Unlocking Regeneration: Scarless Wound Healing and Induced Liver Growth in Humans

Introduction

The human body possesses an extraordinary capacity for repair. A fractured bone, once properly aligned, knits itself back together. A surgical incision, in most cases, closes and heals within weeks. Yet this healing is almost always imperfect. Wounds heal with scar tissue—dense, disorganised collagen that lacks the elasticity, strength and appendages of normal skin. Organs such as the liver, despite their remarkable regenerative capacity after partial resection, reach a limit. When cirrhosis, cancer or acute failure destroys too much liver tissue, the organ cannot recover. At that point, there are only two options: transplantation or death.

The limitations of natural healing have long been accepted as inevitable. A growing body of evidence suggests that this acceptance may have been premature. By harnessing the mechanisms of cellular reprogramming—the ability to convert one cell type into another, to reverse pathological differentiation, and to co‑opt developmental pathways that have been dormant since embryonic life—researchers are now achieving scarless wound healing and induced organ growth in preclinical models. The convergence of three distinct lines of investigation—genetic reprogramming of profibrotic fibroblasts, chemical reprogramming of hepatocyte progenitors, and large‑scale bioprinting of vascularised organ constructs—has brought the field to an inflection point.

This article examines the scientific foundation of regenerative cellular reprogramming, reviews the latest evidence across scarless wound healing and induced liver regeneration, and discusses how technologies such as the Advanced Research Projects Agency for Health (ARPA‑H) PRINT program are translating these discoveries toward clinical reality.

Scarless Wound Healing: Rewriting the Fibroblast Code

The Burden of Scarring

Skin wounds in adult mammals heal through a rapid but imperfect process that prioritises closure over restoration. Fibroblasts—the primary cells responsible for extracellular matrix deposition—shift into a profibrotic state that produces excessive, disorganised collagen I fibres. The resulting scar tissue lacks hair follicles, sebaceous glands and normal mechanical properties. It is weaker than normal skin, prone to contracture and, in severe cases such as burn injury or large trauma, can lead to permanent disfigurement and functional impairment.

The socioeconomic burden of scarring is substantial. Over 100 million new scars form annually in the United States alone. The global economic burden of scarring has been estimated to exceed $64 billion by 2032. Existing clinical interventions, including laser therapy, cryotherapy and corticosteroid injections, primarily address scar appearance with limited efficacy in restoring normal skin function. Developing effective strategies for scar prevention and regenerative healing remains an urgent unmet clinical need.

The Engrailed‑1 Fibroblast Paradigm

A fundamental breakthrough in understanding scar formation has come from the identification of two functionally opposed fibroblast lineages. In adult skin, two distinct fibroblast subtypes have been identified based on expression of the homeobox transcription factor Engrailed‑1 (En1). En1 lineage‑negative fibroblasts (ENFs) are pro‑regenerative, depositing a provisional fibronectin‑rich matrix and activating Wnt/Trps1 pathways that restore normal skin structure and appendages. En1 lineage‑positive fibroblasts (EPFs) are profibrotic, depositing excessive, dense and parallel collagen I fibres that form scars.

The key insight—and the therapeutic opportunity—lies in the plasticity of this system. En1 can be postnatally activated in ENFs following injury, converting them into EPFs and tipping the balance toward fibrosis. If this conversion could be prevented or reversed, scar formation might be prevented and normal skin architecture restored.

Targeted Silencing of Engrailed‑1

A 2025 study in Molecular Therapy reported the development of a nanoscale fibroblast‑mimic carrier (FibroMC) for targeted delivery of En1‑specific small interfering RNA (siEn1) to fibroblasts. The FibroMC was constructed by functionalising FDA‑approved ionisable lipid nanoparticles with fibroblast cell membrane, incorporating membrane proteins such as integrin β1 and N‑cadherin that enable preferential uptake by fibroblasts. This design achieved potent silencing of En1 in all EPF populations both in vitro and in vivo.

The effects were dramatic. FibroMC treatment significantly inhibited collagen I expression and myofibroblast differentiation. A single dose of topical application to the wound effectively restored collagen architecture, regenerated skin appendages, recovered skin mechanical property and ultimately prevented scar formation. These findings demonstrate that FibroMC‑mediated En1 silencing can reverse the profibrotic effect of EPFs, offering a promising therapeutic strategy for scarless wound healing.

The Role of Fibroblast Supracellular Organisation

Scarless healing requires coordinated fibroblast activity extending beyond single‑cell behaviour. A 2025 study in Cell Reports used multi‑modal imaging of fascia explants from lineage‑specific reporter mice to track wound fibroblasts over five days. The results revealed organisation of fibroblasts into supracellular assemblies—sprouting, reticulating and clustering throughout healing. High‑throughput screening of the Prestwick drug library against these fascia explants identified compounds that modulated these behaviours, revealing a spectrum from fibrosis to scarless healing.

Recovery phenotypes correlated with fibroblast sprouting, reticulation and clustering rather than traditional extracellular matrix deposition markers. Two therapeutic categories were identified: compounds that disrupt reticulation or clustering to inhibit scarring, and compounds (including fluvastatin, thiostrepton and fenbendazole) that disrupt sprouting, block pro‑inflammatory fibroblast or myofibroblast commitment, promote angiogenesis, reduce inflammatory infiltration and enable scar‑free regenerative healing with hair follicle papillae regrowth in mice. These findings establish fibroblast supracellular organisation as fundamental to tissue recovery and provide novel therapeutic targets for wound healing and fibrotic disorders.

Stem Cell‑Derived Exosomes for Anti‑Scar Healing

An alternative approach to scarless healing has emerged from mesenchymal stem cell (MSC) biology. A 2025 study published in Journal of Nanobiotechnology performed high‑resolution single‑cell RNA sequencing analysis of adult wild‑type and hADSC‑Exos‑treated mice. Exosomes derived from human adipose‑derived mesenchymal stem cells (hADSC‑Exos) influenced epithelial cells and fibroblasts, leading to scar‑free wound healing. Among epithelial cell subtypes, lymphoid enhancer binding factor 1 high proliferating keratinocytes were particularly remodelled by hADSC‑Exos.

Cell‑cell communication between keratinocytes and fibroblasts during anti‑scar healing was modulated by tumour growth factor‑β1, which promotes an epithelial‑mesenchymal plasticity transition cascade. hADSC‑Exos were found to inhibit wound fibrosis through the 14‑3‑3 zeta‑YES‑associated protein‑Hippo signalling pathway. This study enhances understanding of epithelial cell diversity and interactions in wound healing, highlighting hADSC‑Exo‑induced proliferating keratinocytes as potential reprogramming targets for improving wound‑healing strategies.

Induced Liver Regeneration: Growing New Tissue Without Transplantation

The Liver's Remarkable but Limited Regenerative Capacity

The liver is unique among solid organs in its ability to regenerate after injury or partial resection. Following a partial hepatectomy—the surgical removal of up to 70% of liver mass—the remaining tissue can double in size within days and restore full mass within weeks. This remarkable capacity has enabled living‑donor liver transplantation, in which a portion of a healthy donor's liver is removed and transplanted into a recipient, with both organs regenerating to full size.

This regenerative capacity has limits. In chronic liver disease—cirrhosis, viral hepatitis, alcohol‑related liver disease or non‑alcoholic steatohepatitis—repeated injury and fibrosis exhaust the liver's regenerative machinery. Hepatocytes enter a state of replicative senescence. Progenitor pools are depleted. Eventually, liver function declines irreversibly, and the only option is transplantation.

Liver diseases contribute to approximately two million deaths globally each year. Liver transplantation remains the gold‑standard therapy, but its clinical application is severely hindered by donor organ shortage and a high incidence of post‑transplant immune rejection. Developing strategies to induce endogenous liver regeneration—to wake dormant progenitor cells or to reprogram non‑hepatic cells into functional hepatocytes—has become a central goal of regenerative medicine.

Chemical Reprogramming of Liver Progenitors

Chemical reprogramming—the use of small molecules to emulate extrinsic signalling cues—has emerged as a promising therapeutic strategy for liver regeneration. Unlike genetic reprogramming with viral vectors, chemical reprogramming avoids the risks of insertional mutagenesis and immune rejection, offering a safer path to clinical translation.

A 2025 study in Regenerative Therapy explored chemically induced liver progenitors (CLiP) as a potential therapeutic agent for metabolic liver diseases. Mature hepatocytes were isolated from rats and treated with a three‑small‑molecule cocktail consisting of a ROCK inhibitor, a TGFβ‑1 inhibitor and a GSK3 inhibitor. The resulting CLiP cells exhibited enhanced proliferative capacity in vitro. When transplanted into Nagase analbuminemic rats (a model of congenital hypoalbuminaemia) through portal vein injection, CLiP transplantation combined with portal branch ligation to induce liver regenerative stimulus resulted in significant elevation of serum albumin levels.

A separate study reported that a cocktail of three small molecules—Y‑27632, A83‑01 and CHIR99021 (YAC)—converts mature hepatocytes into proliferative bipotent cells that can be induced into hepatocytes and cholangiocytes. Interestingly, follow‑up experiments suggested that bipotent cells may be derived from resident liver progenitor cells whose proliferative activity is promoted by YAC. A simple and efficient sorting scheme was developed to harvest high‑purity and high‑yield liver progenitor cells. Inducible bipotency of purified progenitor cells was verified, and they were found to spontaneously differentiate into hepatocytes and cholangiocytes due to changes in proliferative status even without induction. During differentiation, some hepatocytes spontaneously reconverted to progenitor cells under certain conditions, such as release of contact inhibition.

The Hedgehog Agonist Breakthrough

A 2025 study reported a novel technology for robust expansion of quiescent liver stem cells from mice using the Hedgehog agonist HhAg1.5 over three weeks. Hedgehog signalling is a critical developmental pathway that governs tissue patterning and stem cell maintenance, but becomes quiescent in adult liver. By reactivating this pathway with a small‑molecule agonist, researchers broke the quiescence of non‑injured liver stem cells, providing a promising viable substitute for primary hepatocytes for regenerative medicine and for life‑threatening metabolic liver diseases.

Dynamic Extracellular Matrix for Hepatocyte Organoid Reprogramming

The extracellular matrix (ECM) is not merely a passive scaffold but an active regulator of cell behaviour. A 2025 study in PMC engineered a dynamic ECM system using thrombospondin‑1 (THBS1) to propel hepatocyte organoid reprogramming and improve mouse liver regeneration post‑transplantation. THBS1 treatment induced reprogramming effects in hepatocyte organoids, akin to reprogramming observed in organoids transfected with Oct4, Sox2, Klf4 and c‑Myc—the classic Yamanaka reprogramming factors.

Transplanting hepatocyte organoids presenting reprogramming effects into a 70% hepatectomy model demonstrated improved liver regeneration, underscoring the potential of the THBS1‑based dynamic ECM system in organoid manipulation and liver regeneration.

Metabolic Reprogramming in Liver Regeneration

A 2025 study in Nature Communications uncovered a surprising metabolic adaptation in regenerating liver. The liver uses ammonia—a toxic byproduct of protein metabolism normally detoxified through the urea cycle—to support de novo pyrimidine synthesis and cell proliferation. Suppression of de novo pyrimidine synthesis prevented proliferation in regenerating liver, suppressing liver regrowth. This research uncovers a metabolic reprogramming mechanism in which a toxic byproduct is redirected toward anabolic pathways essential for liver regeneration, opening new therapeutic avenues for enhancing regenerative capacity.

Large‑Scale Bioprinting: Engineering Organs from Scratch

The Vascularisation Problem

The greatest barrier to engineering functional organs is vascularisation. Without a dense network of blood vessels capable of delivering oxygen and nutrients and removing waste, engineered tissue constructs remain limited in size to a few hundred micrometres—the diffusion limit of oxygen. This is insufficient for human‑scale organs, which require billions of cells distributed across centimetre‑scale volumes.

TRACKS: Combining 3D Printing with Guided Vascular Self‑Assembly

A 2026 study in Cell Biomaterials introduced topological railways for assisting cellular kinetic sculpting (TRACKS), a platform that combines 3D printing of sacrificial templates with guided vascular self‑assembly to generate vascular networks across mouse organ‑scale tissues. Using selective laser sintering of sacrificial isomalt templates to pattern vascular‑promoting "tracks" across murine organ‑scale tissue constructs, the researchers demonstrated that patterned tracks architecturally guide host‑mediated vascularisation within fibrin and GelMA constructs upon implantation in mice.

Whereas the inclusion of tracks improved the vascularisation response within both matrices, GelMA constructs demonstrated greater implant stability after one week in vivo. Subsequent implantation of densely cellularised GelMA constructs generated widespread, volumetric circulatory integration via both track‑guided and self‑assembled new blood vessels. This platform enables the generation of vascular networks spanning large, engineered tissues that can fully integrate with host circulation and represents a significant step toward clinically translatable organ‑scale tissues.

Optimising Hydrogel Architectures for Vascular Infiltration

A 2025 study in Biomaterials Science utilised digital light projection (DLP)‑based stereolithography to 3D bioprint GelMA or PEGDA hydrogels, exploring various channel designs to enhance tissue infiltration and vascularisation in rodent models. GelMA and PEGDA hydrogels were found to be mechanically robust, biocompatible and to support in vivo vascular infiltration. Channel diameter significantly influenced vascularisation, with one‑millimetre channels yielding the highest infiltration, while channel length had minimal impact. Among five tested architectures, one design (GEO3) promoted the greatest vascular ingrowth, establishing a tunable hydrogel platform for prevascularised tissue engineering applications.

Fabricating Bioartificial Livers

A 2026 editorial commentary in Hepatobiliary Surgery and Nutrition reviewed progress in fabricating transplantable, vascularised and cholangiogenic bioartificial livers via 3D bioprinting. Liver organoids stand out for bridging the gap between two‑dimensional cell cultures and native hepatic tissue. These self‑organising three‑dimensional structures recapitulate the delicate architectural and functional interactions between hepatocytes, non‑parenchymal cells and the extracellular matrix within the physiological hepatic microenvironment. They can generate vasculature, bile ducts, functional hepatobiliary connections and key liver functions.

The NEOLIVER project, funded by the European Union, aims to develop large, dense and vascularised fully functional bioprinted liver constructs suitable for transplantation. Through laser‑induced forward transfer (LIFT) bioprinting techniques, researchers will create a vascularised liver construct via precise spatial deposition of spheroids and vessels at high density. By integrating this technology with extrusion‑based bioprinted vessels for blood supply, the goal is to generate one of the first autologous bioprinted livers ready for transplantation.

The ARPA‑H PRINT Program: From Research to Clinical Reality

A $176.8 Million Commitment

In January 2026, the Advanced Research Projects Agency for Health (ARPA‑H), within the U.S. Department of Health and Human Services, announced the research and development teams receiving awards from its Personalized Regenerative Immunocompetent Nanotechnology Tissue (PRINT) program. PRINT will use state‑of‑the‑art bioprinting technology and a regenerative medicine approach to three‑dimensionally print personalised, on‑demand human organs that do not require immunosuppressive drugs. The goal is to use either a patient's own cells or cells from a biobank to quickly—within hours—produce immune‑matched replacement organs, such as kidneys, hearts and livers.

Alicia Jackson, Ph.D., ARPA‑H Director, stated that developing universally matched organs had never been done before in the history of transplantation and that printing a precisely matched, functional human organ would fundamentally change what is possible in transplant medicine and would save countless lives. PRINT Program Manager Ryan Spitler, Ph.D., noted that the program required major breakthroughs in cell manufacturing, bioreactor design and 3D printing technology to reliably build organs that function like the real thing, but that if successful, the advances could dramatically reduce wait times, eliminate the need for lifelong immunosuppressive drugs and open the door to bioprinted solutions for many other organs in the future.

Performer Teams

Several performer teams have received PRINT awards. Carnegie Mellon University aims to create a cost‑effective immune‑silent bioprinted liver that is ready for first‑in‑human trials in five years. The team will produce human‑sized and functional bioprinted livers, initially for acute liver failure with the long‑term goal of addressing all liver failure. Wake Forest University seeks to produce clinical‑grade vascularised renal tissue to augment renal function in patients suffering from kidney disease, using a patient's own cells combined with a bioink that supports long‑term viability of implanted cells. The Wyss Institute and the University of Texas Southwestern Medical Center are also developing artificial liver constructs.

A separate University of Texas Southwestern award will use patients' own cells and innovative bioprinting technology to create functional artificial liver tissue. The Mayo Clinic is also collaborating on the PRINT program, which focuses on restoring normal tissue function as a bridge to transplantation.

The Pipeline Beyond: Bioprinted Kidneys, Hearts and More

The PRINT program’s broader goal extends beyond the liver. Wake Forest Institute for Regenerative Medicine (WFIRM) has received a five‑year federal award of up to $24.8 million to produce bioprinted, vascularised kidney tissue that augments renal function. The implantable kidney tissue will be made from a patient's own cells combined with a bioink that supports long‑term viability. The project integrates cell manufacturing, bioprinters and bioinks, and bioreactors into an end‑to‑end workflow that produces clinical‑grade, functional kidney tissue comprised of all major renal cell types. If successful, the technical advances and platform technologies generated by PRINT will guide regeneration of other challenging organs, such as the pancreas and lungs.

WFIRM has more than two decades of experience with a variety of 3D printing techniques to create human tissues and is an international leader in translating scientific discovery into clinical therapies, with many world firsts including the development and implantation of the first engineered organ in a patient. Over 500 people at the institute work on more than 40 different tissues and organs.

Challenges and Future Directions

Despite remarkable progress, significant challenges remain. Scalable manufacturing of bioprinted organs requires breakthroughs in cell manufacturing, bioreactor design and printing technology. The need for rapid—within hours—production of immune‑matched organs pushes the limits of current bioprinting capabilities. Regulatory approval for bioprinted organs will require extensive safety and efficacy data, and a clear pathway for approval of living therapeutic constructs is still being established.

The transition from research tool to clinical therapeutic requires validation in large, prospective clinical trials; standardisation of protocols across laboratories; cost reduction; integration with existing clinical workflows; and training for surgeons and clinicians.

Nevertheless, the trajectory is clear. The first clinical trials of bioprinted tissues are already approaching. The NEOLIVER project aims to generate transplantable bioartificial livers. The PRINT program targets first‑in‑human trials within five years. The convergence of genetic reprogramming, small‑molecule chemical reprogramming and advanced bioprinting technologies is creating a pipeline of regenerative therapies that was unimaginable a decade ago.

Conclusion

The ability to unlock regeneration in humans—to heal wounds without scars and to grow functional organ tissue without transplantation—is moving from science fiction to clinical reality. Advances in fibroblast reprogramming, chemical induction of liver progenitors and large‑scale bioprinting of vascularised organ constructs have each contributed essential insights and technologies. The identification of En1 as a master regulator of fibroblast fate has enabled targeted silencing strategies that reverse profibrotic differentiation and restore normal skin architecture. Small‑molecule cocktails that activate Hedgehog signalling or promote liver progenitor expansion offer new ways to induce endogenous regeneration without genetic modification. The ARPA‑H PRINT program, with its $176.8 million investment and aggressive five‑year timeline, is translating these foundational discoveries into implantable, vascularised, immune‑matched organs.

The convergence of these technologies has brought the field to an inflection point. The first scarless wound therapies are advancing toward clinical testing. The first transplantable bioprinted livers are expected to enter human trials within five years. The foundation for engineered replacement organs is being laid across multiple biomaterial platforms and cell sources.

The body's natural limitations on healing and regeneration—long accepted as inevitable—are being systematically dismantled. The tools to reprogram fibroblasts, to reactivate dormant liver stem cells and to print vascularised organ constructs are being assembled. The result will be a fundamentally new approach to treating injury and disease—one that replaces the management of organ failure with the regeneration of organ function.

RegenerativeMedicine

ScarlessHealing

Bioprinting

LiverRegeneration #CellularReprogramming

OrganTransplant

NoMoreScars

ARPAH #Signals

ImmuneMatched

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