterial, including a highly sensitive biodegradable pressure sensor for monitoring vital physiological pressures and a biodegradable ultrasonic transducer for blood-brain barrier opening that can be used to facilitate the delivery of drugs into the brain. These significant applications, which have not been achieved so far by conventional piezoelectric materials and bulk piezoelectric PLLA, demonstrate the PLLA nanofibers as a powerful material platform that offers a profound impact on various medical fields including drug delivery, tissue engineering, and implanted medical devices.

Piezoelectric Biomaterials for Sensors and Actuators.

Recent advances in materials, manufacturing, biotechnology, and microelectromechanical systems (MEMS) have fostered many exciting biosensors and bioactuators that are based on biocompatible piezoelectric materials. These biodevices can be safely integrated with biological systems for applications such as sensing biological forces, stimulating tissue growth and healing, as well as diagnosing medical problems. Herein, the principles, applications, future opportunities, and challenges of piezoelectric biomaterials for medical uses are reviewed thoroughly. Modern piezoelectric biosensors/bioactuators are developed with new materials and advanced methods in microfabrication/encapsulation to avoid the toxicity of conventional lead-based piezoelectric materials. Intriguingly, some piezoelectric materials are biodegradable in nature, which eliminates the need for invasive implant extraction. Together, these advancements in the field of piezoelectric materials and microsystems can spark a new age in the field of medicine.

Biodegradable Piezoelectric Force Sensor.

Measuring vital physiological pressures is important for monitoring health status, preventing the buildup of dangerous internal forces in impaired organs, and enabling novel approaches of using mechanical stimulation for tissue regeneration. Pressure sensors are often required to be implanted and directly integrated with native soft biological systems. Therefore, the devices should be flexible and at the same time biodegradable to avoid invasive removal surgery that can damage directly interfaced tissues. Despite recent achievements in degradable electronic devices, there is still a tremendous need to develop a force sensor which only relies on safe medical materials and requires no complex fabrication process to provide accurate information on important biophysiological forces. Here, we present a strategy for material processing, electromechanical analysis, device fabrication, and assessment of a piezoelectric Poly-l-lactide (PLLA) polymer to create a biodegradable, biocompatible piezoelectric force sensor, which only employs medical materials used commonly in Food and Drug Administration-approved implants, for the monitoring of biological forces. We show the sensor can precisely measure pressures in a wide range of 0-18 kPa and sustain a reliable performance for a period of 4 d in an aqueous environment. We also demonstrate this PLLA piezoelectric sensor can be implanted inside the abdominal cavity of a mouse to monitor the pressure of diaphragmatic contraction. This piezoelectric sensor offers an appealing alternative to present biodegradable electronic devices for the monitoring of intraorgan pressures. The sensor can be integrated with tissues and organs, forming self-sensing bionic systems to enable many exciting applications in regenerative medicine, drug delivery, and medical devices.

3D nano- and micro-patterning of biomaterials for controlled drug delivery.

Recently, there has been an emerging interest in controlling 3D structures and designing novel 3D shapes for drug carriers at nano- and micro-scales. Certain 3D shapes and structures of drug particles enable transportation of the drugs to desired areas of the body, allow drugs to target specific cells and tissues, and influence release kinetics. Advanced nano- and micro-manufacturing methods including 3D printing, photolithography-based processes, microfluidics and DNA origami have been developed to generate defined 3D shapes and structures for drug carriers. This paper reviews the importance of 3D structures and shapes on controlled drug delivery, and the current state-of-the-art technologies that allow the creation of novel 3D drug carriers at nano- and micro-scales.