Ellen T. Roche

A bioinspired soft actuated material.

A class of soft actuated materials that can achieve lifelike motion is presented. By embedding pneumatic actuators in a soft material inspired by a biological muscle fibril architecture, and developing a simple finite element simulation of the same, tunable biomimetic motion can be achieved with fully soft structures, exemplified here by an active left ventricle simulator.

Drug and cell delivery for cardiac regeneration

The spectrum of ischaemic cardiomyopathy, encompassing acute myocardial infarction to congestive heart failure is a significant clinical issue in the modern era. This group of diseases is an enormous source of morbidity and mortality and underlies significant healthcare costs worldwide. Cardiac regenerative therapy, whereby pro-regenerative cells, drugs or growth factors are administered to damaged and ischaemic myocardium has demonstrated significant potential, especially preclinically. While some of these strategies have demonstrated a measure of success in clinical trials, tangible clinical translation has been slow. To date, the majority of clinical studies and a significant number of preclinical studies have utilised relatively simple delivery methods for regenerative therapeutics, such as simple systemic administration or local injection in saline carrier vehicles. Here, we review cardiac regenerative strategies with a particular focus on advanced delivery concepts as a potential means to enhance treatment efficacy and tolerability and ultimately, clinical translation. These include (i) delivery of therapeutic agents in biomaterial carriers, (ii) nanoparticulate encapsulation, (iii) multimodal therapeutic strategies and (iv) localised, minimally invasive delivery via percutaneous transcatheter systems.

Comparison of biomaterial delivery vehicles for improving acute retention of stem cells in the infarcted heart

Cell delivery to the infarcted heart has emerged as a promising therapy, but is limited by very low acute retention and engraftment of cells. The objective of this study was to compare a panel of biomaterials to evaluate if acute retention can be improved with a biomaterial carrier. Cells were quantified post-implantation in a rat myocardial infarct model in five groups (n = 7-8); saline injection (current clinical standard), two injectable hydrogels (alginate, chitosan/β-glycerophosphate (chitosan/ß-GP)) and two epicardial patches (alginate, collagen). Human mesenchymal stem cells (hMSCs) were delivered to the infarct border zone with each biomaterial. At 24 h, retained cells were quantified by fluorescence. All biomaterials produced superior fluorescence to saline control, with approximately 8- and 14-fold increases with alginate and chitosan/β-GP injectables, and 47 and 59-fold increases achieved with collagen and alginate patches, respectively. Immunohistochemical analysis qualitatively confirmed these findings. All four biomaterials retained 50-60% of cells that were present immediately following transplantation, compared to 10% for the saline control. In conclusion, all four biomaterials were demonstrated to more efficiently deliver and retain cells when compared to a saline control. Biomaterial-based delivery approaches show promise for future development of efficient in vivo delivery techniques.

Biologic-free mechanically induced muscle regeneration

Significance Much progress has been made toward the development of drug and cell therapies for the treatment of severely injured skeletal muscle, although reliable clinical therapies still do not exist. In contrast, this work demonstrates that biphasic ferrogels with a capacity for large, fatigue-resistant deformations can be used to mechanically stimulate and regenerate injured muscle tissue without the use of growth factors or cells. These biologic-free scaffolds exhibit a potential immunomodulatory role when stimulated and could potentially translate rapidly to the clinic. The therapeutic use of direct mechanical stimulation of injured tissues via externally actuated biomaterials could establish a new paradigm for regenerative medicine broadly. Severe skeletal muscle injuries are common and can lead to extensive fibrosis, scarring, and loss of function. Clinically, no therapeutic intervention exists that allows for a full functional restoration. As a result, both drug and cellular therapies are being widely investigated for treatment of muscle injury. Because muscle is known to respond to mechanical loading, we investigated instead whether a material system capable of massage-like compressions could promote regeneration. Magnetic actuation of biphasic ferrogel scaffolds implanted at the site of muscle injury resulted in uniform cyclic compressions that led to reduced fibrous capsule formation around the implant, as well as reduced fibrosis and inflammation in the injured muscle. In contrast, no significant effect of ferrogel actuation on muscle vascularization or perfusion was found. Strikingly, ferrogel-driven mechanical compressions led to enhanced muscle regeneration and a ∼threefold increase in maximum contractile force of the treated muscle at 2 wk compared with no-treatment controls. Although this study focuses on the repair of severely injured skeletal muscle, magnetically stimulated bioagent-free ferrogels may find broad utility in the field of regenerative medicine.

Soft robotic sleeve supports heart function

A soft robotic sleeve modeled on the structure of the human heart assists cardiovascular function in an ex vivo and in vivo porcine model of heart failure. Robots have a change of heart Ventricular assist devices help failing hearts function by pumping blood but require monitoring and anticoagulant therapy to prevent blood clot formation. Roche et al. created a soft robotic device with material properties similar to those of native heart tissue that sits snugly around the heart and provides ventricular assistance without ever contacting blood. The robotic sleeve uses compressed air to power artificial silicone muscles that compress and twist, mimicking the movements of the normal human heart. The authors show that the artificial muscles could be selectively activated to twist, compress, or simultaneously perform both actions on one side or both sides of the heart. The device increased cardiac ejection volume in vitro and when implanted in adult pigs during drug-induced cardiac arrest. There is much interest in form-fitting, low-modulus, implantable devices or soft robots that can mimic or assist in complex biological functions such as the contraction of heart muscle. We present a soft robotic sleeve that is implanted around the heart and actively compresses and twists to act as a cardiac ventricular assist device. The sleeve does not contact blood, obviating the need for anticoagulation therapy or blood thinners, and reduces complications with current ventricular assist devices, such as clotting and infection. Our approach used a biologically inspired design to orient individual contracting elements or actuators in a layered helical and circumferential fashion, mimicking the orientation of the outer two muscle layers of the mammalian heart. The resulting implantable soft robot mimicked the form and function of the native heart, with a stiffness value of the same order of magnitude as that of the heart tissue. We demonstrated feasibility of this soft sleeve device for supporting heart function in a porcine model of acute heart failure. The soft robotic sleeve can be customized to patient-specific needs and may have the potential to act as a bridge to transplant for patients with heart failure.

Biomaterial-Enhanced Cell and Drug Delivery: Lessons Learned in the Cardiac Field and Future Perspectives.

Heart failure is a significant clinical issue. It is the cause of enormous healthcare costs worldwide and results in significant morbidity and mortality. Cardiac regenerative therapy has progressed considerably from clinical and preclinical studies delivering simple suspensions of cells, macromolecule, and small molecules to more advanced delivery methods utilizing biomaterial scaffolds as depots for localized targeted delivery to the damaged and ischemic myocardium. Here, regenerative strategies for cardiac tissue engineering with a focus on advanced delivery strategies and the use of multimodal therapeutic strategies are reviewed.

Generating an ex vivo vascular model.

Realistic ex vivo anthropometric vascular environments are required for endovascular device optimization and for preclinical evaluation of interventional procedures. The objective of this research is to build an anthropomorphic model of the human carotid artery. The combination of magnetic resonance angiography image processing and computer-aided design and manufacturing techniques allowed fabrication of multicomponent morphologically precise casts of the carotid artery. The lost core technique was used to produce a hollow vessel prototype incorporating polyvinyl alcohol cryogel (PVA-C) as a tissue-mimicking vessel wall material. PVA-C was mechanically characterized by uniaxial tensile testing after different numbers of freeze/thaw cycles. The novel model construction approach outlined in this study accounts for the morphologic complexities of the human vasculature, and proved successful for the production of realistic compliant ex vivo arterial model.

A New Laparoscopic Morcellator Using an Actuated Wire Mesh and Bag

Laparoscopic morcellation is a technique used in gynecological surgeries such as hysterectomy and myomectomy to remove uteri and uterine fibroids (leiomyomas) through a small abdominal incision. Current morcellators use blades or bipolar energy to cut tissue into small pieces that are then removed through laparoscopic ports in a piecewise manner. These existing approaches have several limitations; (1) they are time consuming as the tissue must be manually moved over the devices during the cutting step and removal is piecewise, (2) they can lead to accidental damage to surrounding healthy tissue inside the body and (3) they do not provide safe containment of tissue during the morcellation process which can lead to seeding (spreading and regrowth) of benign or potentially cancerous tissue. This paper describes a laparoscopic morcellator that overcomes these limitations through a new design that is based on an enclosed, motor-actuated mesh that applies only an inward-directed cutting force to the tissue after it has been loaded into the protective mesh and bag. The deterministic design approach that led to this concept is presented along with the detailed electromechanical design. The prototype is tested on soft vegetables and an animal model to demonstrate successful morcellation and how the device would be compatible with current clinical practice. Results show that the time required to morcellate with the new device for a set of tests on animal tissue is relatively uniform across samples with widely varying parameters. Including tissue manipulation and extraction time, the new device is shown to have an improvement in terms of speed over current morcellators. The mean time for cutting animal tissue ranging from 100 g to 360 g was 30 s with small variations due to initial conditions. The time for cutting is expected to remain approximately constant as tissue size increases. There is also minimal risk of the protective bag ripping due to the inward-cutting action of the mesh, thereby potentially significantly reducing the risk of seeding during clinical procedures; thus, further increasing patient safety. Finally, this design may be applicable to other procedures involving removal of tissue in nongynecologic surgeries, such as full or partial kidney or spleen removal.

SOFT PNEUMATIC ARTIFICIAL MUSCLES WITH LOW THRESHOLD PRESSURES FOR A CARDIAC COMPRESSION DEVICE

In this paper, we present the design, fabrication and characterization of fully soft pneumatic artificial muscles (PAMs) with low threshold pressures that are intended for direct cardiac compression (DCC). McKibben type PAMs typically have a threshold pressure of at least 100 kPa and require rigid end fittings which may damage soft tissue and cause local stress concentrations, and thus failure points in the actuator. The actuator design we present is a variant on the McKibben PAM with the following key differences: the nylon mesh is embedded in the elastomeric tube, and closure of the end of the tube is achieved without rigid ends. The actuators were tested to investigate the effects of mesh geometry and elastomer material on force output, contraction, and rise time. Lower initial mean braid angles and softer elastomer materials provided the best force, contraction, and rise times; Up to 50 N of force, 24% contraction, and response times of 0.05 s were achieved at 100 kPa. The actuators exhibited low threshold pressures (<5 kPa) and high rupture pressures (138 kPa – 720 kPa) which suggest safe operation for the DCC application. These results demonstrate that the actuators can achieve forces, displacements, and rise times suitable to assist with cardiac function.

A light-reflecting balloon catheter for atraumatic tissue defect repair

A catheter-based technology reflects light to activate a photocurable adhesive for minimally invasive, atraumatic tissue defect closure. Catheter device lights the way to tissue closure Closing small defects in the body typically requires stitching of tissues during surgery. Toward a minimally invasive approach, Roche et al. engineered a balloon catheter with a reflective surface coating that could be used to adhere biodegradable patches to tissues. The device unfolds the patch and its adhesive, delivers ultraviolet (UV) light, and then applies pressure to stabilize the adhesive as the light cures the polymer. The authors demonstrated catheter-mediated application of the photocurable polymer patch in vivo in rat tissue, with minimal inflammation and complete animal survival, as well as in a challenging septal defect in the beating hearts of pigs. The device was also used to seal porcine stomach ulcers and abdominal hernias ex vivo, suggesting versatility of this approach in repairing defects more easily and atraumatically than sutures. A congenital or iatrogenic tissue defect often requires closure by open surgery or metallic components that can erode tissue. Biodegradable, hydrophobic light-activated adhesives represent an attractive alternative to sutures, but lack a specifically designed minimally invasive delivery tool, which limits their clinical translation. We developed a multifunctional, catheter-based technology with no implantable rigid components that functions by unfolding an adhesive-loaded elastic patch and deploying a double-balloon design to stabilize and apply pressure to the patch against the tissue defect site. The device uses a fiber-optic system and reflective metallic coating to uniformly disperse ultraviolet light for adhesive activation. Using this device, we demonstrate closure on the distal side of a defect in porcine abdominal wall, stomach, and heart tissue ex vivo. The catheter was further evaluated as a potential tool for tissue closure in vivo in rat heart and abdomen and as a perventricular tool for closure of a challenging cardiac septal defect in a large animal (porcine) model. Patches attached to the heart and abdominal wall with the device showed similar inflammatory response as sutures, with 100% small animal survival, indicating safety. In the large animal model, a ventricular septal defect in a beating heart was reduced to <1.6 mm. This new therapeutic platform has utility in a range of clinical scenarios that warrant minimally invasive and atraumatic repair of hard-to-reach defects.