With the ever-changing landscape of translational research, the medical device and pharmaceutical industries increasingly license technologies with the added value of clinical and/or pre-clinical data rather than those in earlier stages of development. Universities have the potential to fill the gap in product development from academic laboratories through enhanced student training and increased implementation of some development and manufacturing activities that are traditionally found only in the private sector. A development roadmap is described from initial product feasibility through commercialization in the context of efficient development practices. The specific challenges in the design and development of biomaterial-based medical devices are described in the context of this development path with an emphasis on unique challenges for academic laboratories.
Elastin calcification occurs in bioprosthetic heart valve implants. The authors have developed a rat subdermal model to study purified elastin calcification. Purified elastin implants undergo severe calcification within 21 day period and it is found to be poorly crystallin hydroxyapatite by X-ray analysis. Aluminum chloride pretreatment of elastin inhibits its calcification due to the strong binding of aluminum ions to elastin leading to the alteration in elastin structures.
The St. Jude Medical (SJM) Epic valve has been designed to diminish the risk of prosthetic valve endocarditis by the use of silver-coated polyester fabric, and to inhibit dystrophic calcification by the use of ethanol pretreatment.A 20-week juvenile sheep mitral valve implant model was used to determine safety and efficacy of the device, as well as the rate of silver release and degree of dystrophic calcification. The SJM Epic valves were compared with SJM Biocor porcine valves (not ethanol-pretreated, not silver-modified polyester fabric) and Baxter Carpentier-EdwardsR standard valves.Blood concentrations of silver reached a maximum of 40 p.p.b. within 10 days of SJM Epic valve implantation, and were well below toxic levels (300 p.p.b.). Blood silver concentrations returned to baseline within 30 days after surgery. Maximal silver accumulation occurred in the liver (16.75 mg/g dry weight); concentrations in the brain, spleen, kidney and lung were similar to those reported for other silver-modified prosthetic valves. No statistically significant difference was found in calcium content between SJM Epic and Biocor valves. The fibrous response to the sewing cuff was similar among the three valve types.At all times tested, silver release from the SJM Epic valve led to blood concentrations well below toxic levels. Although calcification in the two SJM valve groups was extremely low, the 20-week sheep model may be insufficiently sensitive to detect differences in calcium accumulation in modern bioprosthetic valves.
Calcification of bioprosthetic heart valves fabricated from glutaraldehyde (GA)-pretreated heterograft tissue is frequently responsible for the clinical failure of these devices. Stentless bioprostheses fabricated from GA-fixed porcine aortic valves pose an important challenge in this regard, as pathologic calcification can affect not only the bioprosthetic cusps, but also the aortic wall segment.A synergistic approach was used to prevent bioprosthetic cusp and aortic wall calcification. Ethanol pretreatment of bioprosthetic heart valves was shown to inhibit cuspal calcification due to multiple mechanisms, including alterations of collagen structure and lipid extraction. AlCl3 pretreatment of bioprostheses to prevent calcification was also investigated; this alters elastin structure, inhibits alkaline phosphatase, and complexes with phosphoesters, thereby inhibiting aortic wall mineralization.Experimental data from rat subdermal implants and sheep mitral replacements showed successful synergism with co-pretreatment of porcine aortic valve bioprostheses with ethanol and AlCl3. Significant inhibition of both cusp and aortic wall calcification was achieved by differential pretreatments that restrict AlCl3 to only the aortic wall, and not the cusp, accompanied by ethanol cuspal exposure. Sequential exposure of bioprostheses, first to AlCl3 and then to ethanol, led to unexpectedly severe cuspal calcification.Differential pretreatment of stentless bioprostheses with ethanol and AlCl3 can effectively inhibit both cuspal and aortic wall calcification.
