A wireless, implantable bioelectronic system for monitoring urinary bladder function following surgical recovery.

Partial cystectomy procedures for urinary bladder-related dysfunction involve long recovery periods, during which urodynamic studies (UDS) intermittently assess lower urinary tract function. However, UDS are not patient-friendly, they exhibit user-to-user variability, and they amount to snapshots in time, limiting the ability to collect continuous, longitudinal data. These procedures also pose the risk of catheter-associated urinary tract infections, which can progress to ascending pyelonephritis due to prolonged lower tract manipulation in high-risk patients. Here, we introduce a fully bladder-implantable platform that allows for continuous, real-time measurements of changes in mechanical strain associated with bladder filling and emptying via wireless telemetry, including a wireless bioresorbable strain gauge validated in a benchtop partial cystectomy model. We demonstrate that this system can reproducibly measure real-time changes in a rodent model up to 30 d postimplantation with minimal foreign body response. Studies in a nonhuman primate partial cystectomy model demonstrate concordance of pressure measurements up to 8 wk compared with traditional UDS. These results suggest that our system can be used as a suitable alternative to UDS for long-term postoperative bladder recovery monitoring.

Multipotent bone marrow cell-seeded polymeric composites drive long-term, definitive urinary bladder tissue regeneration.

To date, there are no efficacious translational solutions for end-stage urinary bladder dysfunction. Current surgical strategies, including urinary diversion and bladder augmentation enterocystoplasty (BAE), utilize autologous intestinal segments (e.g. ileum) to increase bladder capacity to protect renal function. Considered the standard of care, BAE is fraught with numerous short- and long-term clinical complications. Previous clinical trials employing tissue engineering approaches for bladder tissue regeneration have also been unable to translate bench-top findings into clinical practice. Major obstacles still persist that need to be overcome in order to advance tissue-engineered products into the clinical arena. These include scaffold/bladder incongruencies, the acquisition and utility of appropriate cells for anatomic and physiologic tissue recapitulation, and the choice of an appropriate animal model for testing. In this study, we demonstrate that the elastomeric, bladder biomechanocompatible poly(1,8-octamethylene-citrate-co-octanol) (PRS; synthetic) scaffold coseeded with autologous bone marrow-derived mesenchymal stem cells and CD34+ hematopoietic stem/progenitor cells support robust long-term, functional bladder tissue regeneration within the context of a clinically relevant baboon bladder augmentation model simulating bladder trauma. Partially cystectomized baboons were independently augmented with either autologous ileum or stem-cell-seeded small-intestinal submucosa (SIS; a commercially available biological scaffold) or PRS grafts. Stem-cell synergism promoted functional trilayer bladder tissue regeneration, including whole-graft neurovascularization, in both cell-seeded grafts. However, PRS-augmented animals demonstrated fewer clinical complications and more advantageous tissue characterization metrics compared to ileum and SIS-augmented animals. Two-year study data demonstrate that PRS/stem-cell-seeded grafts drive bladder tissue regeneration and are a suitable alternative to BAE.

Decoupling the Influence of Poly(3,4-Ethylenedioxythiophene)-Collagen Composite Characteristics on Cell Stemness.

Conductive polymers (CPs) are widely studied for their ability to influence a myriad of tissue systems. While their mixed ionic/electronic conductivity is commonly considered the primary driver of these benefits, the mechanisms by which CPs influence cell fate remain unclear. In this study, CP-biomaterial interactions are investigated using collagen, due to its widespread prevalence throughout the body and in tissue engineering constructs. Collagen is functionalized with both electrostatically and covalently bound derivatives of the CP poly(3,4-ethylenedioxythiophene) (PEDOT) doped via backbone-tethered sulfonate groups, which enable high solubility and loading to the collagen biomatrix. Intrinsically doped scaffolds are compared to those incorporated with a commercially available PEDOT formulation, which is complexed with polyanionic polystyrene sulfonate (PSS). Low loadings of intrinsically doped PEDOT do not increase substrate conductivity compared to collagen alone, enabling separate investigation into CP loading and conductivity. Interestingly, higher PEDOT loading bolsters human mesenchymal stromal (hMSC) cell gene expression of Oct-4 and NANOG, which are key transcription factors regulating cell stemness. Conductive collagen composites with commercial PEDOT:PSS do not significantly affect the expression of these transcription factors in hMSCs. Furthermore, it is demonstrated that PEDOT regulates cellular fate independently from physical changes to the material but directly to the loading of the polymer.

Enabling Proregenerative Medical Devices via Citrate-Based Biomaterials: Transitioning from Inert to Regenerative Biomaterials.

Regenerative medicine aims to restore tissue and organ function without the use of prosthetics and permanent implants. However, achieving this goal has been elusive, and the field remains mostly an academic discipline with few products widely used in clinical practice. From a materials science perspective, barriers include the lack of proregenerative biomaterials, a complex regulatory process to demonstrate safety and efficacy, and user adoption challenges. Although biomaterials, particularly biodegradable polymers, can play a major role in regenerative medicine, their suboptimal mechanical and degradation properties often limit their use, and they do not support inherent biological processes that facilitate tissue regeneration. As of 2020, nine synthetic biodegradable polymers used in medical devices are cleared or approved for use in the United States of America. Despite the limitations in the design, production, and marketing of these devices, this small number of biodegradable polymers has dominated the resorbable medical device market for the past 50 years. This perspective will review the history and applications of biodegradable polymers used in medical devices, highlight the need and requirements for regenerative biomaterials, and discuss the path behind the recent successful introduction of citrate-based biomaterials for manufacturing innovative medical products aimed at improving the outcome of musculoskeletal surgeries.

A polydiolcitrate-MoS2 composite for 3D printing Radio-opaque, Bioresorbable Vascular Scaffolds.

Implantable polymeric biodegradable devices, such as biodegradable vascular stents or scaffolds, cannot be fully visualized using standard X-ray-based techniques, compromising their performance due to malposition after deployment. To address this challenge, we describe composites of methacrylated poly(1,12 dodecamethylene citrate) (mPDC) and MoS2 nanosheets to fabricate novel X-ray visible radiopaque and photocurable liquid polymer-ceramic composite (mPDC-MoS2). The composite was used as an ink with micro continuous liquid interface production (µCLIP) to fabricate bioresorbable vascular scaffolds (BVS). Prints exhibited excellent crimping and expansion mechanics without strut failures and, importantly, required X-ray visibility in air and muscle tissue. Notably, MoS2 nanosheets displayed physical degradation over time in a PBS environment, indicating the potential for producing bioresorbable devices. mPDC-MoS2 is a promising bioresorbable X-ray-visible composite material suitable for 3D printing medical devices, particularly vascular scaffolds or stents, that require non-invasive X-ray-based monitoring techniques for implantation and evaluation. This innovative composite system holds significant promise for the development of biocompatible and highly visible medical implants, potentially enhancing patient outcomes and reducing medical complications.

Generation of Autologous Vascular Endothelial Cells for Patients with Peripheral Artery Disease.

Peripheral artery disease (PAD) is a prevalent cardiovascular disease with risks of limb loss. Our objective is to establish an autologous cell source for vascular regeneration to achieve limb salvage in PAD. Six PAD patients (age 50-80) were enrolled with their peripheral blood collected to derive vascular endothelial cells (ECs) with two different approaches: (1) endothelial progenitor cell (EPC) approach and (2) induced pluripotent stem cell (iPSC) approach. The iPSC approach successfully generated patient-specific ECs for all PAD patients, while the EPC approach did not yield any colony-forming ECs in any of the patients. The patient-derived iPSC-ECs expressed endothelial markers and exhibited endothelial functions. However, elevated inflammatory status with VCAM-1 expression was observed in the patient-derived cells. Pharmacological treatment with resveratrol resulted in patient-specific responses in cell viability and VCAM-1 expression. Our study demonstrates the potential of iPSC-ECs for autologous regenerative therapy in PAD, offering promise for personalized treatments for ischemic PAD. Our study establishes autologous endothelial cells from induced pluripotent stem cells as a cellular resource for regenerative treatments in peripheral artery disease.

A Miniaturized, Battery-Free, Wireless Wound Monitor That Predicts Wound Closure Rate Early.

Diabetic foot ulcers are chronic wounds that affect millions and increase the risk of amputation and mortality, highlighting the critical need for their early detection. Recent demonstrations of wearable sensors enable real-time wound assessment, but they rely on bulky electronics, making them difficult to interface with wounds. Herein, a miniaturized, wireless, battery-free wound monitor that measures lactate in real-time and seamlessly integrates with bandages for conformal attachment to the wound bed is introduced. Lactate is selected due to its multifaceted role in initiating healing. Studies in healthy and diabetic mice reveal distinct lactate profiles for normal and impaired healing wounds. A mathematical model based on the sensor data predicts wound closure rate within the first 3 days post-injury with ≈76% accuracy, which increases to ≈83% when pH is included. These studies underscore the significance of monitoring biomarkers during the inflammation phase, which can offer several benefits, including short-term use of wound monitors and their easy removal, resulting in lower risks of injury and infection at the wound site. Improvements in prediction accuracy can be achieved by designing mathematical models that build on multiple wound parameters such as pro-inflammatory and metabolic markers. Achieving this goal will require designing multi-analyte wound monitors.

Chromatin reprogramming and bone regeneration in vitro and in vivo via the microtopography-induced constriction of cell nuclei.

Topographical cues on cells can, through contact guidance, alter cellular plasticity and accelerate the regeneration of cultured tissue. Here we show how changes in the nuclear and cellular morphologies of human mesenchymal stromal cells induced by micropillar patterns via contact guidance influence the conformation of the cells' chromatin and their osteogenic differentiation in vitro and in vivo. The micropillars impacted nuclear architecture, lamin A/C multimerization and 3D chromatin conformation, and the ensuing transcriptional reprogramming enhanced the cells' responsiveness to osteogenic differentiation factors and decreased their plasticity and off-target differentiation. In mice with critical-size cranial defects, implants with micropillar patterns inducing nuclear constriction altered the cells' chromatin conformation and enhanced bone regeneration without the need for exogenous signalling molecules. Our findings suggest that medical device topographies could be designed to facilitate bone regeneration via chromatin reprogramming.

Panthenol Citrate Biomaterials Accelerate Wound Healing and Restore Tissue Integrity.

Impaired wound healing is a common complication for diabetic patients and effective diabetic wound management remains a clinical challenge. Furthermore, a significant problem that contributes to patient morbidity is the suboptimal quality of healed skin, which often leads to reoccurring chronic skin wounds. Herein, a novel compound and biomaterial building block, panthenol citrate (PC), is developed. It has interesting fluorescence and absorbance properties, and it is shown that PC can be used in soluble form as a wash solution and as a hydrogel dressing to address impaired wound healing in diabetes. PC exhibits antioxidant, antibacterial, anti-inflammatory, and pro-angiogenic properties, and promotes keratinocyte and dermal fibroblast migration and proliferation. When applied in a splinted excisional wound diabetic rodent model, PC improves re-epithelialization, granulation tissue formation, and neovascularization. It also reduces inflammation and oxidative stress in the wound environment. Most importantly, it improves the regenerated tissue quality with enhanced mechanical strength and electrical properties. Therefore, PC could potentially improve wound care management for diabetic patients and play a beneficial role in other tissue regeneration applications.

Bioresorbable, wireless, and battery-free system for electrotherapy and impedance sensing at wound sites.

Chronic wounds, particularly those associated with diabetes mellitus, represent a growing threat to public health, with additional notable economic impacts. Inflammation associated with these wounds leads to abnormalities in endogenous electrical signals that impede the migration of keratinocytes needed to support the healing process. This observation motivates the treatment of chronic wounds with electrical stimulation therapy, but practical engineering challenges, difficulties in removing stimulation hardware from the wound site, and absence of means to monitor the healing process create barriers to widespread clinical use. Here, we demonstrate a miniaturized wireless, battery-free bioresorbable electrotherapy system that overcomes these challenges. Studies based on a splinted diabetic mouse wound model confirm the efficacy for accelerated wound closure by guiding epithelial migration, modulating inflammation, and promoting vasculogenesis. Changes in the impedance provide means for tracking the healing process. The results demonstrate a simple and effective platform for wound site electrotherapy.

3D-Printed Radiopaque Bioresorbable Stents to Improve Device Visualization.

Bioresorbable stents (BRS) hold great promise for the treatment of many life-threatening luminal diseases. Tracking and monitoring of stents in vivo is critical for avoiding their malposition and inadequate expansion, which often leads to complications and stent failure. However, obtaining high X-ray visibility of polymeric BRS has been challenging because of their intrinsic radiolucency. This study demonstrates the use of photopolymerization-based 3D printing technique to fabricate radiopaque BRS by incorporating iodixanol, a clinical contrast agent, into a bioresorbable citrate-based polymer ink. The successful volumetric dispersion of the iodixanol through the 3D-printing process confers strong X-ray visibility of the produced BRS. Following in vitro degradation, the 3D-printed BRS embedded in chicken muscle maintains high X-ray visibility for at least 4 weeks. Importantly, the 3D-printed radiopaque BRS demonstrates good cytocompatibility and strong mechanical competence in crimping and expansion, which is essential for minimally invasive stent deployment. In addition, it is found that higher loading concentrations of iodixanol, e.g. 10 wt.%, results in more strut fractures in stent crimping and expansion. To conclude, this study introduces a facile strategy to fabricate radiopaque BRS through the incorporation of iodixanol in the 3D printing process, which could potentially increase the clinical success of BRS.

3D-Printed Electroactive Hydrogel Architectures with Sub-100 µm Resolution Promote Myoblast Viability.

3D-printed hydrogel scaffolds functionalized with conductive polymers have demonstrated significant potential in regenerative applications for their structural tunability, physiochemical compatibility, and electroactivity. Controllably generating conductive hydrogels with fine features, however, has proven challenging. Here, micro-continuous liquid interface production (µCLIP) method is utilized to 3D print poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogels. With a unique in-situ polymerization approach, a sulfonated monomer is first incorporated into the hydrogel matrix and subsequently polymerized into a conjugated polyelectrolyte, poly(4-(2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-butane-1 sulfonic acid sodium salt (PEDOT-S). Rod structures are fabricated at different crosslinking levels to investigate PEDOT-S incorporation and its effect on bulk hydrogel electronic and mechanical properties. After demonstrating that PEDOT-S does not significantly compromise the structures of the bulk material, pHEMA scaffolds are fabricated via µCLIP with features smaller than 100 µm. Scaffold characterization confirms PEDOT-S incorporation bolstered conductivity while lowering overall modulus. Finally, C2C12 myoblasts are seeded on PEDOT-pHEMA structures to verify cytocompatibility and the potential of this material in future regenerative applications. PEDOT-pHEMA scaffolds promote increased cell viability relative to their non-conductive counterparts and differentially influence cell organization. Taken together, this study presents a promising new approach for fabricating complex conductive hydrogel structures for regenerative applications.

Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability.

Standard oral rapamycin (that is, Rapamune) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mammalian target of rapamycin (mTOR) inhibitor has a narrow therapeutic window and numerous side effects and provides inadequate protection to transplanted cells and tissues. Furthermore, the hydrophobicity of rapamycin limits its use in parenteral formulations. Here, we demonstrate that subcutaneous delivery via poly(ethylene glycol)-b-poly(propylene sulfide) polymersome nanocarriers significantly alters rapamycin's cellular biodistribution to repurpose its mechanism of action for tolerance, instead of immunosuppression, and minimize side effects. While oral rapamycin inhibits T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes modulate antigen presenting cells in lieu of T cells, significantly improving maintenance of normoglycemia in a clinically relevant, major histocompatibility complex-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug by controlling cellular biodistribution.

Clinical Relevance of Pre-Existing and Treatment-Induced Anti-Poly(Ethylene Glycol) Antibodies.

Abstract: Poly(ethylene glycol) (PEG) is a nontoxic, hydrophilic polymer that is often covalently attached to proteins, drugs, tissues, or materials; a procedure commonly referred to as PEGylation. PEGylation improves solubility, circulation time, and reduces immunogenicity of therapeutic molecules. Currently, there are 21 PEGylated drugs approved by the Food and Drug Administration (FDA), and more in the developmental stage. In addition to the polymer's applications in the clinic, PEG is widely used as a solvent and emulsifying agent in the formulation of cosmetics, cleaning, and personal care products. Due to the ubiquitous presence of the polymer in everyday products, patients can develop antibodies against PEG (αPEG Abs) that can be problematic when a PEGylated drug is administered. These αPEG Abs can provoke hypersensitivity reactions, accelerated drug clearance, and decreased therapeutic efficacy. Herein, we review how the prevalence of PEG in everyday products has induced αPEG Abs within the general public as well as the effect of these Abs on the performance of PEGylated therapeutics. We will focus on clinical manifestations following the administration of PEGylated drugs. Lay Summary: Poly(ethylene glycol) (PEG) is a polymer found in products including cosmetics, personal care products, cleaning agents, medicine, and food. Due to the prevalence of PEG, people can develop antibodies (αPEG Abs) against the polymer, which recognize PEG as foreign. Of note, PEG is frequently incorporated into drug formulations to improve therapeutic efficacy. Complications can arise when a patient receiving a PEGylated drug has previously developed αPEG Abs from interactions with PEG in everyday products. The presence of high concentrations of αPEG Abs in blood can result in decreased treatment efficacy and allergic reactions to a wide range of therapeutics.

Reversibly immortalized keratinocytes (iKera) facilitate re-epithelization and skin wound healing: Potential applications in cell-based skin tissue engineering.

Skin injury is repaired through a multi-phase wound healing process of tissue granulation and re-epithelialization. Any failure in the healing process may lead to chronic non-healing wounds or abnormal scar formation. Although significant progress has been made in developing novel scaffolds and/or cell-based therapeutic strategies to promote wound healing, effective management of large chronic skin wounds remains a clinical challenge. Keratinocytes are critical to re-epithelialization and wound healing. Here, we investigated whether exogenous keratinocytes, in combination with a citrate-based scaffold, enhanced skin wound healing. We first established reversibly immortalized mouse keratinocytes (iKera), and confirmed that the iKera cells expressed keratinocyte markers, and were responsive to UVB treatment, and were non-tumorigenic. In a proof-of-principle experiment, we demonstrated that iKera cells embedded in citrate-based scaffold PPCN provided more effective re-epithelialization and cutaneous wound healing than that of either PPCN or iKera cells alone, in a mouse skin wound model. Thus, these results demonstrate that iKera cells may serve as a valuable skin epithelial source when, combining with appropriate biocompatible scaffolds, to investigate cutaneous wound healing and skin regeneration.

Bioresorbable Multilayer Photonic Cavities as Temporary Implants for Tether-Free Measurements of Regional Tissue Temperatures.

Objective and Impact Statement. Real-time monitoring of the temperatures of regional tissue microenvironments can serve as the diagnostic basis for treating various health conditions and diseases. Introduction. Traditional thermal sensors allow measurements at surfaces or at near-surface regions of the skin or of certain body cavities. Evaluations at depth require implanted devices connected to external readout electronics via physical interfaces that lead to risks for infection and movement constraints for the patient. Also, surgical extraction procedures after a period of need can introduce additional risks and costs. Methods. Here, we report a wireless, bioresorbable class of temperature sensor that exploits multilayer photonic cavities, for continuous optical measurements of regional, deep-tissue microenvironments over a timeframe of interest followed by complete clearance via natural body processes. Results. The designs decouple the influence of detection angle from temperature on the reflection spectra, to enable high accuracy in sensing, as supported by in vitro experiments and optical simulations. Studies with devices implanted into subcutaneous tissues of both awake, freely moving and asleep animal models illustrate the applicability of this technology for in vivo measurements. Conclusion. The results demonstrate the use of bioresorbable materials in advanced photonic structures with unique capabilities in tracking of thermal signatures of tissue microenvironments, with potential relevance to human healthcare.

Stretchable, dynamic covalent polymers for soft, long-lived bioresorbable electronic stimulators designed to facilitate neuromuscular regeneration.

Bioresorbable electronic stimulators are of rapidly growing interest as unusual therapeutic platforms, i.e., bioelectronic medicines, for treating disease states, accelerating wound healing processes and eliminating infections. Here, we present advanced materials that support operation in these systems over clinically relevant timeframes, ultimately bioresorbing harmlessly to benign products without residues, to eliminate the need for surgical extraction. Our findings overcome key challenges of bioresorbable electronic devices by realizing lifetimes that match clinical needs. The devices exploit a bioresorbable dynamic covalent polymer that facilitates tight bonding to itself and other surfaces, as a soft, elastic substrate and encapsulation coating for wireless electronic components. We describe the underlying features and chemical design considerations for this polymer, and the biocompatibility of its constituent materials. In devices with optimized, wireless designs, these polymers enable stable, long-lived operation as distal stimulators in a rat model of peripheral nerve injuries, thereby demonstrating the potential of programmable long-term electrical stimulation for maintaining muscle receptivity and enhancing functional recovery.

Cyclodextrin-modified poly(octamethylene citrate) polymers towards enhanced sorption properties.

Herein, we describe the synthesis of poly(1,8-octamethylene citrate) materials modified in the bulk with 2-hydroxypropyl-ß-cyclodextrin (cPOCCD), biodegradable elastomers with intrinsic sorption properties for drug delivery. The chemical structure, physicochemical properties, in vitro drug loading and release profiles of cPOCCD were investigated. Thus, cPOCCD polyesters absorb the studied drugs more effective and release them for a longer period of time than poly(1,8-octamethylene citrate) materials not containing cyclodextrins.

Stem cell therapy for chronic skin wounds in the era of personalized medicine: From bench to bedside.

With the significant financial burden of chronic cutaneous wounds on the healthcare system, not to the personal burden mention on those individuals afflicted, it has become increasingly essential to improve our clinical treatments. This requires the translation of the most recent benchtop approaches to clinical wound repair as our current treatment modalities have proven insufficient. The most promising potential treatment options rely on stem cell-based therapies. Stem cell proliferation and signaling play crucial roles in every phase of the wound healing process and chronic wounds are often associated with impaired stem cell function. Clinical approaches involving stem cells could thus be utilized in some cases to improve a body's inhibited healing capacity. We aim to present the laboratory research behind the mechanisms and effects of this technology as well as current clinical trials which showcase their therapeutic potential. Given the current problems and complications presented by chronic wounds, we hope to show that developing the clinical applications of stem cell therapies is the rational next step in improving wound care.