Scar-free healing: from embryonic mechanisms to adult therapeutic intervention

Mark W. J. Ferguson1,2* and Sharon O’Kane2

1 UK Centre for Tissue Engineering, School of Biological Sciences, University of Manchester, 3.239 Stopford Building, Oxford Road, Manchester M13 9PT, UK

2 Renovo Limited, Manchester Incubator Building, 48 Grafton Street, Manchester M13 9XX, UK

       In man and domestic animals, scarring in the skin after trauma, surgery, burn or sports injury is a major medical problem, often resulting in adverse aesthetics, loss of function, restriction of tissue movement and/or growth and adverse psychological effects. Current treatments are empirical, unreliable and unpredictable: there are no prescription drugs for the prevention or treatment of dermal scarring. Skin wounds on early mammalian embryos heal perfectly with no scars whereas wounds to adult mammals scar. We investigated the cellular and molecular differences between scar-free healing in embryonic wounds and scar-forming healing in adult wounds. Important differences include the inflammatory response, which in embryonic wounds consists of lower numbers of less differentiated inflammatory cells. This, together with high levels of morphogenetic molecules involved in skin growth and morphogenesis, means that the growth factor profile in a healing embryonic wound is very different from that in an adult wound. Thus, embryonic wounds that heal without a scar have low levels of TGFβ1 and TGFβ2, low levels of platelet-derived growth factor and high levels of TGFβ3. We have experimentally manipulated healing adult wounds in mice, rats and pigs to mimic the scar-free embryonic profile, e.g. neutralizing PDGF, neutralizing TGFβ1 and TGFβ2 or adding exogenous TGFβ3. These experiments result in scar-free wound healing in the adult. Such experiments have allowed the identification of therapeutic targets to which we have developed novel pharmaceutical molecules, which markedly improve or completely prevent scarring during adult wound healing in experimental animals. Some of these new drugs have successfully completed safety and other studies, such that they have entered human clinical trials with approval from the appropriate regulatory authorities. Initial trials involve application of the drug or placebo in a double-blind randomized design, to experimental incision or punch biopsy wounds under the arms of human volunteers. Based on encouraging results from such human volunteer studies, the lead drugs have now entered human patient-based trials e.g. in skin graft donor sites. We consider the evolutionary context of wound healing, scarring and regeneration. We hypothesize that evolutionary pressures have been exerted on intermediate sized, widespread, dirty wounds with considerable tissue damage e.g. bites, bruises and contusions. Modern wounds (e.g. resulting from trauma or surgery) caused by sharp objects and healing in a clean or sterile environment with close tissue apposition are new occurrences, not previously encountered in nature and to which the evolutionary selected wound healing responses are somewhat inappropriate. We also demonstrate that both repair with scarring and regeneration can occur within the same animal, including man, and indeed within the same tissue, thereby suggesting that they share similar mechanisms and regulators. Consequently, by subtly altering the ratio of growth factors present during adult wound healing, we can induce adult wounds to heal perfectly with no scars, with accelerated healing and with no adverse effects, e.g. on wound strength or wound infection rates. This means that scarring may no longer be an inevitable consequence of modern injury or surgery and that a completely new pharmaceutical approach to the prevention of human scarring is now possible. Scarring after injury occurs in many tissues in addition to the skin. Thus scar-improving drugs could have widespread benefits and prevent complications in several tissues, e.g. prevention of blindness after scarring due to eye injury, facilitation of neuronal reconnections in the central and peripheral nervous system by the elimination of glial scarring, restitution of normal gut and reproductive function by preventing strictures and adhesions after injury to the gastrointestinal or reproductive systems, and restoration of locomotor function by preventing scarring in tendons and ligaments.

Keywords: wound healing; scarring; transforming growth factor beta; regeneration; skin pharmaceuticals; regenerative medicine

Provider confdence in the telemedicine spine evaluation: results from a global study

Francis Lovecchio1  · Grant J. Riew2  · Dino Samartzis3,4 · Philip K. Louie5  · Niccole Germscheid6  · Howard S. An3,4 ·

Jason Pui Yin Cheung7  · Norman Chutkan8  · Gary Michael Mallow3,4 · Marko H.  Neva9  · Frank M. Phillips3,4 ·

Daniel M. Sciubba10 · Mohammad El‑Sharkawi11 · Marcelo Valacco12 · Michael H.  McCarthy13 · Melvin C. Makhni2  ·

Sravisht Iyer1

1 Department of Orthopaedic Surgery, Hospital for Special Surgery,  New York, NY, USA

2 Department of Orthopaedic Surgery, Brigham and Women’s Hospital, Harvard Medical School,  Boston, MA, USA

3 Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA

4 The International Spine Research and Innovation Initiative, Rush University Medical Center,  Chicago, IL, USA

5 Neuroscience Institute, Virginia Mason Medical Center,  Seattle, WA, USA

6 Research Department, AO Spine International, Davos, Switzerland

7 Department of Orthopaedics & Traumatology, The University of Hong Kong, Hong Kong SAR, China

8 Department of Orthopaedic Surgery, University of Arizona College of Medicine, Phoenix, AZ, USA

9 Department of Orthopaedic and Trauma Surgery, Tampere University Hospital, Tampere, Finland

10 Department of Neurosurgery, Baltimore, MD, USA, John Hopkins University, Baltimore, MD, USA

11 Department of Orthopaedic and Trauma Surgery, Assiut University Medical School, Assiut, Egypt

12 Department of Orthopaedics, Churruca Hospital de Buenos Aires, Buenos Aires, Argentina

13 Indiana Spine Group,  Carmel, IN, USA

Received: 22 September 2020 / Accepted: 27 October 2020 / Published online: 22 November 2020

© The Author(s) 2020

Abstract

Purpose To utilize data from a global spine surgeon survey to elucidate (1) overall confidence in the telemedicine evaluation and (2) determinants of provider confidence.

Methods Members of AO Spine International were sent a survey encompassing participant’s experience with, perception of,and comparison of telemedicine to in-person visits. The survey was designed through a Delphi approach, with four rounds of

question review by the multi-disciplinary authors. Data were stratified by provider age, experience, telemedicine platform, trust in telemedicine, and specialty.

Results Four hundred and eighty-five surgeons participated in the survey. The global effort included respondents from Africa (19.9%), Asia Pacific (19.7%), Europe (24.3%), North America (9.4%), and South America (26.6%). Providers felt that physical exam-based tasks (e.g., provocative testing, assessing neurologic deficits/myelopathy, etc.) were inferior to inperson exams, while communication-based aspects (e.g., history taking, imaging review, etc.) were equivalent. Participants who performed greater than 50 visits were more likely to believe telemedicine was at least equivalent to in-person visits in the ability to make an accurate diagnosis (OR 2.37, 95% C.I. 1.03–5.43). Compared to in-person encounters, video (versus phone only) visits were associated with increased confidence in the ability of telemedicine to formulate and communicate a treatment plan (OR 3.88, 95% C.I. 1.71–8.84).

Conclusion Spine surgeons are confident in the ability of telemedicine to communicate with patients, but are concerned about its capacity to accurately make physical exam-based diagnoses. Future research should concentrate on standardizing the remote examination and the development of appropriate use criteria in order to increase provider confidence in telemedicine technology.

Keywords Telemedicine · Spine surgery · Examination · International · Survey

Designing Futuristic Telemedicine Using Artificial Intelligence and Robotics in the COVID-19 Era

Sonu Bhaskar, Sian Bradley, [...], and Maciej Banach Additional article information

Abstract