Hydrogels for cardiac tissue engineering. NPG Asia Mater , 6:e Chang, W. A short discourse on vascular tissue engineering. NPJ Regen. Chiang, T. K, et al. Clinical translation of tissue engineered trachea graft. Coenen, A. Elastic materials for tissue engineering applications, natural, synthetic and hybrid polymers.
Acta Biomater , 79, 60— Cooper, D. Xenotransplantation — the current status and prospects. Editorial The final verdict on Paolo Macchiarini, guilty of misconduct. Lancet CrossRef Full Text.
Elliott, M. Tracheal replacement therapy with a stem cell-seeded graft, Lessons from compassionate use application of a GMP-compliant tissue-engineered medicin. Stem Cells Transl. Fukunishi, T. Gao, L. Autologous matrix-induced chondrogenesis; a systematic review of the clinical evidence. Sports Med. Groeber, F. Skin tissue engineering. Drug Deliv. Huang, B. Cell-based tissue engineering strategies used in the clinical repair of articular cartilage.
Biomaterials 98, 1— Hussey, G. Extracellular matrix-based materials for regenerative medicine. Im, G. Biomaterials 32, — International Standards Organization Joseph, D.
Autologous cell seeded biodegradable scaffold for augmentation cystoplasty, Phase II study in children and adolescents with spina bifid. Jungebluth, P. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanoscomposite, a proof of concept stud. Kamel, R. J, et al. Tissue engineering of skin. Li, X. Transplantation of hUC-MSCs seeded collagen scaffolds reduced scar formation and promotes functional recovery in canines with chronic spinal cord injury.
Maughan, E. Autologous cell seeding in tracheal tissue engineerin. Stem Cell Rep. Metcalfe, A. Tissue engineering of replacement skin, the crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration.
Interface 4, — Miyagawa, S. Phase I clinical trial of autologous stem cell sheet transplantation therapy for treating cardiomyopathy. Amer Am. Heart Ass. Morille, M. PLGA-based microcarriers induce mesenchymal stem cell chondrogenesis and stimulate cartilage repair in osteoarthriti. Biomaterials 88, 60— Morrison, R. Mitigation of tracheobronchomalacia with 3D-printed personalized medical devices in pediatric case. Mosala Nezhad, Z.
Interactive Inter. Thorac Surg. Novikova, L. Trimethylene carbonate-caprolactone conduit with poly-p-dioxanone microfilaments to promote regeneration after spinal cord injury. Acta Biomater. Otsuka, F. The importance of the endothelium in atherosclerosis and coronary stenting.
Pangarkar, N. Advanced Tissue Sciences Inc, learning from the past, a case study for regenerative medicine. Perri, G. Early and late failure of tissue-engineered pulmonary valve conduits used for right ventricular outflow tract reconstruction in patients with congenital heart disease.
Cardio-Thorac Surg , 41, — Petrosyan, A. Decellularized renal matrix and regenerative medicine of the kidney; a different point of view.
Part B. Pokrywczynska, M. Is the poly L-lactide-co-caprolactone nanofibrous membrane suitable for urinary bladder regeneration. Siddiqi, S. Tissue engineering of the trachea, what is the hold-up?
Simon, P. Cardio-Thorac Surg. Stone, R. A bioengineered living cell construct activates an acute wound healing response in venous leg ulcer. Svetanoff, W. Updates on surgical repair of tracheobronchomalaci. Lung Health Dis. Google Scholar. Tan, H. Ter Horst, B. Advances in keratinocyte delivery in burn wound care. Urciuolo, A. Decellularized tissue for muscle regeneration. Vacanti, C. The history of tissue engineering. Van Ba, O. Bladder tissue engineering, a literature review. Biological background of dermal substitutes.
Burns 36, — VanderLaan, P. Practical approach to the evaluation of prosthetic mechanical and tissue replacement heart valves. Vardar, E. IGFcontaining multi-layered collagen-fibrin hybrid scaffolds for bladder tissue engineering. Acta Biomater , 41, 75— Vig, K. Advances in skin regeneration using tissue engineering. Vunjak-Novakovic, G. Tissue engineering of the heart, an evolving paradigm.
Thorac Cardiovasc Surg , —5. Williams, D. Benefit and risk in tissue engineering. Mat Today 7, 24— To engineer is to create, the link between engineering and regeneration. Trends in Biotech. On the nature of biomaterials. Biomaterials ;30, — The biomaterials conundrum in tissue engineering. Biocompatibility pathways, Biomaterials-induced sterile inflammation, mechanotransduction, and principles of biocompatibility contro.
ACS Biomater. Amsterdam: Elsevier , — Wu, Z. Treatment of myocardial infarction with gene — modified mesenchymal stem cells in a small molecular hydrogel.
This scaffold was seeded with cultured urothelial cells suspended in fibrin glue, which they have reported to be a reliable vehicle for transplantation of cultured cells El-Kassaby et al. The matrix was applied in an onlay fashion to the urethral plate and resulted in successful urethral reconstruction in 24 of 28 patients. All 24 had improved uroflowmetry and urethral caliber at a mean follow-up of 37 months and did not require any additional procedures.
These investigators reported a similar technique several years prior with successful outcome in 3 of 4 patients, though with limited follow-up Surgical procedures for stress urinary incontinence SUI seek to improve the coaptation pressure of the urethra-sphincter complex by means of injectable bulking agents e.
There is an increasing body of work investigating the potential for autologous myoblast and stem cell therapies for rhabdosphincter regeneration. The most impressive study to date was published by Strasser et al. They showed improvement in urinary incontinence, rhabdosphincter thickness and contractility assessed by ultrasound , and quality of life scores on a prevalidated questionnaire instrument.
The same investigators achieved near identical treatment results in a later group of 20 female patients accrued after the original trial Another group of patients that included 42 women and 21 men with SUI also underwent autologous myoblasts injections, which included men who previously underwent radical prostatectomy or brachytherapy for prostate cancer.
They reported a successful cure rate in 39 of 42 women This study demonstrates the feasibility of this endoscopic injection therapy for men with SUI after local therapy for prostate cancer The authors noted the importance of endoscopic ultrasound as a reliable method to guide precise delivery of injection therapy and subsequent objective evaluation of the rhabdosphincter. In addition, the clinical efficacy demonstrated through a randomized control trial represents an appropriate level of sophistication that should be applied to clinical trials whenever possible in evaluating stem cell and TE technology.
Lecoeur et al. Rhabdosphincter injury was induced by endoscopic electrocautery, followed by implantation of myofibers both longitudinally along the urethra, and focally away from the native sphincter applied in a circumferential orientation, functionally generating a new sphincter in vivo.
This cluster of circularly oriented muscle fibers exhibited reproducible contractions adequate to establish recordable urethral peak pressure on urodynamic evaluation 30 d after implantation. Suppression of tonic activity by curare suggests neural innervation of this sphincter complex.
Histologic evaluation verified resulting nerve fiber development in the vicinity of the implanted myotubules, and neural tissue was present in greater density than surrounding tissue. Both these points suggest concomitant neuronal development and innervation of the transplanted myofibers.
Autograft, allograft, xenograft, and synthetic materials are all options for suburethral slings. Like any tissue substitute, each has its own inherent advantages and disadvantages. Tissue-engineered slings have been successfully created and implanted into rats with sciatic nerve injury. They were shown to maintain measurable leak point pressures in contrast to controls that were also denervated but did not undergo a sling procedure.
The tissue-engineered slings were composed of SIS seeded with muscle-derived cells, and this construct did not show any significant difference in leak point pressure compared with sling material made of SIS alone.
Despite this, the study showed the feasibility of applying slings to a reproducible sciatic nerve injury rat model and demonstration of leak point pressure measurements Disease processes of the penis include ambiguous genitalia requiring penile reconstruction, trauma, erectile dysfunction, and Peyronie's disease.
The field of TE is making significant strides in the development of potential treatments for these various structural disorders of the phallus, many of which have inadequate current therapies. Peyronie's disease is a condition of the penis that results in plastic induration and marked curvature with erections. It is usually associated with the presence of an inflammatory reaction and fibrotic plaque in the tunica albuginea. The prevelance is estimated at 0.
There are several published reports describing use of fascial, venous, and synthetic grafts to repair defects in tunica albuginea in the setting of penile trauma or treatment of Peyronie's disease 67 — In clinical studies, Breyer et al.
There were no significant differences regarding erectile dysfunction pre- and postoperatively as determined on a previously published erectile dysfunction diagnostic questionnaire tool More recent animal studies describe the successful creation of tissue-engineered corporal grafts paving the way for future replacement strategies. Joo et al. Histologic analysis verified tissue integration without excessive scarring or contracture 2 month following surgery.
Of particular interest are descriptions of engineered replacements for damaged erectile tissues within the corporal bodies. Falke et al. Processed acellular rabbit corpora seeded with human corpus cavernosa muscle and endothelial cells were implanted in mice and subsequently generated well vascularized corporal tissues Although functional studies have not been performed, the preliminary studies appear promising.
Multiple investigators have attempted interposition of autologous nerve grafts during radical prostatectomy for cancer in an attempt at preservation of erectile function.
Clinical trials using sural nerve interposition have shown only limited success 74 — More recently, May et al. These collagen based nerve scaffolds were seeded with autologous Schwann cells and interposed in large nerve defects. These authors included their own animal studies, which showed the return of erectile function in rats grafted with bioartificial nerve scaffolds after cavernous nerve ablation. These seeded scaffolds were shown to be superior to both interposed autologous nerve graft interposition and unseeded silicone nerve conduits Additional studies in erectile dysfunction have examined gene therapy applications to enhance endothelial vasodilatation of the corporal bodies, ultimately upregulating erectile response.
Induced mutation in several target genes has been described to upregulate the production of nitric oxide and other vasodilatory proteins Deng et al. In a series of experiments, this group demonstrated in vivo directed protein upregulation using intracavernosal injection of viral vehicles carrying selected mutant genes for transfection. They suggested in vitro transfection of mesenchymal stem cells with subsequent cell injection as therapy for corporal dysfunction.
Histologic evaluation verified the increased tissue concentration of targeted proteins and the morphologic verification of incorporated stem cells, which remained within the corpora up to 3 week postinjection. Another recent report using stem cell injection therapy of corpora cavernosa has also demonstrated in vivo differentiation of these cells into corporal tissue The fields of TE and stem cell research continue to search for novel techniques of tissue replacement and rehabilitation in the genitourinary tract.
In identifying possible replacements for current treatment strategies, recent studies have included randomized controlled trials for cell injection therapy, and animal studies utilizing genetically enhanced stem cells that render metabolically programmed tissue substitutes.
The latter shows great promise for attaining directed cellular function and protein upregulation, and is a new application of stem cell gene therapy. The use of adult stem cells, specifically autologous progenitor cells obtained from biopsy, appears to have sufficient clinical utility for in vitro expansion and autologous tissue generation, thus avoiding the controversies surrounding the use of hESCs. Science : — Vacanti CA The history of tissue engineering.
J Cell Mol Med 10 : — Article Google Scholar. Vacanti JP Tissue engineering: a 20 year personal perspective [editorial]. Tissue Eng 13 : — World J Urol 18 : 1. Tissue Eng 12 : — Atala A Recent developments in tissue engineering and regenerative medicine.
Curr Opin Pediatr 18 : — Urol Int 78 : 23— Eur Urol 52 : — Urology 54 : — Atala A Future perspective in reconstructive surgery using tissue engineering. Urol Clin North Am 26 : — J Urol : — Ann N Y Acad Sci : 10— Br J Urol 82 : — Atala A Tissue engineering for the replacement of organ function in the genitourinary system.
Am J Transplant 4 : 58— Stem Cells 23 : — Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69 : 11— Deuel TF Growth factors. Academic Press, New York, pp — Google Scholar. Trends Biotechnol 16 : — Keller G Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev 19 : — Becker C, Gerhard J Stem cells for regeneration of urological structures.
Eur Urol 51 : — Nat Biotechnol 18 : — Mol Med 6 : 88— Kennedy D Stem cells: still here, still waiting. Science : Thus, a key challenge for the development of innovative therapies is how it will be adopted and implemented in existing clinical practice Gardner and Webster, Access to established cell-manufacturing facilities and close alliances between the scientists and clinicians is essential to navigating this obstacle.
The decision to partner with an established company that already markets TEMPs may facilitate clinical integration through access to their facilities, expertise in the product market sector, and an existing clientele base. The decision to partner with an existing company or establish a start-up company both carry unique challenges.
Developing a new company requires significant effort to receive buy-in from investors or venture capital funding. In this route of clinical translation, the hire of a consultant is a common and recommended practice. Consultants can offer keen insight into navigating regulatory pathways and market infiltration, often with many years of expertise in several professions. When hiring, a consultant contract should be drafted with specific and definitive language to ensure no confusion over the expectations, inclusions, and exclusions of the agreement.
The Technology Transfer Office can also be a valuable assistant for product translation. With a concerted effort to apportion technologies, knowledge, and facilities between institutions, the Technology Transfer Office aims to ensure accessibility and dissemination of new scientific developments to a wide range of users Lu et al.
The associated costs of bringing a TEMP to market can be quite high and may demand several rounds of financing, in addition, to support in development from investors. Securing investors can be more difficult for TEMPs; often people hesitate to invest in regenerative medicine technologies due to a lack of clarity on regulatory pathways, clinical translation, and reimbursement Bertram et al.
To ameliorate investor opinion, the most important factors in securing investments are clarity in value proposition and proof of concept. Funding allocation is the most direct form of translational support, often granted with the guarantee of a return.
An intermediate form of return or reassurance takes the form of peer-reviewed publications. Specifically, financial risk can be reduced by the successful demonstration of clinically relevant TEMPs against clinical standards in an academic setting through the publication of their technology in high-profile journals.
Robust evidence of proof of concept, through high quality measurable clinical data, guarantees a strong device history file Hollister and Murphy, High-impact papers can be very beneficial to maintaining and securing scientific and investment partners, and from which strong patents can evolve naturally.
As the product is further developed, clinical trials must be carefully constructed to validate efficacy and safety. While developing a repository of strong academic and clinical data, a successful company must maintain financial security, design a feasible path toward translation, and have partners who champion the technology. The TEMP field has a long history of companies that failed to reach commercial success.
Since its beginnings in the s, the TEMPs industry has been through many ups and downs as new high-profile companies fail to meet the scientific, regulatory, and public expectations set for them. This burgeoning market represents the numerous companies that are entering the commercial phase of their product development. Kim et al. Of those companies, most focus on point-of-care technology utilizing autologous cell treatments. Currently, the market has accepted simplified autologous cell therapy products, but many companies are moving forward with more complex allogeneic therapies, and their fate will, in part, be determined by the regulatory approval process.
Regulation represents one of the most significant hurdles for TEMPs. Eighty six percent of all clinical trials fail to get FDA approval and reach a clinical setting, resulting in significant economic burdens Wong et al. Successful regulatory strategy starts before the product is ever presented in the office at the FDA, and investigators should be aware of the potential regulatory path that their invention could take in order to ease the path further down the road.
The FDA rarely dictates to a company the tests they must perform in order to prove that their product is safe. Instead, it is a collaborative discussion where the company is responsible for formulating a regulation plan, and the FDA either approves of the plan or recommends changes.
The structure and intensity of that plan can vary widely by product but is heavily influenced by the center under which the product falls. In the past, a medical product would fall under one of three possible classifications: a device, a biologic, or a drug, and be sent to the appropriate center.
With the advent of TEMPs, it is no longer as easy of a task to make those distinctions. Now, a product may be a novel scaffold that releases a drug at a controlled rate or a combination therapy that includes both stem cells and drug treatment.
The Office of Combination Products OCP was founded to help solve this problem by offering guidance to companies on determining which center they should approach for approval.
The critical consideration for investigators is understanding that choice of Center for regulation can significantly affect the time to market. These are not strict rules but is an illustration of how different classifications can affect the overall health of the startup. In general, the highest risk component of the product determines its regulatory pathway.
Figure 2 illustrates a generalized flow chart of the path a TEMP will follow. Considerations should be made at the bench to what is already approved and how is the current product going to be approved to decrease the resources required to get FDA approval. Figure 2. Products defined as devices have arguably the most direct approval process. Class I devices are considered the lowest risk. In general, these devices are of simple design, such as tongue depressors.
Seventy four percent of class I devices follow the exempt pathway which does not require premarket notification or approval. Class II products are more complicated devices but are typically non-implantable, non-invasive, and non-significant risk. A few class II devices will fall under exempt status, but the majority follow the premarket notification, k pathway. The k pathway requires proving that the device is similar in usage, risk, and efficacy to products available before The final classification is a class III device, which constitutes products of the highest risk.
These devices require premarket approval, the most stringent regulation process in the CDRH and include preclinical and clinical trials. There has been a recent trend toward companies attempting to utilize the k pathway to avoid the burden of clinical trials Van Norman, b.
The most effective way for TEMP devices to utilize this pathway is through the use of pre-approved components when available. Simplification of the product also helps by minimizing risk and concerns over component interaction.
CDER governs their regulatory process through the investigational new drug pathway which has three classifications; investigator, treatment, and emergency. A majority of products will fall under investigator classification, which allows new drugs or drugs with new indications to be studied through clinical trials.
Treatment classifications are for drugs which treat a small population that cannot be investigated through the normal pathway. Emergency classification options are for drugs that require approval in a time frame that is unrealistic using the standard method.
The investigational new drug pathway requires clinical trials, which results in an often-protracted time difference between CDER and the other two centers. The cost of conducting clinical trials and the low success rate is prohibitive to startup companies and limits the ability for a single product to spin out of a research lab.
However, there are paths investigators can take to make sure their TEMP reaches the clinical market. Strategic partnerships with large companies can provide investigators the resources needed to get through clinical trials. Investigators should critically evaluate what effects their research will have on their future market and whether an established company would welcome a new product. Startup companies have options as well.
During the initial investigation, small markets may not seem appealing for entrepreneurs. However, treatment new drug pathways make it more feasible to enter the smaller markets first. Those markets can then pay for future clinical trials and provide data for investors. Products composed of living tissues or products potentially derived from living tissues are defined as biologics and are regulated by the CBER 6.
Human tissues that do not fall under the designation face a potentially complicated and extensive regulatory pathway. The biologics regulatory process is a hybrid of the device and drug regulatory processes. Device biologics follow the k and premarket approval process similar to devices but with additional biologic related regulations. Certain biologics, such as vaccines, follow the investigational new drug pathway. A biologics license application is required for any manufacturers of biological products and covers the manufacturing process and medical effects of the product.
Human tissues face special scrutiny, especially with the fears over transmittable diseases. Investigators should consider the source of the tissue and its original function. Matching the function between the source and the product can ease regulatory concerns and quicken the review process.
Xenograft tissues that serve the same functions in TEMPs products fall under device biologics and may undergo a simplified regulatory pathway. Autologous vs. From, an industry perspective, sourcing the product from allogeneic tissues allows for decrease production costs and improved quality assurance.
Autologous tissues have the benefits of reduced regulation and decreased rejection concerns. Deciding between components can and should occur during bench-top research.
Switching components before the inception of a human clinical trial is challenging due to the need to possibly generate new preclinical trial data. The pressures of survival in academia, such as publishing, can lead investigators to add components to their inventions that have incremental benefits but allow their research product to be innovative.
Although this approach can lead to an improved product in the clinic, it can have added unnecessary complications to the regulatory FDA approval process.
Additionally, the FDA works on precedent, comparing new products to those that have been approved previously. The most direct way to move through the FDA and reach the market is to be able to compare some or all of the product to previously approved products.
Each added component or incremental change will be scrutinized and can result in additional time and testing prior to approval. Investigators need to weigh the benefits of including a new component with the added resources needed to justify its presence. Not every minor improvement should be implemented. Deciding on what to components to include after benchtop studies is problematic because it is often too late and too expensive to make the changes even for established companies.
By looking ahead and planning for the regulatory process, investigators can eliminate potential research options and focus on the key components that deliver the most value. On the reverse side, the EMA regulatory process is often considered too quick to approve Van Norman, a. Medicines based on genes, cells, and tissues are regulated by the same pathway and are termed as advanced therapy medicinal products ATMPs by EMA.
This program provides insight and guidance on the necessary tests and studies required for the development of ATMPs. Additionally, researchers can also consult EMA to validate whether their product qualifies as an ATMP before applying for market authorization 7.
Clinical trials have been conducted for a wide range of pathophysiological conditions using ATMPs; however oncological, musculoskeletal, cardiovascular and immunological disease appear to be the priority areas Boran et al. The application for MA begins with the submission of a comprehensive dossier to CAT that provides details of the product to be reviewed.
Scientific specialists at CAT review the quality, safety, and efficacy of ATMPs and prepare a draft opinion based on the non-clinical and clinical data provided by the developers Salmikangas et al. Until February , the CAT had received a total of 22 MA applications, out of which 13 applications received a positive draft, and 4 received a negative draft, whereas 5 applications were withdrawn 9.
After authorization EMA continues to monitor the ATMPs in the market through its post-marketing surveillance program to ensure patient safety Celis et al. Furthermore, the clinical promise of the approved ATMPs has not translated in to commercial success.
The major impediments in the success of ATMPs in the EU include; high development cost, complex regulatory procedures, lack of efficient pricing and reimbursement schemes, limited target population, and potential risk associated with the use of ATMPs especially gene therapy Abou-El-Enein et al. Early efforts shall be made to ensure that the product under development categorizes as an ATMP.
Once the product category has been determined manufacturers can seek help from EMA to ascertain the quality standards purity, stability, etc. During the developmental phase of the product, manufacturers may request certification of quality and non-clinical data to ensure that they are working in the right direction to obtain market authorization Adherence to these critical steps will significantly alleviate the risk of products fading out in infancy and facing MA rejections.
Despite optimism for the future of the TEMP market, it is important to note that the hurdles that caused so many companies to fail still exist. Dermagraft is one of the most infamous tissue engineered products currently on the market, due to failures of Advance Tissue Sciences Inc. Pangarkar et al. Dermagraft is a potential dermal skin replacement, created by dermal fibroblasts grown on a 3D scaffold.
By all accounts, Dermagraft was a product that worked, particularly for diabetic foot ulcers Marston et al. The business side of the product, however, proved to be much more challenging. From the beginning, the owners of Dermagraft faced issues with governmental approval, overestimation of market potential, and market penetration. Clinical trials of Dermagraft started in , with expectations for FDA approval by The delay in FDA approval can be contributed to many different controversial aspects of the approval process, however, it is fair to say there was confusion and uncertainty on both the parts of the FDA and ATS on how regulation of TEMPs should be handled.
For example, in , the FDA requested additional clinical trials for Dermagraft, despite an expert advisory committee recommending the product for approval Pangarkar et al.
In subsequent clinical trials, ATS changed their testing parameters, leading to contention with the FDA over the success of the trial Pangarkar et al. However, the same arguments over our understanding of how TEMPs interact with the human body still plague the review process and can lead to significant delays in approval and could impose a sizeable financial burden on startups.
At the same time, revenue from the few successful products failed to meet projections that ATS had set for them. This mismatch in sales emphasizes the need to understand and plan for the low market penetration that is experienced by many TEMPs.
As discussed previously, health care systems are slow to adopt the radical changes inherent to TEMPs, which can lead to overestimations of market potential and over promising to investors. Lower, more realistic market projections can protect companies from investment scares.
Despite achieving FDA approval and showing clinical benefits, Dermagraft has failed again and again to turn a profit, revealing how much deeper and more complicated developing a TEMP can be. One potential reason for the failure of Dermagraft is its price. Shire reportedly blamed changes in federal Medicare coverage of wound-healing products on their decision to sell Dermagraft Fikes, As a more recently developed field, TEMPs can have difficulty proving their long-term cost benefits to health coverage providers, which in turn can affect their market penetration.
This issue can be traced back to investigators, who often fail to account for the potential manufacturing repercussions during the benchtop decisions. Investigators should take this as a sign that health care is warming to the idea of TEMPs. The path from the bench to human application is potentially long with many unexpected turns and potentially full of minefields, where each decision can have far-reaching consequences.
In order to increase the likelihood of clinical success, investigators need to look beyond the benchtop and consider the direction their research will follow and allow those considerations to guide and shape their research plans. This approach includes identifying and developing a clear understanding of a clinical need and establishing a research program to address that human need.
Bedside to bench and back again not only increases the likelihood for the successful transition to the clinic but also impacts benchtop research. By understanding how their research can fit into the future, investigators can develop effective impact statements, increased the relevance and applicability of their research, and develop strategic partnerships.
By moving beyond scientific constraints that prevent clinical translation of TEMPs, investigators can develop strategies for developing successful technologies.
BO was involved in the conception, writing, drafting, and editing of this article.
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