About

Lachlan James Smith, Ph.D., is a Professor of Orthopaedic Surgery at the Perelman School of Medicine at the University of Pennsylvania, affiliated with the McKay Orthopaedic Research Laboratory. His research focuses on the pathophysiology and treatment of degenerative and developmental disorders affecting the spine and synovial joints. His work encompasses basic mechanistic studies, translational studies in animal models, and clinical studies in human patients, utilizing advanced techniques in molecular biology, biochemistry, and bioengineering. Dr. Smith's research bridges tissue engineering, biomaterials, drug delivery, and stem cell fields, aiming to arrest disease progression, restore spine and joint function, and promote long-term tissue regeneration. He employs novel large and small animal models to study disease etiology and evaluate therapeutics, working within a multidisciplinary team of biologists, bioengineers, clinicians, and veterinarians.

Research topics

• Medicine
• Biomedical engineering
• Materials science
• Biology
• Anatomy

Selected publications

• In vitro evaluation of therapeutic beta-glucuronidase enzyme uptake and penetration in articular cartilage

  Molecular Genetics and Metabolism · 2026-02-01

  articleSenior author
  PublisherDOI

• Advancing Basic and Preclinical Spine Research: Highlights From the ORS PSRS 7th International Spine Research Symposium.

  Open Access CRIS of the University of Bern · 2026-03-01

  articleOpen access

  The seventh biennial ORS-PSRS International Spine Research Symposium was held from November 10-14, 2024, at Skytop Lodge in Pennsylvania, USA. Jointly organized by the PSRS and ORS, the meeting brought together over 195 participants from 13 countries. Selected contributors were invited to submit full-length manuscripts for this JOR Spine Special Issue.

  PublisherDOI

• Comparative proteomic analysis of saliva, urine, and serum in mucopolysaccharidosis type I patients

  Molecular Genetics and Metabolism · 2026-02-01

  articleSenior author
  PublisherDOI

• A Decade of Leadership and Impact: Celebrating 10 Years of the ORS Spine Section

  JOR Spine · 2026-04-13

  articleOpen access

  As we celebrate the 10th anniversary of the Spine Section of the Orthopaedic Research Society (ORS), we reflect on a decade defined by visionary leadership, scientific excellence, and a steadfast commitment to advancing spine research. What began as a focused initiative within the ORS to unify spine investigators has grown into a vibrant, international community of scientists and clinicians at all career stages dedicated to transforming musculoskeletal health through collaboration, education, discovery, and translation. Since its inception, the ORS Spine Section has expanded not only in membership but also in scientific scope, global engagement, and leadership development. This growth is a testament to the dedication of past and present Chairs and Officers, whose selfless contributions and countless hours of service cemented the foundation on which the Section proudly stands today.

  PublisherDOI

• Advancing Basic and Preclinical Spine Research: Highlights From the <scp>ORS PSRS</scp> 7th International Spine Research Symposium

  JOR Spine · 2026-02-19 · 1 citations

  articleOpen access

  The seventh biennial ORS-PSRS International Spine Research Symposium was held from November 10-14, 2024, at Skytop Lodge in Pennsylvania, USA. Jointly organized by the PSRS and ORS, the meeting brought together over 195 participants from 13 countries. Selected contributors were invited to submit full-length manuscripts for this JOR Spine Special Issue. The seventh edition of the biennial ORS–PSRS International Spine Research Symposium took place from November 10 to 14, 2024, at Skytop Lodge, located in the Pocono Mountains of northeastern Pennsylvania, USA. Co-hosted by the Philadelphia Spine Research Society (PSRS) and the Orthopaedic Research Society (ORS), the meeting brought together 195 researchers and clinicians from 13 countries to discuss recent progress in basic and preclinical spine research (Figure 1). Over three and a half days, the program comprised 20 invited lectures, 29 oral presentations, and 126 poster presentations, with trainee-led work accounting for the majority of contributions. Scientific sessions addressed a broad range of topics, including spinal development, disease mechanisms, pain biology, genetics, phenotyping approaches, biomechanics, experimental models, and emerging therapeutic strategies. A highlight of the meeting was the presentation of the sixth PSRS Lifetime Achievement Award to Professor Mauro Alini, in recognition of his seminal contributions to intervertebral disc (IVD) mechanobiology and tissue engineering. Excellence in trainee research was recognized through three podium awards and six poster awards supported by the PSRS. Additional distinctions, sponsored by the ORS Spine Section, acknowledged innovative research, studies addressing health disparities, translational impact, and outstanding achievements by early-career investigators. To promote broader participation, seven diversity fellowships were awarded to trainees from underrepresented groups. The scientific program also featured a dedicated workshop on funding opportunities and strategies at the National Institutes of Health (NIH), presented by three NIH Program Directors. Outside the formal sessions, attendees networked and held informal discussions while enjoying the late-autumn setting of the Pocono Mountains. Consistent with longstanding tradition, the symposium concluded with a spine-themed quiz evening organized and led by trainee members of the ORS Spine Section. This Special Issue of JOR Spine brings together original research articles and reviews authored by symposium award recipients, discussion leaders, and invited faculty contributors. Taken as a whole, the collected works explore the convergence of aging, biological processes, and biomechanics, and emphasize the importance of integrative perspectives that consider interactions across tissues, organs, and scientific disciplines. These articles reflect the broad spectrum of spine research undertaken by these attendees, collectively advancing understanding of spine disease pathophysiology and moving us closer to more effective treatments for patients with back pain. This includes novel insights into network modeling [1] and improved spine kinematics models [2]. Mehta et al. [3] described novel methods for using age and spinal level as predictors in mice and humans. Hutchinson et al. [4] provided a systematic review on sex hormones and their role in bone and joint tissues. Peeters et al. [2] described a novel spine biomechanics model and reviewed the relevant literature. Min Kyu et al. [5] described how total RNA isolation from IVDs of mice and rats can be optimized. Crump et al. [6], and Soubrier et al. [7], both presented cell signaling under two-axial loading profiles in the first study [6] and six-axial loading profiles and their effects in the second study [7] using bovine live ex vivo organ culture models. Bhadouria et al. [8] described the impact of age and injury on the biomechanics of the lumbar IVD using an ex vivo mouse model. The paper by Nüesch et al. [9] presents novel descriptive data on internalization evidence showing that IVD cells take up Cutibacterium agnes and Staphylococcus aureus in non-herniated IVD tissue. These data further support a previously formulated hypothesis that bacteria might be responsible for the pain and radiologic picture of Modic type 1 changes on magnetic resonance imaging [10]. While the topic remains controversial and requires further work, the question arises as to whether the human IVD possesses a natural microbiome that compensates for imbalances that might be exacerbated by metabolic changes and other inflammatory processes. Jain et al. [11] published a systematic review on needle puncture-induced animal models of disc degeneration. Hasler et al. [12] described novel insights into the mechanobiology of IVD cells using a commercial cell stretcher device that uses polydimethylsiloxane (PDMS) and a customized design where the stiffness was customized and adapted for spine research. Lisiewski et al. [13] investigated how polarized M1 or M2 macrophage co-cultures, with or without tumor necrosis factor (TNF), could counteract negative changes in extracellular matrix (ECM) content in a rat IVD explant model. Gonzalez et al. [14] examined the effects of vascular endothelial growth factor (VEGF) on the degeneration and innervation of the IVD adjacent to an injury. Anderson et al. [15] described how metastatic spine disease alters the spinal load-to-strength ratio. The movement patterns and the physical function between chronic low back pain patients with nociplastic and nociceptive pain mechanisms were compared by Archibeck et al. [16]. Overall, this was an exceptionally high-level scientific meeting, which we highly recommend attending the next time it is held in November 2026. Benjamin Gantenbein: conceptualization, investigation, funding acquisition, writing – original draft. Lachlan J. Smith: conceptionalization, investigation, funding acquisition, writing – reviewing. Makarand V. Risbud: conceptionalization, investigation, funding acquisition. Chitra L. Dahia: conceptualization, funding acquisition, writing – reviewing. Sponsorship for the symposium from participating academic institutions and support from ORS staff are gratefully acknowledged. Funding from the National Institutes of Health (NIH) for this symposium (R13AR084851) is also gratefully acknowledged. C.L.D. received additional funding support from NIH (R01AR077145 and R01AG070079); L.J.S. received additional support from the NIH (R01AR077435) and the United States Department of Veterans Affairs (I01RX001321). M.V.R. received additional support from the NIH (R01AR055655, R01AR074813, and R01AG073349). B.G. acknowledges his recent and current funding sources, namely from the EU (iPSpine, 825925 & disc4all MSC ITN, 955735) and three Swiss National Science Foundation projects (310030E_192674/1, 40B2-0_211510/1, & CSRK3_237950). This study was supported by National Institutes of Health (NIH) (R13AR084851). B.G., C.L.D., L.J.S., and M.V.R. are members of the JOR Spine Advisory Review Board. C.L.D. is a current ORS Spine Section officer. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

  PublisherOA PDFDOI

• Porous microcarriers for sustained delivery of mRNA-lipid nanoparticles to treat joint disease in the mucopolysaccharidoses

  Molecular Genetics and Metabolism · 2025-01-30

  articleSenior author
  PublisherDOI

• In vitro development and in vivo evaluation of intra-articular GUSB mRNA therapy for mucopolysaccharidosis type VII

  Molecular Genetics and Metabolism · 2025-01-30

  articleSenior author
  PublisherDOI

• In Vivo Measurements Reveal Increased Nucleus Pulposus Lactate and Oxygen Concentrations in a Goat Model of Intervertebral Disc Degeneration

  JOR Spine · 2025-05-27 · 4 citations

  articleOpen accessCorresponding

  Introduction: Intervertebral disc degeneration is strongly implicated as a cause of low back pain. Although the precise pathophysiological mechanisms remain elusive, perturbations in nutrition that adversely impact the cellular microenvironment of the central nucleus pulposus (NP) may be contributing factors. A comprehensive understanding of this microenvironment, including changes in nutrient availability as a function of degeneration, is critical for the development of effective cell-based treatments. The goal of this study was to adapt brain tissue oxygen probes and microdialysis catheters for in situ determination of relative NP oxygen, glucose, and lactate levels in a preclinical goat model of disc degeneration. Methods: Following ex vivo technical refinement in bovine caudal discs, baseline metabolite measurements were performed in vivo in the lumbar discs of 3 large frame goats. Degeneration was then induced via injection of chondroitinase ABC (ChABC) into the NP, and measurements were repeated after 12 weeks. Degeneration severity was graded using magnetic resonance imaging (MRI) and histology, and vertebral endplate porosity was assessed using microcomputed tomography. Results: Oxygen and lactate levels in goat NPs were significantly higher in degenerate compared to healthy discs, while glucose levels were not significantly different. ChABC-injected discs exhibited higher vertebral endplate porosity, worse histological and MRI grades, and a spectrum of cartilage endplate damage compared to healthy discs. There were significant positive correlations between MRI grade and both NP oxygen and lactate levels. Discussion: We successfully adapted techniques including surgical placement, equilibration time, flow rate, and detection method for in situ measurement of oxygen, glucose, and lactate in a goat model of disc degeneration. Interestingly, while increased lactate with degeneration was expected, increased oxygen levels were unexpected. Our findings may, in part, be explained by associated alterations in disc and endplate structure, and motivate future studies to comprehensively establish the underlying mechanisms in this model.

  PublisherOA PDFDOI

• Postnatal progression of skeletal disease in mucopolysaccharidosis type VI dogs: Preliminary findings

  Molecular Genetics and Metabolism · 2025-01-30

  article1st authorCorresponding
  PublisherDOI

• Upper respiratory tract immunization with Pam2Cys-adjuvanted spike protein vaccine achieves sterilizing protection against SARS-CoV-2

  Frontiers in Immunology · 2025-09-02

  articleOpen access

  Injected COVID-19 vaccines protect against severe disease, but do not induce robust mucosal immune responses. Nasal vaccines offer the advantage of local immunity to block viral infection and transmission. Previously we showed immunization of a Pam 2 Cys-adjuvanted SARS-CoV-2 vaccine to the upper and lower respiratory tracts (URT/LRT) induced protective immune responses in the lungs. However, URT/LRT immunization is not representative of nasal vaccines for clinical use that exclusively target the URT. Here, we show that delivery to only the URT with Pam 2 Cys and spike protein effectively induced strong SARS-CoV-2 specific immune responses in the nasal mucosa. When delivered in a low volume so that vaccine exposure was limited to the URT, Pam 2 Cys/spike protein induced local SARS-CoV-2-specific Th17 cells and neutralizing antibodies to a similar level to inhaled vaccination reaching both the URT and LRT. We compared URT versus URT/LRT delivery as booster vaccinations following parenteral immunization and found that URT vaccination concentrated the immune response to the URT rather than the lungs. Importantly, URT immunization or boosting induced sterilizing immunity in K18-hACE2 mice challenged with homologous SARS-CoV-2. Thus, booster vaccination to the URT alone with Pam 2 Cys/spike achieved robust nasal immunity against SARS-CoV-2 and is a promising strategy for clinical development.

  PublisherOA PDFDOI

Recent grants

• Dynamic heterogeneity of nucleus pulposus cells from development to degeneration

  NIH · $391k · 2021–2024

• Bioactive Injectable Implants for Functional Intervertebral Disc Regeneration

  NIH · 2026–2029

• Mechanisms of Vertebral Bone Disease in Mucopolysaccharidosis VII

  NIH · $240k · 2014–2018

• Pathogenesis and Treatment of Bone Disease in the Mucopolysaccharidoses

  NIH · $1.9M · 2017–2024

• Neutralizing the degenerate disc microenvironment to enhance the efficacy of therapeutic stem cells

  NIH · $2.7M · 2021–2026

Frequent coauthors

• Beth S. Slomine

  Kennedy Krieger Institute

  180 shared

• Frank W. Moler

  University of Michigan–Ann Arbor

  144 shared

• James R. Christensen

  Johns Hopkins University

  144 shared

• Richard Holubkov

  University of Utah

  144 shared

• J. Michael Dean

  University of Utah

  108 shared

• Faye S. Silverstein

  University of Michigan–Ann Arbor

  108 shared

• Robert L. Mauck

  Philadelphia VA Medical Center

  95 shared

• M. Nyc

  Children's Hospital of Philadelphia

  72 shared

Education

• Ph.D., Pathology

  University of Adelaide

  2008

• B.E., Mechatronic Engineering

  University of Adelaide

  2001