Category Archives: Regenerative Medicine

Dennis M. Hester, Ph.D., an accomplished biotech professional with over 30 years of experience in regulatory affairs, quality assurance and product development, appointed as Senior Vice President, Chemistry, Manufacturing and Controls

Sumitra M. Ghate, a proven regulatory affairs leader with over 25 years of pharmaceutical and biotech product development experience, appointed as Vice President, Regulatory Affairs

MIAMI, FL / ACCESSWIRE / October 25, 2021 / iTolerance, Inc. ("iTolerance" or the "Company"), a biotechnology company focused on the development of innovative regenerative medicines, today announced the appointments of and Dennis M. Hester, Ph.D., Senior Vice President of Chemistry, Manufacturing and Controls, effective July 2021, and Sumitra M. Ghate, Vice President, Regulatory Affairs, effective October 2021, to the Company's executive leadership team.

"We are pleased to welcome Dennis and Sumitra to the iTolerance leadership team. The ability to attract two industry-leading executives with such accomplished backgrounds represents a noteworthy achievement for the Company and speaks volumes to the potential of our regenerative medicine technology platform, iTOL-100," stated Dr. Anthony Japour, Chief Executive Officer of iTolerance. "With this leadership team in place, I believe we are now well positioned to execute on our development strategy as we work to advance our lead program, iTOL-101, toward a first-in-human study as quickly as possible."

Dennis M. Hester, Ph.D.

Senior Vice President, Chemistry, Manufacturing and Controls

Dr. Hester commented, "Regenerative medicine has the potential to be an important tool in the way physicians treat diseases. However, one significant drawback to cell/organioid implantation today is the need for patients to be on life-long immunosuppression due to the risk or rejection. I believe that iTolerance's technology may have the ability to solve that problem by creating localized immune tolerance. I am excited to be joining the team to drive iTOL-100 forward, opening up the possibilities of regenerative medicine."

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Dr. Hester has been involved with product development for over 30 years and has spent the last 20 years working with a broad range of therapeutic agents, formulation technologies and routes of administration. His experience spans small molecule solid oral therapeutics, a broad range of inhalation formulations, and peptide, protein and cell based sterile injectable products, for use in a number of indications including diabetes, infectious diseases and oncology. Dr. Hester has an impressive track record of successfully leading programs into, and through, clinical development resulting in launch readiness and/or commercial sales. He has contributed to over two dozen INDs and the approval of six commercial products with a number of compounds presently in late-stage clinical development.

Prior to joining iTolerance, Dr. Hester served as Senior Vice President, Technical Operations, with responsibilities for Regulatory Affairs, Quality Assurance, and Technical Operations including Chemistry, Manufacturing and Controls (CMC) at Calidi Biotherapeutics. Prior to joining Calidi, Dr. Hester held leadership roles at a number of companies including Vice President, Product Development and Head of CMC at Mirati Therapeutics, Senior Director, Pharmaceutical Sciences and Head of CMC at Aragon Pharmaceuticals and Director, Pharmaceutical Development and Head of CMC at Intellikine, Inc. Additionally, Dennis obtained extensive biologics experience while working at Nektar Therapeutics, Amylin Pharmaceuticals and other companies as a full time employee or as a consultant.

Dr. Hester holds a Ph.D. in Physical Chemistry from the University of Southern California, an American Chemical Society Accredited Bachelor of Science degree in Chemistry from the United States Air Force Academy and is an inventor on seven issued patents.

Sumitra M. Ghate

Vice President, Regulatory Affairs

"Type 1 Diabetes is a significant unmet medical need and even with advances in insulin therapy, patients struggle to maintain glycemic targets and disease management can be a significant burden to these patients and their families. Regenerative medicine offers a potential solution, but chronic immunosuppression remains a challenge. I believe iTOL-101 can overcome this issue and has the potential to be a curative therapy for Type 1 Diabetes. I am thrilled to be joining the team as we work to advance iTOL-101 in a first-in-human clinical study in the near-term," added Ms. Ghate.

Ms. Ghate is an accomplished regulatory affairs leader with over twenty-five years of drug, biologic, and device development experience in the pharmaceutical and biotech industry. She has extensive expertise in developing and executing strong global regulatory strategies to minimize regulatory risk and accelerate development timelines. Over the course of her career, she has led the development of over twenty INDs and CTAs and three initial marketing applications, along with multiple marketing supplements.

Prior to joining iTolerance, Ms. Ghate's roles included Head of Regulatory Affairs at Histogenics Corporation, a regenerative medicine company developing a late phase tissue-engineered combination product. She also worked at Eli Lilly and Company across a nearly 20-year tenure in areas of CMC and regulatory with over ten years focused on diabetes. Most recently, she served as President of Artimus Regulatory Consulting, LLC providing strategic regulatory guidance for drugs and biologics, including regenerative medicine products. Additionally, she partnered with Bruder Consulting and Venture Group in the areas of regulatory strategy, FDA interactions, and regulatory submissions for cell therapy and tissue repair products.

Ms. Ghate received her BS in Organismal Biology and her BA in Chemistry from the University of Kansas. Additionally, she earned her US and EU Regulatory Affairs Certification (RAC) from the Regulatory Affairs Professional Society.

About iTolerance, Inc.

iTolerance isa privately held biotechnology company focused on the development of innovative regenerative medicines. The Company's lead program, iTOL-101, is an adjunct therapy with pancreatic islet cell implant currently in development for the treatment of or as a potential breakthrough cure for Type 1 Diabetes. iTOL-101 has demonstrated compelling efficacy in non-human primate studies. The Company plans to advance iTOL-101 towards an IND and first-in-man study. Additionally, the Company is advancing its regenerative cell therapy platform to fuel a robust pipeline addressing high-value indications. For more information, please visit itolerance.com.

Investor ContactJenene ThomasChief Executive OfficerJTC Team, LLCT: 833.475.8247iTolerance@jtcir.com

SOURCE: iTolerance, Inc.

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iTolerance, Inc. Strengthens Leadership Team with Key Appointments to Advance Regenerative Medicine Platform - Yahoo Finance

SOUTH SAN FRANCISCO, Calif., Oct. 21, 2021 (GLOBE NEWSWIRE) -- Senti Bio, a leading gene circuit company, today announced that its co-founder and chief executive officer, Tim Lu, MD, PhD, has been appointed to the Alliance for Regenerative Medicines (ARM) 2022 Board of Directors.

ARM envisions a world where advanced therapies are able to successfully alter current medical practices by treating the root causes of disease and disordersand I am honored to support this mission, said Dr. Lu. We are witnessing an era of unprecedented innovation and growth in this field, particularly in the areas of cell and gene therapy, and I look forward to working with ARMs board members of accomplished scientists and leaders to continue to support and inspire ARMs mission.

Lu added, I believe that cell and gene therapies have the potential to truly revolutionize the practice of medicine and, at Senti, we are proud to be a part of this exciting convergence of science and technology. 2021 has been an incredible year for our company so far: we initiated two partnerships in gene circuit-enabled cell and gene therapies, presented a suite of new data supporting our proprietary off-the-shelf NK cell programs at major conferences, and commenced the buildout of a wholly-owned cell therapy manufacturing facility. These are significant steps toward developing smarter medicines for patients using our gene circuit platform.

"We are pleased to welcome Tim Lu, CEO of Senti Biosciences, to the ARM Board of Directors," said Janet Lambert, CEO of ARM. "Our sector is poised to shape healthcare for years to come and our Board will be instrumental in advancing the delivery of transformative therapies for patients globally, while helping to eradicate barriers and legacy policies that could slow access.

About ARM and its Executive Committee and Board of DirectorsARMs Executive Committee and Board of Directors oversee the formation and execution of ARMs strategic priorities and focus areas over the coming year. Each group is held to an annual reelection or rotation process, with nominations and approval by the ARM membership and current Board. ARM promotes legislative, regulatory and reimbursement initiatives to advance regenerative medicines, which includes cell therapies, gene therapies and tissue-based therapies. Early products to market have demonstrated profound benefits that are helping thousands of patients worldwide. Hundreds of additional product candidates contribute to a robust pipeline of potentially life-changing regenerative medicines and advanced therapies.

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About Senti BioOur mission is to create a new generation of smarter medicines that outmaneuver complex diseases in ways previously inconceivable. To accomplish this mission, we are building a synthetic biology platform that we believe may enable us to program next-generation cell and gene therapies with what we refer to as gene circuits. These gene circuits, which are created from novel and proprietary combinations of DNA sequences, are designed to reprogram cells with biological logic to sense inputs, compute decisions and respond to their cellular environments. We aim to design gene circuits to improve the intelligence of cell and gene therapies in order to enhance their therapeutic effectiveness against a broad range of diseases that conventional medicines do not readily address. For more information, please visit the Senti Bio website at https://www.sentibio.com.

Find more information at sentibio.comFollow us on Linkedin: Senti BiosciencesFollow us on Twitter: @SentiBio

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Senti Bio CEO Appointed to The Alliance for Regenerative Medicine 2022 Board of Directors - Yahoo Finance

20,000 sq. ft. biofabrication facility will operate from Houstons East End Maker Hub

HOUSTON, October 27, 2021--(BUSINESS WIRE)--Volumetric, a Houston-based biofabrication start-up company developing biomaterials and advanced 3D bioprinting technologies, announced today it has entered into an agreement to be acquired by 3D Systems (NYSE:DDD) in a deal structured as $45 million closing payment, with up to $355 million additional opportunity linked to a series of milestone earnouts upon the attainment of significant steps in the demonstration of human applications.

"We are so excited to join 3D Systems and its joint development program with United Therapeutics Corporation, working together to deliver on the promise of regenerative medicine," says Jordan Miller, PhD, Co-Founder and President of Volumetric. "We will build out our R&D pipeline right here in Houston, next to the dozens of other innovative life sciences companies we have been working with, and alongside, for the past three years."

The Volumetric team is comprised of bioengineers led by Dr. Miller together with Co-Founder and COO Bagrat Grigoryan, PhD. The group has been quietly developing a vertically integrated platform of bioprinting solutions targeted at a new class of therapies for organ-scale diseases whole replacement organs. Miller, currently an Associate Professor of Bioengineering at Rice University, will lead the biofabrication effort in Houston for 3D Systems as Chief Scientist for Regenerative Medicine.

"The vital organs inside of the human body are the most complicated structures in the known universe," says Dr. Miller. "Just as a vibrant city needs roads, a vital organ needs vasculature. Our work to date at Volumetric has focused on 3D bioprinting the intricate blood vessel architecture that is crucial for the function of these organs."

"Manufacturing human organs represents a transformative opportunity to reduce serious organ disease states worldwide," said Dr. Grigoryan, who will join 3D Systems as a Vice President of Regenerative Medicine. "Broadening our teams ability to deliver on the promise of organ therapy is a win for patients and medical care around the world, as well as Volumetric shareholders who believed in our promise from early phase development."

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Drs. Miller and Grigoryans leading-edge approach for generating physiologically relevant blood vessel architecture was featured on the cover of Science in May 2019 and further reported on by Forbes, TechCrunch, Scientific American, Fierce Biotech, and Fortune. Volumetric participated in the San Francisco-based accelerator Y Combinator in 2020, raising venture funds to further the companys R&D efforts.

The merger will establish a new 20,000 sq. ft. facility within Houstons East End Maker Hub, currently completing its first phase buildout. The Houston effort builds on an existing and accelerating partnership between 3D Systems and United Therapeutics (NASDAQ:UTHR) to establish the feasibility and commercialization of bioprinted human organs.

"We are thrilled that 3D Systems shares Volumetrics vision for the future of human medicine. This acquisition and expansion integrates seamlessly with our growing hub for life sciences and biofabrication here in Houston," says Bill McKeon, President and CEO, Texas Medical Center ("TMC"). TMC has been working with Volumetric since its inception through TMC Innovation and investment through TMC Venture Fund.

"Volumetric is already successful in its space with innovative light-based bioprinting," says Jeffrey Graves, PhD, President and CEO of 3D Systems. "This acquisition and integration of Volumetric into the 3D Systems family advances our commitment to healthcare."

"New parts for people. Thats Volumetrics mission and the full potential of this acquisition for humanity," says Sergio Ruiz, Managing Director of Methuselah Fund, a principal investor in Volumetric.

"While we do cutting-edge research and development, our facility will also serve to educate and foster experimentation and engagement across disciplines, the only way that these monumental challenges can be solved." says Grigoryan.

"Developing a roadmap for engineered organs could improve the lives of millions of patients who are not able to receive organ transplants today," says Miller. "We wont be satisfied until were in a post-scarcity world for organ transplantation.

"We are working for a world where people wont have to die so that others can live."

About Volumetric

Founded in 2018 by bioengineers Jordan Miller, PhD, and Bagrat Grigoryan, PhD, Volumetric is empowering the next generation of advanced biofabrication with high quality materials and systems for 3D bioprinting. Its world-class team of engineers has developed a vertically integrated platform of bioprinting solutions targeted at a new class of therapies for organ-scale diseases whole replacement organs. For more information visit volumetricbio.com.

About 3D Systems

More than 30 years ago, 3D Systems brought the innovation of 3D printing to the manufacturing industry. Today, as the leading additive manufacturing solutions partner, we bring innovation, performance, and reliability to every interaction - empowering our customers to create products and business models never before possible. Thanks to our unique offering of hardware, software, materials, and services, each application-specific solution is powered by the expertise of our application engineers who collaborate with customers to transform how they deliver their products and services. 3D Systems solutions address a variety of advanced applications in healthcare and industrial markets such as medical and dental, aerospace & defense, automotive, and durable goods. More information on the company is available at http://www.3dsystems.com.

pH Partners, LLC served as financial advisor to Volumetric while Shearman & Sterling LLP served as Volumetrics lead legal advisor.

View source version on businesswire.com: https://www.businesswire.com/news/home/20211027006115/en/

Contacts

Media Contacts on behalf of Volumetric Jennifer L. Horspool949-933-4300Jennifer@engagementpr.com

Chelsi Smith214-217-7300 ext.1304956-358-3300 (Cell)csmith@piercom.com

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Volumetric to Be Acquired by 3D Systems to Advance Tissue and Organ Manufacturing - Yahoo Finance

Chugai Pharmaceutical Co., Ltd.

TWOCELLS Co., Ltd.

Completion of Enrollment in Phase III Comparative Study for

Investigational Regenerative Cellular Medicine (gMSC1) for Knee Chondrogenesis Using Allogeneic 3D Artificial Tissue of MSC

TOKYO, October 27, 2021 --Chugai Pharmaceutical Co., Ltd.(TOKYO: 4519) and TWOCELLS Co., Ltd.

(Head Office: Hiroshima City, Hiroshima; President and CEO: Toshiki Hiura; hereafter, TWOCELLS) announced completion of target enrollment into a Phase III comparative study for an investigational regenerative cellular medicine for chondrogenesis in the knee (development number "gMSC1"), with surgery on the 70th patient.

This study examines the safety and efficacy of transplanting gMSC1, a three-dimensional artificial tissue of allogeneic MSCs, in comparison with microfracture surgery for patients with symptomatic traumatic cartilage defects or osteochondritis dissecans in the knee. The enrollment had started on November 29, 2017 and completed with the 70th surgery, fully enrolling the target number of patients. Going forward, the primary endpoints of histological evaluation of the cartilage and subjective symptoms will be analyzed at week 52 after surgery.

"The articular cartilage in the knee plays an important role in assisting with smooth leg movement. It has a very limited regenerative capacity, and various methods of treatment are under investigation for damages on the cartilage. gMSC1 aims to repair the cartilage in the knee as a regenerative cell therapy which does not require the patient's own tissue taken from their joint, potentially paving the way for solving unmet medical needs in existing treatments. We hope that the assessment ahead will prove the value of gMSC1, Chugai's first regenerative medicine project, and its benefit for patients," said Dr. Osamu Okuda, President and CEO of Chugai.

Toshiki Hiura, President and CEO of TWOCELLS, said, "Despite significant impact from COVID-19 pandemic, we have successfully completed enrollment in the study. Supported by the partnership with Chugai, we, here in Hiroshima, are smoothly advancing the development of basic technologies required for allogenic tissues, the provision of tissues from donors and establishing a GCTP-compatible facility to manufacture final products in Japan for the first time. We will build commercial production capacity as early as possible and strive to make regenerative medicine a familiar treatment option."

Chugai and TWOCELLS concluded a licensing agreement for gMSC1 in 2016. Under the agreement, TWOCELLS is conducting the clinical trial, and responsible for manufacture and supply of gMSC1. Chugai has joint development and exclusive distribution rights for gMSC1 in Japan and is responsible for regulatory application.

To provide more patients with an innovative treatment option as soon as possible, Chugai and TWOCELLS will work on the practical application of the cartilage regenerative therapy using allogenic synovium-derived mesenchymal stem cell, which is the first of its kind in the world.

TWOCELLS and Chugai Announce Performing Surgery of the First Patient in Phase III Trial for "gMSC1," a Regenerative Cellular Medicine for Chondrogenesis in the Knee (press release on November 29, 2017) https://www.chugai-pharm.co.jp/english/news/detail/20171129170000_50.html

Chugai and TWO CELLS Announce a License Agreement for "gMSC1" a Regenerative Cellular Medicine for Chondrogenesis in the Knee (press release on April 25, 2016) https://www.chugai-pharm.co.jp/english/news/detail/20160425150000_144.html

Sources of reference for the study:

Japan Pharmaceutical Information Center (JAPIC) Drug Information Database

http://www.clinicaltrials.jp/user/cteSearch.jsp

About gMSC

gMSC1 is a tissue-engineered medical product currently developed by TWOCELLS and was prepared for the regenerative chondrogenesis using synovium-derived mesenchymal stem cell (MSC) in collaboration with Osaka University and Hiroshima University. This product is a scaffold-free allogeneic 3D artificial tissue of MSC provided by TWOCELLS with their own technologies and serum-free medium (STK1 and STK2), which is expected to provide an effective treatment for cartilage regeneration. Development of gMSC1 has been supported by JST (Japan Science and Technology Agency), NEDO (New Energy and Industrial Technology Development Organization), the Ministry of Economy, Trade and Industry, and AMED (Japan Agency for Medical Research and Development).

About Chugai

Chugai Pharmaceutical is one of Japan's leading research-based pharmaceutical companies with strengths in biotechnology products. Chugai, based in Tokyo, specializes in prescription pharmaceuticals and is listed on the 1st section of the Tokyo Stock Exchange. As an important member of the Roche Group, Chugai is actively involved in R&D activities in Japan and abroad. Specifically, Chugai is working to develop innovative products which may satisfy the unmet medical needs.

About TWOCELLS

TWOCELLS is a bio-venture company established in Hiroshima in 2003, aiming to promote regenerative medicine so that patients may have a new treatment option. By particularly targeting MSC (mesenchymal stem cell), it is engaging in the development of cellular medicine with MSC, peri-MSC culturing technique and a system for regenerative medicine.

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Completion of Enrollment in Phase III Comparative Study for Investigational Regenerative Cellular Medicine (gMSC1) for Knee Chondrogenesis Using...

At Nov. 9 Event, Management and Key Opinion Leaders to Review Detailed FX-322 Clinical Study Results in Patients with Sensorineural Hearing Loss (SNHL) and Design of New FX-322-208 Phase 2b Study

Company to Introduce a Second Hearing Restoration Program with a Differentiated Biological Profile and Greater Coverage into the Cochlea, Providing Potential to Expand Addressable SNHL Patient Populations

Key Research Findings for a Novel Remyelinating Agent Being Advanced for Multiple Sclerosis (MS) also to be Presented

LEXINGTON, Mass., October 27, 2021--(BUSINESS WIRE)--Frequency Therapeutics, Inc. (Nasdaq: FREQ), a clinical-stage regenerative medicine company focused on developing therapeutics to activate a persons innate regenerative potential to restore function, today announced that the Company will be hosting a virtual R&D event on November 9, 2021.

At the event, Frequencys clinical leaders will provide a detailed review of data from nearly 170 subjects dosed with FX-322. A rigorous statistical analysis of these clinical data uncovered the patient populations most likely to benefit from FX-322 and these patients are now being recruited in the Companys recently initiated FX-322 Phase 2b study (FX-322-208). Key opinion leaders in auditory science and clinical study design will provide insights on FX-322 clinical results and the strategy supporting the new FX-322-208 trial.

The FX-322-208 study is designed to demonstrate improved speech perception in an enriched population of individuals with SNHL where statistically significant and clinically meaningful hearing improvements in speech perception were observed in prior trials. The U.S. Food and Drug Administration (FDA) recently agreed with speech perception as the primary endpoint for FX-322 development, including for the FX-322-208 study and all future FX-322 studies.

In addition to discussing clinical development advances, the company will unveil two new advanced research programs:

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A new candidate to treat sensorineural hearing loss that delivers a regenerative therapeutic that may provide greater coverage and increased potency at the site of action within the inner ear, that may enable the treatment of different SNHL patient populations at varying dose levels and;

A novel approach for remyelination in multiple sclerosis, including in vivo findings showing potent biological activity and a comparison of this program to other leading approaches.

Event Details and Agenda:

The webcast event is scheduled for November 9 from 8 a.m. to 10 a.m. ET, and will include a live Q&A session. Following are the list of management and key opinion leaders that are expected to present and their areas of focus:

David L. Lucchino, Chief Executive Officer: Strategic Company overview.

Robert S. Langer, ScD, a Frequency Therapeutics scientific co-founder and MIT Institute Professor: Pioneering a new category in regenerative medicine.

Carl LeBel, PhD, Chief Development Officer: FX-322 hearing restoration program and the clinical development path.

Sumit Dhar, PhD, Hugh Knowles Professor of Hearing Science and Associate Provost for Faculty at Northwestern University: Cochlear pathology and the impact of high frequencies on speech perception.

Kevin Franck, PhD, SVP, Strategic Marketing and New Product Planning: FX-322 clinical data and review of responders.

Steven D. Targum, MD, Scientific Director, Signant Health: Best-practice approaches for addressing placebo response in clinical trials.

Christopher Loose, PhD, Chief Scientific Officer: Continued progenitor cell activation (PCA) research, drug delivery advances and overview of a new regenerative hearing program.

Sanjay Magavi, PhD, VP, Myelination Research: In Vivo data for a novel pre-clinical program for remyelination in multiple sclerosis.

To register for the virtual event and watch a live webcast of the presentation, please visit the Investors & Media section of the Frequency Therapeutics website at https://investors.frequencytx.com/2021_Virtual_R-D_Event. An archived replay will be available for at least 30 days following the presentation.

About Frequency Therapeutics

Frequency Therapeutics is leading a new category in regenerative medicine that aims to restore human function first in hearing loss and then in multiple sclerosis (MS) by developing therapeutics that activate a persons innate regenerative potential within the body through the activation of progenitor cells. Frequencys hearing research focuses on cochlear restoration and auditory repair, and its lead asset, FX-322, is a small-molecule product candidate that is the first to show statistically significant and clinically meaningful hearing improvements in clinical trials for sensorineural hearing loss. Frequency is also following early restorative signals in MS to develop medicines with the same underlying regenerative science being brought to hearing loss.

Headquartered in Lexington, Mass., Frequency has an ex-U.S. license and collaboration agreement with Astellas Pharma Inc. for FX-322, as well as additional collaboration and licensing agreements with academic and nonprofit research organizations including Massachusetts Eye and Ear, Mass General Brigham, the Massachusetts Institute of Technology, the Scripps Research Institute and Cambridge Enterprises Limited. For more information, visit http://www.frequencytx.com and follow Frequency on Twitter @Frequencytx.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the design of the new Phase 2 trial of FX-322, including, the type of SNHL that the enrolled patients will have, the interpretation and implications of the results and learnings of other FX-322 clinical studies, the acceptance by the FDA of particular endpoints in the Companys trials, the treatment potential of FX-322 as well as the novel approach for remyelination in multiple sclerosis and our new candidate to treat SNHL, the speakers, timing of and topics to be discussed during the R&D event,, the ability of our technology platform to provide patient benefit, the ability to continue to develop our Progenitor Cell Activation (PCA) platform and identify additional product candidates, and the potential application of the PCA platform to other diseases.

These forward-looking statements are based on managements current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: the impact of COVID-19 on the Companys ongoing and planned clinical trials, research and development and manufacturing activities, the relocation of the Companys offices and laboratory facilities, the Companys business and financial markets; the Company has incurred and will continue to incur significant losses and is not and may never be profitable; the Companys need for additional funding to complete development and commercialization of any product candidate; the Companys dependence on the development of FX-322; the unproven approach of the PCA platform; the lengthy, expensive and uncertain process of clinical drug development and regulatory approval; limited experience successfully obtaining marketing approval for and commercializing product candidates; the results of earlier clinical trials not being indicative of the results from later clinical trials; differences between preliminary or interim data and final data; adverse events or undesirable side effects; disruptions at the FDA and other regulatory agencies; failure to identify additional product candidates; new or changed legislation; failure to maintain Fast Track designation for FX-322 and such designation failing to result in faster development or regulatory review or approval; costly and damaging litigation, including related to product liability or intellectual property or brought by stockholders; dependence on Astellas Pharma Inc. for the development and commercialization of FX-322 outside of the United States; misconduct by employees or independent contractors; reliance on third parties, including to conduct clinical trials and manufacture product candidates; compliance with laws and regulations, including healthcare and environmental, health, and safety laws and regulations; failure to obtain, maintain and enforce protection of patents and other intellectual property; security breaches or failure to protect private personal information; attracting and retaining key personnel; and ability to manage growth.

These and other important factors discussed under the caption "Risk factors" in the Companys Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 12, 2021 and its other reports filed with the SEC could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent managements estimates as of the date of this press release. While the Company may elect to update such forward-looking statements at some point in the future, it disclaims any obligation to do so, even if subsequent events cause its views to change. These forward-looking statements should not be relied upon as representing the Companys views as of any date subsequent to the date of this press release.

View source version on businesswire.com: https://www.businesswire.com/news/home/20211027005536/en/

Contacts

Investors:Carlo Tanzi, Ph.D.Kendall Investor Relationsctanzi@kendallir.com 617-914-0008

Media:Suzanne DayFrequency Therapeuticssday@frequencytx.com 781-496-2211

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Frequency Therapeutics Virtual R&D Event to Detail FX-322 Clinical Advances, a New Program for Hearing Restoration and In Vivo Data from its MS...

Published: Oct. 27, 2021 at 3:30 AM CDT|Updated: 21 hours ago

FRANKFURT, Germany, Oct. 27, 2021 /PRNewswire/ European Wellness Academy (EWA), the educational arm of European Wellness Biomedical Group (EWG), has signed an agreement to carry out joint scientific research on the efficacy of peptides, cell therapy, exosomes and cell reprogramming for rejuvenation in premature murine aging models.

EWA was represented by its Group Chairman, Prof. Dr. Mike Chan, while Heidelberg University was represented by its Commercial Managing Director, Katrin Erk and its Head of Institute of Anatomy and Cell Biology III, Prof. Dr. Thomas Skutella.

The cutting-edge therapeutics used for the studies include precursor (progenitor) stem cells (PSC), precursor cells (Frozen Organo Crygenics (FOC)), Mito Organelle (MO), Nano Organo Peptides (NOP) and exosomes.

Their studies include in vitro experiments concentrating on the effects of the products on the aging of somatic cells and cellular senescence, which is known to contribute to disease onset and progression. Investigated exosomes include neuronal stem cells (NSCs), mesenchymal stem cells (MSCs), cardiomyocytes, kidney progenitors and hepatocytes.

EWA and Heidelberg University will also conduct in vivo experiments to demonstrate both safety and efficacy of the therapeutics, whereby the proof of effectivity will be recorded in the life span, histopathological and molecular criteria of neurodegeneration including Alzheimer/dementia, and system degeneration disorders including those affecting the immune system, skin, cardio, lung, kidney, liver, stomach/intestine/gut, eye, and muscular dystrophy.

Other criteria included are cartilage/joint/bone regeneration including knees/joints/hips, cervical, thoracic, lumbar, pelvic and musculoskeletal disorder, as well as endocrine disorders like endocrinal dysfunction due to over and underproduction of hormones and other activity pattern under the sleep wake cycle.

The ongoing specially designed studies are coordinated and designed by Prof. Dr. Thomas Skutella of Heidelberg University, a world-renowned research university and one of Germany's Top 3, Prof. Dr.Mike Chan and scientists of EWG.

European Wellness Academy

Located in Germany, Switzerland, Greece and Malaysia, EWA is a UK CPD authorised body with a premium training and development wing that revolves around cutting-edge Bio-Regenerative Medicine modalities for practitioners and researchers. The Academy has extensive years of combined clinical experience and a core academic team comprising of qualified clinicians and scientists with multiple international affiliations and accreditations.

https://ewacademy.euhttps://european-wellness.eu/

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SOURCE European Wellness Biomedical Group

The above press release was provided courtesy of PRNewswire. The views, opinions and statements in the press release are not endorsed by Gray Media Group nor do they necessarily state or reflect those of Gray Media Group, Inc.

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European Wellness Collaborates with Heidelberg University Germany to Conduct Efficacy Studies of Peptides and Cell Therapy Research - WTOK

The global Cell-Based Regenerative Medicine market is anticipated to observe noteworthy growth in the upcoming years. Growing need for businesses to examine areas of commotion, the extent of disruption, and fortify contingency planning to boost business continuity in the future years is driving the growth of the market.

As per a recent survey by insightSLICE, The globalCell-Based Regenerative Medicinemarket research report by therapy, applications and economic forecasts, company profiles and global, regional and country industry overviews.

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Competitive Landscape

Some of the major players in the Cell-Based Regenerative Medicine market are Acelity (KCI Concepts),Cook Biotech Inc., Organogenesis Inc.,Vericel Corporation, Osiris Therapeutics, Inc., andNuVasive, Inc.,Medtronic,Stryker Corporation,Integra LifeSciences, and C.R. Bard.

Segmentation Overview:

By Therapy:immunotherapy, cell therapy, tissue engineering, and gene therapy

By Applications:oncology, orthopedic & musculoskeletal disorders, dermatology, and cardiology

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TheCell-Based Regenerative Medicine Reportprovides industry professionals and strategists, corporate analysts, associations, government departments and regulatory bodies with independent forecasts and competitive intelligence on the healthcare market.

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About Us:

insightSLICE is a market intelligence and strategy consulting company. The company provides tailor-made and off the shelf market research studies. The prime focus of the company is on strategy consulting to provide end-to-end solutions.

Media ContactCompany Name: insightSLICEContact Person: AlexEmail: Send EmailPhone: +1 (707) 736 6633Country: United StatesWebsite: https://www.insightslice.com/cell-based-regenerative-medicine-market

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Cell-Based Regenerative Medicine Market Growth, Size, Share, Trends, COVID-19 Impact Analysis, and Forecasts to 2031 - Digital Journal

Small (or short) interfering RNA (siRNA) is the predominant RNA interference (RNAi) tool used for instigating short-term silencing of protein-coding genes. Simply put, these are naturally occurring molecules that silence genes that encode specific proteins.

Image Credit: Love Employee/Shutterstock.com

This means that siRNA demonstrates significant potential for therapeutic use, given its capacity to control protein levels. However, one of the main drawbacks with siRNA is that researchers have had difficulty transmitting the molecules to the site of action in the body, the cytosol target of cells, as a result of the bodys immune response.1

To overcome the challenges associated with siRNA delivery, a team of researchers in the Netherlands has been working to develop hybrid nanoparticles that protect and transmit siRNA into target cells.

The system the team is using relies on a combination of liposomes and extracellular vesicles (EVs), which offer unique properties that package and protect siRNA against enzyme degradation.

The hybrid nanoparticles have a hydrophobic coating, thanks to the amphiphilic nature of the liposomes, which provides adequate shielding against the bodys immune response. Additionally, as EVs can easily pass through the outer membrane of a cell, the siRNA can be delivered to the site of action as intended.

The method employed by the researchers uses a dehydration technique to produce a thin lipid film which can then be rehydrated in a water-based mixture containing the EVs and siRNA. This then generates the liposome-EV-siRNA hybrid nanoparticles, which allows for a target-based delivery system.

We show that with increasing relativeEV content in our hybrids, uptake into cells becomes no longer dictated by the liposome content ... Thus, the EV surface molecules now seem to dictate which cells can internalize and process these hybrids.

Pieter Vader, Lead Researcher and Professor of Experimental Cardiology and Regenerative Medicine at the University of Utrecht

By modifying the hybrid formulation and experimenting with the liposome to EV ratio, the researchers found that it was possible to choose into which cells the siRNA would take. The team also discovered that various cell types had the capacity to receive the hybrid nanoparticles without a toxic or adverse reaction this included kidney, nerve and ovarian cell types.

The ability to alter the ratio of the liposome-EV-siRNA formulation is important in designing cell-targeting drugs as it potentially means that only diseased cell types would be targeted, reducing any risk or undesirable side-effects.

Thus, hybrid nanoparticles could integrate the functional properties of both liposomes and EVs and offer a best of both worlds particle for the therapeutic delivery of siRNA.1

The team also looked at the therapeutic outcome when the hybrid formulation was induced with EVs from a specific stem cell population: the results remarkably demonstrated recovery and healing in breast cancer cells. This shows great promise for the future of drug development, especially when designing new drugs that target cancer and degenerative diseases.

While the results of this study make significant strides for the use of hybrid nanoparticles in siRNA delivery, Vader and his team have some way to go before this treatment technology will be rolled out commercially.

Its too soon to tell where the most potential lies for our delivery system, but we know that EVs derived from progenitor cells have intrinsic regenerative properties ... Thus, regenerative medicine applications seem most logical.

Pieter Vader, Lead Researcher and Professor of Experimental Cardiology and Regenerative Medicine at the University of Utrecht

Despite being some way off commercial viability, this recent study clearly demonstrates future potential for using hybrid nanotechnology for effective drug delivery to treat various cancers and other difficult-to-treat, degenerative diseases.

Continue reading: Manifesting Multidisciplinary Nanomedicine Research with the Multiscale Metrology Suite

Evers, M., Et. Al. (2021) Functional siRNA Delivery by Extracellular VesicleLiposome Hybrid Nanoparticles.Advanced Healthcare Materials, Available at: https://doi.org/10.1002/adhm.202101202

Disclaimer: The views expressed here are those of the author expressed in their private capacity and do not necessarily represent the views of AZoM.com Limited T/A AZoNetwork the owner and operator of this website. This disclaimer forms part of the Terms and conditions of use of this website.

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Using Hybrid Nanoparticles to Deliver siRNA to Different Cell Types - AZoNano

5.2 Importance of DPSCs in personalized regenerative medicine

Regenerative medicine has the potential to heal or replace tissues and organs damaged by age, disease, or trauma, as well as to normalize congenital defects. Regenerative medicine substitutes for or regenerates damaged human cells, tissues and/or organs in order to restore their normal functioning [11]. Tissue engineering is an integral part of modern regenerative medicine. Tissue engineering involves the application of adult and/or stem cells, usage of cellular regeneration enhancing scaffolds and microenvironments, and important bioactive molecules and growth factors [12,13]. The success of tissue engineering and cellular regeneration is dependent on the biocompatibility of the scaffolds/molecules used, management of immune rejection and chronic inflammation and control of bacterial infections [13,14]. Recently, Dental Stem Cells (DSCs) are gaining more attention as a stem cell source in regenerative medicine due to its higher clonality, proliferation potential and the capacity to retain stemness even after long-term cryopreservation [15]. Several studies have provided evidence that human dental pulp contains precursor cells, named dental pulp stem cells (hDPSC). These cells have self-renewal potential and multilineage differentiation capacity. As these cell cells can be easily isolated, cultured and cryopreserved, they form an attractive stem cell source for futuristic tissue engineering purposes [16].

Dental Stem Cells (DSCs) are mesenchymal cell populations that exhibit self-renewal capacity and multidifferentiation potential [17,18]. As mentioned earlier, Dental Pulp Stem Cells (DPSCs) are the first identified and characterized DSCs [2]. Currently, there are five main types of DSCs [19,20]. They are: stem cells from exfoliated deciduous teeth (SHED) [3], periodontal ligament stem cells (PDLSCs) [21], and dental follicle precursor cells (DFPCs) [22], stem cells from apical papilla (SCAP) [23]. All these stem cells except SHED are capable of forming permanent teeth [19]. Since these cells are easily accessible, and they prevail throughout the lifetime of human beings, they are widely studied in regenerative medicine as a source of autologous stem cells. These cells find applications in regenerative therapies including oro-facial, neurologic, ocular, cardiovascular, diabetic, renal, muscular dystrophy and autoimmune conditions [19,20]. In this chapter, we aim to highlight the recent developments and findings in the field of DPSC mediated regenerative medicine. Indeed, DPSCs can be used for clinical applications in a wide array of diseases. But, only the most relevant findings with regards to regenerative medicine associated with DPSCs is discussed in the current chapter.

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Regenerative Medicine - an overview | ScienceDirect Topics

Abstract

Organ and tissue loss through disease and injury motivate the development of therapies that can regenerate tissues and decrease reliance on transplantations. Regenerative medicine, an interdisciplinary field that applies engineering and life science principles to promote regeneration, can potentially restore diseased and injured tissues and whole organs. Since the inception of the field several decades ago, a number of regenerative medicine therapies, including those designed for wound healing and orthopedics applications, have received Food and Drug Administration (FDA) approval and are now commercially available. These therapies and other regenerative medicine approaches currently being studied in preclinical and clinical settings will be covered in this review. Specifically, developments in fabricating sophisticated grafts and tissue mimics and technologies for integrating grafts with host vasculature will be discussed. Enhancing the intrinsic regenerative capacity of the host by altering its environment, whether with cell injections or immune modulation, will be addressed, as well as methods for exploiting recently developed cell sources. Finally, we propose directions for current and future regenerative medicine therapies.

Keywords: regenerative medicine, tissue engineering, biomaterials, review

Regenerative medicine has the potential to heal or replace tissues and organs damaged by age, disease, or trauma, as well as to normalize congenital defects. Promising preclinical and clinical data to date support the possibility for treating both chronic diseases and acute insults, and for regenerative medicine to abet maladies occurring across a wide array of organ systems and contexts, including dermal wounds, cardiovascular diseases and traumas, treatments for certain types of cancer, and more (13). The current therapy of transplantation of intact organs and tissues to treat organ and tissue failures and loss suffers from limited donor supply and often severe immune complications, but these obstacles may potentially be bypassed through the use of regenerative medicine strategies (4).

The field of regenerative medicine encompasses numerous strategies, including the use of materials and de novo generated cells, as well as various combinations thereof, to take the place of missing tissue, effectively replacing it both structurally and functionally, or to contribute to tissue healing (5). The body's innate healing response may also be leveraged to promote regeneration, although adult humans possess limited regenerative capacity in comparison with lower vertebrates (6). This review will first discuss regenerative medicine therapies that have reached the market. Preclinical and early clinical work to alter the physiological environment of the patient by the introduction of materials, living cells, or growth factors either to replace lost tissue or to enhance the body's innate healing and repair mechanisms will then be reviewed. Strategies for improving the structural sophistication of implantable grafts and effectively using recently developed cell sources will also be discussed. Finally, potential future directions in the field will be proposed. Due to the considerable overlap in how researchers use the terms regenerative medicine and tissue engineering, we group these activities together in this review under the heading of regenerative medicine.

Since tissue engineering and regenerative medicine emerged as an industry about two decades ago, a number of therapies have received Food and Drug Administration (FDA) clearance or approval and are commercially available (). The delivery of therapeutic cells that directly contribute to the structure and function of new tissues is a principle paradigm of regenerative medicine to date (7, 8). The cells used in these therapies are either autologous or allogeneic and are typically differentiated cells that still maintain proliferative capacity. For example, Carticel, the first FDA-approved biologic product in the orthopedic field, uses autologous chondrocytes for the treatment of focal articular cartilage defects. Here, autologous chondrocytes are harvested from articular cartilage, expanded ex vivo, and implanted at the site of injury, resulting in recovery comparable with that observed using microfracture and mosaicplasty techniques (9). Other examples include laViv, which involves the injection of autologous fibroblasts to improve the appearance of nasolabial fold wrinkles; Celution, a medical device that extracts cells from adipose tissue derived from liposuction; Epicel, autologous keratinocytes for severe burn wounds; and the harvest of cord blood to obtain hematopoietic progenitor and stem cells. Autologous cells require harvest of a patient's tissue, typically creating a new wound site, and their use often necessitates a delay before treatment as the cells are culture-expanded. Allogeneic cell sources with low antigenicity [for example, human foreskin fibroblasts used in the fabrication of wound-healing grafts (GINTUIT, Apligraf) (10)] allow off-the-shelf tissues to be mass produced, while also diminishing the risk of an adverse immune reaction.

Regenerative medicine FDA-approved products

Materials are often an important component of current regenerative medicine strategies because the material can mimic the native extracellular matrix (ECM) of tissues and direct cell behavior, contribute to the structure and function of new tissue, and locally present growth factors (11). For example, 3D polymer scaffolds are used to promote expansion of chondrocytes in cartilage repair [e.g., matrix-induced autologous chondrocyte implantation (MACI)] and provide a scaffold for fibroblasts in the treatment of venous ulcers (Dermagraft) (12). Decellularized donor tissues are also used to promote wound healing (Dermapure, a variety of proprietary bone allografts) (13) or as tissue substitutes (CryoLife and Toronto's heart valve substitutes and cardiac patches) (14). A material alone can sometimes provide cues for regeneration and graft or implant integration, as in the case of bioglass-based grafts that permit fusion with bone (15). Incorporation of growth factors that promote healing or regeneration into biomaterials can provide a local and sustained presentation of these factors, and this approach has been exploited to promote wound healing by delivery of platelet derived growth factor (PDGF) (Regranex) and bone formation via delivery of bone morphogenic proteins 2 and 7 (Infuse, Stryker's OP-1) (16). However, complications can arise with these strategies (Infuse, Regranex black box warning) (17, 18), likely due to the poor control over factor release kinetics with the currently used materials.

The efficacies of regenerative medicine products that have been cleared or approved by the FDA to date vary but are generally better or at least comparable with preexisting products (9). They provide benefit in terms of healing and regeneration but are unable to fully resolve injuries or diseases (1921). Introducing new products to the market is made difficult by the large time and monetary investments required to earn FDA approval in this field. For drugs and biologics, the progression from concept to market involves numerous phases of clinical testing, can require more than a dozen years of development and testing, and entails an average cost ranging from $802 million to $2.6 billion per drug (22, 23). In contrast, medical devices, a broad category that includes noncellular products, such as acellular matrices, generally reach the market after only 37 years of development and may undergo an expedited process if they are demonstrated to be similar to preexisting devices (24). As such, acellular products may be preferable from a regulatory and development perspective, compared with cell-based products, due to the less arduous approval process.

A broad range of strategies at both the preclinical and clinical stages of investigation are currently being explored. The subsequent subsections will overview these different strategies, which have been broken up into three broad categories: (i) recapitulating organ and tissue structure via scaffold fabrication, 3D bioprinting, and self assembly; (ii) integrating grafts with the host via vascularization and innervation; and (iii) altering the host environment to induce therapeutic responses, particularly through cell infusion and modulating the immune system. Finally, methods for exploiting recently identified and developed cell sources for regenerative medicine will be mentioned.

Because tissue and organ architecture is deeply connected with function, the ability to recreate structure is typically believed to be essential for successful recapitulation of healthy tissue (25). One strategy to capture organ structure and material composition in engineered tissues is to decellularize organs and to recellularize before transplantation. Decellularization removes immunogenic cells and molecules, while theoretically retaining structure as well as the mechanical properties and material composition of the native extracellular matrix (26, 27). This approach has been executed in conjunction with bioreactors and used in animal models of disease with lungs, kidneys, liver, pancreas, and heart (25, 2831). Decellularized tissues, without the recellularization step, have also reached the market as medical devices, as noted above, and have been used to repair large muscle defects in a human patient (32). A variation on this approach involves the engineering of blood vessels in vitro and their subsequent decellularization before placement in patients requiring kidney dialysis (33). Despite these successes, a number of challenges remain. Mechanical properties of tissues and organs may be affected by the decellularization process, the process may remove various types and amounts of ECM-associated signaling molecules, and the processed tissue may degrade over time after transplantation without commensurate replacement by host cells (34, 35). The detergents and procedures used to strip cells and other immunogenic components from donor organs and techniques to recellularize stripped tissue before implantation are actively being optimized.

Synthetic scaffolds may also be fabricated that possess at least some aspects of the material properties and structure of target tissue (36). Scaffolds have been fabricated from naturally derived materials, such as purified extracellular matrix components or algae-derived alginate, or from synthetic polymers, such as poly(lactide-coglycolide) and poly(ethylene glycol); hydrogels are composed largely of water and are often used to form scaffolds due to their compositional similarity to tissue (37, 38). These polymers can be engineered to be biodegradable, enabling gradual replacement of the scaffold by the cells seeded in the graft as well as by host cells (39). For example, this approach was used to fabricate tissue-engineered vascular grafts (TEVGs), which have entered clinical trials, for treating congenital heart defects in both pediatric and adult patients (40) (). It was found using animal models that the seeded cells in TEVGs did not contribute structurally to the graft once in the host, but rather orchestrated the inflammatory response that aided in host vascular cells populating the graft to form the new blood vessel (41, 42). Biodegradable vascular grafts seeded with cells, cultured so that the cells produced extracellular matrix and subsequently decellularized, are undergoing clinical trials in the context of end-stage renal failure (Humacyte) (33). Scaffolds that encompass a wide spectrum of mechanical properties have been engineered both to provide bulk mechanical support to the forming tissue and to provide instructive cues to adherent cells (11). For example, soft fibrincollagen hydrogels have been explored as lymph node mimics (43) whereas more rapidly degrading alginate hydrogels improved regeneration of critical defects in bone (44). In some cases, the polymer's mechanical properties alone are believed to produce a therapeutic effect. For example, injection of alginate hydrogels to the left ventricle reduced the progression of heart failure in models of dilated cardiomyopathy (45) and is currently undergoing clinical trials (Algisyl). Combining materials with different properties can enhance scaffold performance, as was the case of composite polyglycolide and collagen scaffolds that were seeded with cells and served as bladder replacements for human patients (46). In another example, an electrospun nanofiber mesh combined with peptide-modified alginate hydrogel and loaded with bone morphogenic protein 2 improved bone formation in critically sized defects (47). Medical imaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) can be used to create 3D images of replacement tissues, sometimes based on the patient's own body (48, 49) (). These 3D images can then be used as molds to fabricate scaffolds that are tailored specifically for the patient. For example, CT images of a patient were used for fabricating polyurethane and polyethylene-based synthetic trachea, which were then seeded with cells (50). Small building blocks, often consisting of cells embedded in a small volume of hydrogel, can also be assembled into tissue-like structures with defined architectures and cell patterning using a variety of recently developed techniques (51, 52) ().

Regenerative medicine strategies that recapitulate tissue and organ structure. (A) Scanning electron microscopy image of a TEVG cross-section. Reproduced with permission from ref. 41. (B) Engineered bladder consisting of a polyglycolide and collagen composite scaffold, fabricated based on CT image of patient and seeded with cells. Reproduced with permission from ref. 46. (C) CT image of bone regeneration in critically sized defects without (Left) and with (Right) nanofiber mesh and alginate scaffold loaded with growth factor. Reproduced with permission from ref. 47. (D) Small hydrogel building blocks are assembled into tissue-like structures with microrobots. Reproduced from ref. 52, with permission from Nature Communications. (E) Blueprint for 3D bioprinting of a heart valve using microextrusion printing, with different colors representing different cell types. (F) Printed product. Reproduced with permission from ref. 59. (G) Intestinal crypt stem cells seeded with supporting Paneth cells self-assemble into organoids in culture. Reproduced from ref. 67, with permission from Nature.

Although cell placement within scaffolds is generally poor controlled, 3D bioprinting can create structures that combine high resolution control over material and cell placement within engineered constructs (53). Two of the most commonly used bioprinting strategies are inkjet and microextrusion (54). Inkjet bioprinting uses pressure pulses, created by brief electrical heating or acoustic waves, to create droplets of ink that contains cells at the nozzle (55, 56). Microextrusion bioprinting dispenses a continuous stream of ink onto a stage (57). Both are being actively used to fabricate a wide range of tissues. For example, inkjet bioprinting has been used to engineer cartilage by alternating layer-by-layer depositions of electrospun polycaprolactone fibers and chondrocytes suspended in a fibrincollagen matrix. Cells deposited this way were found to produce collagen II and glycosaminoglycans after implantation (58). Microextrusion printing has been used to fabricate aortic valve replacements using cells embedded in an alginate/gelatin hydrogel mixture. Two cell types, smooth muscle cells and interstitial cells, were printed into two separate regions, comprising the valve root and leaflets, respectively (59) (). Microextrusion printing of inks with different gelation temperatures has been used to print complex 3D tubular networks, which were then seeded with endothelial cells to mimic vasculature (60). Several 3D bioprinting machines are commercially available and offer different capabilities and bioprinting strategies (54). Although extremely promising, bioprinting strategies often suffer trade-offs in terms of feature resolution, cell viability, and printing resolution, and developing bioprinting technologies that excel in all three aspects is an important area of research in this field (54).

In some situations, it may be possible to engineer new tissues with scaffold-free approaches. Cell sheet technology relies on the retrieval of a confluent sheet of cells from a temperature-responsive substrate, which allows cellcell adhesion and signaling molecules, as well as ECM molecules deposited by the cells themselves, to remain intact (61, 62). Successive sheets can be layered to produce thicker constructs (63). This approach has been explored in a variety of contexts, including corneal reconstruction (64). Autologous oral mucosal cells have been grown into sheets, harvested, and implanted, resulting in reepithelialization of human corneas (64). Autonomous cellular self-assembly may also be used to create tissues and be used to complement bioprinting. For example, vascular cells aggregated into multicellular spheroids were printed in layer-by-layer fashion, using microextrusion, alongside agarose rods; hollow and branching structures that resembled a vascular network resulted after physical removal of the agarose once the cells formed a continuous structure (65). Given the appropriate cues and initial cell composition, even complex structures may form autonomously (66). For example, intestinal crypt-like structures can be grown from a single crypt base columnar stem cell in 3D culture in conjunction with augmented Wnt signaling (67) (). Understanding the biological processes that drive and direct self-assembly will aid in fully taking advantage of this approach. The ability to induce autonomous self-assembly of the modular components of organs, such as intestinal crypts, kidney nephrons, and lung alveoli, could be especially powerful for the construction of organs with complex structures.

To contribute functionally and structurally to the body, implanted grafts need to be properly integrated with the body. For cell-based implants, integration with host vasculature is of primary importance for graft success () (68). Most cells in the body are located within 100 m from the nearest capillary, the distance within which nutrient exchange and oxygen diffusion from the bloodstream can effectively occur (68). To vascularize engineered tissues, the body's own angiogenic response may be exploited via the presentation of angiogenic growth factors (69). A variety of growth factors have been implicated in angiogenesis, including vascular endothelial growth factor (VEGF), angiopoietin (Ang), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) (70, 71). However, application of growth factors may not be effectual without proper delivery modality, due to their short half-life in vivo and the potential toxicity and systemic effects of bolus delivery (45). Sustained release of VEGF, bFGF, Ang, and PDGF leads to robust angiogenic responses and can rescue ischemic limbs from necrosis (45, 72, 73). Providing a sequence of angiogenic factors that first initiate and then promote maturation of newly formed vessels can yield more functional networks (74) (), and mimicking development via delivery of both promoters and inhibitors of angiogenesis from distinct spatial locations can create tightly defined angiogenic zones (75).

Strategies for vascularizing and innervating tissue-engineered graft. (A) Tissue-engineered graft may be vascularized before implantation: for example, by self-assembly of seeded endothelial cells or by host blood vessels in a process mediated by growth factor release. Compared with bolus injection of VEGF and PDGF (B), sustained release of the same growth factors from a polymeric scaffold (C) led to a higher density of vessels and formation of larger and thicker vessels. Reproduced from ref. 74, with permission from Nature Biotechnology. (D) Scaffold vascularized by being implanted in the omentum before implantation at the injury site. Reproduced with permission from ref. 83. (E) Biodegradable microfluidic device surgically connected to vasculature. Reproduced with permission from ref. 85. Compared with blank scaffold (F), scaffolds delivering VEGF (G) increase innervation of injured skeletal muscle. Reproduced from ref. 97, with permission from Molecular Therapy.

Another approach to promote graft vascularization at the target site is to prevascularize the graft or target site before implantation. Endothelial cells and their progenitors can self-organize into vascular networks when transplanted on an appropriate scaffold (7679). Combining endothelial cells with tissue-specific cells on a scaffold before transplantation can yield tissues that are both better vascularized and possess tissue-specific function (80). It is also possible to create a vascular pedicle for an engineered tissue that facilitates subsequent transplantation; this approach has been demonstrated in the context of both bone and cardiac patches by first placing a scaffold around a large host vessel or on richly vascularized tissue, and then moving the engineered tissue to its final anatomic location once it becomes vascularized at the original site (8183) (). This strategy was successfully used to vascularize an entire mandible replacement, which was later engrafted in a human patient (84). Microfluidic and micropatterning techniques are currently being explored to engineer vascular networks that can be anastomosed to the femoral artery (85, 86) (). The site for cell delivery may also be prevascularized to enhance cell survival and function, as in a recent report demonstrating that placement of a catheter device allowed the site to become vascularized due to the host foreign body response to the material; this device significantly improved the efficacy of pancreatic cells subsequently injected into the device (87).

Innervation by the host will also be required for proper function and full integration of many tissues (88, 89), and is particularly important in tissues where motor control, as in skeletal tissue, or sensation, as in the epidermis, provides a key function (90, 91). Innervation of engineered tissues may be induced by growth factors, as has been shown in the induction of nerve growth from mouse embryonic dorsal root ganglia to epithelial tissue in an in vitro model (92). Hydrogels patterned with channels that are subsequently loaded with appropriate extracellular matrices and growth factors can guide nerve growth upon implantation, and this approach has been used to support nerve regeneration after injury (93, 94). Angiogenesis and nerve growth are known to share certain signaling pathways (95), and this connection has been exploited via the controlled delivery of VEGF using biomaterials to promote axon regrowth in regenerating skeletal muscle (96, 97) ().

Administration of cells can induce therapeutic responses by indirect means, such as secretion of growth factors and interaction with host cells, without significant incorporation of the cells into the host or having the transplanted cells form a bulk tissue (98). For example, infusion of human umbilical cord blood cells can aid in stroke recovery due to enhanced angiogenesis (99), which in turn may have induced neuroblast migration to the site of injury. Similarly, transplanted macrophages can promote liver repair by activating hepatic progenitor cells (100). Transplanted cells can also normalize the injured or diseased environment, by altering the ECM, and improve tissue regeneration via this mechanism. For example, some types of epidermolysis bullosa (EB), a rare genetic skin blistering disorder, are associated with a failure of type VII collagen deposition in the basement membrane. Allogeneic injected fibroblasts were found to deposit type VII collagen deposition, thereby temporarily correcting disease morphology (101). A prototypical example of transplanted cells inducing a regenerative effect is the administration of mesenchymal stem cells (MSCs), which are being widely explored both preclinically and clinically to improve cardiac regeneration after infarction, and to treat graft-versus-host disease, multiple sclerosis, and brain trauma (2, 102) (). Positive effects of MSC therapy are observed, despite the MSCs being concentrated with some methods of application in the lungs and poor MSC engraftment in the diseased tissue (103). This finding suggests that a systemic paracrine modality is sufficient to produce a therapeutic response in some situations. In other situations, cellcell contact may be required. For example, MSCs can inhibit T-cell proliferation and dampen inflammation, and this effect is believed to at least partially depend on direct contact of the transplanted MSCs with host immune cells (104). Cells are often infused, typically intravenously, in current clinical trials, but cells administered in this manner often experience rapid clearance, which may explain their limited efficacy (105). Immunocloaking strategies, such as with hydrogel encapsulation of both cell suspensions and small cell clusters and hydrogel cloaking of whole organs, can lead to increased cell residency time and delayed allograft rejection (106, 107) (). Coating infused cells with targeting antibodies and peptides, sometimes in conjunction with lipidation strategies, known as cell painting, has been shown to improve residency time at target tissue site (108). Infused cells can also be modified genetically to express a targeting ligand to control their biodistribution (109).

Illustrations of regenerative medicine therapies that modulate host environment. (A) Injected cells, such as MSCs, can release cytokines and interact with host cells to induce a regenerative response. (B) Polyethylene glycol hydrogel (green) conformally coating pancreatic islets (blue) can support islets after injection. (Scale bar: 200 m.) Reproduced with permission from ref. 107.

Although the goal of regenerative medicine has long been to avoid rejection of the new tissue by the host immune system, it is becoming increasingly clear that the immune system also plays a major role in regulating regeneration, both impairing and contributing to the healing process and engraftment (110, 111). At the extreme end of immune reactions is immune rejection, which is a serious obstacle to the integration of grafts created with allogeneic cells. Immune engineering approaches have shown promise in inducing allograft tolerance: for example, by engineering the responses of immune cells such as dendritic cells and regulatory T cells (112, 113). Changing the properties of implanted scaffolds can also reduce the inflammation that accompanies implantation of a foreign object. For example, decreasing scaffold hydrophobicity and the availability of adhesion ligands can reduce inflammatory responses, and scaffolds with aligned fibrous topography experience less fibrous encapsulation upon implantation (114). Adaptive immune cells may actively inhibit even endogenous regeneration, as shown when depletion of CD8 T cells improved bone fracture healing in a preclinical model (115). Engineering the local immune response may thus allow active promotion of regeneration. For example, the release of cytokines to polarize macrophages to M2 phenotypes, which are considered to be antiinflammatory and proregeneration, was found to increase Schwann cell infiltration and axonal growth in a nerve gap model (116).

Most regenerative medicine strategies rely on an ample cell source, but identifying and obtaining sufficient numbers of therapeutic cells is often a challenge. Stem, progenitor, and differentiated cells derived from both adult and embryonic tissues are widely being explored in regenerative medicine although adult tissue-derived cells are the dominant cell type used clinically to date due to both their ready availability and perceived safety (8). All FDA-approved regenerative medicine therapies to date and the vast majority of strategies explored in the clinic use adult tissue-derived cells. There is great interest in obtaining greater numbers of stem cells from adult tissues and in identifying stem cell populations suitable for therapeutic use in tissues historically thought not to harbor stem cells (117). Basic studies aiming to understand the processes that control stem cell renewal are being leveraged for both purposes, with the prototypical example being studies with hematopoietic stem cells (HSCs) (3). For example, exposure of HSCs in vitro to cytokines that are present in the HSC niche leads to significant HSC expansion, but this increase in number is accompanied by a loss of repopulation potential (118, 119). Coculture of HSCs with cells implicated in the HSC niche and in microenvironments engineered to mimic native bone marrow may improve maintenance of HSC stemness during expansion, enhancing stem cell numbers for transplantation. For example, direct contact of HSCs with MSCs grown in a 3D environment induces greater CD34+ expansion than with MSCs grown on 2D substrate (120). Another example is that culture of skeletal muscle stem cells on substrates with mechanical properties similar to normal muscle leads to greater stem cell expansion (121) and can even rescue impaired proliferative ability in stem cells from aged animals (122).

Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent potentially infinite sources of cells for regeneration and are moving toward clinical use (123, 124). ES cells are derived from blastocyst-stage embryos and have been shown to be pluripotent, giving rise to tissues from all three germ layers (125). Several phase I clinical trials using ES cells have been completed, without reports of safety concerns (Geron, Advanced Cell Technology, Viacyte). iPS cells are formed from differentiated somatic cells exposed to a suitable set of transcription factors that induce pluripotency (126). iPS cells are an attractive cell source because they can be generated from a patient's own cells, thus potentially circumventing the ethical issues of ES and rejection of the transplanted cells (127, 128). Although iPS cells are typically created by first dedifferentiating adult cells to an ES-like state, strategies that induce reprogramming without entering a pluripotent stage have attracted attention due to their quicker action and anticipation of a reduced risk for tumor formation (129). Direct reprogramming in vivo by retroviral injection has been reported to result in greater efficiency of conversion, compared with ex vivo manipulation, and allows in vitro culture and transplantation to be bypassed (130). Strategies developed for controlled release of morphogens that direct regeneration could potentially be adapted for controlling delivery of new genetic information to target cells in vivo, to improve direct reprogramming. Cells resulting from both direct reprogramming and iPS cell differentiation methods have been explored for generating cells relevant to a variety of tissues, including cardiomyocytes, vascular and hematopoietic cells, hepatocytes, pancreatic cells, and neural cells (131). Because ES and iPS cells can form tumors, a tight level of control over the fate of each cell is crucial for their safe application. High-throughput screens of iPS cells can determine the optimal dosages of developmental factors to achieve lineage specification and minimize persistence of pluripotent cells (132). High-throughput screens have also been useful for discovering synthetic materials for iPS culture, which would allow culture in defined, xenogen-free conditions (133). In addition, the same principles used to engineer cellular grafts from differentiated cells are being leveraged to create appropriate microenvironments for reprogramming. For example, culture on polyacrylamide gel substrates with elastic moduli similar to the heart was found to enable longer term survival of iPS-derived cardiomyocytes, compared with other moduli (134). In another study, culture of iPS cell-derived cardiac tissue in hydrogels with aligned fibers, and in the presence of electrical stimulation, enhanced expression of genes associated with cardiac maturation (135).

To date, regenerative medicine has led to new, FDA-approved therapies being used to treat a number of pathologies. Considerable research has enabled the fabrication of sophisticated grafts that exploit properties of scaffolding materials and cell manipulation technologies for controlling cell behavior and repairing tissue. These scaffolds can be molded to fit the patient's anatomy and be fabricated with substantial control over spatial positioning of cells. Strategies are being developed to improve graft integration with the host vasculature and nervous system, particularly through controlled release of growth factors and vascular cell seeding, and the body's healing response can be elicited and augmented in a variety of ways, including immune system modulation. New cell sources for transplantation that address the limited cell supply that hampered many past efforts are also being developed.

A number of issues will be important for the advancement of regenerative medicine as a field. First, stem cells, whether isolated from adult tissue or induced, will often require tight control over their behavior to increase their safety profile and efficacy after transplantation. The creation of microenvironments, often modeled on various stem cell niches that provide specific cues, including morphogens and physical properties, or have the capacity to genetically manipulate target cells, will likely be key to promoting optimal regenerative responses from therapeutic cells. Second, the creation of large engineered replacement tissues will require technologies that enable fully vascularized grafts to be anastomosed with host vessels at the time of transplant, allowing for graft survival. Thirdly, creating a proregeneration environment within the patient may dramatically improve outcomes of regenerative medicine strategies in general. An improved understanding of the immune system's role in regeneration may aid this goal, as would technologies that promote a desirable immune response. A better understanding of how age, disease state, and the microbiome of the patient affect regeneration will likely also be important for advancing the field in many situations (136138). Finally, 3D human tissue culture models of disease may allow testing of regenerative medicine approaches in human biology, as contrasted to the animal models currently used in preclinical studies. Increased accuracy of disease models may improve the efficacy of regenerative medicine strategies and enhance the translation to the clinic of promising approaches (139).

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Regenerative medicine: Current therapies and future directions