Abstract
This review describes the first studies on successful conversion of porcine soft-tissue bioprostheses into viable permanently functional tissue in humans. This process includes gradual degradation of the porcine tissue, with concomitant neo-vascularization and reconstruction of the implanted bioprosthesis with human cells and extracellular matrix. Such a reconstruction process is referred to in this review as “humanization”. Humanization was achieved with porcine bone-patellar-tendon-bone (BTB), replacing torn anterior-cruciate-ligament (ACL) in patients. In addition to its possible use in orthopedic surgery, it is suggested that this humanization method should be studied as a possible mechanism for converting implanted porcine bioprosthetic heart-valves (BHV) into viable tissue valves in young patients. Presently, these patients are only implanted with mechanical heart-valves, which require constant anticoagulation therapy. The processing of porcine bioprostheses, which enables humanization, includes elimination of α-gal epitopes and partial (incomplete) crosslinking with glutaraldehyde. Studies on implantation of porcine BTB bioprostheses indicated that enzymatic elimination of α-gal epitopes prevents subsequent accelerated destruction of implanted tissues by the natural anti-Gal antibody, whereas the partial crosslinking by glutaraldehyde molecules results in their function as “speed bumps” that slow the infiltration of macrophages. Anti-non gal antibodies produced against porcine antigens in implanted bioprostheses recruit macrophages, which infiltrate at a pace that enables slow degradation of the porcine tissue, neo-vascularization, and infiltration of fibroblasts. These fibroblasts align with the porcine collagen-fibers scaffold, secrete their collagen-fibers and other extracellular-matrix (ECM) components, and gradually replace porcine tissues degraded by macrophages with autologous functional viable tissue. Porcine BTB implanted in patients completes humanization into autologous ACL within ~2 years. The similarities in cells and ECM comprising heart-valves and tendons, raises the possibility that porcine BHV undergoing a similar processing, may also undergo humanization, resulting in formation of an autologous, viable, permanently functional, non-calcifying heart-valves.
Highlights
This review describes preclinical and clinical studies of a novel method that enables the conversion of soft tissue porcine bioprostheses into human autologous functional tissue in patients with torn anterior cruciate ligament (ACL), and further discusses the potential applicability of this method to bioprosthetic porcine heart valves (BHV)
BHV crosslinked by glutaraldehyde are the most common bioprosthesis used in the clinic [1,2,3]
We hypothesized that the process of humanization of soft tissue porcine bioprosthesis implants may involve the physiologic mechanisms of repair and regeneration observed in wound healing [72,73,74]
Summary
As discussed below, removal of carbohydrate antigens does not eliminate the elicited antibody production against the multiple porcine protein antigens which are immunogenic in humans These shortcomings of BHV might be resolved if bioprostheses could be gradually converted post implantation into autologous heart valves. This process of gradual, in situ reconstruction of an animal originated bioprosthesis into a human viable, functional tissue is referred to in this review as “humanization” of the bioprosthesis, a term previously used for in vitro humanization of bone [27]. Based on the results of humanization of BTB in replacing torn ACL, we suggest that it would be of interest to determine whether a similar processing of BHV may enable humanization of these bioprostheses in young patients with impaired heart valves
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