Table 2.

Clinical trials using natural biomaterials in cardiac repair.

Study	Description	References
Intracoronary delivery of engineered alginate implants—IK-5001 bioabsorbable cardiac matrix (BCM) (Bellerophon LLC)Clinical trial unique identifier: NCT01226563	• Testing safety and feasibility of strategy in patients recovering from an extensive MI • 27 patients with moderate-to-large ST-segment-elevation MI (STEMI) enrolled after successful revascularization • Within 7 days of MI, a 2 mm alginate implant was delivered by injection through the coronary artery related to the infarct • Implant injection didn't impair coronary flow or myocardial perfusion, shown by coronary angiography 3 min after injection • Implant did not cause any further myocardial injury • Assessment by 12-lead echocardiograms, 24 h Holter monitoring, blood tests, and heart failure questionnaires were carried out at 30, 90, and 180 days post-treatment • A 6-month follow-up with these tests showed that the implant was tolerated and caused no serious arrythmias, blood test abnormalities, other adverse effects, or death • Left ventricular preservation and ejection fracture was shown to be preserved compared to previous reports • Promising results led to a further study with IK-5001	(295)
IK-5001 multicenter, international, randomized, double-blind, controlled trialClinical trial unique identifier: NCT01226563	• Comparing the bioabsorbable cardiac matrix (BCM) with saline control to assess LV dilation and adverse clinical events within 6-months • 303 patients with large infarct areas after percutaneous coronary intervention (PCI) of a STEMI were enrolled • Randomized into groups and 201 given BCM and 101 given saline injection into the artery related to the infarct between 2 and 5 days after PCI • A 6-month follow up showed there was no significant difference in left ventricular end-diastolic volume index between the groups, with 14.1 ± 28.9 mL/m2 in the BCM group compared to 11.7 ± 26.9 mL/m2 in the saline group • No significant difference in Kansas City Cardiomyopathy Questionnaire score, New York Heart Association functional class, and 6-min walk time • Primary safety outcomes (cardiovascular death, further MI, stent thrombosis, target-vessel revascularization, significant arrhythmia, myocardial rupture) were similar between the two groups with 11.6% for BCM and 9.1% for saline, p = 0.37 • Concluded that BCM did not reduce left ventricular remodeling or adverse cardiac events after 6-months.	(296)
Intramyocardial injection of alginate hydrogel—Algisyl-LVRTM (LoneStar Heart Inc.)Clinical trial unique identifier: NCT00847964	• Testing safety and feasibility in patients with dilated cardiomyopathy • 11 patients with symptomatic heart failure were enrolled in the study, but only 3 were reported • Injection of material into left ventricular wall during scheduled coronary artery bypass graft surgery (CABG) • A 3-month follow-up of the three patients showed a substantial decrease in end-systolic and end-diastolic volume • The patients also showed an increase in ejection fraction from 32 ± 8% to 47 ± 18%, and a 35% decrease in myofiber stress • Promising results, however very small number of patients is a limitation, and the simultaneous CABG procedure may have an unclear contribution to the results. The results however do show a greater change and more rapid improvement than reported after CABG treatment alone	(297)
Algisyl-LVRTM international, multi-center, prospective, randomized, controlled trial (AUGMENT-HF)Clinical trial unique identifier: NCT01311791	• A trial to evaluate the safety and benefits of an alginate hydrogel for left ventricular modification • 78 enrolled patients with advanced chronic heart failure were randomized and 40 treated with alginate hydrogel injection directly into the left ventricle muscle in combination with the standard medical therapy, and 38 treated with the standard medical therapy alone • 35 patients who were treated with the alginate hydrogel had no device-related complications, 3 patients died within 30 days of surgery (8.6%) • At a 6-month follow-up the alginate hydrogel treatment showed an improvement in peak VO2 compared to the control, where p = 0.014 • The 6-min walk time and New York Heart Association functional class was also more improved in patients who underwent alginate hydrogel treatment compared to the control group • 58 of the initial 78 patients with heart failure completed 12-months of follow-up. There were nine deaths in the alginate hydrogel treatment group and four deaths in the control group • At the 12-month follow-up, alginate hydrogel was associated with improved peak VO2 compared to the control, where p < 0.001 • Statistically significant improvements in the 6-minute walk time, New York Heart Association functional class, and VO2 at anaerobic threshold were reported • This trial showed that the addition of the alginate hydrogel was more effective in improving patients' symptoms and exercise capacity compared to the standard medical treatment alone	(184, 298)
A Phase I, Open-label Study of the Effects of Percutaneous Administration of an Extracellular Matrix Hydrogel, VentriGel, Following Myocardial InfarctionClinical trial unique identifier: NCT02305602	• A trial to evaluate the safety and feasibility, and effects of VentriGel, an extracellular matrix hydrogel, delivered via trans-endocardial injection in post-MI patients • 15 enrolled patients who had had a first STEMI and treated with PCI in the last 3 years, with evidence of left ventricular dysfunction and remodeling • Approximately half of the enrolled patients were treated <12 months after MI and the other half more than 12 months after MI • VentriGel was well-tolerated with no deaths or patient dropouts from the trial • One patient suffered two cardiac events—cardiogenic shock and complete heart block—and one patient developed an intracardiac thrombus. These were reported as possibly due to the procedure, and no other adverse events due to either the VentriGel or the injection procedure were reported • The 6-min walk time was assessed at 3 and 6-month follow-ups, and VentriGel treatment was found to significantly increase the maximum distance walked at p = 0.004 • New York Heart Association functional class significantly decreased, p = 0.041, at 1, 3, and 6-month follow-ups, as with the heart failure questionnaire which significantly decreased, p = 0.045, at 1-month and non-significantly decreased at 3 and 6-months • MRI to evaluate cardiac function at 6-month follow-ups of 14 of the patients showed maintained or decreased left ventricular end-diastolic or end-systolic volume in comparison to baseline at the final follow-up, with this occurring predominantly in patients over 12 months post-MI over those <12 months post-MI • No significant changes were recorded in the ejection fraction or infarct scar size • This trial supports the safety and feasibility of VentriGel in post-MI patients, and improvements in left ventricular remodeling were observed • This first study using an injectable ECM hydrogel could lead to further randomized, controlled, larger clinical trials	(299)