Single-Administration Long-Acting Microarray Patch with Ultrahigh Loading Capacity and Multiple Releases of Thermally Stable Antibodies.

Current antibody (Ab) therapies require development of stable formulations and an optimal delivery system. Here, we present a new strategy to create a single-administration long-lasting Ab-delivery microarray (MA) patch, which can carry high doses of thermally stabilized Abs. The MA fabricated by an additive three-dimensional manufacturing technology can be fully embedded into the skin via a single application to deliver doses of Abs at multiple programmable time points, thus sustaining Ab concentrations in systemic circulation. We developed an MA formulation that stabilized and delivered human immunoglobulins (hIg) in a time-controlled manner while maintaining their structure and functionality. As an example, the b12 Ab─a broadly neutralizing Ab against HIV-1─maintained antiviral activity in vitro after MA manufacturing and heat exposure. Pharmacokinetic studies of MA patch-delivered hIg in rats successfully provided a proof of concept for concurrent and time-delayed Ab delivery. These MA patches codeliver different Abs, providing a tool for expanded protection against viral infections or combination HIV therapy and prevention.

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.

Highly piezoelectric, biodegradable, and flexible amino acid nanofibers for medical applications.

Amino acid crystals are an attractive piezoelectric material as they have an ultrahigh piezoelectric coefficient and have an appealing safety profile for medical implant applications. Unfortunately, solvent-cast films made from glycine crystals are brittle, quickly dissolve in body fluid, and lack crystal orientation control, reducing the overall piezoelectric effect. Here, we present a material processing strategy to create biodegradable, flexible, and piezoelectric nanofibers of glycine crystals embedded inside polycaprolactone (PCL). The glycine-PCL nanofiber film exhibits stable piezoelectric performance with a high ultrasound output of 334 kPa [under 0.15 voltage root-mean-square (Vrms)], which outperforms the state-of-the-art biodegradable transducers. We use this material to fabricate a biodegradable ultrasound transducer for facilitating the delivery of chemotherapeutic drug to the brain. The device remarkably enhances the animal survival time (twofold) in mice-bearing orthotopic glioblastoma models. The piezoelectric glycine-PCL presented here could offer an excellent platform not only for glioblastoma therapy but also for developing medical implantation fields.

Transdermal delivery for gene therapy.

Gene therapy is a critical constituent of treatment approaches for genetic diseases and has gained tremendous attention. Treating and preventing diseases at the genetic level using genetic materials such as DNA or RNAs could be a new avenue in medicine. However, delivering genes is always a challenge as these molecules are sensitive to various enzymes inside the body, often produce systemic toxicity, and suffer from off-targeting problems. In this regard, transdermal delivery has emerged as an appealing approach to enable a high efficiency and low toxicity of genetic medicines. This review systematically summarizes outstanding transdermal gene delivery methods for applications in skin cancer treatment, vaccination, wound healing, and other therapies.

A Single-Administration Microneedle Skin Patch for Multi-Burst Release of Vaccine against SARS-CoV-2.

The necessity for multiple injections and cold-chain storage has contributed to suboptimal vaccine utilization, especially in pandemic situations. Thermally-stable and single-administration vaccines hold a great potential to revolutionize the global immunization process. Here, a new approach to thermally stabilize protein-based antigens is presented and a new high-throughput antigen-loading process is devised to create a single-administration, pulsatile-release microneedle (MN) patch which can deliver a recombinant SARS-CoV-2 S1-RBD protein-a model for the COVID-19 vaccine. Nearly 100% of the protein antigen could be stabilized at temperatures up to 100 °C for at least 1 h and at an average human body temperature (37 °C) for up to 4 months. Arrays of the stabilized S1-RBD formulations can be loaded into the MN shells via a single-alignment assembly step. The fabricated MNs are administered at a single time into the skin of rats and induce antibody response which could neutralize authentic SARS-CoV-2 viruses, providing similar immunogenic effect to that induced by multiple bolus injections of the same antigen stored in conventional cold-chain conditions. The MN system presented herein could offer the key solution to global immunization campaigns by avoiding low patient compliance, the requirement for cold-chain storage, and the need for multiple booster injections.

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.