Challenges in IBD Research 2024: Novel Technologies.

Novel technology is one of the five focus areas of the Challenges in Inflammatory Bowel Disease (IBD) Research 2024 document. Building off the Challenges in IBD Research 2019 document, the Foundation aims to provide a comprehensive overview of current gaps in IBD research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in interception, remission, and restoration for these diseases. The document is the result of a multidisciplinary collaboration from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. Specifically, the Novel Technologies section focuses on addressing key research gaps to enable interception and improve remission rates in IBD. This includes testing predictions of disease onset and progression, developing novel technologies tailored to specific phenotypes, and facilitating collaborative translation of science into diagnostics, devices, and therapeutics. Proposed priority actions outlined in the document include real-time measurement of biological changes preceding disease onset, more effective quantification of fibrosis, exploration of technologies for local treatment of fistulas, and the development of drug delivery platforms for precise, location-restricted therapies. Additionally, there is a strong emphasis on fostering collaboration between various stakeholders to accelerate progress in IBD research and treatment. Addressing these research gaps necessitates the exploration and implementation of bio-engineered novel technologies spanning a spectrum from materials to systems. By harnessing innovative ideas and technologies, there's a collective effort to enhance patient care and outcomes for individuals affected by IBD.

Technology drives medical progress, solving clinical challenges and enhancing patient care in inflammatory bowel disease (IBD). Collaborative efforts focus on addressing research gaps to improve interception, restoration, and remission rates, utilizing innovative technologies for better patient outcomes.

Chitosan Poly(vinyl alcohol) Methacrylate Hydrogels for Tissue Engineering Scaffolds.

A major challenge in tissue engineering scaffolds is controlling scaffold degradation rates during healing while maintaining mechanical properties to support tissue formation. Hydrogels are three-dimensional matrices that are widely applied as tissue scaffolds based on their unique properties that can mimic the extracellular matrix. In this study, we develop a hybrid natural/synthetic hydrogel platform to tune the properties for tissue engineering scaffold applications. We modified chitosan and poly(vinyl alcohol) (PVA) with photo-cross-linkable methacrylate functional groups and then synthesized a library of chitosan PVA methacrylate hydrogels (ChiPVAMA) with two different photoinitiators, Irgacure 2959 (I2959) and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP). ChiPVAMA hydrogels showed tunability in degradation rates and mechanical properties based on both the polymer content and photoinitiator type. This tunability could enable their application in a range of tissue scaffold applications. In a 2D scratch wound healing assay, all hydrogel samples induced faster wound closure compared to a gauze clinical wound dressing control. NIH/3T3 cells encapsulated in hydrogels showed a high viability (∼92%) over 14 days, demonstrating the capacity of this system as a supportive cell scaffold. In addition, hydrogels containing a higher chitosan content demonstrated a high antibacterial capacity. Overall, ChiPVAMA hydrogels provide a potential tissue engineering scaffold that is tunable, degradable, and suitable for cell growth.

Solvent-free synthesis of biostable segmented polyurethane shape memory polymers for biomedical applications.

Biostable shape memory polymers that remain stable in physiological conditions are beneficial for user-defined shape recovery in response to a specific stimulus. For potential commercialization and biocompatibility considerations, biomaterial synthesis must be simple and scalable. Hence, a library of biostable and cytocompatible shape memory polymers with tunable thermomechanical properties based on hard segment content was synthesized using a solvent-free method. Polymer surface chemistry, thermomechanical and shape memory properties, and biostability were assessed. We also investigated the effects of processing methods on thermomechanical and shape memory properties. All polymers showed high glass transition temperatures (>50 °C), which indicates that their temporary shape could be preserved after implantation. Polymers also demonstrate high shape fixity (73-80%) and shape recovery (93-95%). Minimal mass loss (<5%) was observed in accelerated oxidative (20% H2O2) and hydrolytic (0.1 M NaOH) media. Additionally, minimal shape recovery (∼0%) occurred in programmed samples with higher hard segment content that were stored in degradation media. After 40 days of storage in media, programmed samples recovered their primary shapes upon heating to temperatures above their transition temperature. Annealing to above the polymer melting point and solvent casting of polymers improved shape memory and thermal properties. To enable their potential use as biomaterial scaffolds, fiber formation of synthesized polyurethanes was compared with those of samples synthesized using a previously reported solvent-based method. The new method provided polymers that can form fibrous scaffolds with improved mechanical and shape memory properties, which is attributed to the higher molecular weight and crystalline content of polymers synthesized using the new, solvent-free approach. These biostable segmented polyurethanes could be coupled with a range of components that respond to specific stimuli, such as enzymes, magnetic field, pH, or light, to enable a specific shape change response, which could be coupled with drug and/or bioactive material delivery in future work.

Self-Defensive Antimicrobial Shape Memory Polyurethanes with Honey-Based Compounds.

Infection treatment plays a crucial role in aiding the body in wound healing. To that end, we developed a library of antimicrobial polymers based on segmented shape memory polyurethanes with nondrug-based antimicrobials (i.e., honey-based phenolic acids (PAs)) using both chemical and physical incorporation approaches. The antimicrobial shape memory polymers (SMPs) have high transition temperatures (>55 °C) to enable maintenance of temporary, programmed shapes in physiological conditions unless a specific external stimulus is present. Polymers showed tunable mechanical and shape memory properties by changing the ratio, chemistry, and incorporation method of PAs. Cytocompatible (∼100% cell viability) synthesized polymers inhibited growth rates of Staphylococcus aureus (∼100% with physically incorporated PAs and >80% with chemically incorporated PAs) and Escherichia coli (∼100% for samples with cinnamic acid (physical and chemical)). Crystal violet assays showed that all formulations inhibit biofilm formation in surrounding solutions, and chemically incorporated samples showed surface antibiofilm properties with S. aureus. Molecular dynamics simulations confirm that PAs have higher levels of interactions with S. aureus cell membranes than E. coli. Long-term antimicrobial properties were measured after storage of the sample in aqueous conditions; the polymers retained their antimicrobial properties against E. coli after up to 20 days. As a proof of concept, magnetic particles were incorporated into the polymer to trigger user-defined shape recovery by applying an external magnetic field. Shape recovery disrupted preformed S. aureus biofilms on polymer surfaces. This antimicrobial biomaterial platform could enable user- or environmentally controlled shape change and/or antimicrobial release to enhance infection treatment efforts.

Antibacterial and Cytocompatible pH-Responsive Peptide Hydrogel.

A short peptide, FHHF-11, was designed to change stiffness as a function of pH due to changing degree of protonation of histidines. As pH changes in the physiologically relevant range, G' was measured at 0 Pa (pH 6) and 50,000 Pa (pH 8). This peptide-based hydrogel is antimicrobial and cytocompatible with skin cells (fibroblasts). It was demonstrated that the incorporation of unnatural AzAla tryptophan analog residue improves the antimicrobial properties of the hydrogel. The material developed can have a practical application and be a paradigm shift in the approach to wound treatment, and it will improve healing outcomes for millions of patients each year.

Dual Burst and Sustained Release of p-Coumaric Acid from Shape Memory Polymer Foams for Polymicrobial Infection Prevention in Trauma-Related Hemorrhagic Wounds.

Hemorrhage is the primary cause of trauma-related death. Of patients that survive, polymicrobial infection occurs in 39% of traumatic wounds within a week of injury. Moreover, traumatic wounds are susceptible to hospital-acquired and drug-resistant bacterial infections. Thus, hemostatic dressings with antimicrobial properties could reduce morbidity and mortality to enhance traumatic wound healing. To that end, p-coumaric acid (PCA) was incorporated into hemostatic shape memory polymer foams by two mechanisms (chemical and physical) to produce dual PCA (DPCA) foams. DPCA foams demonstrated excellent antimicrobial and antibiofilm properties against native Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis; co-cultures of E. coli and S. aureus; and drug-resistant S. aureus and S. epidermidis at short (1 h) and long (7 days) time points. Resistance against biofilm formation on the sample surfaces was also observed. In ex vivo experiments in a porcine skin wound model, DPCA foams exhibited similarly high antimicrobial properties as those observed in vitro, indicating that PCA was released from the DPCA foam to successfully inhibit bacterial growth. DPCA foams consistently showed improved antimicrobial properties relative to those of clinical control foams containing silver nanoparticles (AgNPs) against single and mixed species bacteria, single and mixed species biofilms, and bacteria in the ex vivo wound model. This system could allow for physically incorporated PCA to first be released into traumatic wounds directly after application for instant wound disinfection. Then, more tightly tethered PCA can be continuously released into the wound for up to 7 days to kill additional bacteria and protect against biofilms.

Antimicrobial PVA Hydrogels with Tunable Mechanical Properties and Antimicrobial Release Profiles.

Hydrogels are broadly employed in wound healing applications due to their high water content and tissue-mimicking mechanical properties. Healing is hindered by infection in many types of wound, including Crohn's fistulas, tunneling wounds that form between different portions of the digestive system in Crohn's disease patients. Owing to the rise of drug-resistant infections, alternate approaches are required to treat wound infections beyond traditional antibiotics. To address this clinical need, we designed a water-responsive shape memory polymer (SMP) hydrogel, with natural antimicrobials in the form of phenolic acids (PAs), for potential use in wound filling and healing. The shape memory properties could allow for implantation in a low-profile shape, followed by expansion and would filling, while the PAs provide localized delivery of antimicrobials. Here, we developed a urethane-crosslinked poly(vinyl alcohol) hydrogel with cinnamic (CA), p-coumaric (PCA), and caffeic (Ca-A) acid chemically or physically incorporated at varied concentrations. We examined the effects of incorporated PAs on antimicrobial, mechanical, and shape memory properties, and on cell viability. Materials with physically incorporated PAs showed improved antibacterial properties with lower biofilm formation on hydrogel surfaces. Both modulus and elongation at break could be increased simultaneously in hydrogels after both forms of PA incorporation. Cellular response in terms of initial viability and growth over time varied based on PA structure and concentration. Shape memory properties were not negatively affected by PA incorporation. These PA-containing hydrogels with antimicrobial properties could provide a new option for wound filling, infection control, and healing. Furthermore, PA content and structure provide novel tools for tuning material properties independently of network chemistry, which could be harnessed in a range of materials systems and biomedical applications.

Bacterial protease-responsive shape memory polymers for infection surveillance and biofilm inhibition in chronic wounds.

Chronic wound healing is often negatively impacted by infection. Efficient infection assessment is crucial for effective treatment, and biofilm inhibition could improve treatment efficacy. To that end, we developed a bacterial protease-responsive shape memory polymer based on a segmented polyurethane with incorporated poly(glutamic acid) peptide (PU-Pep). Poly(glutamic acid) degrades in response to bacterial proteases to trigger shape recovery of PU-Pep films that are programmed into a secondary shape. These materials have transition temperatures well above body temperature (~60°C), which enables stable storage in temporary shapes after implantation. Synthesized polymers have high shape fixity (~74%-88%), shape recovery (~93%-95%), and cytocompatibility (~100%). Strained PU-Pep samples underwent shape recovery within ≤24 h in response to the V8 enzyme from Staphylococcus aureus (S. aureus, ~50% recovery) and multiple bacteria strains (S. aureus [~40%], Staphylococcus epidermidis [~30%], and Escherichia coli [~25%]), and they had minimal shape change in response to media controls and mammalian cells. Shape recovery of strained PU-Pep samples prevented biofilm formation on the sample surfaces, and resulting attached planktonic bacteria were vulnerable to applied treatments. PU-Pep with physically incorporated antimicrobials simultaneously prevented biofilm formation and killed isolated bacteria. PU-Pep dressings displayed visible shape change and resistance to biofilm formation in in vitro and ex vivo models. In the in vitro model, PU-Pep shape change also disrupted pre-formed biofilm structures. This novel bacterial protease-responsive biomaterial could serve as a wound dressing that changes shape specifically during bacterial colonization to alert clinicians to infection and make biofilm-associated infections easier to treat.

In vitro and in vivo degradation correlations for polyurethane foams with tunable degradation rates.

Polyurethane foams present a tunable biomaterial platform with potential for use in a range of regenerative medicine applications. Achieving a balance between scaffold degradation rates and tissue ingrowth is vital for successful wound healing, and significant in vivo testing is required to understand these processes. Vigorous in vitro testing can minimize the number of animals that are required to gather reliable data; however, it is difficult to accurately select in vitro degradation conditions that can effectively mimic in vivo results. To that end, we performed a comprehensive in vitro assessment of the degradation of porous shape memory polyurethane foams with tunable degradation rates using varying concentrations of hydrogen peroxide to identify the medium that closely mimics measured in vivo degradation rates. Material degradation was studied over 12 weeks in vitro in 1%, 2%, or 3% hydrogen peroxide and in vivo in subcutaneous pockets in Sprague Dawley rats. We found that the in vitro degradation conditions that best predicted in vivo degradation rates varied based on the number of mechanisms by which the polymer degraded and the polymer hydrophilicity. Namely, more hydrophilic materials that degrade by both hydrolysis and oxidation require lower concentrations of hydrogen peroxide (1%) to mimic in vivo rates, while more hydrophobic scaffolds that degrade by oxidation alone require higher concentrations of hydrogen peroxide (3%) to model in vivo degradation. This information can be used to rationally select in vitro degradation conditions that accurately identify in vivo degradation rates prior to characterization in an animal model.

Highly Porous Gas-Blown Hydrogels for Direct Cell Encapsulation with High Cell Viability.

Cell transplant therapies show potential as treatments for a large number of diseases. The encapsulation of cells within hydrogels is often used to mimic the extracellular matrix and protect cells from the body's immune response. However, cell encapsulation can be limited in terms of both scaffold size and cell viability due to poor nutrient and waste transport throughout the bulk of larger volume hydrogels. Strategies to address this issue include creating prevascularized or porous structured materials. For example, cell-laden hydrogels can be formed by porogen leaching or three-dimensional printing, but these techniques involve the use of multiple materials, long preparation times, and/or specialized equipment. Postfabrication cell seeding in porous scaffolds can result in inconsistent cell density throughout scaffold volumes and typically requires a bioreactor to ensure even cell distribution. In this study, we developed a highly cytocompatible direct cell encapsulation method during the rapid fabrication of porous hydrogels. Using sodium bicarbonate and citric acid as blowing agents, we employed photocurable polymers to produce highly porous materials within a matter of minutes. Cells were directly encapsulated within methacrylated poly(vinyl alcohol), poly(ethylene glycol), and gelatin hydrogels at viabilities as high as 93% by controlling solution variables, such as citric acid content, viscosity, pH, and curing time. Cell viability within the resulting porous constructs was high (>80%) over 14 days of analysis with multiple cell types. This work provides a simple, versatile, and tunable method for cell encapsulation within highly porous constructs that can be built upon in future work for the delivery of cell-based therapies. Impact Statement This simple method to obtain cell-laden hydrogel foams allows direct cell encapsulation within biomaterials without the need for porogens or microcarriers, while maintaining high cell viability. The successful encapsulation of multiple cell types into gas-blown hydrogels with varied chemistries shows the versatility of this method. While this work focuses on photocrosslinkable polymers, any quick gelling material could be used for foam fabrication in expansion of this work. The potential future impact of this work on the treatment of diseases and injuries that utilize cell therapies is wide-ranging.

Antimicrobial Shape Memory Polymer Hydrogels for Chronic Wound Dressings.

Chronic wounds can remain open for several months and have high risks of amputation due to infection. Dressing materials to treat chronic wounds should be conformable for irregular wound geometries, maintain a moist wound bed, and reduce infection risks. To that end, we developed cytocompatible shape memory polyurethane-based poly(ethylene glycol) (PEG) hydrogels that allow facile delivery to the wound site. Plant-based phenolic acids were physically incorporated onto the hydrogel scaffolds to provide antimicrobial properties. These materials were tested to confirm their shape memory properties, cytocompatibility, and antibacterial properties. The incorporation of phenolic acids provides a new mechanism for tuning intermolecular bonding in the hydrogels and corollary mechanical and shape memory properties. Phenolic acid-containing hydrogels demonstrated an increased shape recovery ratio (1.35× higher than the control formulation), and materials with cytocompatibility >90% were identified. Antimicrobial properties were retained over 20 days in hydrogels with higher phenolic acid content. Phenolic acid retention and antimicrobial efficacy were dependent upon phenolic acid structures and interactions with the polymer backbone. This novel hydrogel system provides a platform for future development as a chronic wound dressing material that is easy to implant and reduces infection risks.

Magnetically Actuated Shape Memory Polymers for On-Demand Drug Delivery.

Repeated use of intravenous infusions to deliver drugs can cause nerve damage, pain, and infection. There is an unmet need for a drug delivery method that administers drugs on demand for prolonged use. Here, we developed magnetically responsive shape memory polymers (SMPs) to enhance control over drug release. Iron oxide magnetic nanoparticles (mnps) were synthesized and incorporated into previously developed SMPs to enable magnetically induced shape memory effects that can be activated remotely via the application of an alternating magnetic field. These materials were tested for their shape memory properties (dynamic mechanical analysis), cytocompatibility (3T3 fibroblast viability), and tunable drug delivery rates (UV−VIS to evaluate the release of incorporated doxorubicin, 6-mercaptopurine, and/or rhodamine). All polymer composites had >75% cytocompatibility over 72 h. Altering the polymer chemistry and mnp content provided methods to tune drug release. Namely, linear polymers with higher mnp content had faster drug release. Highly cross-linked polymer networks with lower mnp content slowed drug release. Shape memory properties and polymer/drug interactions provided additional variables to tune drug delivery rates. Polymers that were fixed in a strained secondary shape had a slower release rate compared with unstrained polymers, and hydrophobic drugs were released more slowly than hydrophilic drugs. Using these design principles, a single material with gradient chemistry and dual drug loading was synthesized, which provided a unique mechanism to deliver two drugs from a single scaffold with distinct delivery profiles. This system could be employed in future work to provide controlled release of selected drug combinations with enhanced control over release as compared with previous approaches.

Shape Memory Polymer Foams with Phenolic Acid-Based Antioxidant Properties.

Phenolic acids (PAs) are natural antioxidant agents in the plant kingdom that are part of the human diet. The introduction of naturally occurring PAs into the network of synthetic shape memory polymer (SMP) polyurethane (PU) foams during foam fabrication can impart antioxidant properties to the resulting scaffolds. In previous work, PA-containing SMP foams were synthesized to provide materials that retained the desirable shape memory properties of SMP PU foams with additional antimicrobial properties that were derived from PAs. Here, we explore the impact of PA incorporation on SMP foam antioxidant properties. We investigated the antioxidant effects of PA-containing SMP foams in terms of in vitro oxidative degradation resistance and cellular antioxidant activity. The PA foams showed surprising variability; p-coumaric acid (PCA)-based SMP foams exhibited the most potent antioxidant properties in terms of slowing oxidative degradation in H2O2. However, PCA foams did not effectively reduce reactive oxygen species (ROS) in short-term cellular assays. Vanillic acid (VA)- and ferulic acid (FA)-based SMP foams slowed oxidative degradation in H2O2 to lesser extents than the PCA foams, but they demonstrated higher capabilities for scavenging ROS to alter cellular activity. All PA foams exhibited a continuous release of PAs over two weeks. Based on these results, we hypothesize that PAs must be released from SMP foams to provide adequate antioxidant properties; slower release may enable higher resistance to long-term oxidative degradation, and faster release may result in higher cellular antioxidant effects. Overall, PCA, VA, and FA foams provide a new tool for tuning oxidative degradation rates and extending potential foam lifetime in the wound. VA and FA foams induced cellular antioxidant activity that could help promote wound healing by scavenging ROS and protecting cells. This work could contribute a wound dressing material that safely releases antimicrobial and antioxidant PAs into the wound at a continuous rate to ideally improve healing outcomes. Furthermore, this methodology could be applied to other oxidatively degradable biomaterial systems to enhance control over degradation rates and to provide multifunctional scaffolds for healing.

Shape Memory Polymer Foams With Phenolic Acid-Based Antioxidant and Antimicrobial Properties for Traumatic Wound Healing.

The leading cause of trauma-related death before arrival at a hospital is uncontrolled blood loss. Upon arrival at the hospital, microbial infections in traumatic wounds become an additional factor that increases mortality. The development of hemostatic materials with antimicrobial and antioxidant properties could improve morbidity and mortality in these wounds. To that end, phenolic acids (PAs) were successfully incorporated into the network of shape memory polymer (SMP) polyurethane foams by reacting them with isocyanates. Resulting PA-containing SMP foam shape memory properties, antimicrobial and antioxidant activity, and blood and cell interactions were characterized. Results showed that p-coumaric, vanillic, and ferulic acids were successfully incorporated into the SMP foams. The PA-containing SMP foams retained the antimicrobial and antioxidant properties of the incorporated PAs, with ∼20% H2O2 scavenging and excellent antimicrobial properties again E. coli (∼5X reduction in CFUs vs. control foams), S. aureus (∼4.5X reduction in CFUs vs. control foams, with comparable CFU counts to clinical control), and S. epidermidis (∼25-120X reduction in CFUs vs. control foams, with comparable CFU counts to clinical control). Additionally, appropriate thermal and shape memory properties of PA foams could enable stable storage in low-profile secondary geometries at temperatures up to ∼55°C and rapid expand within ∼2 min after exposure to water in body temperature blood. PA foams had high cytocompatibility (>80%), non-hemolytic properties, and platelet attachment and activation, with improved cytocompatibility and hemocompatibility in comparison with clinical, silver-based controls. The incorporation of PAs provides a natural non-antibiotic approach to antimicrobial SMP foams with antioxidant properties. This system could improve outcomes in traumatic wounds to potentially reduce bleeding-related deaths and subsequent infections.

The Collagen Receptor Discoidin Domain Receptor 1b Enhances Integrin ß1-Mediated Cell Migration by Interacting With Talin and Promoting Rac1 Activation.

Integrins and discoidin domain receptors (DDRs) 1 and 2 promote cell adhesion and migration on both fibrillar and non fibrillar collagens. Collagen I contains DDR and integrin selective binding motifs; however, the relative contribution of these two receptors in regulating cell migration is unclear. DDR1 has five isoforms (DDR1a-e), with most cells expressing the DDR1a and DDR1b isoforms. We show that human embryonic kidney 293 cells expressing DDR1b migrate more than DDR1a expressing cells on DDR selective substrata as well as on collagen I in vitro. In addition, DDR1b expressing cells show increased lung colonization after tail vein injection in nude mice. DDR1a and DDR1b differ from each other by an extra 37 amino acids in the DDR1b cytoplasmic domain. Interestingly, these 37 amino acids contain an NPxY motif which is a central control module within the cytoplasmic domain of ß integrins and acts by binding scaffold proteins, including talin. Using purified recombinant DDR1 cytoplasmic tail proteins, we show that DDR1b directly binds talin with higher affinity than DDR1a. In cells, DDR1b, but not DDR1a, colocalizes with talin and integrin ß1 to focal adhesions and enhances integrin ß1-mediated cell migration. Moreover, we show that DDR1b promotes cell migration by enhancing Rac1 activation. Mechanistically DDR1b interacts with the GTPase-activating protein (GAP) Breakpoint cluster region protein (BCR) thus reducing its GAP activity and enhancing Rac activation. Our study identifies DDR1b as a major driver of cell migration and talin and BCR as key players in the interplay between integrins and DDR1b in regulating cell migration.

Shape memory polymer foams with tunable interconnectivity using off-the-shelf foaming components.

The ability to easily and safety tune pore structures of gas-blown polyurethane shape memory polymer (SMP) foams could improve their outcomes as hemostatic dressings or tissue engineering scaffolds and enable overall commercialization efforts. Incorporating physical blowing agents into the polymer mix can be used to tune pore size and interconnectivity without altering foam chemistry. Enovate (HFC-254fa) is a commonly used physical blowing agent in gas-blown foams, but the Environmental Protection Agency (EPA) considers its use unacceptable because it is a hydrofluorocarbon that contributes to global warming. Here, off-the-shelf solvents accepted for use by the EPA, acetone, dimethyoxymethane (methylal), and methyl formate, were used as physical blowing agents by adding small volumes during foam fabrication. Increasing the physical blowing agent volume resulted in greater pore interconnectivity while maintaining SMP foam chemical and thermal properties. Pore size and interconnectivity also impacted cell and blood interactions with the foams. This work provides a safe and easy method for tuning SMP foam interconnectivity to aid in future commercialization efforts in a range of potential biomedical applications.

Shape memory polymer hydrogels with cell-responsive degradation mechanisms for Crohn's fistula closure.

Crohn's disease, a form of inflammatory bowel disease, commonly results in fistulas, tunneling wounds between portions of the urinary, reproductive, and/or digestive systems. These tunneling wounds cause pain, infection, and abscess formation. Of Crohn's patients with fistula formation, 83% undergo surgical intervention to either drain or bypass the fistula openings, and ~23% of these patients ultimately require bowel resections. Current treatment options, such as setons, fibrin glues, and bioprosthetic plugs, are prone to infection, dislodging, and/or require a secondary removal surgery. Thus, there is a need for fistula filling material that can be easily and stably implanted and then degraded during fistula healing to eliminate the need for removal. Here, the development of a shape memory polymer hydrogel foam containing polyvinyl alcohol (PVA) and cornstarch (CS) with a disulfide polyurethane crosslinker is presented. These materials undergo controlled degradation by amylase, which is present in the digestive tract, and by reducing thiol species such as glutathione/dithiothreitol. Increasing CS content and using lower molecular weight PVA can be used to increase the degradation rate of the materials while maintaining shape memory properties that could be utilized for easy implantation. This material platform is based on low-cost and easily accessible components and provides a biomaterial scaffold with cell-responsive degradation mechanisms for future potential use in Crohn's fistula treatment.

Hemostatic shape memory polymer foams with improved survival in a lethal traumatic hemorrhage model.

Although there are many hemostatic agents available for use on the battlefield, uncontrolled hemorrhage is still the primary cause of preventable death. Current hemostatic dressings include QuikClot® Combat Gauze (QCCG) and XStat®, which have inadequate success in reducing mortality. To address this need, a new hemostatic material was developed using shape memory polymer (SMP) foams, which demonstrate biocompatibility, rapid clotting, and shape recovery to fill the wound site. SMP foam hemostatic efficacy was examined in a lethal, noncompressible porcine liver injury model over 6 h following injury. Wounds were packed with SMP foams, XStat, or QCCG and compared in terms of time to bleeding cessation, total blood loss, and animal survival. The hemostatic material properties and in vitro blood interactions were also characterized. SMP foams decreased blood loss and active bleeding time in comparison with XStat and QCCG. Most importantly, SMP foams increased the 6 h survival rate by 50% and 37% (vs. XStat and QCCG, respectively) with significant increases in survival times. Based upon in vitro characterizations, this result is attributed to the low stiffness and shape filling capabilities of SMP foams. This study demonstrates that SMP foams have promise for improving upon current clinically available hemostatic dressings and that hemostatic material properties are important to consider in designing devices for noncompressible bleeding control. STATEMENT OF SIGNIFICANCE: Uncontrolled hemorrhage is the leading cause of preventable death on the battlefield, and it accounts for approximately 1.5 million deaths each year. New biomaterials are required for improved hemorrhage control, particularly in noncompressible wounds in the torso. Here, we compared shape memory polymer (SMP) foams with two clinical dressings, QuikClot Combat Gauze and XStat, in a pig model of lethal liver injury. SMP foam treatment reduced bleeding times and blood loss and significantly improved animal survival. After further material characterization, we determined that the improved outcomes with SMP foams are likely due to their low stiffness and controlled shape change after implantation, which enabled their delivery to the liver injuries without inducing further wound tearing. Overall, SMP foams provide a promising option for hemorrhage control.

Biostable Shape Memory Polymer Foams for Smart Biomaterial Applications.

Polyurethane foams provide a wide range of applications as a biomaterial system due to the ability to tune their physical, chemical, and biological properties to meet the requirements of the intended applications. Another key parameter that determines the usability of this biomaterial is its degradability under body conditions. Several current approaches focus on slowing the degradation rate for applications that require the implant to be present for a longer time frame (over 100 days). Here, biostable shape memory polymer (SMP) foams were synthesized with added ether-containing monomers to tune the degradation rates. The physical, thermal and shape memory properties of these foams were characterized along with their cytocompatibility and blood interactions. Degradation profiles were assessed in vitro in oxidative (3% H2O2; real-time) and hydrolytic media (0.1 M NaOH; accelerated) at 37 °C. The resulting foams had tunable degradation rates, with up 15% mass remaining after 108 days, and controlled erosion profiles. These easy-to-use, shape-filling SMP foams have the potential for various biomaterial applications where longer-term stability without the need for implant removal is desired.

Shape Memory Polymer Foams with Tunable Degradation Profiles.

Uncontrolled hemorrhage is the leading cause of preventable death on the battlefield and results in ∼1.5 million deaths each year. The primary current treatment options are gauze and/or tourniquets, which are ineffective for up to 80% of wounds. Additionally, most hemostatic materials must be removed from the patient within <12 h, which limits their applicability in remote scenarios and can cause additional bleeding upon removal. Here, degradable shape memory polymer (SMP) foams were synthesized to overcome these limitations. SMP foams were modified with oxidatively labile ether groups and hydrolytically labile ester groups to degrade after implantation. Foam physical, thermal, and shape memory properties were assessed along with cytocompatibility and blood interactions. Degradation profiles were obtained in vitro in oxidative and hydrolytic media (3% H2O2 (oxidation) and 0.1 M NaOH (hydrolysis) at 37 °C). The resulting foams had tunable, clinically relevant degradation rates, with complete mass loss within 30-60 days. These SMP foams have potential to provide an easy-to-use, shape-filling hemostatic dressing that can be left in place during traumatic wound healing with future potential use in regenerative medicine applications.